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Bacterial Infections In Diabetes

ABSTRACT

Bacteria are microscopic single-celled organisms that exist in millions inside and outside the human body. Some bacteria are harmful and can cause a multitude of diseases in human beings. Diabetes mellitus, being a global pandemic, serves as an important cause of susceptibility to bacterial infections. Uncontrolled hyperglycemia is associated with impaired innate and adaptive immune responses that predispose to bacterial infections. In addition, chronic complications of diabetes like neuropathy (sensorimotor and autonomic) and peripheral vascular disease can lead to skin ulcerations with secondary bacterial infections. Diabetes also increases the incidence of infection related mortality. The relationship of diabetes and bacterial infections can be reciprocal, with certain infections like periodontitis exacerbating insulin resistance. Abnormalities in the bacterial flora of the gastrointestinal tract can play a role in the development of diabetes. Bacteria can infect any organ in the human body, the most common sites of infection in diabetes being the urinary tract, respiratory tract, skin, and soft tissues. Certain bacterial infections are very specific for diabetes like emphysematous pyelonephritis, emphysematous cholecystitis, and malignant otitis externa. Different antibiotic regimens (empirical and culture-specific) have been recommended for different bacterial infections, depending upon the site and severity. Our chapter gives an overview of the various bacteria, important from the standpoint of diabetes. We have also discussed the epidemiology and pathogenesis of bacterial infections in diabetes. In addition, we have highlighted the spectrum of bacterial infections and their management in diabetes. Stringent glycemic control, vaccination, adequate foot care practices, source control are some of the preventive measures to avoid bacterial infections in diabetes. Adequate knowledge about the spectrum and management of bacterial infections is important to prevent morbidity and mortality in diabetes.

INTRODUCTION

Diabetes is on the rise worldwide, with a global prevalence in adults in 2019 being 9.3% of the world population. In total numbers, this reflects a population of 463 million people with diabetes worldwide in 2019, with a projection of an increase to 700 million adults by 2045. A further 1.1 million children and adolescents under the age of 20, live with type 1 diabetes (1). The association between diabetes and bacterial infections is well recognized clinically and further adds to the morbidity associated with diabetes and its complications (2).

 

Patients with diabetes have a two-fold higher risk of community-acquired bacterial infections such as pneumococcal, streptococcal, and enterobacterial infections as compared with patients without diabetes (3-5). Urinary tract infections are more frequent in patients with diabetes. Janifer et al reported a high prevalence of 42.8% in 1157 South Indian subjects with type 2 diabetes (6). In a large retrospective cohort study in England comparing 102,493 patients with diabetes mellitus vs. n = 203,518 matched control subjects, incidence rate ratios (IRR) for infection-related hospitalizations were 3.71 (95% CI, 3.27 to 4.21) in those with type 1 diabetes mellitus and 1.88 (95% CI, 1.83 to 1.92) in those with type 2 diabetes mellitus (7). Diabetes is also associated with an average twofold higher risk of infection related mortality compared with individuals without diabetes (8).

 

Increased incidence and severity of bacterial infections in diabetes has been linked to an impaired innate and adaptive immune responses within the hyperglycemic environment (9).

Apart from hyperglycemia, other chronic complications of diabetes may also predispose patients to infections. For example, neuropathy in combination with peripheral vascular disease in diabetes can lead to ulcerations in the skin and secondary infections (10).

There is a bidirectional relationship between diabetes and bacterial infections. While diabetes increases the susceptibility to bacterial infections and its complications, chronic infections such as periodontitis is associated with increased pro inflammatory cytokines which can exacerbate insulin resistance and worsen glycemic control (11). There is a recent growing evidence that abnormalities in the microbiota composition can have a major role in the development of diabetes (12).

 

Awareness regarding the complex inter relationships between diabetes and associated bacterial infections is important for prevention and prompt treatment. A wide spectrum of bacterial infections such as malignant otitis externa, emphysematous pyelonephritis, emphysematous cholecystitis tend to be more common in diabetics than in others, and other infections may be more severe in diabetics than in nondiabetics (13). Infections may also be the first manifestation of long-standing unrecognized diabetes (14). The following figure illustrates the classification of medically important bacteria (15).

Fig 1. Classification of medically important bacteria

 

EPIDEMIOLOGY OF COMMON BACTERIAL INFECTIONS IN DIABETES

Epidemiology of common bacterial infections in diabetes with associated pathogens is shown in Table 1.

Table 1. Epidemiology of Common Bacterial Infections in Diabetes with Associated Pathogens

 

Epidemiology

Pathogens

Ref

Bacterial meningitis

Relative Risk = 2.2 (95% CI, 1.9–2.6) in diabetes compared to patients without diabetes

S pneumonia

Listeria monocytogenes

16

Malignant otitis externa

Odds ratio of prior diabetes in Malignant otitis externa is 10.07 (95% CI, 8.15-12.44)

 

Pseudomonas aeruginosa

17,18

Periodontitis

Odds Ratio = 1.34 (95% CI, 1.07–1.74) for periodontitis in diabetes  compared to patients without diabetes

 

Staphylococcus species

Streptococcus species

Bacillus species

E. Coli

19,20

Community Acquired pneumonia

(CAP)

Relative risk = 1.64 (95% CI 1.55–1.73) for CAP in patients with diabetes

 

Streptococcus pneumoniae

Legionella

Haemophilus influenza

21,22

Hospital Acquired pneumonia

Incidence Rate Ratio = 1.21, (95% CI,1.03–1.42) for postoperative pneumonia in diabetes

 

Pseudomonas species

Staphylococcus aureus

 

23, 24

Infective endocarditis

Odds ratio =1.9 (95% confidence interval 1.8-2.1)

 

Streptococcus viridans

Staphylococus aureus

Enterococcus species

25,26

Emphysematous Cholecystitis (EC)

60% of patients with EC had diabetes

Clostridium perfringens

Escherichia coli

27,28

Pyogenic liver abscess

Relative Risk = 3.6 (95% CI 2.9-4.5) in diabetes

 

 

 

Klebsiella pneumoniae

29,30

Urinary tract Infections

In patients with type 1 DM, adjusted odds ratio = 1.96 (95 % CI, 1.49–2.58)

In patients  with type 2 diabetes, adjusted Odds ratio = 1.24 (95 % CI, 1.10–1.39)

 

Escherichia coli

 

Other Enterobacteriaceae such as Klebsiella spp., Proteus spp., Enterobacter spp., and Enterococci

 

31,32

Bacterial skin and mucous membrane infections

In patients with type 1 DM, adjusted odds ratio = 1.59 (95 % CI, 1.12–2.24)

In patients  with type 2 diabetes, adjusted Odds ratio = 1.33 (95 % CI, 1.15–1.54)

 

Folliculitis        Group A streptococcus

                         Staphylococcus Aureus

 

 

Furunculosis     Streptococcus pneumoniae

Cellulitis

 

 

31, 33

Osteomyelitis of foot

20% of diabetic foot infections were associated with osteomyelitis.

 

More often poly-microbial

 

Gram positive : Staphylococcus aureus, Staphylococcus epidermidis, Streptococci, Enterobacteriaceae

 

Gram Negative : Escherichia coliKlebsiella pneumonia,  ProteusPseudomonas aeruginosa

 

34,35

GLYCEMIC CONTROL AND RISK OF INFECTIONS

Poor glycemic control increases the risk of infections in diabetes. A recent study examined the association between glycemic control in 85,312 patients with diabetes mellitus aged 40–89 years and the incidence of infection (36).  Infection rates rose steadily with HbA1c, which was particularly evident among those with HbA1c >11% (36).

 INCREASED INCIDENCE OF INFECTIONS IN DIABETES: PATHOPHYSIOLOGY

Infections are an important concern in individuals with diabetes due to the immune system’s failure to fight off invading pathogens (37). Diabetes progression itself is associated with immune dysfunction; autoimmunity in T1DM and low-grade chronic inflammation in T2DM (38).

 

Numerous studies have investigated the diabetes-related mechanisms that impair the host’s defence against pathogens. These mechanisms include a complex interplay between the host’s innate immunity and adaptive immunity (39, 40, 41). As noted earlier, chronic complications of diabetes can also predispose to infections (10).

The proposed mechanisms for increased susceptibility to infections in diabetes are depicted in figure 2.

Fig 2. Complex interactions between immune dysregulation (both innate and adaptive) from glycemic status, organism specific factors and diabetic complications plays major role in development of diabetes related infections.

Innate immunity

Cellular innate immunity is affected in uncontrolled diabetes. The steps involved in pathogen elimination by polymorphonuclear (PMN) leucocytes are:

(a) PMN adhesion to vascular endothelium, initially via the cell surface adhesion molecule L-selectin and then integrins

(b) transmigration through the vessel wall down a chemotactic gradient

(c) phagocytosis and microbial killing (2).

Hyperglycemia induces an increase in intracellular calcium concentration thereby reducing adenosine triphosphate (ATP) levels, which in turn leads to reduced phagocytic ability of polymorphonuclear cells. Correction of hyperglycemia leads to a significant reduction in intracellular calcium levels, an increase in ATP content, and improved phagocytosis (42). The hyperglycemic environment also inhibits glucose-6-phosphate dehydrogenase (G6PD) with resultant increase in apoptosis of polymorphonuclear leukocytes, and reduced polymorphonuclear leukocyte transmigration through the endothelium. Superoxide production is reduced in parallel with increasing glycemic exposure and consequently results in decreased microbial killing (2). Hyperglycemia is associated with increased formation of advanced glycation end products (AGE). AGE albumin has been shown to bind to the receptor for AGE (RAGE) present on neutrophils. This binding inhibits transendothelial migration and Staphylococcus aureus induced production of reactive oxygen species (ROS), resulting in impaired bacterial killing (43). Hyperglycemia also adversely affects the humoral component of innate immunity. Deficiency of C4 complement as well as decreased complement activation has been demonstrated in diabetes. This results in decreased opsonisation and phagocytosis of microbes. (44,45). Increased duration of cytokine response, increased pro-inflammatory cytokine gene expression and impaired local cytokine production leads to a dysregulated cytokine response in uncontrolled diabetes further increasing susceptibility to severe infections (46, 47, 48). 

Adaptive Immunity

There are two broad classes of adaptive immunity responses—antibody responses and cell-mediated immune responses, which are carried out by B cells and T cells respectively. In antibody responses, B cells are activated to secrete immunoglobulins which bind to the invading microbial antigens and block their binding to receptors on host cells. Antibody binding also marks invading pathogens for destruction by the phagocytes (49). Decreased levels of circulating immunoglobulins (IgG antibodies) as well as increased non enzymatic glycation of IgG antibodies leading to quantitative and qualitative defects in the humoral responses have been demonstrated in uncontrolled diabetes (50,51).

 

In cell-mediated immune responses, the second class of adaptive immune response, T cells which are activated by certain cytokines and antigen presenting cells, react directly against a foreign antigen that is presented to them on the surface of a host cell or themselves secrete cytokines that activate macrophages to destroy the invading microbes after phagocytosis (47). Dysregulation between anti-inflammatory and proinflammatory cytokines and defects at the level of antigen presenting cells in uncontrolled diabetes leads to dysfunction of T cells (52, 53). The role of immune systems and pathogenesis of bacterial infections is depicted in figure 3.

Fig 3. Pathogenesis of bacterial infections in diabetes. Describes role of various components of innate and adaptive immunity in pathogenesis of bacterial infection in diabetes; G6PD-Glucose 6 phosphate dehydrogenase; PMN-Polymorphonuclear cells; NADPH – Nicotinamide adenine dinucleotide phosphate; ROS- Reactive oxygen species; ATP -Adenosine triphosphate; AGEs- Advanced glycation end products; RAGE-Receptor for advanced glycation end products. 

Chronic Complications of Diabetes Predisposing to Infections

Over 50% of men and women with diabetes have bladder dysfunction which may impair voiding and increase the risk for urinary tract infections (54). The presence of renal disease and urinary incontinence in women are also predisposing factors for urinary tract infections. Diabetic cystopathy secondary to autonomic nervous dysfunction in long standing diabetes is characterized by a loss of sensation of bladder distension leading to decreased frequency of voiding and increased post-void residual urine volume. The possibility that voiding disorders may contribute to UTI should be considered in all diabetic patients (55).  

 

Peripheral diabetic neuropathy contributes to motor, autonomic, and sensory components of neuropathic foot ulcers. Damage to motor neurons of the foot musculature may lead to an imbalance of flexors and extensors, anatomic deformities, and eventual skin ulcerations. Damage to autonomic nerves impairs sweat gland function in the foot leading to a decreased ability to moisturize skin, resulting in epidermal cracks and skin breakdown. Lastly, the affected sensory component results in a loss of sensation of foot and reduced awareness of minor injuries (56). With ischemia, often as a result of related peripheral arterial disease, neuropathy can result in impaired barrier defences, skin ulcers with poor healing, and an increased risk of secondary infections and gangrene (57).

 

Pulmonary autonomic neuropathy in diabetes reduces mucociliary clearance and predisposes the lung to infections. Furthermore, hyperglycemia and insulin resistance impair collective surfactant D-mediated host defences of the lung in diabetes. Loose junctions between airway epithelial cells, which increase the transepithelial glucose gradient along with an increase in the glucose concentration of the airway surface liquid due to hyperglycemia, may dampen the airway defence against infection, resulting in lung bacterial overgrowth in diabetes (58).

SPECTRUM OF BACTERIAL INFECTIONS

Head and Neck Infections

BACTERIAL MENINGITIS

The majority of bacterial meningitis cases in adults is caused by Streptococcus pneumoniae. Listeria monocytogenes meningitis is more often found in elderly patients (>60 years) and those with acquired immune-deficiencies, such as diabetes. Immunodeficiency associated with diabetes is also a predisposing factor for pneumococcal and Haemophilus influenzae meningitis. Patients with bacterial meningitis and diabetes mellitus are older, have more comorbidities, frequently present with altered mental status and have higher mortality. In patients with diabetes, empirical antibiotics should include Cefotaxime/ ceftriaxone plus amoxicillin/ampicillin/ penicillin G (16, 59, 60).

MALIGNANT OTITIS EXTERNA

 Malignant otitis externa (MOE) is an invasive, potentially life-threatening infection of the external ear and skull base. MOE affects immunocompromised individuals and its presentation in an otherwise healthy individual should prompt an investigation for diabetes mellitus or other immune-deficiencies. In most cases, the causative agent of MOE is Pseudomonas aeruginosa. Typical patients with MOE are elderly individuals who have diabetes and severe, unremitting otalgia, aural fullness, otorrhea, and conductive hearing loss. Headache, temporomandibular joint pain, and decreased oral intake secondary to trismus may also be present. Findings of pain disproportionate to the examination, otorrhea, and granulation tissue along the floor of the ear canal at the bony–cartilaginous junction are usually the first nonspecific signs and symptoms of MOE. Important principles of treatment include aggressive control of diabetes and culture directed antibiotic therapy for at least 6-8 weeks. Although surgical intervention is no longer standard of care for MOE, it does require biopsy and culture, and may require local debridement of granulation tissue and bony sequestration or drainage of associated abscess. Long-term monotherapy with oral ciprofloxacin (750 mg twice daily) has been proposed as the preferred initial antibiotic regimen. However, microbial resistance to ciprofloxacin has been described and numerous studies have proposed carbapenem or third- generation cephalosporins as the initial empirical treatment. Recurrence rates of 15% to 20% have been reported for MOE (18, 61, 62). The risk factors for malignant otitis externa and its pathogenesis in diabetes are depicted in figure 4.

Fig 4. Risk factors for Malignant Otitis Externa and its pathogenesis in diabetes

PERIODONTITIS

Periodontitis is a complex chronic inflammatory condition in which inflammation in the periodontal tissues is stimulated by the long-term presence of the subgingival biofilm (figure 5). Periodontitis is a slowly progressing disease but the tissue destruction that occurs is largely irreversible. In the early stages, the condition is typically asymptomatic, is not usually painful, and many patients are unaware until the condition has progressed enough to result in tooth mobility. Advanced periodontitis is characterized by gingival erythema and edema, gingival bleeding, gingival recession, tooth mobility, suppuration from periodontal pockets, and tooth loss. In a randomized clinical trial, intensive periodontal treatment was associated with better glycemic control (A1C 8.3% vs 7.8% in control subjects and intensive treatment group respectively). Oral and periodontal health should be promoted as integral components of diabetes management (63, 64).

Fig 5. Chronic periodontitis with gingival inflammation in a patient with poorly controlled diabetes

DEEP NECK SPACE INFECTIONS/ABSCESS

Patients with diabetes are susceptible to spreading deep neck infections with a high frequency of complications, including tracheostomy and prolonged hospital stay. Odontogenic infections and upper airway infections are the leading reported causes of deep neck infections and the most common organism isolated is Klebsiella pneumoniae.  Early open surgical drainage remains the most appropriate method of treating deep neck abscesses. The choice of empirical antimicrobial agents in diabetic patients should take into account the agents effective against Klebsiella pneumoniae (65).

Respiratory Infections

COMMUNITY ACQUIRED PNEUMONIA

Patients with diabetes are at high risk of hospitalization due to community acquired pneumonia (CAP) (figure 6). Atypical clinical features like impaired consciousness and more severe pneumonia at admission are reported in patients with diabetes. Acute onset of disease, cough, purulent sputum, and pleuritic chest pain are less frequent among patients with diabetes. S. pneumonia, Legionella, and H influenza are frequent causative organisms of pneumonia in diabetes (22). Studies have also reported increased incidence of Klebsiella and pneumococcal pneumonia (3, 66). Independent risk factors for mortality in patients with diabetes and CAP are advanced age, bacteremia, septic shock at admission, and gram-negative pneumonia (22). The American Thoracic Society guidelines recommend combination therapy with amoxicillin/ clavulanic acid/ cephalosporin and macrolide/ doxycycline or monotherapy with respiratory fluoroquinolone for initial outpatient treatment in patients with diabetes. Beta lactam + macrolide or beta-lactam + fluoroquinolone is recommended in cases of severe in-patient pneumonia. Coverage for Pseudomonas aeruginosa is recommended in case of prior respiratory isolation, recent hospitalization with parenteral antibiotics treatment, and locally validated risk factors for Pseudomonas aeruginosa (67). The American Diabetes Association recommends vaccination against pneumococcal strains with one dose of PPSV23 (pneumococcal polysaccharide vaccine) between the ages of 19–64 years and another dose after 65 years of age. The PCV13 (pneumococcal conjugate vaccine) is no longer routinely recommended for patients over 65 years of age because of the declining rates of pneumonia due to these strains. All children are recommended to receive a four-dose series of PCV13 by 15 months of age. For children with diabetes who have incomplete series by ages 2–5 years, a catch-up schedule is recommended to ensure that these children have four doses. Children with diabetes between 6–18 years of age are also advised to receive one dose of PPSV23, preferably after receipt of PCV13 (68).

Fig 6. Radiographs of lower respiratory tract infection. A- Postero-anterior view radiograph of chest showing right middle lobe and left lower lobe consolidation in a patient with diabetes. B- Postero-anterior view radiograph of chest showing right lower lobe consolidation in a patient with diabetes

Cardiovascular Infections  

INFECTIVE ENDOCARDITIS

Infective endocarditis (IE) in diabetes is associated with poorer outcomes (figures 7 and 8). Diabetes mellitus was associated with increased mortality, acute heart failure, stroke, atrioventricular block, septic shock, and cardiogenic shock. The clinical profile of native valve infective endocarditis (NVIE) patients with diabetes is reported to be different compared to those without diabetes. Patients with diabetes had higher rates of comorbidities, and IE risk factors such as older age, and hemodialysis. They were less likely to have structural heart disease (valvular heart disease and congenital heart disease) and intravenous drug abuse. Patients with diabetes had higher rates of staphylococcus species, enterococci, and gram-negative microorganisms reflecting the increased health care utilization in DM patients, exposing them to nosocomial infections (26). Ampicillin with flucloxacillin or oxacillin with gentamicin is recommended as initial empirical therapy in community acquired native valves or late prosthetic valves (≥ 12 months post-surgery) endocarditis. Vancomycin with gentamicin and rifampicin is recommended in early PVE (<12 months post-surgery) or nosocomial and non-nosocomial healthcare associated endocarditis (69).

Fig 7. Two-dimensional Echocardiography of a patient with diabetes showing aortic root abscess (red arrowhead) and vegetations attached to aorto-mitral continuity (blue arrowhead), suggestive of infective endocarditis

 

Fig 8. Two-dimensional echocardiography in a patient with diabetes, showing large vegetation (blue arrowhead) attached to the posterior mitral leaflet, suggestive of infective endocarditis

Gastrointestinal Infections  

EMPHYSEMATOUS CHOLECYSTITIS

Emphysematous cholecystitis (EC) is an uncommon but serious biliary tract infection that occurs in increased frequency with male preponderance among diabetics. The common causative organisms are Clostridium perfringens and E. coli (28). Clinical findings of EC may be indistinguishable from those of uncomplicated cholecystitis although occasional crepitus may be present in some patients. The emphysematous infection is diagnosed by radiographic demonstration of gas on plain films or by CT. The treatment of choice is rapid surgical removal of the gallbladder and broad-spectrum antimicrobial therapy. Mortality caused by this infection is substantially higher than that of uncomplicated cholecystitis, ranging 15% to 25% compared with less than 4 percent (13).

LIVER ABSCESS

Diabetes is a strong, potentially modifiable risk factor for pyogenic liver abscess (figure 9). Pyogenic liver abscess patients with diabetes are older, with isolate of Klebsiella. pneumoniae being the predominant pathogen and require an increased use of combined antibiotic therapy with carbapenems. However, these patients have fewer abdominal surgeries and fewer E. coli infections as compared to patients without diabetes. In addition, poorly controlled glycemia in pyogenic liver abscess patients is associated with high incidence of fever and abscesses in both the lobes of the liver (29, 30).

Fig 9. Contrast enhanced axial (A) and sagittal (B) CT images showing multifocal well defined hypodense lesions involving both lobes of liver suggestive of liver abscesses in a patient with diabetes 

Urinary Tract Infections

The urinary tract is the most frequent site of infection in patients with diabetes (8, 70, 71). The spectrum of urinary tract infections in these patients ranges from asymptomatic bacteriuria (ASB) to lower UTI (cystitis), pyelonephritis, and severe urosepsis. Serious complications of UTI, such as emphysematous cystitis and pyelonephritis (figure 10), renal abscesses and renal papillary necrosis, are all encountered more frequently in type 2 diabetes than in the general population (72, 73).

Figure 10. Emphysematous pyelonephritis. Non contrast CT abdomen of a 45-year-old female with emphysematous pyelonephritis showing bilateral enlarged kidney with evidence of abscess formation on either side (black arrowheads) and air pockets in left kidney

 

The most common pathogens isolated from diabetic patients with UTI are E. coli, other Enterobacteriaceae such as Klebsiella spp., Proteus spp., Enterobacter spp., and Enterococci. Patients with diabetes are more prone to have resistant pathogens as the cause of their UTI, including extended-spectrum β-lactamase-positive Enterobacteriaceae, fluoroquinolone-resistant uropathogens, carbapenem-resistant Enterobacteriaceae, and vancomycin-resistant Enterococci. (32, 74).

 

As a general rule, treatment of UTI in diabetic patients is similar to that of UTI in non-diabetic patients. Antibiotic choice should be guided by local susceptibility patterns of uropathogens. First-line treatment recommendations for various types of UTI are detailed in Table 2 (74).

 

Table 2. First Line Antibiotics for Various Types of UTI in Diabetes

Type of urinary tract infection (UTI)

Gender

Antibiotic treatment

Route

Dosage

Duration of treatment

Asymptomatic bacteriuria

Male and female

None

 

 

 

Acute cystitis

Female

Nitrofurantoin

Per oral

100 mg BD/TDS

5 days

Complicated lower UTI  (catheter associated UTI)

Male and female

Ciprofloxacin

Per oral

200-500 mg BD

7-14 days

Ofloxacin

Per oral

200 mg BD

7-14 days

Trimethoprim-Sulfamethoxazole

Per oral

960 mg BD

7-14 days

Cefuroxime

Per oral

500 mg BD

7-14 days

Uncomplicated pyelonephritis

Female

Ciprofloxacin

Intravenous

400 mg BD

7 days

Ciprofloxacin

Per oral

500 mg BD

7 days

Ofloxacin

Intravenous

400 mg BD

7 days

Gentamicin

Intravenous

5 mg/kg OD

7 days

Cefuroxime

Intravenous

750 mg TDS

7-14 days

Cefuroxime

Per oral

500 mg BD

7-14 days

Complicated pyelonephritis/urosepsis

Male and female

Ciprofloxacin

Intravenous

400 mg BD

10-14 days

Ofloxacin

Intravenous

400 mg BD

10-14 days

Gentamicin

Intravenous

5 mg/kg OD

10-14 days

Amikacin

Intravenous

15 mg/kg OD

10-14 days

Piperacillin-Tazobactum

Intravenous

4.5 g TDS

10-14 days

Ertapenem

Intravenous

1 g OD

10-14 days

OD-once daily, BD-twice daily, TDS-thrice daily

Skin and Soft Tissue Infections 

Skin and soft tissue infections (SSTI) cause a substantial morbidity in patients with diabetes (75). SSTIs commonly seen in diabetes include cellulitis, abscess, decubitus ulcer, folliculitis, impetigo, carbuncle and furuncle, and surgical site infections. SSTI-associated complications such as gangrene, osteomyelitis, bacteremia, sepsis, and SSTI-associated hospitalizations are higher in patients with diabetes compared to those without diabetes (76).

FOOT INFECTIONS IN DIABETES

Foot infections in diabetes remain the most frequent complication requiring hospitalization and the most common precipitating event leading to lower extremity amputation (figure 11) (77-79).

Fig 11.  A-Trophic changes in the bilateral feet of a patient with diabetes with clawing of toes, thickened toe nails, loss of hair and shiny skin texture. B-Infected foot ulcer with slough in the plantar aspect of heel of a patient with diabetes. C-Another infected foot ulcer involving the entire sole in a patient with diabetes, the ulcer shows presence of granulation tissue along with oozing of pus and slough

 

Outcomes in patients presenting with an infected foot ulcer are poor. In one large prospective study at the end of one year, the ulcer had healed in only 46% (and it later recurred in 10% of these), while 15% had died and 17% required a lower extremity amputation (80). There are various validated classification systems to assess the severity and prognosis of foot ulcers and infection. One such scoring system is the SINBAD system which grades area, depth, sepsis, arteriopathy, and denervation plus site as either 0 or 1 point creating an easy to use scoring system that can achieve a maximum of 6 points (81). The IWGDF (International Working Group on the Diabetic Foot) infection classification is recommended to characterize and guide infection management in diabetic foot infections. The IWGDF/IDSA (Infectious Diseases Society of America) classification consists of four grades of severity for diabetic foot infection (Table 3) (82, 83).

 

Table 3. IWGDF/IDSA Classification for Foot Infections

Clinical classification of infection, with definitions

IWGDF classification

Uninfected

No systemic or local symptoms or signs of infection

 

1 (Uninfected)

Infected

·       At least, 2 of these items are present

·       Local swelling or induration

·       Erythema >0.5 cm around the wound

·       Local tenderness or pain

·       Local increased warmth

·       Purulent discharge

And no other cause(s) of an inflammatory response of the skin (eg. trauma, gout, acute Charcot neuro-osteoarthropathy, fracture, thrombosis or venous stasis)

 

Infection with no systemic manifestation involving:

·       only the skin or subcutaneous tissue (not any deeper tissues) and

·       any erythema present does not extend >2 cm around the wound

2 (mild infection)

Infection with no systemic manifestation involving:

·       erythema extending ≥ 2 cm from the wound margin, and/or

·       tissue deeper than skin and subcutaneous tissue (e.g., tendon, muscle, joint, bone)

3 (moderate infection)

Any foot infection with associated systemic manifestations (of the systemic inflammatory response syndrome [SIRS]), as mentioned by ≥2 of the following:

·       Temperature >38 degree celsius or <36 degree Celsius

·       Heart rate >90 beats/ minute

·       Respiratory rate >20 breaths/minute or PaCO2 <4.3 kPa (32 mm Hg)

·       White blood cell count >12,000/mm3 or <4000/mm3 or >10% immature (band) forms

 

4 (Severe infection)

Infection involving bone (osteomyelitis)

Add ‘O’ after 3 or 4

 

The empirical antibiotic choice is guided by the history, clinical examination, severity of infection, likely etiological agent, and previous antimicrobial sensitivity pattern. Studies from temperate climates in North America and Europe have consistently demonstrated that the most common pathogens in diabetic foot infections are aerobic gram-positive cocci, especially Staphylococus aureus, and to a lesser extent, streptococci and coagulase-negative staphylococci. More recent studies of diabetic foot infections from patients in tropical/subtropical climates (mainly Asia and northern Africa) have shown that aerobic gram-negative bacilli are often isolated, either alone or in combination with gram-positive cocci. Empirical treatment aimed at Pseudomonas aeruginosa, which usually requires either an additional or broad-spectrum agent should be considered in tropical/subtropical climates or if Pseudomonas aeruginosa has been isolated from previous cultures of the affected patient. Obligate anaerobes can play a role in diabetic foot infections, especially in ischemic limbs and in case of abscesses. Empirical treatment of these pathogens, e.g., with an imidazole (metronidazole), or beta-lactam with beta lactamase inhibitor, should be considered for diabetic foot infection associated with ischemia or a foul-smelling discharge. THE IWGDF guidelines on empirical antibiotic therapy for diabetic foot infections are outlined in table 4 (83).

 

Table 4. Empirical Antibiotic Therapy Recommended by IWGDF Guidelines for Diabetic Foot Infections

Severity of infection

Additional factors

Usual pathogen(s)

Potential empirical regimens

Mild

No complicating features

Gram positive cocci

Semi synthetic penicillin; 1st generation cephalosporins

Beta lactam allergy or intolerance

Gram positive cocci

Clindamycin;Fluroquinolone;Trimethoprim-sulfamethoxazole;Macrolide;Doxycycline

 

Recent antibiotic exposure

Gram positive cocci + Gram negative rods

β-lactamase inhibitor-amoxicillin/clavulanate; Trimethorpim-sulfamethoxazole; Fluoroquinolone

High risk for MRSA

MRSA

Linezolid; Trimethoprim-sulfamethoxazole; doxycycline; macrolide

Moderate or severe

No complicating features

Gram positive cocci ± Gram negative rods

β-lactamase inhibitor-amoxicillin/clavulanate; second or third generation cephalosoporins

 

Recent antibiotic exposure

Gram positive cocci ± Gram negative rods

β-lactamase 2-ticarcillin/clavulanate, piperacillin/tazobactum; 3rd generation cephalosporins; group I carbapenems (depends on prior therapy)

 

Macerated ulcer or warm climate

Gram negative rods including pseudomonas

β-lactamase 2-ticarcillin/clavulanate, piperacillin/tazobactum; semi synthetic penicillins + ceftazidime; semi synthetic penicillins + ciprofloxacin; group 2 carbapenems

 

Ischemic limb/necrosis/gas forming

Gram positive cocci ± Gram negative rods ± Anaerobes

β-lactamase inhibitor or 2; group 1 or 2 carbapenems; 2nd or 3rd generation cephalosporins + clindamycin or metronidazole

 

MRSA risk factors

MRSA

Consider adding or substituting with glycopeptides; linezolid; daptomycin; fusidic acid; trimethoprim-sulfamethoxazole ± rifampicin; doxycycline

 

Risk factors for resistant gram negative rods

ESBL

(Extended spectrum beta lactamase producing bacteria)

Carbapenem; Aminoglycoside and Colistin; Fluoroquinolone

MRSA-Methicillin resistant Staph aureus ; 1st generation cephalosporins-Cefadroxil, cefazolin, cephalexin; 2nd generation cephalosporins-Cefotetan, cefoxitin, cefuroxime, cefprozil; 3rd generation cephalosporins-Cefixime, cefotaxime, cefpodoxime; β-lactamase 2-ticarcillin/clavulanate, piperacillin/tazobactum; group 1 carbapenem: ertapenem; group 2 carbapenem: imipenem, meropenem, doripenem

FOURNIER’S GANGRENE

Fournier's gangrene (FG) is a fulminant form of infective necrotising fasciitis of the perineal, genital, or perianal regions, which commonly affects men with diabetes (figure 12) (84). Diabetes mellitus is reported to be present in 20%–70% of patients with Fournier’s gangrene (85). FG shows vast heterogeneity in clinical presentation, from insidious onset and slow progression to rapid onset and fulminant course, the latter being the more common presentation. The local signs and symptoms are usually dramatic with significant pain and swelling. The patient also has pronounced systemic signs; usually out of proportion to the local extent of the disease. Crepitus of the inflamed tissues is a common feature because of the presence of gas forming organisms. As the subcutaneous inflammation worsens, necrotic patches start appearing over the overlying skin and progress to extensive necrosis (86).

 

There has been an associated increased incidence of FG with the use of SGLT2 inhibitors in diabetes. The US Food and Drug Administration (FDA) has identified 55 cases of FG in patients receiving SGLT2 inhibitors between 2013 and 2019, out of which 39 were men and 16 were women (87). Time to onset of FG after initiation of SGLT2-inhibitors varied considerably, ranging from 5 days to 49 months (87). All patients were sick and had surgical debridement. Three patients died (87).  SGLT2-inhibitors cause glycosuria that can enhance the growth of bacterial flora in the urogenital milieu. This in turn increases the risk of urogenital infections, including FG. All types of SGLT2-inhibitors have been associated with FG. The FDA has issued a warning about the risk of FG to be added to the prescribing information of all SGLT2-inhibitors and to the patient medication guide.

 

Cultures from the wounds commonly show poly microbial infections by aerobes and anaerobes, which include coliforms, klebsiella, streptococci, staphylococci, clostridia, bacteroides, and corynebacteria (88). FG has a high mortality rate of 40% (85) and warrants an aggressive multimodal approach, which includes haemodynamic stabilisation, broad spectrum antibiotics and surgical debridement (86).

Fig 12. Fournier’s gangrene. Redness, swelling of the scrotum, penis and perineal tissues with necrosis and sloughing of the overlying skin

NECROTIZING FASCIITIS

Necrotizing fasciitis (NF) has been defined as a severe soft-tissue infection that causes extensive necrosis of subcutaneous tissue and fascia, relatively sparing the muscle and skin tissue (figure 13) (89). Based on bacterial culture results, NF is classified into the following categories: type I, which consists of synergistic polymicrobial infection; type II, representing infections caused by group A Streptococcus alone or combined with Staphylococcus; and type III, which comprises infections caused by Vibrio species (90).  Diabetic NF patients are reported to be more susceptible to polymicrobial and monomicrobial Klebsiella pneumoniae infections, which should be considered when choosing empirical antibiotics for these patients (91).

Fig 13. A and B Necrotizing fasciitis; black necrotic tissue and slough seen invading the subcutaneous tissues and fascia

INFECTION MIMICS IN DIABETES

Charcot Neuroarthropathy   

Charcot neuroarthropathy is a limb-threatening, destructive process that occurs in patients with neuropathy associated with medical diseases such as diabetes mellitus. Clinicians treating diabetic patients should be aware that the early signs of acute Charcot neuroarthropathy, such as pain, warmth, edema mimic foot infection. Early detection and prompt treatment can prevent joint and bone destruction, which, if untreated, can lead to morbidity and high-level amputation. The differentiation between acute presentations of Charcot’s joint and osteomyelitis is often difficult because the two conditions have many features in common. However, the lack of systemic sepsis or fever, significant hyperglycemia and leukocytosis may direct the diagnosis towards neuropathic joint (92, 93).

INFECTIONS AS A RISK FACTOR FOR DIABETES

Infections have been documented as a predisposing factor for Type 2 Diabetes Mellitus. Recent studies have revealed H. pylori infections to be significantly higher among diabetic patients than in non-diabetic patients (94, 95). Evidence suggests that advanced periodontitis also compromises glycemic control. Furthermore, periodontal treatment has been associated with improvement in glycemic control (63, 64). Abnormalities in the microbiota composition can have a major role in the development of obesity and diabetes. A reduced microbial diversity is associated with inflammation, insulin-resistance, and adiposity.  A rise in the Firmicutes/Bacteroidetes ratio is found to be related to a low-grade inflammation and to an increased capability of harvesting energy from food. Changes in some metabolites, such as short-chain fatty acids (SCFAs), produced by gut microbiota, and decreased amounts of the Akkermansia muciniphila are associated with the presence of type 2 diabetes (12). Increased pro inflammatory cytokine response in infections leads to insulin resistance. Even pathogen products, such as lipopolysaccharide and peptidoglycans, can cause insulin resistance leading to development of diabetes (96).

CONCLUSION

Awareness regarding the spectrum and severity of infections, in diabetes, is essential for prevention and prompt treatment. Strict glycemic control, proper choice of antibiotics and source control form the cornerstones of management. Preventive measures like vaccination and foot care practises go a long way in reducing infection related morbidity and mortality in diabetes.

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Etiologic Classification of Diabetes Mellitus

 

Table 1 lists the various disorders that can either cause or contribute to the development of diabetes and the Endotext chapters where these disorders are discussed in detail.

 

 

Table 1. Etiologic Classification Of Diabetes Mellitus

Disorders

Endotext Chapter

Type 1 Diabetes

Pathogenesis of Type 1A Diabetes

Type 2 Diabetes

Pathogenesis of Type 2 Diabetes

Gestational Diabetes

Gestational Diabetes

Genetic defects of beta-cell development and function

MODY

Diagnosis and Clinical Management of Monogenic Diabetes

Neonatal Diabetes

Diagnosis and Clinical Management of Monogenic Diabetes

Mitochondrial DNA

Atypical Forms of Diabetes

Genetic defects in insulin action

Type A insulin resistance

Atypical Forms of Diabetes

Leprechaunism

Atypical Forms of Diabetes

Rabson-Mendenhall syndrome

Atypical Forms of Diabetes

Lipoatrophic diabetes

Lipodystrophy Syndromes: Presentation and Treatment*

Diseases of the exocrine pancreas

Pancreatitis

Atypical Forms of Diabetes

Trauma/pancreatectomy

Atypical Forms of Diabetes

Neoplasia

Atypical Forms of Diabetes

Cystic fibrosis

Atypical Forms of Diabetes

Iron overload (hemochromatosis, thalassemia, etc.)

Atypical Forms of Diabetes

Fibrocalculous pancreatic diabetes

Fibrocalculous Pancreatic Diabetes**

Endocrinopathies

Acromegaly

Cushing’s syndrome

Glucagonoma

Pheochromocytoma

Hyperthyroidism

Somatostatinoma

Primary Hyperaldosteronism

Atypical Forms of Diabetes

Diabetes Mellitus After Solid Organ Transplantation

Diabetes Mellitus After Solid Organ Transplantation

Drug- or chemical-induced hyperglycemia

Vacor

Pentamidine

Nicotinic acid

Glucocorticoids

Growth Hormone

Diazoxide

Check point inhibitors

Dilantin

Interferon alpha

Immune suppressants

Others (statins, psychotropic drugs, b-Adrenergic agonists, thiazides, etc.)

Atypical Forms of Diabetes

Infections

Congenital rubella

Atypical Forms of Diabetes

HCV

Atypical Forms of Diabetes

COVID-19

Atypical Forms of Diabetes

HIV

Diabetes in People Living with HIV

Immune-mediated diabetes

Latent Autoimmune Diabetes in Adults (LADA)

Atypical Forms of Diabetes

Stiff-man syndrome

Atypical Forms of Diabetes

Anti-insulin receptor antibodies

Atypical Forms of Diabetes

Autoimmune Polyglandular Syndromes

Autoimmune Polyglandular Syndromes***

Diabetes of unknown cause

Ketosis-prone diabetes (Flatbush diabetes)

Atypical Forms of Diabetes

Other genetic syndromes sometimes associated with diabetes

Down syndrome

Klinefelter syndrome

Turner syndrome

Wolfram syndrome

Friedreich ataxia

Huntington chorea

Bardet-Biedl syndrome (Laurence-Moon-Biedl syndrome)

Myotonic dystrophy

Porphyria

Prader-Willi syndrome

Alström syndrome

Others

Atypical Forms of Diabetes

Unless indicated chapters are located in the

*Chapter in Diagnosis and Treatment of Diseases of Lipid and Lipoprotein Metabolism section

**Chapter in Tropical Medicine section

***Chapter in Disorders that Affect Multiple Organs section

 

 

 

Control of Energy Expenditure in Humans

ABSTRACT

 

Resting and meal-related energy requirements can be assessed by measuring energy expenditure with indirect calorimetry. The indicated method to assess free-living energy expenditure is the doubly labelled water technique. Variation in energy expenditure is mainly a function of body size and composition (resting energy expenditure) and of physical activity (activity energy expenditure). Thus, energy expenditure can be calculated with a prediction equation for resting energy expenditure, based on height, age, weight and sex, in combination with the measurement of the physical activity level of a subject with a doubly labelled water validated accelerometer for movement registration. Energy balance in humans is maintained by adjusting energy intake to energy expenditure. Over- and underfeeding induces changes in activity-induced and maintenance energy expenditure as a function of changes in body weight and body composition. Additionally, underfeeding causes a metabolic adaptation as reflected in a reduction of maintenance energy expenditure below predicted values and defined as adaptive thermogenesis. When intake exceeds energy requirements, the excess is primarily stored as body fat. As a substrate for energy metabolism, fat is less likely to be oxidized for fuel than carbohydrate or protein. Consumed fat is mostly stored before oxidation, especially in heavier people, increasing the likelihood of creating a positive energy balance. An activity-induced increase in energy requirement is typically followed by an increase in energy intake, whereas a reduction in physical activity does not result in an equivalent reduction of energy intake. Thus, preventing weight gain is more effectively reached by eating less than by moving more.

 

MEASURING ENERGY EXPENDITURE

 

Living can be regarded as a combustion process. The metabolism of an organism requires energy production by the combustion of fuel in the form of carbohydrate, protein, fat, or alcohol. In this process oxygen is consumed and carbon dioxide produced. Measuring energy expenditure means measuring heat production or heat loss, and this is known as direct calorimetry. The measurement of heat production by measuring oxygen consumption and/or carbon dioxide production is called indirect calorimetry.

 

Early calorimeters for the measurement of energy expenditure were direct calorimeters. At the end of the 18th century Lavoisier constructed one of the first calorimeters, measuring energy expenditure in a guinea pig. The animal was placed in a wire cage, which occupied the center of an apparatus. The surrounding space was filled with chunks of ice (Figure 1). As the ice melted from the animal's body heat, the water was collected in a container, and weighed. The ice cavity was surrounded by a space filled with snow to maintain a constant temperature. Thus, no heat could dissipate from the surroundings to the inner ice jacket. Today, heat loss is measured in a calorimeter by removing the heat with a cooling stream of air or water or measuring the heat flow through the wall. In the first case, heat conduction through the wall of the calorimeter is prevented and the flow of heat is measured by the product of temperature difference between inflow and outflow and the rate of flow of the cooling medium. In the latter case instead of preventing heat flow through the wall, the rate of this flow is measured from differences in temperature over the wall. This method is known as gradient layer calorimetry.

Figure 1. Lavoisier’s calorimeter. Heat expended by the animal melts the ice in the inner jacket. Snow in the outer jacket prevents heat exchange with the surrounding environment (From reference (1)).

In indirect calorimetry, heat production is calculated from chemical processes. Knowing, for example, that the oxidation of 1 mol glucose requires 6 mol oxygen and produces 6 mol water, 6 mol carbon dioxide and 2.8 MJ heat, the heat production can be calculated from oxygen consumption or carbon dioxide production. Heat production and the energy equivalent of oxygen and carbon dioxide varies with the nutrient oxidized (Tables 1 and 2).

 

Table 1. Gaseous Exchange and Heat Production of Metabolized Nutrients

Nutrient

Consumption oxygen (l/g)

Production carbon dioxide (l/g)

Heat (kJ/g)

Carbohydrate

0.829

0.829

17.5

Protein

0.967

0.775

18.1

Fat

2.019

1.427

39.6

 

Brouwer (2) drew up simple formulae for calculating the heat production and the quantities of carbohydrate (C), protein (P) and fat (F) oxidized from oxygen consumption, carbon dioxide production and urine-nitrogen loss. The principle of the calculation consists of three equations with the mentioned three measured variables:

 

Oxygen consumption              = 0.829 C + 0.967 P + 2.019 F

Carbon dioxide production      = 0.829 C + 0.775 P + 1.427 F

Heat production                       = 21.1 C + 18.7 P + 19.6 F

 

Usually, only urine nitrogen is measured when information on the contribution of C, P, and F to energy production is needed. Protein oxidation (g) is calculated as 6.25 x urine-nitrogen (g), and subsequently oxygen consumption and carbon dioxide production can be corrected for protein oxidation to allow calculation of carbohydrate and fat oxidation. The general formula for the calculation of energy production (E) derived from these figures is: 

 

E = 16.20 * oxygen consumption + 5.00 * carbon dioxide production - 0.95 P.

 

In this formula the contribution of protein (P) to energy production (E), the so-called protein correction, is very small. In the case of a normal protein oxidation of 10-15 per cent of the daily energy production, the protein correction for the calculation of E is about one per cent. For this reason, in the calculation of energy production, the protein correction is often neglected.

 

Metabolizable energy is available for energy production in the form of heat and for external work. At present, the state of the art for assessing total energy expenditure is with indirect calorimetry. With indirect calorimetry, the energy expenditure is calculated from gaseous exchange of oxygen and carbon dioxide. The result is the total energy expenditure of the body for heat production and work output. With direct calorimetry, only heat loss is measured. At rest, total energy expenditure is converted to heat. During physical activity, there is work output as well. The proportion of energy expenditure for external work is the work efficiency. At rest, indirect calorimetry-assessed energy expenditure matches heat loss as measured with direct calorimetry. During physical activity, heat loss is systematically lower than indirect calorimetry-assessed energy expenditure and can be up to 25% lower than total energy expenditure during endurance exercise. The difference increases with exercise intensity. For example, during cycling, indirect calorimetry assessed energy expenditure matches the sum of heat loss and power output (3) and work efficiency during cycling, the power output divided by energy expenditure, is in the range of 15 to 25%.

 

Current techniques utilizing indirect calorimetry for the measurement of energy expenditure in humans include a facemask or ventilated hood, respiration chamber (whole room calorimeter), and the doubly labelled water method. A facemask is typically used to measure energy expenditure during standardized activities on a treadmill or a cycle ergometer. A ventilated hood is used to measure resting energy expenditure and energy expenditure during nutrient processing and absorption (diet-induced energy expenditure). A respiration chamber is an airtight room that is ventilated with fresh air, with the only difference between a usually, ventilated hood system and respiration chamber being size. In a respiration chamber the subject is fully enclosed instead of enclosing the head only, allowing physical activity depending on the size of the chamber. For measurements under a hood or in a respiration chamber, air is pumped through the system and blown into a mixing chamber where a sample is taken for analysis. Measurements taken are those of the airflow and of the oxygen and carbon dioxide concentrations of the air flowing in and out. The most common device to measure the airflow is a dry gas meter comparable to that used to measure natural gas consumption at home. The oxygen and carbon dioxide concentrations are commonly measured with a paramagnetic oxygen analyzer and an infrared carbon dioxide analyzer respectively. The airflow is adjusted to keep differences in oxygen and carbon dioxide concentrations between inlet and outlet within a range of 0.5 to 1.0%. For adults, this means airflow rates around 50 l/min at rest under a hood, 50-100 l/min when sedentary in a respiration chamber, while in exercising subjects the flow has to be increased to over 100 l/min. In the latter situation, one has to choose a compromise for the flow rate when measurements are to be continued over 24 hours that include active and inactive intervals. During exercise bouts, the 1% carbon dioxide level should not be surpassed for long. During times of rest, like an overnight sleep, the level should not fall too far below the optimal measuring range of 0.5-1.0%. Changing the flow rate during an observation interval reduces the accuracy of the measurements due to the response time of the system. Though the flow rate of a hood and a chamber system is comparable, the volume of a respiration chamber is more than 20 times the volume of a ventilated hood. Consequently, the minimum length of an observation period under a hood is about 0.5 hours and in a respiration chamber in the order of 5-10 hours.

 

The doubly labelled water method is an innovative variant on indirect calorimetry based on the discovery that oxygen in the respiratory carbon dioxide is in isotopic equilibrium with the oxygen in body water. This technique involves enriching the body water with an isotope of oxygen and an isotope of hydrogen and then determining the washout kinetics of both isotopes. Doubly labelled water provides an excellent method to measure total energy expenditure in unrestrained humans in their normal surroundings over a time period of one to four weeks. After enriching the body water with labelled oxygen and hydrogen by drinking doubly labelled water, most of the oxygen isotope is lost as water, but some is also lost as carbon dioxide because CO2 in body fluids is in isotopic equilibrium with body water due to exchange in the bicarbonate pools (4). The hydrogen isotope is lost as water only. Thus, the washout for the oxygen isotope is faster than for the hydrogen isotope, and the difference represents the CO2 production. The isotopes of choice are the stable, heavy, isotopes of oxygen and hydrogen, oxygen-18 (18O) and deuterium (2H), since these avoid the need to use radioactivity and can be used safely. Both isotopes naturally occur in drinking water and thus in body water. The CO2 production, calculated from the difference in elimination between the two isotopes, is a measure of metabolism. In practice, the observation duration is set by the biological half-life of the isotopes as a function of the level of the energy expenditure. The minimum observation duration is about three days in subjects with high energy turnover like premature infants or endurance athletes. The maximum duration is 30 days or about 4 weeks in elderly (sedentary) subjects. An observation period begins with collection of a baseline sample. Then, a weighed isotope dose is administered, usually a mixture of 10% 18O and 6% 2H in water. For a 70 kg adult, between 100-150 cc water would be used. Subsequently, the isotopes equilibrate with the body water and the initial sample is collected. The equilibration time is dependent on body size and metabolic rate. For an adult the equilibration would take between 4-8 hours. During equilibration, the subject usually does not consume any food or drink. After collecting the initial sample, the subject performs routines according to the instructions of the experimenter. Body water samples (blood, saliva or urine) are collected at regular intervals until the end of the observation period. The doubly labelled water method gives precise and accurate information on carbon dioxide production. Converting carbon dioxide production to energy expenditure needs information on the energy equivalent of CO2 (Table 2), which can be calculated with additional information on the substrate mixture being oxidized. One option is the calculation of the energy equivalent from the macronutrient composition of the diet. In energy balance, substrate intake and substrate utilization are assumed to be identical.

 

Table 2. Energy Equivalents of Oxygen and Carbon Dioxide

Nutrient

Oxygen (kJ/l)

Carbon dioxide (kJ/l)

Carbohydrate

21.1

21.1

Protein

18.7

23.4

Fat

19.6

27.8

 

ENERGY EXPENDITURE AND COMPONENTS

 

Daily energy expenditure consists of four components: 1) sleeping metabolic rate, 2) the energy cost of arousal, 3) the thermic effect of food (or diet-induced energy expenditure (DEE)), and 4) the energy cost of physical activity or activity-induced energy expenditure (AEE). Usually, sleeping metabolic rate and the energy cost of arousal are combined and referred to as resting energy expenditure (REE). Overnight when one sleeps quietly, food intake and physical activity are generally low or absent and energy expenditure gradually decreases to a daily minimum before increasing upon awakening (Figure 2). Then, increases in energy expenditure during arousal are primarily the result of activity-induced energy expenditure as well as diet-induced energy expenditure. Thus, energy expenditure varies throughout a day as a function of body size and body composition (the major components determining REE), physical activity as determinant of AEE, and food intake as determinant of DEE.

Figure 2. Average energy expenditure (upper line) and physical activity (lower line) as measured over a 24-h interval in a respiration chamber. Arrows denote meal times. Data are the average of 37 subjects, 17 women and 20 men, age 20-35 y and body mass index 20-30 kg/m2 (5).

Resting energy expenditure is defined as the metabolic rate required to maintain vital physiological functions of an individual that is in rest, awake, in a fasted state, and in a thermoneutral environment. To perform an accurate measurement of REE, a subject is instructed not to exercise the day before, to fast overnight, transported to a laboratory after waking up in the morning and habituated for 15-30 min to the testing procedure under a ventilated hood, before the actual measurement of 20-30 min, at a comfortable room temperature of 22-24 0C (6).

 

Standardizing to fat-free mass as an estimate of metabolic body size is most commonly used in the literature to compare REE between individuals. However, although fat-free body mass is a strong predictor of REE, energy expenditure should not be solely divided by the absolute fat-free mass value as the relationship between energy expenditure and fat-free mass has an Y-intercept (the value for energy expenditure when fat-free mass is theoretically absent) that is not zero (Figure 3). For example, fat-free adjusted REE is significantly different between women and men (Figure 3, 0.143±0.012 and 0.128±0.080 MJ/kg for women and men, respectively, P < 0.0001). The smaller the fat-free mass, the higher the REE/ fat-free mass ratio and thus the REE per kg fat-free mass is on average higher in women than men. Instead, a more accurate approach for comparing REE data is by regression analysis that includes both fat-free mass and fat mass as covariates.

 

REE (MJ/d) = 1.39 + 0.93 fat-free mass (kg) + 0.039 fat mass (kg), r2 = 0.93.

 

Using this equation, gender no longer comes out as a significant contributor to the explained variation in the group of women and men (Figure 3).

 

Figure 3. Resting energy expenditure (REE) plotted as a function of fat-free mass for the subjects from reference 5 as described in Figure (2) (17 women: closed symbols; 20 men: open symbols) with the calculated linear regression line (REE (MJ/d) = 2.27 + 0.091 fat-free mass (kg), r2 = 0.78).

Diet-induced energy expenditure is defined as the energy-required for intestinal absorption of nutrients, the initial steps of their metabolism and the storage of the absorbed but not immediately oxidized nutrients during the post-prandial period. As such, the amount of food ingested quantified as the energy content of the food is a determinant of DEE. The most common way to express DEE is derived from the difference between energy expenditure after food consumption and REE, divided by the rate of nutrient energy administration. Theoretically, based on the amount of ATP required for the initial steps of metabolism and storage, the DEE is different for each nutrient. Reported DEE values for separate nutrients are 0 to 3% for fat, 5 to 10% for carbohydrate, and 20 to 30% for protein (7). In healthy subjects in energy balance with a mixed diet, DEE represents about 10% of the total amount of energy ingested over 24 hours.

 

A typical mean pattern of DEE throughout the day is presented in Figure 4. Data are from a study where DEE was calculated by plotting the residual of the individual relationship between energy expenditure and physical activity in time, as measured over 30-min intervals from a 24-h observation in a respiration chamber. The level of REE after waking up in the morning, and directly before the first meal, was defined as basal metabolic rate. Resting metabolic rate had still not returned to basal metabolic rate before lunch four hours after breakfast, or before dinner at five hours after lunch. Instead, basal metabolic rate was restored overnight, approximately eight hours after dinner consumption.

Figure 4. The mean pattern of resting energy expenditure throughout the day, where arrows denote meal times (adapted from reference (8)).

Activity-induced energy expenditure, the most variable component of daily energy expenditure, is derived from total energy expenditure (TEE) minus resting energy expenditure and diet-induced energy expenditure.

 

AEE = TEE – REE – DEE.

 

Total energy expenditure is measured with doubly labelled water as described above. When diet induced energy expenditure is assumed to be 10% of TEE in subjects consuming the average mixed diet and being in energy balance, AEE can be calculated as: AEE = 0.9 TEE – REE.

 

A frequently used method to quantify the physical activity level (PAL) of a subject is to express TEE as a multiple of REE:

 

PAL = TEE/REE.

 

This assumes that the variation in total energy expenditure is due to body size and physical activity. The effect of body size is corrected for by expressing TEE as a multiple of REE. Data on daily energy expenditure, as measured with doubly labelled water, permit the evaluation of limits to the physical activity level. In our site, data were compiled for more than 500 subjects, where energy expenditure was measured over an interval of two weeks with the same protocol. The sample excludes individuals aged less than 18 years, involved in interventions of restricted or forced excess energy intake, whose physical activity including athletic performance, who were pregnant or lactating, and with an acute or chronic illness. The sample includes similar numbers of women and men, with a wide range for age, height, weight, and body mass index. Despite the wide variation in subject characteristics, a narrow range of the physical activity level (between 1.1 and 2.75) amongst the subjects was found (Figure 5) with no sex differences (9).

 

The physical activity level of a subject can be classified in three categories as defined by the last Food and Agriculture Organization/World Health (FAO/WHO/UNU) expert consultation on human energy requirements (10). The physical activity for sedentary and light activity lifestyles ranges between 1.40 and 1.69, for moderately active or active lifestyles between 1.70 and 1.99, and for vigorously active lifestyles between 2.00 and 2.40. An active lifestyle improves heath parameters like insulin sensitivity (11). Higher PAL values, while difficult to maintain over a long period, generally result in weight loss.

 

An alternative for the measurement of energy expenditure with indirect calorimetry is a prediction equation for resting energy expenditure, in combination with an estimation of activity energy expenditure from measurement of body movement with an accelerometer. Typically, prediction equations for resting energy expenditure can explain 70-80% of the variation from race, height, age, weight and gender of a subject (12). Doubly labelled water studies show the best accelerometers for movement registration so far can explain 50-70% of variation in activity energy expenditure (13).

Figure 5. Frequency distribution of the value of the physical activity level (PAL) calculated as the total energy expenditure / resting energy expenditure, in a group of 556 healthy adults, women closed bars and men open bars (data from reference (9)).

DETERMINANTS OF ENERGY EXPENDITURE

 

The main determinants of energy expenditure are body size and body composition, food intake, and physical activity. Additional determinants are ambient temperature and health. As most people are able to live in a thermoneutral environment or prevent heat loss with appropriate clothing, energy expenditure is not affected by ambient temperature for longer time intervals.

Body size and body composition determine REE, the largest component of daily energy expenditure (Figure 6). Energy expenditure is generally higher in men than in women because men generally have a larger metabolic body size. They are on average heavier than women and for the same weight men have relatively more fat-free mass. For similar reasons, gaining weight implicates gaining fat mass and fat-free mass, and daily energy expenditure is generally higher in people who are overweight and have obesity compared with people who are lean matched for age, height and gender. This higher energy expenditure in people with obesity is mainly a consequence of higher resting energy expenditure than people who are lean (Figure 6).

Figure 6. The three components of energy expenditure: resting energy expenditure (closed bar), diet-induced energy expenditure (stippled bar), and activity-induced energy expenditure (open bar) as observed in subjects who are lean and who have obesity. In the lean group, women and men weighed 61 kg and 74 kg with 29% and 17% body fat, respectively. In the group with obesity, subjects were, on average, 40 kg heavier, where 70% of the additional weight was fat mass and 30% fat-free mass. The figure illustrates the higher energy expenditure (primarily in resting energy expenditure) in men than women and in those with obesity compared to those who are lean. (After reference (14)).

Food intake affects all three components of daily (total) energy expenditure: REE, DEE and AEE. The most obvious effect is on DEE, which represents about 10% of the amount of daily energy ingested. Thus, changing energy intake changes total energy expenditure accordingly. Overeating induces an additional increase for storage of excess energy, estimated at about 10 % of the energy surplus (15). When overfeeding is lower than twice the maintenance requirements, there does not seem to be an effect of this overfeeding on physical activity (16). Undereating induces a decrease in REE, DEE and AEE. Undereating induces weight loss accompanied by adaptive thermogenesis, a disproportional or greater than expected reduction of REE. The reduction in REE is sustained even while weight loss is maintained (17). Weight loss due to a negative energy balance is accompanied by a decrease in AEE as well. Here, the decrease is due to less body movement and a lower cost to move a smaller body mass. The reduction in body movement recovers to baseline values or higher when weight loss in maintained (18). A classic example of the effect of undereating on energy expenditure is the Minnesota Experiment from the 1950’s (19). Energy intake of normal-weight men was reduced for 24 weeks from 14.6 MJ/d to 6.6 MJ/d. The subjects reached a new energy balance by saving 8 MJ/d (Table 3). Of the total saving of 8 MJ/d the main part stemmed from reduced AEE, which was mainly due to moving less.

 

Table 3. Energy Saved by 24 Weeks Underfeeding in the Minnesota Experiment (19)

 

MJ/d

% of saving

Explanation

Resting energy expenditure

2.6

32

65% for a decreased bodyweight

35% for a lowered tissue metabolism

Diet-induced expenditure

0.8

10

 

Activity-induced expenditure

4.7

58

40% for a decreased bodyweight

60% for less body movement

Total

8.0

   

 

Activity induced energy expenditure is the most variable component of daily expenditure and can be increased through exercise. Variation in energy expenditure between subjects is a function of body size and physical activity, where AEE is an important contributor. Most of the variation in AEE is accounted for by genetic factors. Genes determine for a large part whether a person is prone to engage in activities and how much energy is expended for these activities (20). Exercise training can increase AEE. However, under some conditions the added exercise expenditure is compensated for by a reduction of non-training activity. Examples are non-ad libitum food intake and older age (Figure 7).

 

Figure 7. The physical activity level, total energy expenditure as a multiple of resting energy expenditure, before (open bar) and at the end of a training program (closed bar), for eight studies displayed in a sequence of age of the participants as displayed on the horizontal axis (After reference (21)).

Activity-induced energy expenditure does not increase linearly with increasing physical activity. For example, novice runners training to run a half marathon could increase the training amount without a change in AEE (22). In the selected group of sedentary subjects, the initial training-induced increase in AEE was twice as high as predicted from the training load. However, subsequent training allowed a doubling of the training load for the same AEE, probably through an improvement of exercise economy. Similarly, exercise training has been shown to decrease the energetic cost of walking in older adults (23).

 

Physical activity level reaches a maximum value of 2.0-2.4 (Figure 7). Higher values can be reached over shorter time intervals. For example, runners in a 140-day transcontinental race across the USA showed an initial increase in PAL from a pre-race value of 1.76 to 3.76 over the first five days of running (24). In the final week (week 20) of running, PAL had decreased to a mean value of 2.81. This subsequent decrease in PAL during sustained physical activity was hypothesized to have resulted from a limit in alimentary energy supply.

 

During negative energy balance, additional exercise is compensated by a reduction of non-training activity. In elderly subjects, exercise training has a similar compensatory effect on spontaneous physical activity, even under ad-libitum food conditions. Despite the absence of an effect of exercise training on total energy expenditure in elderly people, there are many beneficial effects of exercise training like aerobic capacity, endurance, flexibility, and range of motion.

 

ENERGY BALANCE

 

Adult humans maintain weight stability through a balance between energy intake and energy expenditure. When weight is stable, the energy store of the body does not fluctuate much, as evident by constancy in body weight and body composition. This weight constancy can be achieved through the balanced control of energy intake and expenditure. This balance does not, however, take place on an immediate basis. For example, on days with high energy expenditure, energy intake is usually normal or even below normal. The 'matching' increase in energy intake comes several days afterwards (25). Energy intake can change by at least a factor of three when adapting to changes in energy expenditure. Under sedentary living conditions the energy balance is maintained at about 1.5 times basal metabolic rate (BMR), while during sustained exercise levels of 4.5 times BMR are reached (26).

 

Humans are discontinuous eaters and continuous metabolizers. An animal that takes its food in meals, such as a human, periodically consumes more than their physiological needs even when in (daily) energy balance. During meal-related hyperphagia, metabolites are initially stored then mobilized during inter-meal intervals of energy deficiency. This pattern of intermittent feeding and fasting has consequences for energy expenditure (Figure 4). During and after a meal, expended energy increases to process the ingested food, while energy deficiency before a new meal is started can lead to a reduction of energy expenditure. The latter probably does not occur during short-term energy deficiency. However, people tend to be less energetic during prolonged inter-meal intervals or extended fasts.

 

Disturbances of energy balance result in energy mobilization from, or energy storage in, body reserves. Energy intake occurs via macronutrients consumed in meals in the form of carbohydrate, protein, fat and alcohol. During positive energy balance, excess energy is stored as carbohydrate in glycogen, primarily in the liver, and as fat in adipose depots. The storage capacity for carbohydrate is small, typically covering energy needs during the overnight fast that accompanies sleep. Longer-term shortages are mainly covered by mobilization of the larger energy stores in fat. On days with a positive energy balance, protein and carbohydrate intake match protein and carbohydrate oxidation and the difference between energy intake and energy expenditure shows up in a positive fat balance (27). In the early morning, at arousal, carbohydrate oxidation goes up and continues to increase at the first food intake of the day (28). After awakening, initial energy (‘fast’) requirements are met by glycogen reserves. Subsequently, carbohydrate requirement is higher at breakfast, and one eats relatively more fat at the evening dinner (29,30).

 

Energy balance does not equate to substrate balance, and when in substrate balance one does not produce energy just from the foods consumed. Fat, as a substrate for energy metabolism is at the bottom of the oxidation hierarchy that determines fuel selection and studies show a direct link between macronutrient balance for fat and energy balance. Changes in alcohol, protein, and carbohydrate intake elicit auto regulatory adjustments in oxidation whereas a change in fat intake fails to elicit such a response, or only in the long term (31).

 

One explanation for this macronutrient oxidation disparity is the routing of dietary fat. Fat metabolism can be traced with isotope-labelled fatty acids. Oxidation and adipose tissue uptake of dietary fat can be measured by adding fatty acid labelled with heavy hydrogen (2H) to meals. Upon oxidation, these deuterated fatty acids enrich the body water with deuterium, which is subsequently detectable in urine. Therefore, the urine enrichment for deuterium is a measure of dietary fat oxidation. The first label appears in the urine in about two hours and the peak concentration is reached after 12-24h (Figure 8). After 24 hours, 5-30% of the fat from a meal is oxidized and the remaining part partitioned to the reserves. The percentage of dietary fat oxidation is independent of the composition of the meal with respect to protein, carbohydrate and fat. However, there is a clear relation of dietary fat oxidation with the body fat content. The larger the fat mass, the lower the fractional oxidation of the fat consumed on the same day (32). The observed reduction in dietary fat oxidation in subjects with greater body fat may therefore play a role in expression and maintenance of human obesity. This low dietary fat oxidation makes subjects prone to weight gain.

Figure 8. Cumulative oxidation (mean ± standard deviation) of dietary fat as a percentage of intake, over time after ingestion, as calculated from tracer recovery in urine produced at two-hour intervals (From reference (32)).

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An Overview of Glucocorticoid-Induced Osteoporosis

ABSTRACT

 

Glucocorticoid (GC)-induced osteoporosis (GCOP) is the most common cause of iatrogenic osteoporosis (OP). Fractures may occur in 30-50% of patients on chronic GC therapy. Most of the epidemiological data associating fracture risk with GC therapy are from the use of oral GCs. The process of bone remodeling is complex, regulated by an intricate network of local and systemic factors. With prolonged GC administration, cortical bone becomes increasingly affected and long bones show increased fragility. As some patients on a low GC dose show bone loss at a much higher rate than others on a higher GC dose, genetics may play a role in determining this difference. Any patient that is treated with long-term GCs should be suspected as suffering from GCOP. Laboratory evaluation for GCOP should include total blood cell count, markers of renal and liver function, serum electrophoresis, serum and 24-hr urine calcium, serum levels of 25-hydroxyvitamin D, alkaline phosphatase, thyroid-stimulating hormone and parathyroid hormone, estradiol in women and total and free testosterone in men. Changes in BMD early on during GC therapy can be detected by dual-energy X-ray absorptiometry (DXA). In patients under GC treatment fractures tend to occur at BMD values that are lower than the conventional threshold T-score of -2.5. Recently simple adjustments for the calculated fracture risk have been presented that take into account glucocorticoid dosage for the Fracture Risk Assessment tool (FRAX). Guidelines for the prevention and treatment of GCOP have been put forth from various authorities. Prevention of GCOP should start as soon as GCs are administered; bone loss is more rapid in the first months of therapy. Patients on GCs should receive supplementation with calcium and vitamin D. There are several antiresorptive agents available for the prevention and treatment of GCOP - bisphosphonates are the most widely used. Teriparatide and denosumab can also be therapies of choice for patients on GC treatment with or without GCOP.

 

INTRODUCTION

 

Glucocorticoid (GC)-induced osteoporosis (GCOP) is often the result of secondary osteoporosis (OP) (1). It is the most common cause of iatrogenic OP; adults aged 20 to 45 years are mainly affected (1-3). Important bone loss may occur with or without other manifestations and its severity is dependent on both the dose and duration of GC treatment (4). From a retrospective study conducted in the United Kingdom the prevalence of chronic use of oral GCs in the general population was shown to be 0.5%; the prevalence was higher in women over 55 years (1.7%) and as high as 2.5% in subjects older than 70 years (5, 6); more recently experts argued that approximately 2% of the population receives long-term GC treatment (7). It is of practical interest to note that only 4%-14% of patients taking oral steroids were receiving treatment for prevention of osteoporosis (mainly by rheumatologists), indicating that GCOP is often underestimated and left untreated (5, 8).

 

EPIDEMIOLOGY

 

The association between glucocorticoid (GC) excess and osteoporosis was first described nearly 80 years ago, but its importance in clinical practice has only recently been recognized (9). Although it shares some similarities with postmenopausal osteoporosis, glucocorticoid-induced osteoporosis (GCOP) has distinct characteristics, including the rapidity of bone loss early after initiation of therapy, the accompanying increase in fracture risk during this time, and the combination of suppressed bone formation and increased bone resorption during the early phase of therapy (10).

 

Although awareness of GCOP amongst health-care professionals has increased over recent years, several studies indicate that its management remains suboptimal (11, 12). Although increased rates of diagnosis and treatment have been reported, possibly as a result of national guidelines, but overall these rates remain low (12, 13).

 

There is clear epidemiological association between GC therapy and fracture risk (14-16). Oral GC therapy is prescribed in up to 2.5% of the elderly population (aged 70-79 years) for a wide range of medical disorders (17). Fractures may occur in 30-50% of patients on chronic GC therapy (18). The vertebrae and femoral neck of the hip are specifically involved (19), whereas risk at the forearm (predominantly consisting of cortical bone), is not increased, confirming that GCs affect predominantly cancellous bone (15). Vertebral fractures associated with GC therapy may be asymptomatic (20). When assessed by X-ray-based morphometric measurements of vertebral bodies, more than 1/3 of postmenopausal women on chronic (> 6 months) oral GC treatment have sustained at least one vertebral fracture (20).

 

Along with the demonstration that fractures can occur early in the course of GC therapy, fracture incidence is also related to the dose and duration of GC exposure (16).

 

Doses as low as 2.5 mg of prednisone equivalents per day can be a risk factor for fracture, but the risk is clearly greater with higher doses. Chronic use is also associated with greater fracture risk (1, 16). When daily amounts of prednisone - or its equivalent - exceed 10 mg on a continuous basis and duration of therapy is greater than 90 days, the risk of fractures at the hip and vertebral sites is increased by 7- and 17-fold respectively (16). The risk of fractures declines after discontinuation of GCs although the recovery of the lost bone is gradual and often incomplete (1, 16).

 

Most of the epidemiological data associating fracture risk with GC therapy, come from the use of oral GCs. There is less data about risk associated with inhaled GCs (21-25); from the data available it can be extrapolated that a small but persistent and clinically significant growth retardation may be expected in children receiving inhaled GCs (26). It is also important to bear in mind that the underlying disorder for which inhaled or systemic GCs is used may also be a cause of bone loss (27). The systemic release of local bone-resorbing cytokines in some of these disorders could stimulate bone loss (28, 29). In addition, there are also local factors to consider. In inflammatory bowel disease, bone loss may be due, in part, to malabsorption of vitamin D, calcium, and other nutrients (28). In chronic lung disease, hypoxia, acidosis, reduced physical activity, and smoking may all contribute to bone loss, independently of the use of inhaled GCs (14, 25, 30, 31).

 

SECONDARY CAUSES/RISK FACTORS OF BONE LOSS

 

Factors, such as advancing age, race, sex, menopausal status, family history of OP and fractures, and secondary causes of OP, such as hyperthyroidism, hyperparathyroidism, Cushing’s syndrome, hypogonadism, diabetes (particularly type 1), renal failure, inflammatory bowel disease, and rheumatoid arthritis can add to the effects of GCOP (14, 32-36). Some of the risk factors for GCOP are common to other forms of OP and can be modified; these include: low calcium and high sodium intake (37), high caffeine intake (when calcium intake is low) (38), tobacco and alcohol use, decreased physical activity, immobilization, and a number of medications (32, 39, 40). Medications/treatments that are administered concomitantly with GCs (such as methotrexate, cyclosporine, heparin, medroxyprogesterone acetate, gonadotropin releasing hormone (GnRH) analogs, levothyroxine, anticonvulsants, or radiotherapy) may add to the disease burden of GCOP.

 

The emerging use of aromatase inhibitors (41), androgen-deprivation therapy in men with prostate cancer (42), and the growing field of bariatric surgery (43) have emerged as novel and important etiologies of secondary osteoporosis.

 

Patients with classical congenital adrenal hyperplasia (CAH)  can be over-treated with GC and show loss of bone mineral density (BMD) (44). The iatrogenic suppression of adrenal androgens production in women with CAH is associated with increased risk for bone loss (45). Young adult men on GCs apparently show more rapid bone loss compared to older men or postmenopausal or premenopausal women. Of note, men are more susceptible to depression-associated bone loss, which may be in part, GC-mediated (46). Postmenopausal women receiving GCs show higher fracture risk compared to premenopausal women that is attributed to lower bone mass when starting GC therapy) (47, 48). Patients with sarcoidosis and those taking steroids to prevent rejection of grafts after heart or kidney transplant, are also more likely to experience rapid bone loss (49-51).

 

CELLULAR AND MOLECULAR MECHANISMS OF GCOP

 

The process of bone remodeling is complex, regulated by an intricate network of local and systemic factors. Although normal bone needs endogenous GCs for its development (for osteoblast differentiation in particular, via inhibition of mesenchymal stem-cell differentiation to adipocytes) (52-54), GCs, at least in mice models, exert negative effects on bone maintenance in old age (by lowering survival of osteoblasts and osteocytes and limiting angiogenesis) (52). Quiescent bone is covered by osteoblasts and osteoclasts. In response to bone-resorbing stimuli, osteoclastic migration and bone resorption are activated. Osteoclasts remove both the organic matrix and the mineral component of the bone, producing a pit. This bone remodeling cycle takes place under a canopy of osteoprogenitor cells (55). In the formation phase, osteoblasts deposit osteoid in the pit, which is then mineralized. In normal bone there is – apparently – no appreciable effect of GCs on osteoclasts (52). Quiescence is restored at completion of the cycle (56). GCs can influence bone remodeling in a number of ways and at any stage of the remodeling cycle (Figure 1). We have to note that regarding animal studies of GCOP experts point to the heterogeneity of used models and the need for their standardization (57).

 

Figure 1. Overview of the mechanisms of glucocorticoid-induced osteoporosis (GCOP). Osteoporosis results from an imbalance between osteoblast and osteoclast activity. BMP-2: bone morphogenic protein-2; Cbfa1: core binding factor a1; Bcl-2: B-cell leukemia/lymphoma-2 apoptosis regulator; Bax: BCL-2-associated X protein; IGF-I: insulin-like growth factor-I; IGFBP: IGF binding protein; IGFBP-rPs: IGFBP-related proteins; HGF: hepatocyte growth factor; RANKL: receptor activator of the nuclear factor-κB ligand; CSF-1: colony-stimulating factor-1; OPG: osteoprotegerin; PGE2: Prostaglandin E 2; PGHS-2 prostaglandin synthase-2

Bone Histomorphometry Under GCs

 

Trabecular bones and the cortical rim of vertebral bodies are more susceptible to the effects GCs compared to the cortical component of long bones (radius, humerus) (58-62). Under GC treatment, lumbar bone shows significantly greater bone loss compared to distal radius. Bone loss is also observed in the proximal femur (particularly at Ward’s triangle, an area rich in trabecular bone) (63, 64). Although bone remodeling is initially turned on with higher bone resorption, over time, resorption parameters fall and bone becomes quiescent (65, 66). Thus, with prolonged GC administration, cortical bone becomes increasingly affected and long bones show increased fragility.

 

Bone biopsies of patients on GC therapy for longer than 12 months show increased bone resorption, a decline in all aspects of bone formation, and decreased trabecular volume. Histomorphometric studies on subjects with GCOP show increased osteoclasts and bone-resorbing sites; bone loss is higher in the metaphyses compared to the diaphyses (67-69). A specific feature of GCOP is the decrease in canopy coverage of bone remodeling sites (52, 55). GCOP differs from post-menopausal OP in terms of microanatomical appearance; in GCOP the number of trabeculae and their surface area are relatively preserved, and individual plates are very thin (trabecular attenuation), although still connected, whereas in post-menopausal OP, trabecular width is relatively preserved but the lamellae are perforated by resorption, with a loss of trabecular surface and continuity (70). Such changes may lead to lower mechanical strength of bone. The particular histology of GCOP may have important implications for pharmacologic intervention: the preservation of thinned trabeculae in GCOP may provide the foundation for new bone apposition. With excess GCs, osteoclasts, over time, preferentially deepen their resorption pits than migrate to new resorption sites (52).

 

Glucocorticoid Receptors (GRs) and Bone

 

There is still no consensus on whether genomic or non-genomic actions of GCs are the major players in GCOP (71). Genomic actions result from the binding of GCs steroids to specific cytoplasmic receptors that belong to the nuclear receptor superfamily. The GC-GR complex can either activate or repress the expression of target genes. While activation requires binding of a dimerized receptor to GC-responsive elements (GREs) in the promoter region of target genes, repression is mainly mediated by interaction between receptor monomers and transcription factors (72). GC-induced osteoblast apoptosis does not require GR dimerization (52). Translation of GR mRNAs produces two GR isoforms; GRα, which is transcriptionally active and GRβ, which can heterodimerize with GRα inhibiting its transcriptional activity (73). In humans, normal osteoblasts, and specific osteoblastic cell lines show GRα expression, whereas mature osteoclasts show no GRα expression. Osteoclasts, in contrast, predominantly show GRβ expression. Osteoblasts and osteoclasts also express mineralocorticoid receptors (MRs) that bind to cortisol and form heterodimers with both GRα and GRβ (74). IL-6, in human osteoblasts, acts as an autocrine positive modulator that upregulates the number of GRs (75, 76). Cortisol, even at physiologic concentrations, modulates negatively the secretion of IL-11, a cytokine that decreases GR expression (77). Consequently, this interplay of cytokines through autocrine/paracrine loops may modulate bone sensitivity to GCs (78).

 

GCs and Osteoblast Activity

 

In response to pharmacologic doses of GCs, osteocytes trigger the protective process of autophagy; with excessive doses of GCs autophagy leads to apoptosis (79). GCs increase the apoptosis of osteoblasts and mature osteocytes via activation of caspase 3 (1, 80-83). Osteoblast/osteocyte apoptosis may involve decreased expression of the pro-survival factor BclXL and increased expression of the proapoptotic factors Bim and Bak (through induction of the leucine zipper E4bp4) (52, 84). Apoptosis is also assisted by GC-induced excess reactive oxygen species (ROS) production and inhibition of Akt, leading to suppression of the Wnt/β-catenin pathway, which is necessary for osteoblastogenesis as well as for cell survival (52, 85). Studies on the proaptototic effect of GCs on osteoblasts/osteocytes, indicate that it may be mediated by the process of endoplasmic reticulum stress (86). Furthermore, GCs reduce osteoblast proliferation and differentiation (62), possibly as a result of GC-induced repression of bone morphogenic protein-2 (BMP-2) and expression of core binding factor a1 (Cbfa1) (84). GCs also modify the expression of osteoblast specific genes, such as osteocalcin. Osteocalcin expression during the development of bone is tightly regulated by GCs, and multiple GREs have been identified on the human and rat osteocalcin promoter region (87, 88). The osteocalcin gene also contains several activator protein-1 (AP-1) sites that apparently contribute to the basal activity of the promoter. Therefore, repression of osteocalcin promoter activity by GCs may also involve interaction between GR and components of the AP-1 complex, independently of DNA binding, as it has been postulated for the collagenase promoter (89, 90).

 

The Wnt signaling pathway is important for osteoblast differentiation and function, bone development and level of peak bone mass (91). Mechanical loading results in increased bone mass in animals that carry activating mutations of Lrp5 (coding for a Wnt coreceptor)(91). Wnt signaling may be implicated in the osseous response to mechanical loading (91) and the observed inhibition of skeletal growth by GCs may be mediated by effects on Wnt signaling (92)by enhancing Dickkopf 1 (Dkk1) expression (which is a Wnt antagonist) and Sost (sclerostin, which is a disruptor of the Wnt-induced Fz-Lrp5/6 complex leading to β-catenin ubiquitination) (52, 62, 93). Interestingly, both short- and long-term GC administration decreases Dkk1 expression in humans whereas only long-term GC administration decreases Sost expression; Wnt signaling involvement in GCOP appears to be time-dependent (52). The inhibition of Wnt signaling is also involved in GC-induced adipocyte differentiation (52).

 

GCs are required for the differentiation of mesenchymal stem cells to bone cells; they can also promote an osteoblastic phenotype (by inhibiting collagenases (MMPs) and reducing collagen type 1 breakdown) (94-96). Impaired osteoblastogenesis by excess GCs involves the reduction in expression of microRNAs (endogenous RNAs of 18-25 nucleotides each that interact with mRNA to alter protein expression) (97), such as miR-29a/miR-34a-5p and reductions in the mRNA expression of Dkk1/receptor activator of the nuclear factor-κB ligand (RANKL) (98).

           

GCs and Osteoclast Activity

 

Compared to effects of GCs on osteoblasts, the effects of GCs on osteoclasts are less known as osteoclast isolation from bone is technically difficult and bone marrow cultures, hematopoietic cell lines and cells derived from giant-cell tumors (used as model systems to study osteoclast differentiation and activity) have produced varying results. GCs stimulate bone resorption (99-101). It has been shown that GCs stimulate osteoclastogenesis through their capacity to bind to the bone surface by altering the expression of N-acetylglucosamine and N-acetylgalactosamine (85, 102). Osteocyte apoptosis, induced by GCs, reduces osteoprotegerin (OPG, the decoy RANKL ligand) (52). GCs may decrease apoptosis and prolong the lifespan of mature osteoclasts (52, 62) but cannot affect directly their bone-resorbing activity, since these cells apparently lack functional GRs (103). GCs suppress calpain 6 (Capn 6) which is enmeshed in β-integrin (a mediator of osteocyte interaction with the osseous matrix) and expression of microtubules’ acetylation/stability within the bone cells cytoskeleton (52). Higher expression of the GR gene in subjects with lower BMD may lead to higher sensitivity of their monocytes/macrophages to GCs to differentiate into osteoclasts (104). Cytokines are also implicated in these actions (see next section on regulation of local bone factors by GCs) (105).

 

GCs and Local Bone Factors (Cytokines, Growth Factors, Prostanoids and Kinases)

 

CYTOKINES

 

Interleukin-1 (IL-1) and -6 (IL-6) induce bone resorption and inhibit bone formation. GCs partially inhibit the production of IL-1 and IL-6 and inhibit the bone resorbing activity of these cytokines (GC therapy could paradoxically protect osseous tissue from IL-induced bone resorption) (106-109). Transforming growth factor beta 1 (TGF-b, which inhibits IL-1-induced bone resorption and stimulates osteoblast activity) is decreased by GCs. (110). Lower levels of TGF-bmay increase the susceptibility of bone to the resorbing effects of IL-1. IL-1 suppression also inhibits the generation of nitric oxide, which modulates osteoclast activity (111). Excess GCs inhibit the expression of IL-11 on osteoblasts (and hinder this cytokine’s effect on their differentiation) independently of GR dimerization (52). GCs interfere with the RANKL-OPG axis. RANKL (which is expressed at high levels in pre-osteoblast/stromal cells) induces osteoclast differentiation in the presence of colony-stimulating factor-1 (CSF-1) by binding to the receptor activator of the nuclear factor-κB (RANK; a member of the TNF family on the surface of octeoclasts(108). OPG is also produced by osteoblasts and is found on their surface. OPG acts as a decoy receptor of RANKL: it binds RANKL and prevents it from binding its osteoclast receptor, therefore inhibiting osteoclast differentiation. GCs enhance RANKL and CSF-1 expression (78), and lower OPG expression in human osteoblasts cells in vitro (112). Serum OPG concentrations are significantly reduced in patients undergoing systemic GC therapy (113). This decrease in OPG is more marked than the GC-induced increase in RANKL (via suppression of miR-17/20a, which targets Rankl) (52), leading to an increased RANKL/OPG ratio that may mediate GC-induced bone resorption (114).

 

GROWTH FACTORS

 

Insulin-like growth factors (IGFs) have an anabolic effect on bone cells that affect IGF-I and IGF-II receptors. IGF-I and IGF-II are weak mitogens (they increase the replication of osteoblasts), they increase type I collagen synthesis and matrix apposition rates and decrease collagenase-3 (metalloproteinase-13) expression by osteoblasts (115, 116). Synthesis of IGF-I in osteoblasts is decreased by GCs via increased expression of the CAAT/enhancer binding protein (C/EBP) β and δ (transcription factors that bind to the IGF-I promoter and halt its transcription) (117). GCs inhibit IGF-II receptor expression in osteoblasts (while they have no effect on IGF-I receptor expression)(118, 119). Since the IGF-II receptor functions as an IGF-binding protein (IGFBP) its inhibition by GCs may result in higher levels of available growth factors although it may also lead to faster degradation of IGF-II. The activity of IGF-I and -II is regulated by at least six IGFBPs that are expressed by osteoblasts (120, 121). IGFBPs in skeletal cells are considered to be local reservoirs and modulators of IGFs. GCs decrease the expression of IGFBP-3, -4, and -5 in osteoblasts (122, 123). IGFBP-5 stimulates bone cell growth (and enhances the effects of IGF-I); its reduction in the bone microenvironment may be relevant to the inhibitory actions of GCs on bone formation and the process of GCOP (124). GCs also increase the synthesis of IGFBP-related proteins (IGFBP-rPs; a family of peptides related to IGFBPs that bind IGFs and are involved in cell growth) (125). Chondrocytes are involved in fracture healing and in OP this process is delayed. Among others, GCs inhibit the activation of GH and IGF-I receptors in chondrocytes and reduce IGF-I and GH receptor expression in these cells (126).

 

Bone cells express transforming growth factor-b (TGF-b) -1, -2, and -3 genes (127). TGF-b stimulates bone collagen synthesis and matrix apposition rates, modifies bone cell replication, stimulates growth and proliferation of osteoblasts but inhibits their differentiation and the expression of osteocalcin (128, 129). TGF-b1 expression in osteoblasts is not modified by GCs. GCs, instead, induce activation of the latent form of TGF-b1 by increasing the levels of bone proteases (130, 131). Two signal-transducing TGF-b receptors are expressed in osteoblasts. GCs shift the binding of TGF-b from these receptors to betaglycan (by increasing the synthesis of this proteoglycan) and oppose the effects of TGF-b osteoblastic cell replication (130).                     

 Hepatocyte growth factor (HGF) is produced by both osteoblasts and osteoclasts. HGF is a potent stimulator of osteoblastic function and a potent suppressor of bone resorption in isolated rat osteoclasts (132). Osteoclast-produced HGF (in an autocrine fashion), may lead to changes in osteoclast shape and stimulate osteoclast migration and chemotaxis, while (in a paracrine fashion) may lead osteoblasts to enter the cell cycle, via DNA synthesis stimulation (132, 133). GCs inhibit the release of HGF in vitro, which suggests that the inhibitory effects on bone resorption of GCs may be in part mediated via regulation of osteoblast-produced HGF (134, 135).

 

Platelet-derived growth factor (PDGF) is a mitogen of bone cells (136). PDGF-A and PDGF–B are expressed in a limited fashion in osteoblasts, and neither the synthesis nor the binding of PDGF appear to be modified by GCs. Specific PDGF-A/B binding proteins are lacking, although SPARC (secreted protein acid rich in cysteine) and osteonectin (a protein abundant in bone matrix) bind and prevent the biologic actions of PDGF-B (137). Since GCs enhance osteonectin expression in osteoblastic cells they may also decrease the activity of PDGF-B in bone (138).

 

PROSTANOIDS

 

Prostaglandins (PGs) are produced by bone cells and affect both bone formation and resorption. PGs (and PGE2 in particular) stimulate bone collagen and non-collagen protein synthesis (139-141). PGs inhibit directly the activity of isolated osteoclasts and increase bone resorption in organ cultures, (probably by promoting osteoclastogenesis) (142). GC-induced inhibition of collagen synthesis in bone, down-regulation of c-fos oncogene expression and reduced osteoblast proliferation are all reversed by exogenous PGE2in vitro, suggesting an important pathogenic role for this PG in GCOP (143-147). GCs interfere with the production of PGs in bone (especially of PGE2) via the decreased expression of cyclooxygenases (the enzymes that convert arachidonic acid into PGs) (148, 149). Osteoblasts express two cyclooxygenases: constitutive prostaglandin synthase-1 (PGHS-1) and inducible prostaglandin synthase-2 (PGHS-2). Apparently, GC-inhibited PG-production in bone is mediated through a decrease in agonist-induced PGHS-2 expression.

 

KINASES

 

GCs modulate intracellular kinases (ERKs, MAPK/JNK and Pyk2) with a proapoptotic effect on the osteoblastic lineage  (150)

 

EXTRASKELETAL MECHANISMS OF GCOP

 

Effects of GCs on Calcium Absorption and Excretion

 

Although there is no consensus regarding the effect of GCs on calcium absorption, they mainly impair intestinal calcium absorption (151-158). GCs have no effect on the intestinal brush border membrane vesicles (159), but decrease synthesis of calcium binding protein and deplete mitochondrial ATP (160). Patients treated with GCs show increased renal calcium loss occasionally leading to the development of secondary hyperparathyroidism (161). In normal subjects receiving GCs the elevation of fasting urinary calcium proceeds the rise in immunoreactive parathyroid hormone (iPTH) (162). In patients on long-term GC therapy, hypercalciuria is most likely due to increased skeletal mobilization of calcium and decreased renal tubular reabsorption that occurs in spite of elevated PTH levels. The GC-induced decrease in bone formation lowers calcium uptake by newly formed bone and elevates the filtered load of calcium. High dietary sodium intake increases renal loss of calcium whereas sodium restriction and thiazide diuretics lower its renal loss (163).

 

Effects of GCs on the Excretion of Phosphorus

 

GCs, acting directly on the kidney and indirectly, via induction of secondary hyperparathyroidism, lower tubular reabsorption of phosphate, leading to phosphaturia (164, 165). Furthermore, GCs increase the amiloride-sensitive Na+/H+ exchange activity in the renal proximal tubule brush border vesicles and decrease the Na+ gradient-dependent phosphate uptake, resulting in  increased acid secretion and phosphaturia (166).

 

GC Effects on Parathyroid Hormone (PTH)

 

A direct stimulatory effect of GCs on PTH secretion may also exist (164, 167, 168). GCs induce a negative calcium balance that leads to secondary hyperparathyroidism; in patients receiving GCs iPTH is increased, that can be suppressed with exogenous calcium and vitamin D (168, 169). Chronic GC administration is accompanied by altered secretory dynamics of PTH; more particularly, it reduces its tonic secretion and increases its pulses (170). However, elevated iPTH levels can also be suppressed following calcium infusion, suggesting that its  elevation is more likely to be secondary to a negative calcium balance caused by GCs, rather than to direct stimulation of PTH secretion (171).

 

Effects of GCs on Vitamin D Metabolism

 

Low, normal, or increased circulating levels of 1,25-dihydroxyvitamin D (1,25-(OH)2D) have been reported in subjects taking GCs (171-174). These differences may originate from variations in the dietary intake and absorption of vitamin D and in exposure to sunlight. The rate of synthesis and clearance of 1,25-(OH)2D is normal in subjects receiving GCs (175). Although the administration in humans of 1,25-(OH)2D improves calcium transport, it does not normalize it (176).

 

GC Effects on Sex Hormones

 

GCs inhibit the secretion of gonadotropins and also show direct effects on the gonads and the target tissues of gonadal steroids. In rats, GCs reduce the action of follicle-stimulating hormone (FSH) on granulosa cells and inhibit the response of luteinizing hormone (LH) to gonadotropin-releasing hormone (GnRH) (177-179).In rats and primates, GCs also decrease GnRH secretion; furthermore, in rats, overexposure to GCs renders their pituitary insensitive to exogenously administered GnRH (180-182).In men and women given GCs the plasma concentrations of estradiol, estrone, dehydroepiandrosterone (DHEAS), androstenedione, and progesterone are decreased (183-185). High-dose GC therapy in women may lead to amenorrhea. Although the exact targets of GC inhibition of steroidogenesis in Leydig or granulosa-theca cells are not fully defined, recent studies have found a GC-responsive upstream promoter region of the cholesterol side-chain cleavage gene (186).  In postmenopausal women an additive effect of GC treatment with estrogen deficiency on bone loss is observed (187, 188).

 

GC Effects on Growth Hormone (GH)

 

GH is an important regulator of both bone formation and bone resorption. in vitro studies have shown that the GH-induced increase in bone formation is twofold: by direct interaction with GH receptors on osteoblasts, and through induction of an endocrine and autocrine/paracrine IGF-I effect (189). In contrast, in animals high endogenous GCs or exogenous exposure can inhibit linear growth and GH secretion in animals. In patients with GCOP a lower GH response to growth hormone–releasing hormone (GHRH) and a positive correlation between GH increment and osteocalcin are observed. This inhibitory effect of GCs on the secretion of GH may be dependent on an increase in somatostatin synthesis and secretion, which inhibits pituitary GH secretion. Arginine, which decreases hypothalamic somatostatin tone, normalizes the GH response to GHRH (190, 191). Bone sensitivity to GH may also reduce by GCs: an up-regulatory effect on GH receptor expression may be implicated (192).

 

GC Effects on Connective Tissue

 

Excess GCs hinder wound healing via suppression of DNA and protein synthesis in fibroblasts and impaired local macrophage recruitment (193, 194).

 

GC Effects on Muscle

 

Common side effects of GC excess include muscle weakness and loss of muscle mass. Alterations of muscle biopsies of GC-treated patients include selective atrophy of type IIa muscle fibers, relative increase in the number of type IIb fibers and decrease in the number of type I fibers (195-197). The main mechanisms implicated in GC-induced myopathy are increased protein catabolism, inhibition of glycogen synthesis, and interference with fatty acid β-oxidation (83). In fact, GCs stimulate ubiquitin-proteasome-dependent protein breakdown in skeletal muscle and regulate calcium-dependent proteolysis (198, 199).Moreover, levels of glycogen synthase, beta-hydroxyacyl-CoA dehydrogenase and citric acid synthase, are lower in muscle from GC-treated patients compared to muscle from disease-matched controls (200). A strong association between steroid myopathy and OP has been described (201).

 

INDIVIDUAL SUSCEPTIBILITY TO GCOP

 

Some patients on a low GC dose show bone loss at a much higher rate than others on a higher GC dose (202). Genetics may play a role in determining this difference. Little is known about the mechanisms of cellular sensitivity to GCs. Individual factors are also important in determining the risk of fractures when GCs are used. Polymorphisms in the GR gene have been linked to the varied degrees of susceptibility to GCs; these could explain the different rates of GC-associated fractures (97). Individuals that are heterozygous for a polymorphism at nucleotide 1,220 (resulting in an Asparagine-to-Serine change at codon 360), had increased BMI, increased blood pressure and lower spine BMD compared to control subjects (203, 204).

 

Another explanation for inter-individual variability among those exposed to GCs is related to differential activity of 11b-hydroxysteroid dehydrogenase (11b-HSD) (205). This enzyme system plays a critical role in the regulation of GCs activity (206). Two distinct 11β-HSD enzymes have been described; 11b-HSD1 (converting cortisone [E] to cortisol [F] and 11b-HSD2 (converting F to E) modulate GC and mineralocorticoid hormone action in target organs (205, 207, 208). 11β-HSD1 is widely expressed in GCs target tissues, including bone (206). The reductase activity does not show a large inter-individual variability, whereas the oxidase activity of 11b-HSD2 has a large inter-individual variability. Subjects with higher oxidase activity at bone level may be at greater risk of developing GCOP (209). Men with OP were shown to have increased endogenous GC availability, via apparent 11b-HSD1 activation (210). The activity of 11β-HSD1 and the potential to generate F from E in human osteoblasts is increased by pro-inflammatory cytokines (TNFa, IL-1b and IL-6) and by GCs themselves (211, 212). During inflammation pro-inflammatory cytokines may potentiate GC actions in bone through an “intracrine” mechanism (209, 213). An increase of 11β-SD1 activity occurs with aging, possibly providing an explanation for the enhanced GC effects in the skeleton of elderly subjects (214).

 

In the future, the characterization of factors accounting for the variability to GC-related bone loss among individuals may identify subjects at higher risk of developing GCOP and, possibly, customize treatment.

 

DIAGNOSIS OF GCOP

 

Medical History and Clinical Evaluation

 

Table 1 summarizes elements from medical history suggestive of GCOP and the modalities available for its diagnosis. Any patient that is treated with long-term (for over a month) GCs should be suspected as suffering from GCOP (215). The risk for GCOP is higher in postmenopausal women, transplant recipients, and patients with sarcoidosis (216-220). Bone loss depends on the dose, route, and duration of GC administration (218-220).

 

Table 1. Clues and Diagnostic Means for GCOP

Medical history

Sex and age

History of OP and/or trauma fractures

History of allergy, chronic inflammatory or autoimmune disease, hematologic, skin and renal disorders, transplantation

Calcium and alcohol intake, smoking, physical activity

Chronic use of anticonvulsants, heparin, immunosuppressants

Menstrual, menopausal or fertility status 

Clinical evaluation

Truncal obesity, edemas, striae, skin atrophy and ecchymoses

Myopathy (myalgias, weakness of the proximal muscles and pelvic girdle)

Assessment of temporal baldness, loss of body hair, gynecomastia, altered pubic hair pattern, decreased testicle and prostate size

Laboratory evaluation

Complete blood cell count, liver and renal function, serum electrophoresis

Serum calcium and phosphate, serum 25-OH-vitamin D, serum alkaline phosphatase, PTH

Osteocalcin, bone-specific alkaline phosphatase, procollagen type I extension propeptides)

Hydroxyproline, hydroxylysine glycosides, hydroxypyridinium cross-links, type I collagen telopeptides)

Thyroid hormone profile, total and free testosterone, estradiol, luteinizing hormone, prolactin, ferritin

Bone mineral density assessment

 

 

Lateral scan (vertebral bodies) and anteroposterior scans (spine, hip) with dual-energy X-ray absorptiometry (DXA) – Trabecular Bone Score (TBS) in lumbar spine (if available)

·                  Assessment of vertebral compression fractures with X-ray        

 

 

Cushingoid clinical features include truncal obesity, skin atrophy with increased fragility and ecchymoses, fluid retention, hyperglycemia, and symptoms of vertebral compression and myopathy. Muscle strength needs to be assessed by a trained physician or specialized physical therapist, with special attention to the testing of proximal muscle groups. A brief exposure to GCs may trigger myopathy that is not always dose-dependent, and is often difficult to differentiate from inflammatory myopathy. However, GC myopathy is characterized by creatinuria and normal muscle enzymes, including aspartate aminotransferase, creatine kinase, and aldolase (195, 201).

 

Men and women on chronic treatment with GCs often have symptoms of hypogonadism, such as decreased libido and sexual activity, and may show low rates of fertility or even infertility. In premenopausal women history taking should assess menstrual periods, since subtle changes, including less bleeding and shortened menstrual periods, may be indications of low estrogen levels. Menstrual irregularities are also common in women with endogenous GC excess.

 

Various respiratory, dermatologic, musculoskeletal, neurologic and gastrointestinal disorders are frequently treated with GCs. Signs and symptoms of such disorders need to be evaluated.

 

Laboratory Tests and Markers of Bone Turnover

 

Laboratory evaluation for GCOP should include total blood cell count, markers of renal and liver function, serum electrophoresis, serum and 24-hr urine calcium, serum levels of 25-hydroxyvitamin D, alkaline phosphatase, thyroid-stimulating hormone and parathyroid hormone, estradiol in women and total and free testosterone in men (218-221).

 

In patients receiving GCs a dose-dependent decrease in serum osteocalcin is found; this is a good indicator of the degree of inhibition of osteoblastic activity (222, 223). Other markers of bone formation, such as total and bone specific alkaline phosphatase and procollagen type I carboxy-propeptide are also lower in under GC therapy (162, 224). In subjects on GC therapy baseline levels of osteocalcin do not always correlate with subsequent bone loss (225-227). In some, but not all, studies of patients treated with GCs, markers of bone resorption (like urinary collagen N-telopeptides [NTX]) are elevated (165, 228-230). In view of such discrepancies, the measurement of serum markers of bone formation and resorption is considered to be of little clinical utility and it is not currently advocated for routine use (217).

 

Bone Mineral Density (BMD) Assessment

 

Changes in BMD early on during GC therapy can be detected by dual-energy X-ray absorptiometry (DXA) and quantitative computed tomography (QCT); classic X-ray studies are useful to detect vertebral compression fractures. Both QCT and DXA can measure cortical and trabecular bone density, however, the former is mostly used to evaluate trabecular bone density, whereas the latter is used to measure cortical and trabecular bone density (231, 232). DXA also helps estimate the risk for fractures, and provides an objective measurement to judge the efficacy of treatment (221, 233, 234). BMD measurement techniques that focus on the vertebral body and exclude the cortical bone of posterior processes, such as lateral DXA scanning, are more sensitive in detecting GCOP (61, 235). However, the selection of a BMD assessment method is influenced by the presence of vertebral deformities, osteophytes, or of calcifications in the aorta that may spuriously elevate spinal BMD values. If this is the case, lateral views of the vertebral bodies are considerably less precise than antero-posterior scans, and therefore less appropriate for following up changes in bone mass. When marked osteophytosis or scoliosis of the spine is seen, proximal femoral densitometry (in the femoral neck) should be chosen (63). The trabecular bone score (TBS), which is a DXA analytical tool that hones on lumber vertebral microarchitecture, may be useful in assessing GCOP (236, 237).

 

In patients under glucocorticoid treatment fractures tend to occur at BMD values that are lower than the conventional threshold T-score of -2.5 (238, 239). A T-score threshold value of – 1.5 SD is usually the cutoff for GCOP in Europe (5), whereas the American College of Rheumatology (ACR) has defined the T-score cut off to – 1.0 SD to separate “normal” from “not normal” BMD (220). Furthermore, the ACR recommends BMD baseline measurements at the lumbar spine and/or hip before starting any GC treatment longer than 6 months (220). At 6 month intervals from the baseline assessment, or at 12 month intervals, if the patient is receiving therapy to prevent bone loss, follow-up measurements should be done (240, 241). For the United States in particular, Medicare reimburses BMD evaluation for patients on chronic treatment with GC doses higher than 7.5 mg/day of prednisolone equivalent (242).

 

The Fracture Risk Assessment tool (FRAX) estimates the 10-year risk for osteoporotic fractures at the hip and other sites. FRAX is criticized since it uses hip BMD, whereas vertebral fractures may be more common than hip fractures in subjects receiving GCs (243). Recently simple adjustments for the calculated fracture risk have been presented that take into account glucocorticoid dosage (244) (Figure 2). Use of FRAX is currently advised to stratify GC-treated patients in low, moderate and high fracture risk categories (245, 246).

Figure 2. Fracture risk stratification and FRAX fracture risk corrections according to glucocorticoid usage (modified from (245); # fracture; T: T-score; postmenop: postmenopausal; corr: corrected; * x 1.15 if glucocorticoid dose > equivalent to 7.5 mg prednisone/day; **x 1.20 if glucocorticoid dose > equivalent to 7.5 mg prednisone/day; ***for > 6months; Z: Z-score; GC Rx: glucocorticoid therapy

PREVENTION AND TREATMENT OF GCOP

 

Guidelines for the prevention and treatment of GCOP have been put forth from the ACR in 2001, in 2010 (220, 247)and more recently in 2017 (245), the UK Consensus group in Management of GCOP (240) and the Belgian Bone Club (248), among others.

 

General Preventive Strategies

 

As soon as GCs are administered prevention of GCOP should start; bone loss is more rapid in the first months of therapy. The minimal effective GC dose should be used. Although alternate day therapy seems attractive it has not been proven to hasten bone loss in adults (202, 249); the persistent depression of adrenal androgen production may be the culprit (250).

 

The concept of “safe dose” for the treatment with oral GCs is controversial (66). More particularly, prednisone given at low doses (2.5-9 mg/d) may affect BMD whereas lower doses (1-4 mg/d) were reported to have very little or no skeletal effect (251, 252). Intravenous high-dose (up to 1 g) methylprednisolone administration is not onerous to bone (253) but even a single oral dose of 2.5 mg of prednisone has an almost immediate negative effect on osteocalcin secretion (254). Alternate-day GC administration may prevent growth retardation in children but not bone loss (202, 249). Thus, despite the ambiguity of the literature, an equivalent dose equal to or higher than 2.5 mg of prednisone per day for a month seems a sensible threshold to give protection against GCOP.

 

Inhaled GCs may be better than oral or systemic GCs vis-à-vis bone health, but still have their osseous tissue complications (22, 255). Newer inhaled GCs (such as budesonide), seem to have less adverse effects on the bone, as indicated by measurements in bone markers (256, 257). Dosing of the inhaled GC is important; beclomethasone dipropionate or budesonide given at low doses for more than one year did not affect spine BMD in asthmatic subjects (257). However, patients treated with high doses of inhaled budesonide or beclomethasone (1.5 mg/day, for at least 12 months) and without prior oral GC treatment for more than 1 month, had a significant decrease in BMD and bone formation markers, with no changes in bone resorption markers (258). In another study, inhaled GCs in adults with chronic lung disease were not associated with increased fracture risk (and more in detail no dose-response curve was verified) (259). Moreover, in children treated with beclomethasone for bronchial asthma, analysis after adjustment for the severity of the underlying disease did not show any association between inhaled GCs and fracture risk (260). Thus, in children, other factors, such as excess body weight, low muscle mass and limited exercise capacity may predispose to low BMD (261).

 

Another factor that should be noted is the change in lifestyle for the prevention of GCOP. Diet should be rich in calcium and protein (262). Alcohol and sodium intake should be reduced (to 1-2 units of alcohol/day (245)), smoking should be stopped and a regular exercise program should be followed (37). Subjects on GCs may benefit if they are protected from falls (217, 263).

 

An important, yet often neglected by most prescribing physicians (93), facet of GC-treatment is the need for proper patient information and acknowledgement regarding untoward effects. A signed relevant patient acknowledgement form should be included in medical charts/files to avoid malpractice litigation (243). 

 

Therapeutic Options

 

Therapy for GCOP aims to prevent and minimize bone loss, to increase BMD and, at least partially, to reverse the effects of GC excess. Some therapies should be continued for as long as GC treatment is pursued. The usual primary outcome in most reported – to date - trials of GCOP-specific treatments, is the change from baseline in vertebral BMD vis-à-vis placebo or other treatments; few trials have also assessed fracture rates (264, 265). 

 CALCIUM AND VITAMIN D SUPPLEMENTATION Patients on GCs should receive supplementation with calcium and vitamin D; this is better than no supplementation or calcium alone (262). A daily dose of 1,500 mg calcium and 800 IU vitamin D (1 μg/day of α-calcidiol or 0.5 of μg/day calcitriol) effectively oppose negative calcium balance (220). A two-year randomized clinical trial demonstrated the efficacy of combined calcium and vitamin D supplementation in preventing bone loss in patients with rheumatoid arthritis treated with low doses of GCs (266). However, these encouraging findings were not replicated in a three-year follow-up study, where the same combination did not show any benefit (267). From randomized clinical trials and meta-analyses it was shown that active metabolites of vitamin D (α-calcidiol and calcitriol) are more effective than vitamin D in maintaining bone density during medium-to-high dose GC treatment (268-271). Treatment with active forms of vitamin D entails a risk of hypercalciuria and hypercalcemia, consequently periodic assessment of serum calcium and creatinine levels at the beginning of the therapy, after 2-4 weeks, and thereafter every 2-3 months is advised (272, 273). Currently - according to the ACR (245) - optimal intake for calcium is set at 1000 mg/day and at 600-800 IU/day for vitamin D.

 

Thiazide diuretics lower urinary calcium excretion. Chronic treatment with thiazides decreased the incidence of hip fracture in elderly patients, and increased BMD in the general population (274-276). This evidence suggests that, together with sodium restriction, they may be useful in opposing calcium loss and secondary hyperparathyroidism caused by chronic GC therapy. However, there are currently no studies showing long-term effect of thiazide diuretics on BMD in patients treated with GCs.

 

ANTIRESORPTIVE THERAPY

 

There are several antiresorptive agents available for the prevention and treatment of GCOP.

 

Bisphosphonates decrease the resorptive activity of osteoclasts, increase osteoclast apoptosis and decrease osteoblast and osteocyte apoptosis (277). Their efficacy in preventing and treating GCOP has been clearly shown in large randomized controlled clinical trials (278-280). Treatment with alendronate for 18 months or two years increased total body BMD, and – according to some studies - significantly decreased risk of vertebral fractures in patients taking GC (281, 282). In a one-year study of patients on GCs having undergone cardiac transplantation subjects given alendronate had lower bone loss compared to subjects on calcitriol or no other treatment (-0.7%, -1.6% and -3.2% for the lumbar spine and -1.7%, -2.1% and -6.2% for the femoral neck BMD, respectively); vertebral fracture rates were not different in the three groups though (283).  In a meta-analysis of published randomized clinical trials of patients with GCOP who were given alendronate for 6-24 months, BMD in the lumbar spine as well as in the femoral neck increased but the fracture rate was not different compared to that of patients who were given only calcium, serving as a control group (284). Similarly, a one-year study with risedronate in patients taking prednisone (7.5 mg/day for at least 6 months) showed an increase in lumbar spine and femoral neck BMD and an impressive – though prone to bias due to limited sample size -  70% decrease in the relative risk of vertebral fractures (285). Zoledronic acid, a long-acting potent bisphosphonate given intravenously (4-10 mg once or twice a year) has excellent anti-OP results (286-291) and has been assessed in GCOP. The HORIZON study lasted for one year and tested the effectiveness of 5 mg intravenous zoledronic acid (n=416) vs. risedronate (n=417) in subjects with GCOP; the former led to greater increase in lumbar bone mineral density and greater decrease in bone turnover compared to the latter (292). The study did not show differences in fracture risk most probably because of its short duration. Pyrexia (particularly in the first three days post-infusion) and worsening of rheumatoid arthritis were noted more often in the zoledronic acid group (292).  

 

Oral bisphosphonates are a first choice for anti-resorptive therapy, followed by intravenous bisphosphonates (245), the latter are a first choice in pediatric GCOP (293). Currently, alendronate po (70 mg/week), risedronate po (35 mg/week or 75 mg on two consecutive days per month) and zolendronic acid iv (5 mg once a year) are recommended to treat men and women receiving GC treatment (247); therapy is advised for at least two years (294). Oral ibandronate (150 mg once a month) given for GCOP in men and women has positive results – particularly regarding spine BMD and vertebral fractures (295).

 

In patients with rheumatoid arthritis and connective tissue diseases who are treated with the RANKL inhibitor denosumab, lumbar spine (296-298) and femoral neck (297) BMD increase. Denosumab sc (60 mg every six months) is henceforth also proposed as treatment for GCOP (245, 299); it is considered to be superior in therapeutic effect on lumbar spine BMD, total hip/femoral neck BMD and vertebral fractures’ incidence compared to bisphosphonates (300, 301). The downside of Denosumab is that its discontinuation is followed by rapid bone loss (302); some experts consider that this makes it less attractive as a treatment for GCOP (303). Denosumab can also be a therapeutic option in patients with renal insufficiency who cannot receive bisphosphonates or teriparatide (243).

 

ANABOLIC THERAPY

 

Anabolic medications enhance bone formation, therefore antagonizing the suppressive effect of GCs on osteoblasts. However, some of the information on the use of these compounds to prevent or treat GCOP comes from small studies.

 

Recombinant PTH administration (400 IU of PTH 1-34; teriparatide) to postmenopausal women on prolonged estrogen replacement, who had developed OP after chronic GC therapy, resulted in increased lumbar spine bone mass, assessed by both DXA and QCT, which was maintained after discontinuation of teriparatide (304, 305). An 18-month long randomized double-blind trial compared teriparatide vs alendronate in subjects with GCOP; the increase in lumbar BMD was higher with teriparatide (+4.6 to +8.1% vs. +2.3 to +3.6%) than for alendronate at 18 months. Better results were noted for those taking low GC doses and fewer vertebral fractures occurred with teriparatide compared to alendronate (0.6% vs 6.1%) whereas the non-vertebral fracture rate did not differ between treatment groups (306). Analogous results were noted when the trial was extended to 3 years: lumbar spine BMD increased by +11.0% for teriparatide vs +5.3% for alendronate whereas the respective femoral neck BMD change was +6.3% vs +3.4% (307). Teriparatide can be a therapy of choice (20 microg/day sc) for patients on GC treatment and/or with GCOP, following intravenous bisphosphonates on a par with denosumab as proposed in the ACR guidelines (245, 247, 308, 309). The combination of teriparatide and bisphosphonates may not have an additive effect on bone (310); it is not advised for GCOP. Nevertheless, bisphosphonates given after stopping teriparatide therapy help maintain the bone formed by teriparatide (311).

 

Sodium fluoride, in combination with either calcium and vitamin D, or cyclic etidronate, improved lumbar spine BMD and trabecular bone volume in GC-treated patients. However, no reduction in the incidence of fractures was observed. Moreover, fluoride induced bone loss at the femoral neck (312, 313). Since most of the evidence indicates that sodium fluoride does not provide architecturally competent bone, its use is currently not recommended for GCOP (220).

 

Anabolic steroids have also been tested in GCOP. Cyclic nandrolone decanoate (50 mg i.m. every three weeks for six months) increased the forearm bone density in GC treated women, 10% of which developed virilizing side effects (314). The typical negative effects of steroids on bone are not present with nandrolone because it is metabolized to dihydrotestosterone (DHT). Similarly, cyclic medroxyprogesterone acetate (200 mg i.m. every 6 weeks for one year) augmented lumbar spine BMD in treated men (315). Currently, there is no recommendation for the use of anabolic steroids for GCOP.

 

GONADAL HORMONE THERAPY

 

Sex hormone treatment should be considered whenever a patient with GC excess develops hypogonadism (278). A retrospective study in postmenopausal women taking GCs found an increased BMD in those who were taking estrogens, compared to increasing bone loss in those who were not (316). Moreover, in a randomized controlled clinical trial of postmenopausal women taking GCs for rheumatoid arthritis, a significant increase in lumbar spine BMD was observed in those receiving hormone replacement therapy (HT) compared to those receiving placebo (317). This evidence suggests the potential benefit of HT in hypoestrogenic women treated with GCs. However, a large randomized clinical trial in postmenopausal women treated with a combination of estrogen and progestin planned to last 8.5 years was interrupted after 5 years, because the overall risks exceeded the benefits of the treatment (318). In the past the ACR recommended oral contraceptives (unless contraindicated) in premenopausal women on GCs who develop oligo-amenorrhea (220) but this option is no longer included in the more recent ACR guidelines. Similarly, adult men with GC excess who develop hypogonadism benefit from testosterone replacement. In GC-treated asthmatic men with testosterone deficiency, i.m. testosterone injections increased lumbar spine but not hip BMD (319). There are no data on the potential benefit of testosterone therapy in GC- treated eugonadal men (247). However, since most studies have shown an increase in prostate size and prostate-specific antigen levels in older men on testosterone supplementation/therapy (320-323), testosterone administration should be monitored with yearly digital examinations and prostate-specific antigen measurements.

 

OTHER THERAPIES

 

In addition to different combinations of the treatments so far discussed, selective estrogen receptor modulators (SERMs) alone or conjugated estrogens/SERMs belong to the pharmaceutic armamentarium against GCOP. SERMs, have positive effects on the bone. Tamoxifen reduces in vitro some of the deleterious effects of GC on the bone (324). Raloxifene, which is currently approved by the United States’ Food and Drug Administration (FDA) for the prevention and treatment of postmenopausal OP, might be a safer alternative to HT in the treatment of GCOP that develops in postmenopausal women (246, 325), given its favorable effects on serum lipids, together with the lack of growth stimulation on endometrial and breast tissues (326-328).

 

FUTURE THERAPEUTIC OPTIONS

 

Currently, denosumab is being evaluated for pediatric GCOP (293). Other newer agents that are tentatively evaluated for the treatment of osteoporosis either inhibit osteoclast resorption or stimulate osteoblast bone forming activity. These include antibodies against RANKL (RANKL inhibitors), recombinant osteoprotegrin, inhibitors of osteoclast enzymes, integrin antagonists and agonists to LRP5 (308).

 

At the time of writing, abaloparatide (PTHrp) and romosozumab (humanized monoclonal antibody that targets sclerostin) have been cleared by the FDA for the treatment of OP in women only (8, 329, 330). One would expect the former to be a good candidate for GCOP in analogy to teriparatide. However, this therapy is not yet approved for GCOP and to the best of our knowledge there are no relevant clinical studies to support its use in GCOP (331). Furthermore, we have to bear in mind that administration of GC > 15 mg/day may attenuate the osseous effects of teriparatide, and this has also been shown with abaloparatide in rodent GCOP models (331, 332). There is an ongoing trial of romosozumab in GCOP but at present this medication has no firm indication for GCOP (313); experimental studies in rodents were encouraging (333).

 

Other promising future therapeutic options target GC therapy per se. These include the use of disease-modifying antirheumatic drugs or tumor-necrosis factor agents, which could lead to the need for lower GC dosage for autoimmune disease. Furthermore, deflazocort (a prednisone derivative) and liposomal prednisone may be less onerous to bone (334). The search continues to find selective GR agonists (SGRMs) that possess the anti-inflammatory benefits of traditional GCs without the associated adverse effects (335). The SGRMs are selective ligands of the GR, which maintain the transrepressive properties of GCs (usually associated with their beneficial anti-inflammatory effect) while they do not have their transactivating properties (usually associated with metabolic negative effects, including perhaps those on the bone). Some of these molecules may represent an alternative to traditional GCs in the chronic treatment of inflammatory disorders (334, 336). Inhibitors to cathepsin K (which is involved in systemic bone resorption) (337) hold promise for treating GCOP (295, 338). There is interest in therapeutic inhibitors of 11b-HSD1 for patients with endogenous hypercortisolemia such as Cushing’s disease; these inhibitors – in theory – could also mitigate GCOP but no relevant research has been put forth (53). 

 

GLUCOCORTICOID DISCONTINUATION AND REVERSIBILITY OF GCOP

 

There is no consensus on the reversibility of GCOP. Bone mineral density increases after curative surgery for Cushing’s disease or interruption of exogenous GC treatment (339-341). A prospective study in patients with rheumatoid arthritis showed partial bone regain after discontinuation of low-dose GC therapy that was given for five months (67). If GCs are discontinued and treatment for GCOP is continued, a return to baseline BMD is to be expected within 9 to 15 months (303). In patients with sarcoidosis younger than 45 years, full recovery of bone mass was reported two years after cessation of therapy (342). However, it is unlikely that the large (10% or more) bone mass that is lost during high-dose GC therapy can be completely regained, with full recovery of the mechanical properties of the bone. The likelihood of bone regain may be negatively correlated with the duration of treatment as well as unknown host-related factors. Most complications of osteoporotic fractures, such as vertebral deformities and chronic back pain, are permanent. A sensible approach is to stop anti-osteoporotic treatment 6 to 12 months after discontinuation of GCs administration (303).

 

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Lipid and Lipoprotein Levels in Patients with Covid-19 Infections

ABSTRACT

Numerous studies have observed a decrease in total cholesterol, LDL-C, HDL-C, and apolipoprotein B and A-I levels in patients with COVID-19 infections, similar to what is observed with other infections. In most studies the decrease in LDL-C and/or HDL-C was more profound the greater the severity of the illness. LDL-C and HDL-C levels were inversely correlated with C-reactive protein (CRP) levels i.e., the lower the LDL-C or HDL-C level the higher the CRP levels. Patients with low HDL-C and/or LDL-C levels at admission to the hospital were at an increased risk of developing severe disease compared to patients with high levels. With recovery from COVID-19 infections the serum lipid levels return towards levels present prior to infection. In patients that failed to survive, total cholesterol, LDL-C, and HDL-C levels were lower at admission to the hospital and continued to decline during the hospitalization. In patients with COVID-19 infections the serum triglyceride levels were variable. Lipoprotein (a) levels increase during COVID-19 infections. Several studies using the UK Biobank and other databases have shown that low HDL-C and apolipoprotein A-I levels measured many years prior to COVID-19 infections were associated with an increased risk of COVID-19 infections and death from infection while LDL-C, apolipoprotein B, lipoprotein (a), and triglyceride levels were not consistently found to be significantly associated with an increased risk. A 10 mg/dl increase in HDL-C or apolipoprotein A1 levels was associated with ∼10% reduced risk of COVID-19 infection. It should be noted that these observations are subject to the caveats of confounding variables and reverse causation effecting the results. Several studies have found that homozygosity for apolipoprotein E4/4 is associated with a 2-3- fold increased risk of COVID-19 infections and this increase was not due to dementia or Alzheimer's disease. During the COVID-19 pandemic, diet, exercise, and lipid lowering therapy should be continued. For those who become symptomatic, lipid lowering therapy, if feasible, should also be continued throughout the duration of the illness. Individuals who are naïve to treatment but for whom lipid lowering therapy is indicated should be started on treatment. Whether lipid lowering drugs have beneficial effects when given prior to or during COVID-19 infections is uncertain but randomized controlled studies are in progress. In patients with severe symptoms of COVID-19 who are too ill to take oral medications, lipid lowering medications may be temporarily suspended. Medications should be re-started when the patient has recovered and able to take oral medications. One needs to be aware that certain drugs that are used to treat COVID-19 infections may interact with lipid lowering drugs. Remdesivir and Paxlovid (nirmatrelvir and ritonavir) are metabolized by the Cyp3A4 pathway and statins that are also metabolized by this pathway should be avoided (atorvastatin, simvastatin, and lovastatin). Because drug therapy for patients with COVID-19 infections is rapidly evolving one needs to be alert for potential drug interactions.  

 

INTRODUCTION 

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), has resulted in a world-wide pandemic. The infection is spread through large respiratory droplets and fine respiratory aerosols. The majority of COVID-19 infections are either asymptomatic or result in only mild disease but in a substantial proportion of patients the infection leads to a respiratory illness requiring hospital care and respiratory support, which can have a fatal outcome. Older age, male gender, obesity, diabetes, cardiovascular disease, and hypertension are some of the pre-existing factors that increase the risk of severe infection and death. As of March 15, 2022, there have been over 6 million deaths worldwide according to the John Hopkins Corona Virus Resource Center.

LIPID ABNORMALITIES IN PATIENTS WITH COVID-19 INFECTIONS

Background

 

Patients with a variety of different infections (gram positive bacterial, gram negative bacterial, viral, tuberculosis, parasites) have similar alterations in plasma lipid levels. Specifically, total cholesterol, LDL-C, and HDL-C levels are decreased while plasma triglyceride levels may be elevated or inappropriately normal for the poor nutritional status (1-12). Apolipoprotein A-I, A-II, and B levels are also reduced (1,7,8). HIV, Epstein-Barr virus, and Dengue fever are viral infections that demonstrate these lipid alterations (13-15). The alterations in lipids correlate with the severity of the underlying infection i.e., the more severe the infection the more severe the alterations in lipid and lipoprotein levels (16-18). During recovery from the infection plasma lipid and lipoprotein abnormalities return towards levels present prior to infection. Of note studies have demonstrated that the degree of reduction in total cholesterol, LDL-C, HDL-C, and apolipoprotein A-I are predictive of mortality in patients with severe sepsis (19-26).

Studies in Patients with COVID-19 

Numerous studies have reported a decrease in total cholesterol, LDL-C, HDL-C, apolipoprotein A-I, and apolipoprotein B levels and variable changes in triglycerides in patients with COVID 19 infections (27-43). An NMR analysis in patients with severe COVID-19 infections revealed a decrease in HDL particles particularly low numbers of small HDL particles and a predominance of small LDL particles compared to larger LDL particles (44). In addition to a decrease in HDL levels changes in HDL protein concentrations occur with decreased apolipoprotein A-I, apolipoprotein A-II, pulmonary surfactant-associated protein B, and paraoxonase and increased serum amyloid A and alpha-1 antitrypsin (34,45). With recovery from the acute COVID-19 infection lipid levels return towards levels present prior to infection (27-29,46,47). LDL-C and HDL-C levels were inversely correlated with C-reactive protein (CRP) levels i.e., the lower the LDL-C or HDL-C level the higher the CRP levels (27,28,31,48,49). The lower the HDL-C and LDL-C levels the greater the severity of the COVID-19 infection (28,30-33,36-38,41,47,48,50). Low LDL-C and/or HDL-C levels at admission to the hospital predicted an increased risk of developing severe disease and mortality and in these very ill patients, lipid levels declined during the hospitalization (27,37,38,40,46,48,50,51). In a meta-analysis of 19 studies and a meta-analysis of 22 studies decreased levels of total cholesterol, HDL-C, and LDL-C was associated with severity and mortality in COVID-19 patients (52,53).

 

In patients with COVID-19 infections serum triglyceride levels were variable. This is likely due to the decreased food intake that commonly occurs in ill patients resulting in a decrease in triglyceride levels. Additionally, the timing of when blood samples were obtained, the use of medications that may affect triglyceride levels (for example glucocorticoids or propofol), or the development of disorders that effect triglyceride levels (for example poorly controlled diabetes) could have confounded the triglyceride results. Severe hypertriglyceridemia (triglycerides > 500mg/dL) occurred in 33.3% of patients with COVID-19 associated acute respiratory distress syndrome treated with propofol compared to only 4.3% of patients with non-COVID-19 acute respiratory distress treated with propofol (54). Of note it has been reported that serum triglyceride levels were elevated in patients with mild or severe infections but not in patients with critical illness (respiratory or multiple organ failure and septic shock) (31). In contrast, a study reported that triglyceride levels were higher in patients that died from COVID-19 compared to patients that were critically ill or non-critically ill (50). In another study a severe outcome was associated with lower HDL-C levels and higher triglyceride levels (55). However, a meta-analysis did not find that triglyceride levels were associated with disease severity in patients with COVID-19 (53). NMR analysis in patients with severe COVID-19 infections revealed an increase in triglyceride rich lipoprotein particles primarily due to an increase in the small and very small subfractions (44). Finally, a patient with a mild COVID-19 infection has been reported to develop marked hypertriglyceridemia due to transient inhibition of lipoprotein lipase activity presumably due to the development of autoantibodies against lipoprotein lipase similar to what has been reported in patients with autoimmune disorders such as systemic lupus erythematosus (56).

 

Lipoprotein (a) levels increase during COVID-19 and appear to be associated with an increased risk of venous thromboembolism (57). It had been hypothesized that an increase in Lp(a) could contribute to some of the clinical abnormalities, such as thrombosis, seen during severe COVID-19 infections and these results support that hypothesis (58).  

 

The potential mechanisms by which infections and inflammation alter lipid and lipoprotein levels and the consequences of these alterations are discussed in the Endotext chapter entitled “The Effect of Inflammation and Infection on Lipids and Lipoproteins” (59).

 

Table 1. Effect of COVID-19 Infection on Lipid and Lipoprotein Levels

Triglycerides- Variable but tend to be increased

Total cholesterol- Decreased

HDL-C- Decreased

LDL-C- Decreased

Small dense LDL- Increased

Lp(a)- Increased

Apolipoprotein A-I- Decreased

Apolipoprotein B- Decreased

 

DO PRE-INFECTION LIPID LEVELS PREDISPOSE TO SEVERE COVID-19 INFECTION?

Background

Numerous observational studies have suggested that low LDL-C and/or HDL-C levels increase the risk of developing infections and sepsis (60-72). Of course, it must be recognized that confounding variables could account for this association. For example, unrecognized disease (for example pulmonary or gastrointestinal disorders) could result in decreased HDL-C and LDL-C levels and independently also increase the risk of infections and sepsis.

 

Studies employing a genetic approach to epidemiology, which reduces the risk of confounding variables and reverse causation, have been used to investigate the relationship of lipid levels with the risk of infections and sepsis. In a study by Madsen and colleagues using two common variants in the genes encoding hepatic lipase and cholesteryl ester transfer protein that regulate HDL-C levels found in 97,166 individuals from the Copenhagen General Population Study that low HDL-C levels increased the risk of infection supporting the observational studies that low HDL-C levels increase the risk of infection (66). In studies by Walley and colleagues HMGCoA reductase and PCSK9 genetic variants that decrease LDL-C levels genetically were not associated with an increased mortality from sepsis suggesting that the observational studies linking low LDL-C with sepsis may have been due to confounding variables (70). In support of this contention a study demonstrated that low LDL-C levels were significantly associated with increased risk of sepsis and admission to intensive care unit, however, this association was found to be due to comorbidities (73). Finally, Trinder and colleagues using the UK Biobank data base (407,558 individuals) demonstrated that elevated levels of HDL-C and LDL-C were associated with a reduced risk of infectious disease related hospitalizations similar to prior observational studies while elevated levels of triglycerides were associated with increased risk of infectious disease related hospitalizations (74). However, this study also employed a genetic approach and found that for genetically determined lipid levels, only increased HDL-C levels were significantly associated with a reduced risk of hospitalizations for infectious disease and mortality from sepsis suggesting that HDL could be causally related to infections (74). Taken together these studies demonstrate that low LDL-C levels that are associated with an increased risk of infections are not likely to be a causal association while the low HDL-C levels that are associated with an increased risk of infection appears to be causal.

 

This protective effect of HDL could be due to HDL particles binding lipopolysaccharide and lipoteichoic acid, compounds that mediate the excessive immune activation in sepsis or to the immunomodulatory, antithrombotic, and antioxidant properties of HDL (6,75). Additionally, HDL may have direct effects on viruses that decrease their infectivity by direct viral inactivation, interference with viral entry into the cell, or inhibition of virus-induced cell fusion (76-79). Finally, HDL has an antiviral effect against SARS-CoV-2 (COVID-19) (80). 

COVID-19 Infections

Several studies using the UK Biobank and other databases have shown that elevated HDL-C and apolipoprotein AI levels measured many years prior to COVID-19 infections were associated with a reduced risk of COVID-19 infections while LDL-C, Apo B, lipoprotein (a) and triglyceride levels were not consistently found to be significantly associated with an increased risk (81-89). Hilser and colleagues found that a 10 mg/dl increase in HDL-C or apolipoprotein A1 levels were associated with ∼10% reduced risk of COVID-19 infection (82). In addition, an increased risk of death from COVID-19 infections was also inversely related to HDL-C and apolipoprotein A1 levels (82). Thus, there is consistent evidence that HDL-C and apolipoprotein A1 levels measured many years prior to COVID-19 play a role in determining the risk of developing COVID-19 infections. It should be noted that these were not genetic based analysis so these observations, as discussed above, are subject to the caveats of confounding variables and reverse causation effecting the results.

 

Aung et al reported that genetically higher exposure to LDL-C was related to increased risk of COVID-19 (84) and Zhang and colleagues reported that genetically determined higher total cholesterol and apolipoprotein B levels might increase susceptibility for COVID-19 (90). However, other studies found no evidence supporting an association of genetically induced increases in LDL-C and apolipoprotein B levels with an increased risk for severe COVID-19 infections (82,91-93). Hilser et al was also unable to demonstrate a link between genetically determined HDL-C and triglyceride levels and COVID-19 infection risk (82). Others have also not been able to demonstrate a genetic link of HDL-C, or triglyceride levels with COVID-19 infections (93). However, a Mendelian randomization study found a causal effect of higher serum triglyceride levels on a greater risk of COVID-19 severity (92). Lp(a) genetic risk scores were similar in COVID-19 infected patient and controls (89). Given the variability of results additional studies are required to determine whether LDL-C, apolipoprotein B, apolipoprotein A-I, HDL-C, or triglyceride levels have a causal role in determining the risk or severity of COVID-19 infections.

 

Several studies have found that homozygosity for apolipoprotein E4/4 is associated with a 2-3- fold increased risk of COVID-19 infections and this increase was not due to dementia or Alzheimer's disease (82,94,95). Interestingly, in patients with HIV, apolipoprotein E4/4 is associated with an accelerated disease progression and death compared with apolipoprotein E3/3 (96). Additionally, individuals who are apolipoprotein E3/4 have an increased inflammatory response to toll receptor ligands compared with patients who are apolipoprotein E3/3 (97). The mechanisms by which apolipoprotein E4/4 increases the risk of COVID 19 infections remains to be elucidated.

LIPID LOWERING DRUGS and COVID-19 INFECTIONS  

Detailed information on cholesterol and triglyceride lowering medications is provided in the Endotext chapters entitled “Cholesterol Lowering Drugs” and Triglyceride Lowering Drugs” (98,99). Only information that is of unique importance with regards to lipid lowering drugs and COVID-19 infections will be discussed in this chapter. For a detailed review of lipid lowering drug therapy in COVID-19 patients see “Managing hyperlipidaemia in patients with COVID-19 and during its pandemic: An expert panel position statement from HEART UK” (100).

Statins

Statins have pleiotropic effects, including decreasing inflammation and oxidative stress, improving endothelial function and immune response, and inhibiting the activation of coagulation cascade, all of which could be beneficial in patients infected with SARS-CoV-2 (101,102). In contrast to these potentially beneficial effects, statins upregulate the ACE2 receptor, the receptor that the SARS-CoV-2 virus uses to enter cells, which could potentially increase the severity of the infection (101,102).

 

Because of the possibility that statins could have beneficial effects on COVID-19 infections there have been a large number of observational studies comparing the severity of disease and/or mortality in patients taking statins vs. patients not taking stains. Most meta-analyses have found that statins reduce severity of disease and/or mortality (103-108). It should be appreciated that these observation studies have potential flaws and cannot definitively prove that statins are beneficial in COVID-19 infections. In a single randomized trial statin therapy did not reduce disease severity or mortality compared to placebo (109). It is worth noting that a meta-analysis of 7 randomized trials with 1720 patients examining the effect of statins in sepsis (not COVID-19 infections) did not demonstrate any benefit compared to placebo (110). However, the absence of harm from statin therapy in the majority of the COVID-19 observational studies and in the single randomized trial makes it reasonable to continue statin therapy in COVID-19 infected patients for their well-recognized benefits on cardiovascular disease.

 

One needs to be aware of potential drug interactions with statins and some of the drugs used to treat COVID-19 infections (see table 3) (100). Remdesivir is metabolized by the Cyp3A4 pathway and statins that are also metabolized by this pathway should be avoided (atorvastatin, simvastatin, and lovastatin) (100). With the antiretroviral drug, nirmatrelvir and ritonavir (Paxlovid), it is recommended to avoid statins metabolized by the Cyp3A4 pathway (atorvastatin, simvastatin, and lovastatin) and use low dose rosuvastatin therapy (100). Tocilizumab by inhibiting IL-6 can increase CYP3A4 activity thereby reducing the LDL-C lowering effect of atorvastatin, simvastatin, and lovastatin.Additionally, certain drugs (for example nirmatrelvir and ritonavir) that treat COVID-19 are only used for a short period of time and temporarily stopping statin therapy may be a reasonable approach.

Ezetimibe

A single study reported that patients taking ezetimibe had significantly reduced odds for SARS-CoV-2 hospitalization (OR=0.513, 95% CI 0.375-0.688) (111). The mechanism for this effect is not clear and additional studies are required.

PCSK9 Inhibitors, Evinacumab, and Bempedoic Acid

There is no information with regards to COVID-19 Infections and these cholesterol lowering drugs.

Bile Acid Sequestrants

There is no information with regards to COVID-19 Infections. Because bile acid sequestrants can bind drugs in the GI tract and decrease their absorption, care must be taken when using other oral medications in patients taking bile acid sequestrants.

Fibrates

Fibrates have anti-inflammatory properties (112). In a cohort study fenofibrate did not reduce the severity of COVID-19 infections (113). In patients treated with tocilizumab the use of fibrates should be suspended (100).

Omega-3-Fatty Acids

Omega-3-fatty acids have anti-inflammatory properties (114). In a randomized trial 2 grams per day of Docosahexaenoic acid (DHA) + Eicosapentaenoic acid (EPA) for 2 weeks improved the clinical symptoms of COVID-19 infection and reduced markers of inflammation (C-reactive protein and erythrocyte sedimentation rate) (115). In another randomized trial the administration of 400mg EPA and 200mg DHA per day decreased severity and improved survival in critically ill patients with COVID-19 infection (116). Additional studies are needed to confirm these intriguing results.  

Niacin

There is no information with regards to COVID-19 Infections.

Lomitapide

Lomitapide is metabolized in the liver through CYP3A4 and lomitapide is also an inhibitor of CYP3A4 (100). Therefore, one needs to be concerned about potential drug interactions.  

Volanesorsen

The major side effect of volanesorsen is thrombocytopenia. Studies have suggested that low platelet levels are associated with an increased risk of severe disease and mortality in patients with COVID-19 infections (100). Therefore, it is recommended that volanesorsen therapy be discontinued in patients infected with COVID-19 until the infection resolves.

Future Studies

There are a large number of on-going randomized trials of the effect of lipid lowering drugs in COVID-19 infections (table 2) (117). For details on these trials see reference (117).

 

Table 2. On-Going Randomized Trials of Lipid Lowering Drugs

 

Number of RCTs

Total Number of Patients

Statins

17

18,215

Fibrates

3

1,050

Niacin

5

1,200

Omega-3 fatty acids

14

21,898

RCTs- randomized controlled trials

 

Interaction Between Drugs to Treat COVID-19 and Lipid Lowering Drugs

The effect of various drugs that are used to treat COVID-19 infections and lipid lowering drugs are shown in table 3. Because drug therapy for patients with COVID-19 infections is rapidly evolving one needs to be alert for the use of new drugs with potential drug interactions.

Table 3. Interactions Between Drugs to Treat Covid-19 and Lipid Lowering Drugs

Covid-19 Drugs

Drug Interactions

Nirmatrelvir and Ritonavir (Paxlovid)

Contraindicated with drugs that are highly dependent on CYP3A for clearance and thereby increases levels of lovastatin, simvastatin, and atorvastatin. Also increases levels of rosuvastatin by a different mechanism but can use low dose.

Monoclonal antibodies against spike protein

No drug interactions

Remdesivir (Veklury)

Metabolized by the Cyp3A4 pathway and therefore should avoid lovastatin, simvastatin, and atorvastatin.

Molnupiravir (Movfor)

No drug interactions

Baricitinib (Olumiant)

No drug interactions

Tocilizumab (Actemra)

Deceasing IL-6 can upregulate CYP3A and reduce the activity of lovastatin, simvastatin, and atorvastatin.

Glucocorticoids

No drug interactions

MANAGEMENT OF HYPERLIPIDEMIA DURING THE COVID-19 PANDEMIC

During the COVID-19 pandemic diet and exercise should be continued and there is no reason to stop lipid lowering therapy. Patients on lipid lowering therapy should continue to take their medications and patients who have indications for starting lipid lowering therapy should be started on therapy (100). In patients who are asymptomatic or have only mild symptoms of COVID-19 they should also continue their lipid lowering medications (100). This is particular important as studies have shown an association with influenza and other respiratory infections and myocardial infarctions (118-120). In patients with severe symptoms of COVID-19 who are too ill to take oral medications, lipid lowering medications may be temporarily suspended (100). Medications should be re-started when the patient has recovered and is able to take oral medications.

 

Liver function test abnormalities are frequently observed in patients with severe COVID-19 infections. If the alanine transaminase (ALT) or aspartate transaminase (AST) is greater than 3 times the upper limit of normal lipid lowering therapy should be stopped (100). Creatine kinase measurements should be considered when clinically indicated and in patients who are critically ill. It is recommended that statin therapy be stopped if creatine kinase rises 10-fold (generally to levels above 2000 IU/L) in asymptomatic patients or at a lower level of 5-fold upper limit of normal in symptomatic patients (100).

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Diabetic Neuropathies

ABSTRACT

 

Diabetic neuropathy (DN) is the most common form of neuropathy in developed countries and may affect about half of all patients with diabetes (DM), contributing to substantial morbidity and mortality and resulting in a huge economic burden. DN encompasses multiple different disorders involving proximal, distal, somatic, and autonomic nerves. It may be acute and self-limiting or a chronic, indolent condition.  DN may progress insidiously or present with clinical symptoms and signs that may mimic those seen in many other diseases.  The proper diagnosis therefore requires a thorough history, clinical and neurological examinations, and exclusion of secondary causes. Distal peripheral neuropathy (DPN) is the most common manifestation and is characteristically symmetric, glove and stocking distribution and a length-dependent sensorimotor polyneuropathy. It develops on a background of long-standing chronic hyperglycemia superimposed upon cardiovascular risk factors. Diagnosis is mainly based on a combination of symptoms and signs and occasionally neurophysiological tests are required. Apart from optimizing glycemic control and cardiovascular risk factor management, there is no approved treatment for the prevention or reversal of DPN. Even tight glycemic control at best limits the progression of DPN in patients with type 1 DM, but not to the same extent in type 2 DM. It has been estimated that between 3 and 25% of persons with DM might experience neuropathic pain. Painful DPN can be difficult to treat, and is associated with reduced quality of life, poor sleep, depression, and anxiety. Pharmacotherapy is the mainstay symptomatic treatment for painful DPN. The reported prevalence of diabetic autonomic neuropathy (DAN) varies widely (7.7 to 90%) depending on the cohort studied and the methods used for diagnosis, and can affect any organ system. Cardiovascular autonomic neuropathy (CAN) is significantly associated with overall mortality and with morbidity, including silent myocardial ischemia, coronary artery disease, stroke, DN progression, and perioperative complications. Cardiovascular reflex tests are the criterion standard in clinical autonomic testing.

 

INTRODUCTION

 

Diabetic neuropathy (DN) is the most common and troublesome complication of diabetes mellitus, leading to the greatest morbidity and mortality resulting in a huge economic burden for diabetes care (1,2). It is the most common form of neuropathy in the developed world, accounting for more hospitalizations than all the other diabetes related complications combined. It is the primary risk factor for complications such as foot ulceration, which is responsible for 50-75% of non-traumatic amputations (3). In the United Kingdom, the cost of managing diabetic foot disease is greater than the combined cost of three of the four most common cancers – breast, lung and prostate (4,5). DN is a set of clinical syndromes that affect distinct regions of the nervous system, singly or combined.  It may be silent and go undetected while exercising its ravages; or it may present with clinical symptoms and signs that, although nonspecific and insidious with slow progression also mimics those seen in many other diseases.

 

SCOPE OF THE PROBLEM

 

Diabetic neuropathy results in a variety of syndromes and can be subdivided into focal/multifocal neuropathies, including diabetic amyotrophy, and symmetric polyneuropathies, including sensorimotor polyneuropathy (DPN). The latter is the most common type. The Toronto Diabetic Neuropathy Expert Group defined DPN as a symmetrical, length-dependent sensorimotor polyneuropathy attributable to metabolic and microvascular alterations as a result of chronic hyperglycemia exposure (diabetes) and cardiovascular risk covariates (6).  Its onset is generally insidious, and without treatment the course is chronic and progressive. The loss of small fiber-mediated sensation results in the loss of thermal and pain perception, whereas large fiber impairment results in loss of touch and vibration perception. Sensory fiber involvement may also result in “positive” symptoms, such as paresthesias and pain, although up to 50% of neuropathic patients are asymptomatic. DPN can be associated with the involvement of the autonomic nervous system, i.e., diabetic autonomic neuropathy (7,8) and in its cardiovascular form is associated with at least a three-fold increased risk for mortality (9,10). Cardiac autonomic dysfunction in patients with diabetes is strongly associated with major cardiovascular events and mortality (11).

 

Painful DPN which occurs in up to 34% of patients with diabetes is defined as ‘pain as a direct consequence of abnormalities in the peripheral somatosensory system in people with diabetes’ (12). Persistent neuropathic pain interferes significantly with quality of life (QOL), impairing sleep and recreation; it also significantly impacts emotional well-being, and is associated with – if not the cause of – depression, anxiety, loss of sleep, and noncompliance with treatment (13).  Painful DPN can pose a significant clinical management challenge and if poorly managed can lead to mood and sleep disturbances. Hence, recognition of psychosocial problems that co-exist with neuropathic pain is critical to the management of painful DPN. For many patients, optimal management of chronic pain may require a multidisciplinary team approach with appropriate behavioral therapy, as well as input from a broad range of healthcare professionals (14). 

 

CLASSIFICATION OF DIABETIC NEUROPATHIES

 

Figure 1 and Table 1 describe the classification first proposed by PK Thomas (15) and modified in a recent Position Statement by the American Diabetes Association (16).

Figure 1. Classification of diabetic neuropathy

 

Table 1.  Classification of Diabetic Neuropathies

A. Diffuse neuropathy

  Distal Symmetrical Peripheral Neuropathy

   • Primarily small-fiber neuropathy

   • Primarily large-fiber neuropathy

   • Mixed small- and large-fiber neuropathy (most common)

  Autonomic

   Cardiovascular

    • Reduced Heart Rate Variability

    • Resting tachycardia

    • Orthostatic hypotension

    • Sudden death (malignant arrhythmia)

   Gastrointestinal

    • Diabetic gastroparesis (gastropathy)

    • Diabetic enteropathy (diarrhea)

    • Colonic hypomotility (constipation)

   Urogenital

    • Diabetic cystopathy (neurogenic bladder)

    • Erectile dysfunction

    • Female sexual dysfunction

   Sudomotor dysfunction

    • Distal hypohydrosis/anhidrosis,

    • Gustatory sweating

   Hypoglycemia unawareness

   Abnormal pupillary function

B. Mononeuropathy (mononeuritis multiplex) (atypical forms)

            Isolated cranial or peripheral nerve (e.g., Cranial Nerve III, ulnar, median, femoral, peroneal)

      Mononeuritis multiplex (if confluent may resemble polyneuropathy)

C. Radiculopathy or polyradiculopathy (atypical forms)

            Radiculoplexus neuropathy (a.k.a. lumbosacral polyradiculopathy, proximal motor amyotrophy)

      Thoracic radiculopathy

D. Nondiabetic neuropathies common in diabetes

          Pressure palsies

          Chronic inflammatory demyelinating polyneuropathy

          Radiculoplexus neuropathy

          Acute painful small-fiber neuropathies (treatment-induced)

 

NATURAL HISTORY OF DIABETIC NEUROPATHIES (DN)

 

The natural history of DPN remains poorly understood, as there are few prospective studies that have examined this. The main reason for this is the lack of standardized methodologies for the diagnosis of DPN. Unlike diabetic retinopathy and nephropathy, the lack of simple, accurate and readily reproducible methods of measuring neuropathy is a major challenge. Furthermore, the methods currently used are not only subjective and reliant on the examiner’s interpretation but tend to diagnose DPN when it’s already well established. Nevertheless, it appears that the most rapid deterioration of nerve function occurs soon after the onset of type 1 diabetes; then within 2-3 years there is a slowing of the progress with a shallower slope to the curve of dysfunction (17).  In contrast, in type 2 diabetes, slowing of nerve conduction velocities (NCVs) may be one of the earliest neuropathic abnormalities and often is present even at diagnosis.  In fact, there is accumulating evidence that indicates that the risk of DPN is increased even in patients with prediabetes. In a large population study conducted in Augsburg, Southern Germany, the prevalence of DPN was 28% in subjects with known diabetes, 13% in impaired glucose tolerance (IGT), 11% among those with impaired fasting glucose and 7% in those with normal glucose tolerance (18). After diagnosis, slowing of NCV generally progresses at a steady rate of approximately 1 m/sec/year, and the level of impairment is positively correlated with duration of diabetes. Moreover, nerve conduction velocities remained stable with intensive therapy but decreased significantly with conventional therapy (19,20). In a long term follow up study of type 2 diabetes patients (9), electrophysiologic abnormalities in the lower limb increased from 8% at baseline to 42% after 10 years; in particular, a decrease in sensory and motor amplitudes (indicating axonal destruction) was more pronounced than the slowing of the NCVs. However, there now appears to be a decline in this rate of evolution. It appears that host factors pertaining to general health, management of risk factors and nerve nutrition are changing/improving. This is particularly important when doing studies on the treatment of DPN, which have always relied on differences between drug treatment and placebo, and have apparently been successful because of the decline in function occurring in placebo-treated patients (21).  Recent studies have pointed out the changing natural history of DPN with the advent of therapeutic lifestyle change and the use of statins and ACE inhibitors, which have slowed the progression of DPN and drastically changed the requirements for placebo-controlled studies (22,23).  It is also important to recognize that DPN is a disorder wherein the prevailing abnormality is loss of axons that electrophysiologically translates to a reduction in amplitudes and not conduction velocities; therefore, changes in NCV may not be an appropriate means of monitoring progress or deterioration of nerve function.  Moreover, small, unmyelinated nerve fibers are affected early in DM and are not assessed in NCV studies. Other methods such as quantitative sensory testing, autonomic function testing, skin biopsy with quantification of intraepidermal nerve fibers (IENF), or corneal confocal microscopy are necessary to identify these patients. These techniques will be discussed in greater depth later in this chapter.

 

Although, the true prevalence is unknown and reports vary, it is estimated to be 30% with a range between 6-54% of patients with diabetes (24). It largely depends on the criteria and sensitivity of the diagnostic tests used to define neuropathy, the population (e.g., hospital/community or urban/rural), or the country surveyed and even the etiology of diabetes (24,25). Eleven to 13% of patients reported DN using a questionnaire based survey (26,27); 42-54% were found to have neuropathy when more sensitive measures such as nerve conduction studies were used (28,29). Neurologic complications occur equally in type 1 and type 2 diabetes mellitus and additionally in various forms of acquired diabetes (30).

 

The major morbidity associated with somatic neuropathy is foot ulceration, the precursor of gangrene and limb loss. Neuropathy increases the risk of amputation 1.7 fold; 12 fold if there is deformity (itself a consequence of neuropathy), and 36 fold if there is a history of previous ulceration (31). For more than a decade now, it has been recognized that a limb is lost to diabetes every 30 seconds worldwide (32). According to the International Diabetes Federation (IDF), lower-limb amputations are ten times more common in people with diabetes than in people without diabetes (32, 33). Each week in England there is about 169 amputations in people with diabetes and almost all of these individuals have DN (34). Amputation is not only devastating in its impact on the individual and their family, but also leads to loss of independence and livelihood. In low-income countries, the financial costs can be equivalent to 5.7 years of annual income, potentially resulting in financial ruin for individuals and their families (35). DN also places a substantial financial burden on health-care systems and society in general.

 

MODIFIABLE RISK FACTORS FOR DPN INCIDENCE AND PROGRESSION

 

In both type 1 and 2 diabetes, chronic hyperglycemia has a key role in the pathogenesis of DPN (36). The benefit of glucose lowering is, however, more pronounced in type 1 diabetes (78% relative risk reduction) (37) compared to type 2 (5-9% relative risk reduction) (38). In fact, the benefit of intensive glucose lowering is greatest in younger patients at early stages of the disease. This treatment effects becomes weaker once nerve damage is established. The relationship between glycemic control and DPN in type 2 diabetes is less clear cut. Even when trials have shown that tighter glucose control might have a modest beneficial effect in preventing progression of DPN in type 2 diabetes, such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study (39), confusion has arisen when it was reported that a self-reported history of DPN at baseline was associated with an increased risk of mortality with intensive glycemic treatment (40). This highlights the differences between the pathogenesis of DPN in type 1 and 2 diabetes and emphasizes the point that many people with type 2 diabetes develop DPN despite adequate glucose control. The presence of other risk factors, weight gain and multiple comorbidities may have significant roles to play. Although hyperglycemia and duration of diabetes play an important role in DPN, other risk factors have been identified. The EURODIAB Prospective Complications study in type 1 diabetes demonstrated that the incidence of DPN is associated with other potentially modifiable cardiovascular risk factors, including hypertriglyceridemia, hypertension, obesity and smoking (41). More recently, data from the ADDITION study also implicated similar cardiovascular risk factors in the pathogenesis of DPN in type 2 diabetes (26).

 

PATHOGENESIS OF DIABETIC NEUROPATHIES

 

Despite considerable research, the pathogenesis of diabetic neuropathy remains undetermined (42).  This is one reason why, despite several clinical trials, there has been relatively little progress in the development of disease-modifying treatments (43). Historically, a number of causative factors have been identified including persistent hyperglycemia, microvascular insufficiency, oxidative and nitrosative stress, defective neurotrophism, and autoimmune-mediated nerve destruction.  Figure 2 summarizes our current view of the pathogenesis of DPN (44). Detailed discussion of the different theories is beyond the scope of this Chapter and there are several excellent recent reviews (45).

Figure 2. Pathogenesis of diabetic neuropathies. Ab, antibody; AGE, advance glycation end products; C’, complement; DAG, diacylglycerol; ET, endothelin; EDHF, endothelium-derived hyperpolarizing factor; GF, growth factor; IGF; insulin-like growth factor; NFkB, nuclear factor kB; NGF, nerve growth factor; NO, nitric oxide; NT3, neurotropin 3; PKC, protein kinase C; PGI2, prostaglandin I2; ROS, reactive oxygen species; TRK, tyrosine kinase.

CLINICAL PRESENTATION

 

The spectrum of clinical neuropathic syndromes described in patients with diabetes mellitus includes dysfunction of almost every segment of the somatic peripheral and autonomic nervous system (16). Each syndrome can be distinguished by its pathophysiologic, therapeutic, and prognostic features.

 

Focal and Multifocal Neuropathies

 

Focal neuropathies comprise focal limb neuropathies and cranial neuropathies.

Focal limb neuropathies are usually due to entrapment, and mononeuropathies must be distinguished from these entrapment syndromes (Table 2) (46). Mononeuropathies often occur in the older population; they have an acute onset, are associated with pain, and have a self-limiting course resolving in 6–8 weeks. Mononeuropathies can involve the median (5.8% of all diabetic neuropathies), ulnar (2.1%), radial (0.6%), and common peroneal nerves (47). Cranial neuropathies in patients with diabetes are extremely rare (0.05%) and occur in older individuals with a long duration of diabetes (48). The commonest cranial neuropathy is the third nerve palsy and patients present with acute onset unilateral pain in the orbit or sometimes with a frontal headache. There is typically ptosis and ophthalmoplegia, although the pupillary response to light is usually spared. Recovery occurs usually over three months (48). The clinical onset and time-scale for recovery, and the focal nature of the lesions on the third cranial nerve, on post-mortem studies suggested an ischemic etiology.  It is important to exclude any other cause of third cranial nerve palsy (aneurysm or tumor) by CT or MR scanning, where the diagnosis is in doubt. Fourth, sixth and seventh cranial nerve palsies have also been described in patients with diabetes, but the association with diabetes is not as strong as that with third cranial nerve palsy.

 

Table 2. Distinguishing Characteristics of Mononeuropathies, Entrapment Syndromes and Distal Symmetrical Polyneuropathy

Feature

Mononeuropathy

Entrapment syndrome

Neuropathy

Onset

Sudden

Gradual

Gradual

Pattern

Single nerve but may be multiple

Single nerve exposed to trauma

Distal symmetrical poly neuropathy

Nerves involved

CN III, VI, VII, ulnar, median, peroneal

Median, ulnar, peroneal, medial and lateral plantar

Mixed, Motor, Sensory, Autonomic

Natural history

Resolves spontaneously

Progressive

Progressive

Treatment

Symptomatic

Rest, splints, local steroids, diuretics, surgery

Tight Glycemic control, Pregabalin, Duloxetine, Antioxidants, “Nutrinerve”, Research Drugs.

Distribution of Sensory loss

Area supplied by the nerve

Area supplied beyond the site of entrapment

Distal and symmetrical. “Glove and Stocking” distribution.

CN, cranial nerves; NSAIDs, non-steroidal anti-inflammatory drugs

 

Entrapment Syndromes

 

These start slowly and will progress and persist without intervention. A number of nerves including the median, ulnar, radial, lateral femoral cutaneous, fibular, and plantar nerves are vulnerable to pressure damage in diabetes. The etiology is multifactorial involving metabolic and ischemic factors, impaired reinnervation, and even obesity. Carpal tunnel syndrome occurs three times as frequently in people with diabetes compared with healthy populations (49) and is found in up to one third of patients with diabetes.  Its increased prevalence in diabetes may be related to repeated undetected trauma, metabolic changes, or accumulation of fluid or edema within the confined space of the carpal tunnel. The diagnosis is confirmed by electrophysiological studies. Treatment consists of rest, aided by placement of a wrist splint in a neutral position to avoid repetitive trauma.  Anti-inflammatory medications and steroid injections are sometimes useful. Surgery should be considered if weakness appears and medical treatment fails (50).  It consists of sectioning the volar carpal ligament or unentrapping the nerves in the ulnar canal or the peroneal nerve at the head of the fibula and release of the medial plantar nerve in the tarsal tunnel amongst others. A more detailed review of other peripheral nerves vulnerable to entrapment in anatomically constraint channels are discussed elsewhere (51).

 

Proximal Motor Neuropathy (Diabetic Amyotrophy) and Chronic Demyelinating Neuropathies

 

For many years proximal neuropathy has been considered a component of DN.  Its pathogenesis was ill understood (52), and its treatment was neglected with the anticipation that the patient would eventually recover, albeit over a period of some 1-2 years and after suffering considerable pain, weakness and disability. The condition has a number of synonyms including diabetic amyotrophy and femoral neuropathy.  It can be clinically identified based on the occurrence of these common features: 1) primarily affects those aged 50 to 60 years old with type 2 diabetes; 2) onset can be gradual or abrupt; 3) presents with severe pain in the thighs, hips and buttocks, followed by significant weakness of the proximal muscles of the lower limbs with inability to rise from the sitting position (positive Gower's maneuver); 4) can start unilaterally and then spread bilaterally; 5) often coexists with distal symmetric polyneuropathy; and 6) is characterized by muscle fasciculation, either spontaneous or provoked by percussion. Pathogenesis is not yet clearly understood although immune-mediated epineural microvasculitis has been demonstrated in some cases. Despite limited evidence of efficacy some immunosuppressive therapy is recommended using high dose steroids or intravenous immunoglobulin (53). Close monitoring and appropriate management of blood glucose is advised if high dose steorids are used (54). The condition can occur secondary to a variety of causes unrelated to diabetes, but which have a greater frequency in patients with diabetes than the general population.  Hence, it is important to exclude other causes such as chronic inflammatory demyelinating polyneuropathy (CIDP), monoclonal gammopathy, circulating GM1 antibodies, and inflammatory vasculitis (55,56). In the classic form of diabetic amyotrophy, axonal loss is the predominant process (57). Electrophysiologic evaluation reveals lumbosacral plexopathy (58). In contrast, if demyelination predominates and the motor deficit affects proximal and distal muscle groups, the diagnoses of CIDP, monoclonal gammopathy of unknown significance, and vasculitis should be considered (59,60).  The diagnosis of these demyelinating conditions is often overlooked although recognition is very important because unlike DN, they are sometimes treatable. Furthermore, they occur 11 times more frequently in patients with diabetes than nondiabetic patients (61,62).  Biopsy of the obturator nerve have revealed deposition of immunoglobulin, demyelination and inflammatory cell infiltrate of the vasa nervorum (63). Cerebrospinal fluid (CSF) protein content is high and lymphocyte count increased.  Treatment options include: intravenous immunoglobulin for CIDP (64), plasma exchange for MGUS, steroids and azathioprine for vasculitis, and withdrawal of drugs or other agents that may have caused vasculitis. It is important to divide proximal syndromes into these two subcategories, because the CIDP variant responds dramatically to intervention (65), whereas amyotrophy runs its own course over months to years. Until more evidence is available, they should be considered separate syndromes.

 

Diabetic Truncal Radiculoneuropathy

 

Diabetic truncal radiculoneuropathy affects middle-aged to elderly patients and has a predilection for male sex (16).  Acute onset of pain is the most important symptom and it occurs in a girdle-like distribution over the lower thoracic or abdominal wall. It can be uni- or bilaterally distributed. Motor weakness is rare but there may be local bulging of the muscle. Patchy sensory loss may be present and other causes of nerve root compression should be excluded. Resolution generally occurs within 4-6 months (16).

 

Rapidly Reversible Hyperglycemic Neuropathy

 

Reversible abnormalities of nerve function may occur in patients with recently diagnosed or poorly controlled diabetes. These are unlikely to be caused by structural abnormalities, as recovery soon follows restoration of euglycemia.  Rapidly reversible hyperglycemic neuropathy usually presents with distal sensory symptoms, and whether these abnormalities result in an increased risk of developing chronic neuropathies in the future remains unknow (8).

 

Generalized Symmetric Polyneuropathy

 

ACUTE SENSORY NEUROPATHY

 

Acute sensory (painful) neuropathy is considered by some authors a distinctive variant of distal symmetrical polyneuropathy (66). The syndrome is characterized by severe pain, cachexia, weight loss, depression and sexual dysfunction. It occurs predominantly in male patients and may appear at any time in the course of both type 1 and type 2 diabetes.  It is self-limiting and invariably responds to simple symptomatic treatment (67). Conditions such as Fabry's disease, amyloidosis, HIV infection, heavy metal poisoning (such as arsenic), and excess alcohol consumption should be excluded. Autonomic nervous system involvement can also occur and can be very disabling.

 

Patients report unremitting burning, deep pain and hyperesthesia especially in the feet. Other symptoms include sharp, stabbing, lancinating pain; “electric shock” like sensations in the lower limbs that appear more frequently during the night; paresthesia; tingling; coldness, and numbness. Signs are usually absent with a relatively normal clinical examination, except for allodynia (exaggerated response to non-noxious stimuli) during sensory testing and, occasionally, absent or reduced ankle reflexes. There are no motor signs and little or no abnormality on nerve conduction studies.

 

Acute sensory neuropathy is usually associated with poor glycemic control but may also appear after sudden improvement of glycemia. Most commonly associated with the onset of insulin therapy, being termed "insulin neuritis",it can also occur with oral hypoglycemic treatment. Patients present with severe neuropathic pain and/or autonomic symptoms with or without an acute worsening of retinopathy.  Although the pathologic basis has not been determined, one hypothesis suggests that changes in blood glucose flux produce alterations in epineural blood flow, leading to ischemia; proinflammatory cytokines from activation of microglia have also been implicated (68). Hence, rapid glycemic changes in patients with uncontrolled diabetes increases the risk of this complication and should be avoided. A 2-3% (10-42mmol/mol) decrease in HbA1c over 3 months is associated with a 20% absolute risk of developing this complication. The risk exceeds 80% with a decreased in HbA1c of >4% (20mmol/mol) (69).  A study using in vivo epineural vessel photography and fluorescein angiography demonstrated abnormalities of epineural vessels including arteriovenous shunting and proliferating new vessels in patients with acute sensory neuropathy (68). Other authors relate this syndrome to diabetic lumbosacral radiculoplexus neuropathy (DLRPN) and propose an immune mediated mechanism (70).

 

The key in the management of this syndrome is achieving and maintaining blood glucose stability (71).  Most patients also require medication for neuropathic pain. The natural history of this disease is resolution of symptoms within one year.

 

CHRONIC SENSORIMOTOR NEUROPATHY OR DISTAL SYMMETRIC POLYNEUROPATY (DPN)

 

The most common form of neuropathy in diabetes is a distal symmetrical polyneuropathy.  It occurs in both type 1 and type 2 DM with similar frequency and may already be present at the time of diagnosis of type 2 DM (18). Sensory symptoms include numbness (‘dead feeling’), paraesthesia, and neuropathic pain (hyperalgesia, allodynia, deep aching, burning and sharp stabbing sensations). Patients do occasionally present paradoxically with a painful/painless leg i.e. painful neuropathic symptoms in the presence of severe sensory loss (72). Symptoms begin in the toes before progressing in a stocking and then a glove distribution as the disease progresses. Unsteadiness or sensory ataxia leading to increased falls risk occurs in advanced neuropathy loss of proprioception, foot deformity, and abnormal muscle sensory function (73). In the absence of painful symptoms, the onset of DPN is insidious whereby patients remain completely asymptomatic and signs discovered by a detailed neurological examination. Unfortunately, DPN is often already established or well advanced when identified by bedside clinical examination.

 

It is critically important to annually (at least) examine the feet of patients with diabetes as loss of protective sensation is the strongest risk factor for diabetic foot ulceration. On physical examination, a symmetrical stocking like distribution of sensory abnormalities in both lower limbs is usually seen. In more severe cases, hands may be involved. All sensory modalities can be affected, particularly vibration, touch and position perceptions (large Aα/β fiber damage); and pain, with abnormal heat and cold temperature perception (small thinly myelinated Aδ and unmyelinated C fiber damage, see Figure 3, 4 and 5; Table 3). Deep tendon reflexes may be absent or reduced, especially in the lower extremities, although this may occur with advancing age in the absence of neuropathy. When DPN is established, small muscle wasting of the foot and extensor halluces longus may be seen but severe weakness is rare and should raise the possibility of a non-diabetic etiology of the neuropathy. High arching of the foot, clawing of the toes with prominent metatarsal heads also become apparent – increasing the risk ulceration (74). A thorough assessment of patient’s footwear is essential. A poor fit, abnormal wear from internal pressure areas and foreign objects found in footwear are common causes of trauma leading to foot ulceration (75).

Figure 3. Clinical presentation of small and large fiber neuropathies. Aα fibers are large myelinated fibers, in charge of motor functions and muscle control. Aα/β fibers are large myelinated fibers too, with sensory functions such as perception to touch, vibration, and position. Aδ fibers are small myelinated fibers, in charge of pain stimuli and cold perception. C fibers can be myelinated or unmyelinated and have both sensory (warm perception and pain) and autonomic functions (blood pressure and heart rate regulation, sweating, etc.)

Figure 4. Clinical manifestations of small fiber neuropathies

Figure 5. Nerve fibers of the skin and their functions

 

Table 3. Subtypes of Neuropathies

Clinical Manifestations of Small Fiber Neuropathies:

•           Small thinly myelinated Aδ and unmyelinated C fibers are affected.

•           Prominent symptoms with burning, superficial, or lancinating pain often accompanied by hyperalgesia, dysesthesia, and allodynia.

•           Progression to numbness and hypoalgesia (Disappearance of pain may not necessarily reflect nerve recovery but rather nerve death, and progression of neuropathy must be excluded by careful examination).

•           Abnormal cold and warm thermal sensation.

•           Abnormal autonomic function with decreased sweating, dry skin, impaired vasomotion and skin blood flow with cold feet.

•           Intact motor strength and deep tendon reflexes.

•           Negative nerve conduction velocity findings.

•           Loss of cutaneous nerve fibers on skin biopsies.

•           Can be diagnosed clinically by reduced sensitivity to 1.0 g Semmes Weinstein monofilament and prickling pain perception using the Waardenberg wheel or similar instrument.

•           Patients at risk of foot ulceration and subsequent gangrene and amputations.

Clinical Manifestations of Large Fiber Neuropathies

•           Large myelinated, rapidly conducting Aα/β fibers are affected and may involve sensory and/or motor nerves.

•           Prominent signs with sensory ataxia (waddling like a duck), wasting of small intrinsic muscles of feet and hands with hammertoe deformities and weakness of hands and feet.

•           Abnormal deep tendon reflexes.

•           Impaired vibration perception (often the first objective evidence), light touch, and joint position perception.

•           Shortening of the Achilles tendon with pes equinus.

•           Symptoms may be minimal: sensation of walking on cotton, floors feeling "strange", inability to turn the pages of a book, or inability to discriminate among coins.  In some patients with severe distal muscle weakness, inability to stand on the toes or heels.

•           Abnormal nerve conduction velocity findings

•           Increased skin blood flow with hot feet.

•           Patients at higher risk of falls, fractures, and development of Charcot Neuroarthropathy

•           Most patients with DPN, however, have a "mixed" variety of neuropathy with both large and small nerve fiber damages.

 

DIAGNOSIS OF DIABETIC NEUROPATHIES

 

Diabetic peripheral neuropathy can be diagnosed by the bedside with careful clinical examination of the feet and legs using simple tools within a few minutes. The basic neurological assessment comprises the general medical and neurological history, inspection of the feet, and neurological examination of sensation using simple semi-quantitative bed-side instruments such as the 10g Semmes-Weinstein monofilament, Neuropen (76) (to assess touch/pressure), NeuroQuick (77) or Tiptherm (78) (temperature), calibrated Rydel-Seiffer tuning fork (vibration), pin-prick (pain), and tendon reflexes (knee and ankle) (Table 4).  In addition, assessment of joint position and motor power should also be assessed. The Rydel Seiffer tuning fork is a 128 Hz tuning fork which allows quantifiable assessment of vibration perception in the feet of diabetic patients. When vibrating, two triangles appear on the graduated scale of 0–8 which join together as the amplitude decreases. The normal range for the graduated tuning fork on the dorsal distal joint of the great toe is ≥5/8 scale units in persons 21-40 years old, ≥4.5/8 in those 41-60 years old, ≥4/8 in individuals 61-71 years old, and ≥3.5/8 scale units in those 72-82 years old (79). In resource, limited settings the simple Ipswich Touch Test can be performed by lightly touching the tips of the first, third and fifth toes (80). It is recommended that a simple foot examination to detect loss of protective foot sensation, pedal pulses, and foot deformity is performed from the diagnosis of type 2 diabetes, 5-years after the diagnosis of type 1 diabetes and annually thereafter (81,82,16). This is performed in order to determine the risk of foot ulceration and prompt early referral for foot protection, regular podiatry or specialist input.

 

Table 4.  Examination - Bedside Sensory Tests

Sensory Modality

Nerve Fiber

Instrument

Associated Sensory Receptors

Vibration

Ab (large)

128 Hz

Tuning fork

Ruffini corpuscle mechanoreceptors

Pain (pinprick)

C (small)

Neuro-tips

Nociceptors for pain and warmth

Pressure

Ab, Aa (large)

1 g and 10 g

Monofilament

Pacinian  corpuscle

Light touch

Ab, Aa (large)

Wisp of cotton

Meissner’s corpuscle

Cold

Ad (small)

Cold tuning fork

Cold thermoreceptors

 

A consensus definition of DPN has been proposed by the Toronto Diabetic Neuropathy Expert Group, see below (6). In a clinical context, the diagnosis of ‘possible’ or ‘probable’ DPN is normally sufficient without the need for specialist investigations. For research purposes further tests are needed for a diagnosis of ‘confirmed’ DPN’, ‘Subclinical’ DPN or small fiber neuropathy.

 

Toronto Classification of DPN (6)

 

1)         Possible DSN: The presence of symptoms or signs of DPN may include the following: symptoms–decreased sensation, positive neuropathic sensory symptoms (e.g., “asleep numbness,” prickling or stabbing, burning or aching pain) predominantly in the toes, feet, or legs; or signs–symmetric decrease of distal sensation or unequivocally decreased or absent ankle reflexes.

 

2)         Probable DPN: The presence of a combination of symptoms and signs of neuropathy including any 2 or more of the following: neuropathic symptoms, decreased distal sensation, or unequivocally decreased or absent ankle reflexes.

 

3)         Confirmed DPN: The presence of an abnormality of nerve conduction and a symptom or symptoms, or a sign or signs, of neuropathy confirm DPN.  If nerve conduction is normal, a validated measure of small fiber neuropathy (with class 1 evidence) may be used. To assess for the severity of DPN, several approaches can be recommended: for e.g., the graded approach outlined above; various continuous measures of sum scores of neurologic signs, symptoms or nerve test scores; scores of functions of activities of daily living; or scores of predetermined tasks or of disability.

 

4)         Subclinical DPN: The presence of no signs or symptoms of neuropathy are confirmed with abnormal nerve conduction or a validated measure of small fiber neuropathy (with class 1 evidence).  Definitions 1, 2, or 3 can be used for clinical practice and definitions 3 or 4 can be used for research studies.

 

5)         Small fiber neuropathy (SFN): SFN should be graded as follows: 1) possible: the presence of length-dependent symptoms and/or clinical signs of small fiber damage; 2) probable: the presence of length-dependent symptoms, clinical signs of small fiber damage, and normal sural nerve conduction; and 3) definite: the presence of length-dependent symptoms, clinical signs of small fiber damage, normal sural nerve conduction, and altered intraepidermal nerve fiber density (IENFD) at the ankle and/or abnormal thermal thresholds at the foot (Figure 4).

 

The following findings should alert the physician to consider causes for DPN other than diabetes and referral for a detailed neurological work-up: 1.) pronounced asymmetry of the neurological deficits, 2.) predominant motor deficits, mononeuropathy, or cranial nerve involvement, 3.) rapid development or progression of the neuropathic impairments, 4.) progression of the neuropathy despite optimal glycemic control, 5.) symptoms from the upper limbs, 6.) family history of non-diabetic neuropathy, and 7.) diagnosis of DPN cannot be ascertained by clinical examination.

 

Conditions Mimicking Diabetic Neuropathy

 

An atypical pattern of presentation of symptoms or signs, i.e., the presence of relevant motor deficits, an asymmetrical or proximal distribution, or rapid progression, always requires referral for electrodiagnostic testing. Furthermore, in the presence of such atypical neuropathic signs and symptoms other forms of neuropathy should be sought and excluded.  A good medical history is essential to exclude other causes of neuropathy: a history of trauma, cancer, unexplained weight loss, fever, substance abuse, or HIV infection suggests that an alternative source should be sought. Screening laboratory tests may be considered: serum B12 with its metabolites, folic acid, thyroid function, full blood count, metabolic profile, and serum free light chains (16).

 

There are a number of conditions that can be mistaken for painful DPN: intermittent claudication in which the pain is exacerbated by walking; Morton’s neuroma, in which the pain and tenderness are localized to the intertarsal space and are elicited by applying pressure with the thumb in the appropriate intertarsal space; osteoarthritis/inflammatory arthritis, in which the pain is confined to the joints, made worse with joint movement or exercise, and associated with morning stiffness that improves with ambulation; radiculopathy in which  the pain originates in the shoulder, arm, thorax, or back and radiates into the legs and feet; Charcot neuropathy in which the pain is localized to the site of the collapse of the bones of the foot, and the foot is hot rather than cold; plantar fasciitis, in which there is shooting or burning in the heel with each step and there is exquisite tenderness in the sole of the foot; and tarsal tunnel syndrome in which the pain and numbness radiate from beneath the medial malleolus to the sole and are localized to the inner side of the foot. These contrast with the pain of DPN which is bilateral, symmetrical, covering the whole foot and particularly the dorsum, and is worse at night interfering with sleep.  

 

Scored Clinical Assessment Tools for Diabetic Peripheral Neuropathy

 

Scored Clinical assessments provide standardized, quantitative, and objective measures to assess for both the severity of symptoms and the degree of neuropathic deficits. These tools which have been subjected to strict validation studies, are sufficiently reproducible but require some minimal training. The most widely used instruments include: the Michigan Neuropathy Screening Instrument Questionnaire (MNSIQ, 15-item self-administered questionnaire), Michigan Neuropathy Screening Instrument (MNSI, MNSIQ plus a structured clinical examination), Michigan Diabetic Neuropathy Score (neurological assessment coupled with nerve conduction studies) (83), Toronto Clinical Neuropathy Score (TCNS, composite score of neuropathy symptoms sensory exam and reflexes) (84), modified TCNS (composite score of neuropathy symptoms and signs) (85), Neuropathy Disability Score (neuropathy signs, including reflexes) (86), Neurological Disability Score (neurological examination of cranial nerves, and upper and lower limbs) (87), the Neuropathy Symptom Score (assessment of sensory, motor and autonomic neuropathy symptoms) (87), and the Neuropathy impairment score (NIS) for neuropathic deficits (impairments) (87). A number of instruments have also been used to assess neuropathic pain and these include: the Neuropathy Total Symptom Score-6 (NTSS-6; measures frequency and intensity of neuropathic symptoms) (88), PainDETECT (patient administered 10-item questionnaire) (89), DN4 (Doleur Neuropathique en 4 Questions; 7 sensory descriptors and 3 clinical signs) (90) and the Neuropathic Pain Symptom Inventory (NPSI; self-administered 12-item questionnaire evaluating different symptoms of neuropathic pain) (91).

 

Objective Devices for the Diagnosis of Neuropathy

 

Nerve conduction studies are the current ‘gold’ standard for the diagnosis of DN. This robust measure also predicts foot ulceration and mortality. However, they are time consuming, labor intensive, costly, and impractical in routine clinical care.

 

Skin biopsy has become a widely used tool to investigate small caliber sensory nerves including somatic unmyelinated intraepidermal nerve fibers (IENF), dermal myelinated nerve fibers, and autonomic nerve fibers in peripheral neuropathies and other conditions (92).  Different techniques for tissue processing and nerve fiber evaluation have been used.  For diagnostic purposes in peripheral neuropathies, the current recommendation is to perform a 3-mm punch skin biopsy at the distal leg and quantification of the linear density of IENF in at least three 50-µm thick sections per biopsy, fixed in 2% PLP or Zamboni's solution, by bright-field immunohistochemistry or immunofluorescence with anti-protein gene product (PGP) 9.5 antibodies (93). Quantification of IENF density appeared more sensitive than sensory nerve conduction study or sural nerve biopsy in diagnosing SFN.

 

Quantitative sensory testing (QST) enables more accurate assessment of sensory deficits - also those related to small fiber function - by applying controlled and quantified stimuli and standardized procedures. Moreover, assessment of thermal thresholds can be a helpful tool in the diagnostic pathway of small fiber polyneuropathy (16).

 

Point of Care Devices for the Diagnosis of DN

 

Significant progress has been made to develop point-of-care (POC) devices that are capable of diagnosing early, subclinical neuropathy. Papanas et al have recently comprehensively reviewed these devices (94). Therefore, we will briefly outline the following devices: the NeuroQuick 77, NeuroPAD (95), NC-Stat DPN-Check (96), Corneal Confocal Microscopy (CCM) (97,98), and Sudoscan (99,100).

 

DPN CHECK

 

The DPN-Check is a novel, user-friendly, handheld POC devices that performs a sural nerve conduction study in three minutes (Figure 6). It is an acceptable proxy to standard nerve conduction studies which are time-consuming, expensive, and often require patients to be seen in specialist’s clinics. The DPN check has been demonstrated to have excellent reliability with an inter- and intra-observer intraclass correlation coefficients of between 0.83 and 0.97 for sensory nerve action potentials respectively (101). It also has good validity with 95% sensitivity and 71% specificity when compared against reference standard nerve conduction study (101) for the diagnosis of DN.

Figure 6. DPN Check device

As detailed above, nerve conduction studies are only an assessment of large nerve fiber function. DPN, on the other hand, usually involves both small and large nerve fibers, with some evidence suggesting small nerve fiber involvement early in its natural history (102,103). Small nerve fibers constitute 80-91% of peripheral nerve fibers and control pain perception, autonomic and sudomotor function. Although intraepidermal nerve fiber density measurement from lower limb skin biopsy is considered the gold standard for the diagnosis of small fiber neuropathy (104,92) it is invasive and hence not suitable for routine screening. However, a number of POC devices have been developed to assess small fiber dysfunction. These include:

 

NEUROQUICK

 

Thinly myelinated Aδ and unmyelinated C-fibers are small caliber nerves that mediate thermal sensation and nociceptive stimuli. Quantitative sensory testing of thermal discrimination thresholds is a non-invasive test used to examine impaired small nerve fiber function. NeuroQuick is a handheld device for quantitative bedside testing of cold thermal perception threshold. It allows near patient assessment of small fiber dysfunction avoiding the use of time-consuming and expensive quantitative sensory testing equipment in a laboratory. To date, one published clinical validation study has been performed in a diabetic population which suggests it is a valid and reliable screening tool for the assessment of small fiber dysfunction (77). Use of NeuroQuick was more sensitive in detecting early DPN compared to the traditional bedside screening tests such as the tuning fork or elaborate thermal testing (77). However, it is a psychophysical test that relies on the cognition/attention of the patient. Furthermore, the coefficients of variation for repeated NeuroQuick measurements ranged between 8.5% and 20.4% (77). Further studies are required to demonstrate whether the NeuroQuick is a useful screening tool to detect small fiber dysfunction in DPN.

 

NEUROPAD    

 

This is a 10-minute test which measures sweat production on the plantar surface of the foot (Figure 7). It is based on a color change in a cobalt compound from blue to pink which produces a categorical output with modest diagnostic performance for DPN compared to electrophysiological assessments. If the patch remains completely or partially blue within 10 min, the result is considered abnormal (105).   No training is required to administer Neuropad, nor does it require responses from the patient. Therefore, this method of assessment may be more suitable for screening in community settings and those with cognitive or communication difficulties who have to respond to other methods of assessment. A number of clinical validation studies (95, 106) have been conducted which demonstrates low sensitivity for large fiber neuropathy (50-64%) but much higher sensitivity for small fiber neuropathy (80%) 107. Neuropad has also shown good reproducibility with intra- and inter-observer coefficient of variation between 4.1% and 5.1% (108).

Figure 7. NeuroPAD

 

CORNEAL CONFOCAL MICROSCOPY 

 

Corneal confocal microscopy (CCM, Figure 8) is a noninvasive technique used to detect small nerve fiber loss in the cornea which correlates with both increasing neuropathic severity and reduced IENFD in patients with diabetes (103,109). A novel technique of real-time mapping permits an area of 3.2 mm² to be mapped with a total of 64 theoretically non-overlapping single 400 µm² images (110). There have been a number of clinical validation studies including one 3.5-year prospective study in T1DM which demonstrated relatively modest to high sensitivity (82%) and specificity (69%) of CCM for the incipient DPN (98). It has good reproducibility for corneal nerve fiber length measurements with intra- and inter-observer intraclass correlation coefficients of 0.72 and 0.73 respectively. Currently, CCM is used in specialist centers, but would suit widespread application given its easy application for patient follow-up. However, large, multicenter, prospective studies are now required to confirm that corneal nerve changes unequivocally reflect the complex pathological processes in the peripheral nerve. Moreover, the establishment of a normative database and technical improvements in automated fiber measurements and wider-area image analysis may be useful to increase diagnostic performance.

Figure 8. Examples of corneal nerve fiber density in a patient with no diabetic neuropathy on the left and with established diabetic neuropathy on the right.

CONTACT HEAT EVOKED POTENTIALS  

 

Contact Heat Evoked Potentials (CHEPS) has been studied in healthy controls, newly diagnosed and established patients with diabetes, and patients with the metabolic syndrome. It does appear that CHEPS is capable of detecting small fiber neuropathy in the absence of other indices, and that CHEPS correlates with quantitative sensory perception and objective tests of small fiber structure (intraepidermal nerve fiber density) (111) and function (cooling detection threshold and cold pain) (112) .

 

SUDOSCAN

 

Sudoscan®, an instrument capable of detecting chloride ion flux in response to a very low current (Figure 9), is an objective and quantitative sudomotor function test with promising sensitivity and specificity in the investigation of DPN (113). The entire evaluation takes only 2 minutes and can be done in an ambulatory setting. A measurement of electrochemical skin conductance (ESC) for the hands and feet, that are rich in sweat glands, is generated from the derivative current associated with the applied voltage. Sensitivity and specificity of foot ESC for classifying DPN were 87.5% and 76.2%, respectively. The area under the ROC curve (AUC) was 0.85 (99).

Figure 9. SUDOSCAN test of sudomotor function being performed

SUMMARY OF POINT OF CARE DEVICES

 

In summary, the sensitivity of point of care devices seems acceptable and perhaps a combination of devices may be used in the future for detecting DPN. However, there is high heterogeneity and patient selection bias in most of the studies. Further studies are needed to evaluate the performance of point of care devices against Wilson criteria for screening of undiagnosed DPN at the population level. Prospective studies of hard endpoints (e.g., foot ulcerations and lower limb amputations) are also necessary to ensure that the benefits of screening are important for patients. The cost-effectiveness of implementing screening using these devices also needs to be carefully appraised. Point of care devices provide rapid, non-invasive tests that could be used as an objective screening test for DPN in busy diabetic clinics, ensuring adherence to current recommendation of annual assessment for all patients with diabetes that remains unfulfilled.

 

Summary of Clinical Assessment of DPN

 

Symptoms of neuropathy can vary markedly from one patient to another. For this reason, a number of symptom screening questionnaires with similar scoring systems have been developed. These questionnaires are useful for patient follow-up and to assess response to treatment. A detailed clinical examination is the key to the diagnosis of DPN.  The latest position statement of the American Diabetes Association recommends that all patients with diabetes be screened for DPN at diagnosis in type 2 DM and 5 years after diagnosis in type 1 DM. DPN screening should be repeated annually and must include sensory examination of the feet and ankle reflexes (16).  One or more of the following can be used to assess sensory function: pinprick (using the Waardenberg wheel or similar instrument), temperature, vibration perception (using 128-Hz tuning fork) or 10-g monofilament pressure perception at the distal halluces. For this last test a simple substitute is to use 25 lb strain fishing line cut into 4 cm and 8 cm lengths, which translate to 10 and 1 g monofilaments respectively (114). The most sensitive measure has been shown to be the vibration detection threshold, although sensitivity of 10-g Semmes-Weinstein monofilament to identify feet at risk varies from 86 to 100% (115,116). Combinations of more than one test have more than 87% sensitivity in detecting DPN (117). Longitudinal studies have shown that these simple tests are good predictors of foot ulcer risk (118). Numerous composite scores to evaluate clinical signs of DN, such as the Neuropathy Impairment Score (NIS) are currently available. These, in combination with symptom scores, are useful in documenting and monitoring neuropathic patients in the clinic (119). Feet should always be examined in detail to detect ulcers, calluses, and deformities, and footwear must be inspected at every visit. However, these simple bedside tests are crude and detect DN very late in its natural history. Even the benefits gained by standardising clinical assessment using scored clinical assessments such as the Michigan Neuropathy Screening Instrument (MNSI) (120), the Toronto Clinical Neuropathy Score (TCNS) (84,85) and the United Kingdom Screening Test (UKST) (86), remain subjective, heavily reliant on the examiners’ interpretations (121). Bedside tests used to aid diagnosis of neuropathy such as the 10g monofilament (122), the Ipswich Touch Test (80), and vibration perception threshold using the tuning fork (123) are not only reliant on patients’ subjective response but are mainly utilised to identify the loss of protective foot sensation and risk of ulceration (124). As such, these tests tend to diagnose DPN when it is already well-established (125). Late diagnosis hampers the benefits of early identification which includes a focus on early, intensified diabetes control, and the prevention of neuropathy-related sequelae. Conversely, the situation is different for the detection of diabetic retinopathy using digital camera-based retinal photography (126) or diabetic kidney disease using blood and urine tests. These developments led to the institution of a robust annual screening program that has led to significant reduction in blindness, such that retinopathy is no longer the commonest cause of blindness in working age adults (127) and reductions in end stage renal failure (128). Unfortunately, by the time neuropathy is detected using these crude tests, it is often very well established and consequently impossible to reverse or even to halt the inexorable neuropathic process.

 

In the clinical research settings nerve conduction studies, quantitative sensory testing, and skin biopsy is used to identify and quantify early, subclinical neuropathy. Multiple studies have proven the value of Quantitative Sensory Testing (QST) measures in the detection of subclinical neuropathy (small fiber neuropathy), the assessment of progression of neuropathy, and the prediction of risk of foot ulceration (117,129,130). These standardized measures of vibration and thermal thresholds also play an important role in multicenter clinical trials as primary efficacy endpoints. A consensus subcommittee of the American Academy of Neurology stated that QST receive a Class II rating as a diagnostic test with a type B strength of recommendation (131).

 

The use of electrophysiologic measures (nerve conduction velocity, NCV) in both clinical practice and multicenter clinical trials is recommended (6, 132). In a long term follow-up study of type 2 patients with diabetes (28) NCV abnormalities in the lower limbs increased from 8% at baseline to 42% after 10 years of disease. A slow progression of NCV abnormalities was seen in the Diabetes Control and Complication Trial (DCCT). The sural and peroneal nerve conduction velocities diminished by 2.8 and 2.7 m/s respectively, over a 5-year period (21). Furthermore, in the same study, patients who were free of neuropathy at baseline had a 40% incidence of abnormal NCV in the conventionally treated group versus 16% in the intensive therapy treated group after 5 years. However, the neurophysiologic findings vary widely depending on the population tested and the type and distribution of the neuropathy. Patients with painful, predominantly small fiber neuropathy have normal studies. There is consistent evidence that small, unmyelinated fibers are affected early in DM and these alterations are not diagnosed by routine NCV studies (45). Therefore, other methods, such as QST, autonomic testing, or skin biopsy with quantification of intraepidermal nerve fibers (IENF) are needed to detect these patients (22,133,134). Nevertheless electrophysiological studies play a key role in ruling out other causes of neuropathy and are essential for the identification of focal and multifocal neuropathies (46,8).

 

Intraepithelial Nerve Fiber Density

 

The importance of the skin biopsy as a diagnostic tool for DPN is increasingly being recognized (45, 135). This technique quantitates small epidermal nerve fibers through antibody staining of the pan-axonal marker protein gene product 9.5 (PGP 9.5). Though minimally invasive (3-mm diameter punch biopsy), it enables a direct study of small fibers, which cannot be evaluated by NCV studies. It has led to the recognition of the small nerve fiber syndrome as part of IGT and the metabolic syndrome (Figure 10). When patients present with the “burning foot or hand syndrome”, evaluation for glucose tolerance and the metabolic syndrome (including waist circumference, blood pressure, and plasma triglyceride and HDL-C levels) becomes mandatory.  Therapeutic life style changes (136) can result in nerve fiber regeneration, reversal of the neuropathy, and alleviation of symptoms (see below). 

Figure 10. Intraepidermal nerve fiber loss in small vessel neuropathy. Loss of cutaneous nerve fibers that stain positive for the neuronal antigen protein gene product 9.5 (PGP 9.5) in metabolic syndrome and diabetes.

It is widely recognized that neuropathy per se can affect the quality of life (QOL) of patients with diabetes. A number of instruments have been developed and validated to assess QOL in DPN. The NeuroQoL measures patients’ perceptions of the impact of neuropathy and foot ulcers (137). The Norfolk QOL questionnaire for DPN is a validated tool addressing specific symptoms and the impact of large, small, and autonomic nerve fiber functions (138). The tool has been used in clinical trials and is available in several validated language versions. It was tested in 262 subjects (healthy controls, controls with diabetes, and DPN patients): differences between DN patients and both diabetes and healthy controls were significant (p<0.05) for all item groupings (small fiber, large fiber, and autonomic nerve function; symptoms; and activities of daily living (ADL). Total QOL scores correlated with total neuropathy scores. The ADL, total scores, and autonomic scores were also greater in controls with diabetes compared to healthy controls (p<0.05), suggesting that diabetes per se impacts some aspects of QO (137).

 

The diagnosis of DPN is mainly a clinical one with the aid of specific diagnostic tests according to the type and severity of the neuropathy. However other non-diabetic causes of neuropathy must always be excluded, depending on the clinical findings (B12 deficiency, hypothyroidism, uremia, CIDP, etc.) (Figure 11).

Figure 11. A diagnostic algorithm for assessment of neurologic deficit and classification of neuropathic syndromes: B12, vitamin B12; BUN, blood urea nitrogen; CHEPS, Contact Heat Evoked Potentials CIDP, chronic inflammatory demyelinating polyneuropathy; EMG, electromyogram; Hx, history; MGUS, monoclonal gammopathy of unknown significance; NCV, nerve conduction studies; NIS, neurologic impairment score (sensory and motor evaluation); NSS, neurologic symptom score; QAFT, quantitative autonomic function tests; QST, quantitative sensory tests; Sudo, sudomotor function testing.

Central Nervous System Involvement

 

Hitherto considered a disease of the peripheral nervous system, there is now mounting evidence of central nervous system (CNS) involvement in DN (Figure 12). Several magnetic resonance imaging studies provide valuable insight into CNS alterations in DN. From the spinal cord (139,140) to the cerebral cortex, structural (141), biochemical (142,143), perfusion (144), and functional changes (145,146) have been described. Although the initial injury may occur in the peripheral nerves, concomitant changes within the CNS may have a crucial role in the pathogenesis and determining clinical phenotype and even treatment response in painful DN.

 

Central nervous system involvement was first recognized in the 1960’s when post-mortem autopsy studies of patients with advanced diabetes found evidence of spinal cord atrophy, demyelination, and axonal loss (147,148). These findings were largely dismissed as being secondary to poor diabetes control and infection (e.g., syphilis) rather than DN. Indeed, the pathological abnormalities in the spinal cord were reported in isolation and not examined in the context of DN related peripheral nerve changes. Subsequent studies performed in the late 70’s and 80’s utilized advances in somatosensory evoked potentials and demonstrated central (brain and spinal cord) slowing in humans with DN (149) and rodent models (150). With the advent and accessibility of demonstrated magnetic resonance imaging in the 90’s and early 00’s, investigators were able to demonstrate clear spinal cord involvement in the form of cervical cord atrophy not only in patients with established DN (140) but also in those with early subclinical DN (139). Subsequent studies have sought to apply advances multimodal magnetic resonance imaging to gain unique insights into brain involvement, particularly brain regions involved with somatosensory and nociception in DN – e.g. primary somatosensory cortex (141) and the thalamus (142). Accompanying the reduction in cervical spine volume is a reduction in primary somatosensory cortical volume in both painful and painless DN (141). Proton magnetic resonance spectroscopy studies have demonstrated evidence of thalamic neuronal dysfunction in painless but not in painful DN – indicating that preservation of thalamic neuronal function may be a prerequisite for the perception of pain in DN (142). In addition, there was also an increase in thalamic vascularity (144), altered thalamic-cortical functional connectivity (146), and a reorganization of the primary somatosensory cortex in patients with painful DN (146). Thus, the involvement of the central nervous system in DN has opened a whole new area of further research and has great potential for future patient stratification and development of new therapeutic targets.

Figure 12. Multimodal magnetic resonance imaging studies of the central nervous system in diabetic neuropathy.

Risk Factors for Diabetic Polyneuropathies

 

Diabetic neuropathy is the end results of a culmination of several etiologically linked pathophysiological processes – some not fully understood. Although hyperglycemia and duration of diabetes play an important role in DN, other risk factors have been identified. The EURODIAB Prospective Complications study demonstrated that the incidence of DN is associated with other potentially modifiable cardiovascular risk factors, including hypertriglyceridemia, hypertension, obesity and smoking (41). In the Look AHEAD study in patients with type 2 diabetes, there was a greater increase in neuropathic symptoms (but not neuropathic signs) in the control cohort (diabetes support and education program) compared to the cohort receiving intensive diet and exercise lifestyle intervention programmed focused on weight loss (151).

 

TREATMENT OF DIABETIC POLYNEUROPATHIES

 

Treatment of DN should be targeted towards a number of different aspects: firstly, treatment of specific underlying pathogenic mechanisms; secondly, treatment of symptoms and improvement in QOL; and thirdly, prevention of progression and treatment of complications of neuropathy.

 

Targeting Risk Factors

 

GLYCEMIC AND METABOLIC CONTROL

 

Several long-term prospective studies that assessed the effects of intensive diabetes therapy on the prevention and progression of chronic diabetic complications have been published. The large randomized trials such as the Diabetes Control and Complications Trial (DCCT) and the UK Prospective Diabetes Study (UKPDS) were not designed to evaluate the effects of intensive diabetes therapy on DPN, but rather to study the influence of such treatment on the development and progression of the chronic diabetic complications (152,153). Thus, only a minority of the patients enrolled in these studies had symptomatic DPN at entry. Studies in patients with type 1 diabetes show that intensive diabetes therapy retards but does not completely prevent the development of DPN.  In the DCCT/EDIC cohort, the benefits of former intensive insulin treatment persisted for 13-14 years after DCCT closeout and provided evidence of a durable effect of prior intensive treatment on DPN and cardiac autonomic neuropathy (“hyperglycemic memory”) (154,155).

 

In contrast, in patients with type 2 diabetes, who represent the vast majority of people with diabetes, the results were largely negative. The UKPDS showed a lower rate of impaired vibration perception threshold (VPT) (VPT >25 V) after 15 years for intensive therapy (IT) vs. conventional therapy (CT) (31% vs. 52%). However, the only additional time point at which VPT reached a significant difference between IT and CT was the 9-year follow-up, whereas the rates after 3, 6, and 12 years did not differ between the groups. Likewise, the rates of absent knee and ankle reflexes as well as the heart rate responses to deep breathing did not differ between the groups (153). In the ADVANCE study including 11,140 patients with type 2 diabetes randomly assigned to either standard glucose control or intensive glucose control, the relative risk reduction (95% CI) for new or worsening neuropathy for intensive vs. standard glucose control after a median of 5 years of follow-up was −4 (−10 to 2), without a significant difference between the groups (156).  Likewise, in the VADT study including 1,791 military veterans (mean age, 60.4 years) who had a suboptimal response to therapy for type 2 diabetes, after a median follow-up of 5.6 years no differences between the two groups on intensive or standard glucose control were observed for DPN or microvascular complications (157). In the ACCORD trial (39), intensive therapy aimed at HbA1c <6.0% was stopped before study end because of higher mortality in that group, and patients were transitioned to standard therapy after 3.7 years on average. At transition, loss of sensation to light touch was significantly improved on intensive vs standard diabetes therapy. At study end after 5 years, MNSI score >2 and loss of sensation to vibration and light touch were significantly improved on intensive vs standard diabetes therapy. However, because of the premature study termination and the aggressive HbA1c goal, the neuropathy outcome in the ACCORD trial is difficult to interpret.

 

In the Steno 2 Study (158), intensified multifactorial risk intervention including intensive diabetes treatment, angiotensin converting enzyme (ACE)-inhibitors, antioxidants, statins, aspirin, and smoking cessation in patients with microalbuminuria showed no effect on DPN after 7.8 (range: 6.9-8.8) years and again at 13.3 years, after the patients were subsequently followed for a mean of 5.5 years.  However, the progression of cardiac autonomic neuropathy (CAN) was reduced by 57%. Thus, there is no evidence that intensive diabetes therapy or a target-driven intensified intervention aimed at multiple risk factors favorably influences the development or progression of DPN as opposed to CAN in patients with type 2 diabetes.  However, the Steno study used only vibration detection, which measures exclusively the changes in large fiber function.

 

DYSLIPIDEMIA  

 

Observational and cross-sectional studies have demonstrated, to varying degrees, an association between lipids and DPN (159). The strongest evidence, however, is for the association of elevated levels of triglycerides and DPN (160). In a study of patients with T2DM there was a graded relationship between triglyceride levels and the risk of lower-limb amputations (160). Likewise, another study demonstrated that hypertriglyceridemia was an independent risk factor of loss of sural (myelinated) nerve fiber density and lower limb amputations (161). In addition to hypertriglyceridemia, low-level of HDL cholesterol is reported to as an independent risk factor for DPN (159). However, clinical studies investigating the effects of statins on the development of DPN are far from conclusive. This is partly because several large statin studies that included patients with diabetes did not report data on the development of microvascular disease (162,163) let alone DPN. The Freemantle Diabetes Study, an observational study with cross-sectional and longitudinal analysis, suggested that statin or fibrate therapy may protect against DPN in T2DM (164). Two subsequent, relatively small, randomized clinical studies have reported improvements in nerve conduction parameters of DPN following 6 to 12 weeks of statin treatment (165,166). The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study has since, demonstrated that fibrates are beneficial in preventing microvascular complications (retinopathy and nephropathy) and non-traumatic lower limb amputations but DPN outcomes have not been reported (167). Subsequently, a patient registry study from Denmark, found that the use of statins before diagnosis of incident diabetes was protective against the development of DPN (168). In summary, whether lipid lowering treatment reduces the risk of DPN —a possibility raised by these data—will need to be addressed in other studies preferably in randomized controlled trials.

 

HYPERTENSION

 

An association between hypertension and DPN has been demonstrated in several observational studies in both T2DM (169,170) and T1DM (171). There is some preliminary evidence from relatively small randomized control trials with improvements in DPN based on clinical and nerve conduction parameters following antihypertensive treatment with angiotensin converting enzyme (ACE) inhibitors (172) and calcium channel blockers (173). However, the significance of this relationship is uncertain as several large intervention studies targeting hypertension (26) studies failed to show a reduction in DPN despite clear benefits in renal and retinal complications (174). One possible explanation is that the methods used in these intervention studies to diagnose/quantify DPN lacked the necessary sensitivity or reliability to diagnose/quantity DPN let alone examine differences between study groups. The heterogeneity in effect size estimates for this outcome in many of these studies supports this view. Another possible explanation for this finding could be the strengthening of guidelines for diabetes care and the more widespread routine use antihypertensive treatment.

 

OBESITY  

 

Several studies have revealed an association between obesity and polyneuropathy even in the presence of normoglycemia (175,176) The prevalence of polyneuropathy, however, increases in obese patients with prediabetes and diabetes (177). Subsequent studies appear to demonstrate that adopting a healthy lifestyle incorporating a balanced diet, regular aerobic and weight-resistance physical activities may reverse the process, particularly if they are undertaken at an early stage of DPN (136,178,179). A randomized control study of a 2.5-hour, weekly supervised treadmill exercise and dietary intervention program aimed at normalizing body mass index or losing 7% baseline body weight in T2DM demonstrated significant improvement in markers (intraepithelial nerve fiber density and regenerative capacity) of DPN (180). However, once DPN is established, restoration of normal weight did not show significant improvement.

 

Targeting Underlying Pathophysiological Mechanisms

 

OXIDATIVE STRESS

 

Several studies have shown that hyperglycemia causes oxidative stress in tissues that are susceptible to complications of diabetes, including peripheral nerves. Figure 2 presents our current understanding of the mechanisms and potential therapeutic pathways for oxidative stress-induced nerve damage. Studies show that hyperglycemia induces an increased presence of markers of oxidative stress, such as superoxide and peroxynitrite ions, and that antioxidant defense moieties are reduced in patients with diabetic peripheral neuropathy (181). Therapies known to reduce oxidative stress are therefore recommended. Therapies that are under investigation include aldose reductase inhibitors (ARIs), α-lipoic acid, γ-linolenic acid, benfotiamine, and protein kinase C (PKC) inhibitors.

 

Advanced glycation end-products (AGE) are the result of non-enzymatic addition of glucose or other saccharides to proteins, lipids, and nucleotides. In diabetes, excess glucose accelerates AGE generation that leads to intra- and extracellular protein cross-linking and protein aggregation. Activation of RAGE (AGE receptors) alters intracellular signaling and gene expression, releases pro-inflammatory molecules, and results in an increased production of reactive oxygen species (ROS) that contribute to diabetic microvascular complications. Aminoguanidine, an inhibitor of AGE formation, showed good results in animal studies but trials in humans have been discontinued because of toxicity (182).  Benfotiamine is a transketolase activator that reduces tissue AGEs. Several independent pilot studies have demonstrated its effectiveness in diabetic polyneuropathy. The BEDIP 3-week study used a 200 mg daily dose, and the BENDIP 6-week study used 300 and 600 mg daily doses; both studies demonstrated subjective improvements in neuropathy scores in the groups receiving benfotiamine, with a pronounced decrease in reported pain levels (183). In a 12-week study, the use of benfotiamine plus vitamin B6/B12 significantly improved nerve conduction velocity in the peroneal nerve along with appreciable improvements in vibratory perception. An alternate combination of benfotiamine (100 mg) and pyridoxine (100 mg) has been shown to improve diabetic polyneuropathy in a small number of patients with diabetes (184,185). The use of benfotiamine in combination with other antioxidant therapies such as α-Lipoic acid (see below) are commercially available.

 

ARIs reduce the flux of glucose through the polyol pathway, inhibiting tissue accumulation of sorbitol and fructose. In a 12-month study of zenarestat a dose dependent improvement in nerve fiber density was shown (186). In a one year trial of fidarestat in Japanese patients with diabetes, improvement of symptoms was shown (187), and a 3 year study of epalrestat showed improved nerve function (NCV) as well as vibration perception (188). Epalrestat is marketed only in Japan and India. Newer ARIs are currently being explored, and some positive results have emerged (189), but it is becoming clear that these may be insufficient per se and combinations of treatments may be needed.

 

Gamma-Linolenic acid can cause significant improvement in clinical and electrophysiological tests for neuropathy (190). Alpha-Lipoic acid or thioctic acid has been used for its antioxidant properties and for its thiol-replenishing redox-modulating properties. A number of studies show its favorable influence on microcirculation and reversal of symptoms of neuropathy (191,192). A meta-analysis including 1,258 patients from four randomized clinical trials concluded that 600 mg of i.v. α-lipoic acid daily significantly reduced symptoms of neuropathy and improved neuropathic deficits (193). The SYDNEY 2 trial showed significant improvement in neuropathic symptoms and neurologic deficits in 181 diabetes patients with 3 different doses of α-lipoic acid compared to placebo over a 5-week period (194). The long-term effects of oral α-lipoic acid on electrophysiology and clinical assessments were examined during the NATHAN-1 study.  The study showed that 4 years of treatment with α-lipoic acid in mild to moderate DSP is well tolerated and improves some neuropathic deficits and symptoms, but not nerve conduction (195). Additional long-term RCTs could further strengthen the rationale for the use of these agents in clinical practice. Safety profiles of α-lipoic acid are favorable during long-term treatment. An overview on the usual dosages of α-lipoic acid and benfothiamine, most frequent adverse events and scientific evidence can be found here (193,196,197,185).

 

Protein kinase C (PKC) activation is a critical step in the pathway to diabetic microvascular complications. It is activated by both hyperglycemia and disordered fatty-acid metabolism, resulting in increased production of vasoconstrictive, angiogenic, and chemotactic cytokines including transforming growth factor β (TGF-β), vascular endothelial growth factor (VEGF), endothelin (ET-1), and intercellular adhesion molecules (ICAMs). A multinational, randomized, phase-2, double blind, placebo-controlled trial with ruboxistaurin (a PKC-β inhibitor) failed to achieve the primary endpoints although significant changes were observed in a number of domains (198). Nevertheless, in a subgroup of patients with less severe DN (sural nerve action potential greater than 0.5 μV) at baseline and clinically significant symptoms, a statistically significant improvement in symptoms and vibratory detection thresholds was observed in the ruboxistaurin-treated groups as compared with placebo (199). A smaller, single center study showed improvement in symptom scores, endothelium dependent skin blood flow measurements, and quality of life scores in the ruboxistaurin treated group (200). These studies and the NATHAN studies have pointed out the change in the natural history of DPN with the advent of therapeutic lifestyle change, statins and ACE inhibitors, which have slowed the progression of DPN and drastically altered the requirements for placebo-controlled studies. Several studies (201,202) have demonstrated that patients with type 1 diabetes who retain some β-cell activity are considerably less prone to developing microvascular complications than those who are completely C-peptide deficient, and that C-peptide may have substantial anti-oxidant, cytoprotective, anti-anabolic, and anti-inflammatory effects.  C-peptide administration for 6 months in type 1 diabetes has been shown to improve sensory nerve function (203).

 

GROWTH FACTORS  

 

There is increasing evidence that there is a deficiency of nerve growth factor (NGF) in diabetes, as well as the dependent neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) and that this contributes to the clinical perturbations in small-fiber function (204). Clinical trials with NGF have not been successful but are subject to certain caveats with regard to design; however, NGF still holds promise for sensory and autonomic neuropathies (205). The pathogenesis of DN includes loss of vasa nervorum, so it is likely that appropriate application of vascular endothelial growth factor (VEGF) would reverse the dysfunction. Introduction of VEGF gene into the muscle of DM animal models improved nerve function (206). However, VEGF gene studies with transfection of the gene into the muscle in humans failed to meet efficacy end points in painful DPN trials 207. Hepatocyte growth factor (208,209) (HGF) is another potent angiogenic cytokine under study for the treatment of painful neuropathy.  INGAP peptide comprises the core active sequence of Islet Neogenesis Associated Protein (INGAP), a pancreatic cytokine that can induce new islet formation and restore euglycemia in diabetic rodents. Maysinger et al showed significant improvement in thermal hypoalgesia in diabetic mice after a 2-week treatment with INGAP peptide (210,211).

 

IMMUNE THERAPY

 

Several different autoantibodies in human sera have been reported that can react with epitopes in neuronal cells and have been associated with DN.  Milicevic et al have reported a 12% incidence of a predominantly motor form of neuropathy in patients with diabetes associated with monosialoganglioside antibodies (anti GM1 antibodies) (63). Perhaps the clearest link between autoimmunity and neuropathy has been the demonstration of an 11-fold increased likelihood of CIDP, multiple motor polyneuropathy, vasculitis, and monoclonal gammopathies in diabetes (61). New data, however, support a predictive role of the presence of antineuronal antibodies on the later development of neuropathy, suggesting that these antibodies may not be innocent bystanders but neurotoxins (212). There may be selected cases, particularly those with autonomic neuropathy, evidence of antineuronal autoimmunity, and CIDP, that may benefit from intravenous immunoglobulin or large dose steroids (59).

 

Summary of Treatment of Diabetic Peripheral Neuropathy

 

In summary, the risk factors for DPN are well recognized and to-date only small-scale intervention studies targeting these risk factors that have used appropriate DPN biomarkers have been conducted. Nevertheless, these have provided preliminary evidence for the efficacy of multifactorial risk factor management in preventing the development and progression of DPN. Hence, early identifications of subjects with insipient/sub-clinical neuropathy using validated, yet novel non-invasive point of care devices will allow larger studies to determine if targeted intensified cardiometabolic risk factor control can prevent clinical DPN or halt disease progression. Unfortunately, despite several clinical trials, there has been relatively little progress in the development of disease modifying treatments despite some advances in the management of symptoms in painful DN, as described below.

 

PAINFUL DIABETIC PERIPHERAL NEUROPATHY

 

Pathogenesis

 

Peripheral neuropathic pain in diabetes is defined as “pain arising as a direct consequence of abnormalities in the peripheral somatosensory system” after exclusion of other causes (213). Nerve damage results in the release of inflammatory mediators which activate intracellular signal transduction pathways in the nociceptor terminal, prompting an increase in the production, transport, and membrane insertion of transducer channels and voltage-gated ion channels (214). Following nerve injury, different types of voltage-gated sodium and calcium channels are up-regulated at the site of the lesion and in the dorsal root ganglion membrane, promoting ectopic spontaneous activity along the primary afferent neuron and determining hyperexcitability associated with lowered activation threshold, hyper-reactivity to stimuli, and abnormal release of neurotransmitters such as substance P and glutamate (215, 216). As a consequence of this hyperactivity in primary afferent nociceptive neurons, important secondary changes may occur in the dorsal horn of the spinal cord and higher up in the central nervous system leading to neuron hyperexcitability. This phenomenon, called central sensitization, is a form of use-dependent synaptic plasticity, considered a major pathophysiological mechanism of neuropathic pain (217).

 

Diagnosis

 

Painful DPN is often underdiagnosed and under treated. Binns-Hall et al. trialed a ‘one-stop’ microvascular screening service, which tested a model for patients to receive combined eye, foot (DPN and painful-DPN), and renal screening (218). A new diagnosis of painful-DPN in this cohort was identified in 25% of participants using the validated screening tool for neuropathic pain, the Doleur Neuropathique en 4 Questions (DN4). Additionally, Daousi et al. found that in a community sample of 350 patients with diabetes 12.5% of patients with painful-DPN had not reported their symptoms to their treating physician (219). This study also found that 39.3% had never received treatment for their painful neuropathy. In the clinical environment, most cases of painful DPN can be diagnosed with a careful history to identify presence of typical painful neuropathic symptoms lasting > 3 months and clinical examination to demonstrate the clinical signs of DPN. In these circumstances and other causes are excluded (see above), there is no need for further investigations.

 

A number of self-administered questionnaires have been developed, validated, translated, and subjected to cross-cultural adaptation both to diagnose and distinguish neuropathic as opposed to non-neuropathic pain  (screening tools such as the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) Pain Scale (220), Douleur Neuropathique en 4 questions (DN4), Neuropathic Pain Questionnaire (NPS) (221), pain DETECT (89) and to assess pain quality and intensity such as the Short-Form McGill Pain Questionnaire (222), the Brief Pain Inventory (BPI) (223), and the Neuropathic Pain Symptom Inventory (NPSI) (224).

 

It is important to assess the intensity (severity) of neuropathic pain as it is helpful when assessing and monitoring response to therapy. The best approach is to use a simple 11-Point numerical rating scale (Likert scale) or a visual analogue scale. In clinical trials of neuropathic pain treatment a number of questionnaires are used to capture the complex, multidimensional impact of chronic pain. According to IMMPACT (Initiative on Methods, Measurement and Pain Assessment in Clinical Trials) the following assessments are performed to assess the efficacy and effectiveness of new treatments: 1. pain intensity measured on a 0 to 10 numerical rating scale (NRS); 2. physical functioning assessed by the Multidimensional Pain Inventory (MPI) and Brief Pain Inventory (BPI) Interferences scale; 3. emotional functioning, assessed by the Beck Depression Inventory (BPI) and Profile of Mood states; and 4. patient rating of overall improvement, assessed by the Patient Global Impression of Change (PGI-C) (225).

 

Quality of Life

 

Over time the persistence of extremely unpleasant painful symptoms can have a profound impact upon its sufferers’ lives. This often results in a poor quality of life (226), disruption of employment (227), and mood disturbance (13). This adds to the burden of suffering and increases the challenge of managing neuropathic effectively. This is further compounded when patients also suffer from other co-morbid conditions associated with diabetes. Painful-DPN is also an expensive condition, incurring high healthcare costs (228). Data from the US found that patients with DPN and painful-DPN have greater healthcare resource utilization and costs than those with diabetes alone (228). Patients with severe painful-DPN incurred five-fold higher annual direct medical costs (USD $30,755) than for patients with diabetes alone (USD $6632) (226).

 

Sensory Profiling  

 

For many years, sensory profiling has been the mainstay for identifying a homogenous subgroup of neuropathic pain patients in clinical pain research. The basis of this approach is that painful symptoms reflect specific pathophysiological mechanisms, which are present to varying degrees in individual patients (229,230). Detailed sensory profiling using quantitative sensory testing (QST) can be used to subgroup patients into more homogenous cohorts (pain phenotypes), which could then be targeted with treatments known to act specifically on pathophysiological pathways underlying the phenotypes (231) (Figure 13). QST refers to a battery of standardized, psychophysical tests (e.g., thermal testing, pin prick, pressure algometry, and von Frey filaments) used to assess central and peripheral nervous system sensory function (232). In DPN, QST has been used for several decades mainly for diagnosing and quantifying the extent of small and large nerve fiber impairment in individuals predominantly with painless DPN. In the context of pain somatosensory phenotyping, a standardized QST protocol was developed by the German Research Network on Neuropathic Pain (DFNS), which includes 12 sensory testing parameters (i.e., cold and warm detection thresholds, paradoxical heat sensations, thermal sensory limen procedure, cold and heat pain thresholds, mechanical detection threshold, mechanical pain threshold, mechanical pain sensitivity, dynamic mechanical allodynia, wind-up ratio, vibration detection threshold, and pressure pain threshold) (232). The positive and negative results of individual patients are obtained by comparison against a normative QST reference dataset, comprised of age- and sex-stratified healthy individuals.

Figure 13. Schematic representation of the generation of pain. (A) Normal: Central terminals of c-afferents project into the dorsal horn and make contact with secondary pain-signaling neurons. Mechanoreceptive Aβ afferents project without synaptic transmission into the dorsal columns (not shown) and also contact secondary afferent dorsal horn neurons. (B) C-fiber sensitization: Spontaneous activity in peripheral nociceptors (peripheral sensitization, black stars) induces changes in the central sensory processing, leading to spinal-cord hyperexcitability (central sensitization, gray star) that causes input from mechanoreceptive Aβ (light touch) and Aδ fibers (punctuate stimuli) to be perceived as pain (allodynia). (C) C-fiber loss: C-nociceptor degeneration and novel synaptic contacts of Aβ fibers with “free” central nociceptive neurons, causing dynamic mechanical allodynia. (D) Central disinhibition: Selective damage of cold-sensitive Aδ fibers that leads to central disinhibition, resulting in cold hyperalgesia. Sympat, sympathetic nerve

Two Distinct Pain Phenotypes – The Non-Irritable and Irritable Nociceptor

 

Application of the QST technique has shown that there are two distinct subgroups of patients who have particular patterns of sensory symptoms and signs: (a) a predominant differentiation with loss of sensory function (non-irritable nociceptor phenotype), and (b) a relatively preserved small fiber function associated with thermal/mechanical hypersensitivity (irritable nociceptor phenotype) (231). Using the DFNS protocol, the PiNS reported that the non-irritable nociceptor was the predominant phenotype in painful DPN, whilst only a minority of patients had the irritable nociceptor phenotype (6.3%) (233). Nevertheless, a small but significant proportion of patients (15%) did demonstrate signs of sensory gain with dynamic mechanical allodynia, often in combination with hyposensitivity across a range of small and large nerve fiber sensory assessments. The presence of allodynia would suggest that aberrant central processing of sensory inputs has an important role in these patients. Recent studies have demonstrated proof-of-concept for using sensory profiling to improve clinical trial efficiency by demonstrating that some treatments are more effective in patients with the irritable versus the non-irritable nociceptor phenotype (230-234). However, most of these studies examined patients with peripheral neuropathy of diverse causes.

 

Phenotype-Driven Therapeutic Experience in Painful DPN

 

Examples of studies that focused on painful DPN include an open label retrospective study using the DFNS protocol, which evaluated key phenotypic differences in sensory profiling associated with response to intravenous lidocaine in patients with severe, intractable painful DPN (235). Patients with the irritable nociceptor phenotype were more likely to respond to intravenous lidocaine, which inactivates sodium channels, compared to the non-irritable nociceptor phenotype (235). In fact, dynamic mechanical allodynia and pain summation to repetitive pinprick stimuli were the only evoked ‘gain of function’ QST parameters that informed treatment response. The presence of these sensory gain parameters suggests aberrant central processing with hyperexcitable neurons driven by abnormal sodium channel regulation, generating ectopic impulses and amplifying afferent sensory inputs. In another painful DPN study by Campbell et al. of topical clonidine, sensory profiling was performed using the capsaicin challenge test (236). The post-hoc analysis demonstrated a significant reduction in pain in the patient subgroup with increased spontaneous pain following cutaneous capsaicin administration, indicating the presence of functioning and sensitized nociceptors. Bouhassira et al. published post-hoc analysis data of treatment response based on sensory profiling using the Neuropathic Pain Symptom Inventory (NPSI) questionnaire from the Combination vs Monotherapy of pregabalin and duloxetine in Diabetic Neuropathy (COMBO-DN) study (237). This study examined the effect of high-dose duloxetine, a serotonin noradrenaline reuptake inhibitor, or pregabalin, a calcium channel blocker, as monotherapy versus combined pregabalin and duloxetine for painful DPN. The investigators showed that adding pregabalin (300 mg) to duloxetine (60 mg) improved the dimensions of ‘pressing pain’ and ‘evoked pain’ more significantly. On the other hand, increasing duloxetine from 60 mg to 120 mg daily improved the dimension ‘paresthesia/dysesthesia’ to a greater extent.

 

SENSORY PHENOTYPING TO PREDICT THERAPEUTIC RESPONSE

 

In a randomized, double-blind, placebo-controlled, and phenotype-stratified study of patients with painful DPN Demant et al. reported that oxcarbazepine was more efficacious for relief of peripheral neuropathic pain in patients with the irritable vs the nonirritable nociceptor phenotype (234).  Based on this and other recent studies, current opinion with regard to neuropathic pain clinical trials recommends a detailed sensory profiling of participants at baseline; and even if there is no significant separation of a drug with placebo, a subgroup analysis can be performed to see if the drug was efficacious in a particular subgroup. If there is a clear signal that this was the case, a further, adequately powered, phenotype stratified trial would be designed.   

 

Sensory profiling can also identify subgroups with altered endogenous pain modulation to predict treatment outcomes of drugs and other interventions that affect a given mechanism. Figure 14 describes the different nerve fibers affected and possible targeted treatments.

 

In a study of pain modulation in DPN, individuals were assessed using QST for conditioned pain modulation (CPM), a psychophysical paradigm in which central pain inhibition is measured via the phenomenon of ‘pain inhibiting pain,’ via the simultaneous administration of a conditioning painful stimulus at a distant body site. The pain in participants with abnormal CPM was more receptive to duloxetine, which is believed to increase descending inhibitory pain pathway activation, than individuals with normal pain modulation, although there was no comparison to placebo in this open-label study (238).

Figure 14. Schematic representation of the generation of pain. (A) Normal: Central terminals of c-afferents project into the dorsal horn and make contact with secondary pain-signaling neurons. Mechanoreceptive Aβ afferents project without synaptic transmission into the dorsal columns (not shown) and also contact secondary afferent dorsal horn neurons. (B) C-fiber sensitization: Spontaneous activity in peripheral nociceptors (peripheral sensitization, black stars) induces changes in the central sensory processing, leading to spinal-cord hyperexcitability (central sensitization, gray star) that causes input from mechanoreceptive Aβ (light touch) and Aδ fibers (punctuate stimuli) to be perceived as pain (allodynia). (C) C-fiber loss: C-nociceptor degeneration and novel synaptic contacts of Aβ fibers with “free” central nociceptive neurons, causing dynamic mechanical allodynia. (D) Central disinhibition: Selective damage of cold-sensitive Aδ fibers that leads to central disinhibition, resulting in cold hyperalgesia. Sympat, sympathetic nerve

Taken together, these studies support the notion that mechanism-based approaches to pain management may be feasible in painful DPN. However, in an elegant mechanistic study, Haroutounian et al examined 14 patients with neuropathic pain of mixed etiology [unilateral foot pain from nerve injury (n=7) and distal polyneuropathy (n=7)] to determine the contribution of primary afferent input in maintaining peripheral neuropathic pain (239). Each patient underwent randomized ultrasound-guided peripheral nerve block with lidocaine versus intravenous lidocaine infusion. They found that peripheral afferent input was critical for maintaining neuropathic pain, but improvement in evoked hypersensitivity was not related to improvements in spontaneous pain intensity. This suggests that further studies are needed to rationalize sensory phenotyping in order to optimize clinical trial outcomes in painful DPN. Moreover, given the rarity of the irritable-nociceptor phenotype, as determined by QST, a single assessment modality may be unlikely to help stratify patients and combining with additional modalities may be necessary (e.g., brain imaging). 

 

Brain Imaging in Painful Diabetic Peripheral Neuropathy

 

Recent advances in neuroimaging provide us with unique insights into the human central nervous system in chronic pain conditions (240). We now have a better understanding how the brain modulates nociceptive inputs to generate the pain experience, and how this is disrupted in patients with painful DPN. However, to date, brain imaging serves mainly as a research tool, with minimal direct application in clinical trials for pain or clinical practice. While mechanistic approaches that require carefully evaluating specific responses to guide therapy have significant appeal (e.g., cold, heat, von Frey etc.), in practice, these are time consuming and may be difficult to implement in busy clinical practices. Furthermore, these are psychophysical measures which rely on patient responses and may be subjective and biased. Sensory profiling methods also do not capture the complex and multidimensional pain experience, which affects emotional and cognitive processing in addition to sensory processing. For example, chronic pain patients often undergo neuropsychological changes, which include changes in emotion and motivation or changes in cognition (241). Chronic pain may also arise after the onset of depression, even in patients without a prior history of pain or depression. Collectively, these clinical insights suggest a better strategy for assessing and treating painful DPN, given it is a chronic disease of dynamic process (e.g., evolution of co-morbid phenotypes such as anxiety or depression), which is not easily reversed in most patients. It is important to determine specific targets that are relevant to pain across individuals, because modulating activation in these targets may provide evidence that a compound engages a target or attenuates nociceptive processing.

 

Structural and functional cortical plasticity is a fundamental property of the human central nervous system, which can adjust to nerve injury. However, it can have maladaptive consequences, possibly resulting in chronic pain. Studies using structural magnetic resonance (MR) neuroimaging have demonstrated a clear reduction in both spinal cord cross-sectional area (139) and primary somatosensory cortex (S1) gray matter volume in patients with DPN (141). These findings are supported by studies in other pain conditions, which have also reported dynamic structural and functional plasticity with profound effects on the brain in patients with neuropathic pain. More recently, it has been demonstrated how brain structural and functional changes are related to painful DPN clinical phenotypes (146). Patients with the painful insensate phenotype have a more pronounced reduction in S1 cortical thickness and a remapping of S1 sensory processing compared to painful DPN subjects with relatively preserved sensation (146). Furthermore, the extent to which S1 cortical structure and function is altered is related to the severity of neuropathy and the magnitude of self-reported pain. These data suggest a dynamic plasticity of the brain in DPN driven by the neuropathic process and may ultimately determine an individual’s clinical pain phenotypes.

Over the last decade, resting-state functional MR imaging (RS-fMRI) – a quick, and simple non-invasive technique – has become an increasingly appealing way to examine spontaneous brain activity in individuals, without relying on external stimulation tasks. During a typical RS-fMRI examination, the hemodynamic response to spontaneous neuronal activity (bold oxygen level dependent, BOLD) signal is acquired whilst subjects are instructed to simply rest in the MR scanner (242). The data acquired is used in brain mapping to evaluate regional interactions or functional connectivity, which occur in a resting state. Most studies use a machine learning approach to identify patterns of functional connectivity, which differentiates patients from controls. RS-fMRI experiments in painful DPN have reported greater thalamic-insula functional connectivity and decreased thalamic-somatosensory cortical functional connectivity in patients with the irritable versus non-irritable nociceptor phenotype (235). There was a significant positive correlation between thalamic-insula functional connectivity with self-reported pain scores (235). Conversely, there was a more significant reduction in thalamic-somatosensory cortical functional connectivity in those with more severe neuropathy. This demonstrates how RS-fMRI measures of functional connectivity relates to both the somatic and non-somatic assessments of painful DPN. In one study, using a machine learning approach to integrate anatomical and functional connectivity data achieved an accuracy of 92% and sensitivity of 90%, indicating good overall performance (235). Multimodal MR imaging combining structural and RS-fMRI has also been used to predict treatment response in painful DPN. Responders to intravenous lidocaine treatment have significantly greater S1 cortical volume and greater functional connectivity between the insular cortex and corticolimbic system compared to non-responders (235). The insular cortex plays a pivotal role in processing the emotion and cognitive dimensions of the chronic pain experience. The corticolimbic circuits have also long been implicated in reward, decision making, and fear learning. Hence, these findings suggest that this network may have a role in determining treatment response in painful DPN.

 

Using advanced multimodal MR neuroimaging, a number of studies have demonstrated alterations in pain processing brain regions, which relate to clinical pain phenotype, treatment response, and behavioral/psychological factors impacted by pain. Taken together, these assessments could serve as a possible Central Pain Signature for painful DPN. The challenge now is to apply this potential pain biomarker at an individual level in order to demonstrate clinical utility. To this end, applying machine learning (243) to leverage brain imaging features from a quick 6-minute RS-fMRI scan to classify individual patients into different clinical pain phenotypes is appealing. Future studies should externally validate and optimize current models in larger patient cohorts to examine if/how such models can be used as biomarkers in clinical trials of pain therapeutics. Although many of the findings described are consistent with neuroimaging studies in other chronic pain conditions, it is difficult to assess convergence of findings across a number of relatively small cohort studies employing different analytical methods to derive complex models involving a large number of distributed brain regions (244). These are important limitations that are being addressed with 1) a number of large scale multi-center studies in progress or in preparation (MAPP consortium (245) and Placebo Imaging consortium (246), and 2) several consensus statements by key stakeholders, promoting standardized approaches and reporting and transparent/sharable models. 

 

General Principals of Managing Painful DPN

 

Managing painful symptoms in DPN may constitute a considerable treatment challenge. The efficacy of a single therapeutic agent is not the rule, and most patients require combination therapy to control the pain. The present ‘trial and error’ approach is to offer the available therapies in a stepwise fashion until an effective treatment is achieved (247,248). Effective pain treatment considers a favorable balance between pain relief and side effects without implying a maximum effect. The following general considerations in the pharmacotherapy of neuropathic pain require attention (249):

 

  • The appropriate and effective drug has to be tried and identified in each patient by carefully titrating the dose based on efficacy and side effects.
  • Lack of efficacy should be judged only after 2-4 weeks of treatment using an adequate dose.
  • As the evidence from clinical trials suggests a > 50% reduction in pain for any monotherapy, combination therapy is considered a ‘robust’ response. A reduction of pain of 30-49% may be considered a ‘clinically relevant’ response.
  • Potential drug interactions have to be considered given the frequent use of polypharmacy in patients with diabetes.

 

For many patients, optimal management of chronic pain may require a multidisciplinary team approach with appropriate behavioral therapy, as well as input from a broad range of healthcare professionals. Here we highlight the common agents used to manage painful DPN and key papers to demonstrate the evidence base. The most recent guidelines for pharmacotherapy for neuropathic pain in general and specifically in painful DPN can be found elsewhere (16,250,251,252,253,254,67, 255,256).

 

ANTIDEPRESSANTS 

 

Antidepressants are commonest agents used in the treatment of chronic neuropathic pain (217). The putative mechanisms of interrupting pain transmission by these agents include inhibition of norepinephrine and/or serotonin reuptake within the endogenous descending pain-inhibitory systems in the brain and spinal cord (257). Antagonism of N-Methyl-D-Aspartate receptors that mediate hyperalgesia and allodynia has also been proposed.

 

Tricyclic Antidepressants (TCAs)

 

Imipramine, amitriptyline, and clomipramine induce a balanced reuptake inhibition of both norepinephrine and serotonin, while desipramine is a relatively selective norepinephrine inhibitor. The most frequent adverse events of tricyclic antidepressants (TCAs) are anticholinergic symptoms including tiredness and dry mouth and may exacerbate cardiovascular and gastrointestinal autonomic neuropathy. The starting dose should be 25 mg (10 mg in frail patients) taken as a single night time dose one hour before sleep. The maximum dose is usually 150 mg per day and doses >100mg should be avoided in the elderly.

 

TCAs should be used with caution in patients with orthostatic hypotension and are contraindicated in patients with unstable angina, recent (<6 months) myocardial infarction, closed-angle glaucoma, heart failure, history of ventricular arrhythmias, significant conduction system disease, and long QT syndrome. Their use is limited by relatively high rates of adverse events and several contraindications.

 

Serotonin Noradrenaline Reuptake Inhibitors (SNRI)

 

The efficacy and safety of duloxetine has been evaluated in 7 RCTs establishing it as a mainstay treatment option in painful DPN. Several systematic reviews demonstrate a moderate strength of evidence for duloxetine reduces neuropathic pain to a clinically meaningful degree in patients with painful DPN (258,259,260). Patients with higher pain intensity tend to respond better than those with lower pain levels. The most frequent side effects of duloxetine (60/120 mg/day) include nausea (16.7/27.4%), somnolence (20.2/28.3%), dizziness (9.6/23%), constipation (4.9/10.6%), dry mouth (7.1/15%), and reduced appetite (2.6/12.4%). These adverse events are usually mild to moderate and transient. To minimize them the starting dose should be 30 mg/day for 4-5 days. In contrast to TCAs and some anticonvulsants, duloxetine does not cause weight gain, but a small increase in fasting blood glucose may occur (261).

 

Venlafaxine is another SNRI that has mixed action on catecholamine uptake. Compared to duloxetine, the strength of evidence for venlafaxine is lower and it could be considered an alternative if duloxetine is not tolerated. At lower doses, venlafaxine inhibits serotonin uptake and at higher doses it inhibits norepinephrine uptake (262). The extended release version of venlafaxine was found to be superior to placebo in painful DPN in non-depressed patients at doses of 150-225 mg daily, and when added to gabapentin there was improved pain, mood, and quality of life (263).  In a 6-week trial comprised of 244 patients the analgesic response rates were 56%, 39%, and 34% in patients given 150-225 mg venlafaxine, 75 mg venlafaxine, and placebo, respectively. Because patients with depression were excluded, the effect of venlafaxine (150-225 mg) was attributed to an analgesic, rather than antidepressant, effect. The most common adverse events were tiredness and nausea (264); additionally, clinically important electrocardiogram changes were found in seven patients in the treatment arm.

 

ANTI-EPILEPTIC DRUGS

 

Calcium Channel Modulators (a2-δ ligands)

 

Gabapentin is an anticonvulsant structurally related to g-aminobutyric acid (GABA), a neurotransmitter that plays a role in pain transmission and modulation. The exact mechanisms of action of this drug in neuropathic pain are not fully elucidated. Among others, they involve an interaction with the L-amino acid transporter system and high affinity binding to the a2-δ subunit of voltage-activated calcium channels. A Cochrane review reported 4 out of 10 patients with painful DPN achieved greater than 50% pain relief with gabapentin compared to placebo (2 out of 10). Pain was reduced by a third or more for 5 in 10 with gabapentin and 4 in 10 with placebo. Over half of those treated did not benefit from worthwhile pain relief but experienced adverse event (265).

 

In contrast to gabapentin, pregabalin is a more specific a2-δ ligand with a 6-fold higher binding affinity. It also has a more rapid onset with a dose-dependent linear pharmacokinetic profiled i.e., 600mg/day being more effective that 300mg/day (266). Hence, the administration (BD vs QDS) and dose titration of pregabalin in considerably easier compared to gabapentin. A recent Cochrane review reported moderate quality evidence for the efficacy of pregabalin in painful DPN compared to placebo (267). 3 or 4 in 10 people had pain reduced by half or more with pregabalin 300 mg or 600 mg daily, and 2 or 3 in 10 with placebo. Pain was reduced by a third or more for 5 or 6 in 10 people with pregabalin 300 mg or 600 mg daily, and 4 or 5 in 10 with placebo.

 

Common side-effects associated with the use of gabapentinoids include weight gain, edema, dizziness, and somnolence. They should be used with caution in patients with congestive cardiac failure (NYHA class III or IV) and renal impairment (dose reduction required). Pooled trial analysis of adverse events showed a higher risk of side-effects with increasing pregabalin dose but not older age (268). The misuse and abuse of gabapentinoids is a growing problem in the US and in Europe necessitating monitoring for signs of misuse/abuse and caution when used in at risk populations (269). Gabapentinoids may also increase the risk of respiratory depression, a serious concern for patients taking opioids or with underlying respiratory impairment (270,271,272).

 

TOPICAL CAPSAICIN

 

C-fibers utilize the neuropeptide substance P as their neurotransmitter, and depletion of axonal substance P (through the use of capsaicin) will often lead to amelioration of the pain. Prolonged application of capsaicin, a highly selective agonist of transient receptor potential vanilloid-1 (TRPV1), depletes stores of substance P, and possibly other neurotransmitters, from sensory nerve endings. This reduces or abolishes the transmission of painful stimuli from the peripheral nerve fibers to the higher centers (273). The 8% capsaicin patch (Qutenza) (274) is authorized for the treatment of peripheral neuropathic pain. In one RCT in painful DPN, a single application of 8% capsaicin patch applied for 30min provided modest pain relief for up to 3 months (275). Specialist trained staff are required for application which can be repeated every 2-3 months. A Cochrane review of low dose (0.025% and 0.075%) topical capsaicin cream was not able to provide any recommendations due to insufficient data (276).

 

LIDOCAINE 

 

Lidocaine has unique analgesic properties. Although the exact mechanism by which intravenous lidocaine provides systemic analgesia is unknown, it is thought to have both peripheral and central mechanisms of action (277,278,279). It exhibits state-dependent binding where sodium channels that are rapidly and repeatedly activated and inactivated are more readily blocked (280). This state-dependence is thought to be very important in limiting the hyperexcitability of cells exhibiting abnormal activity. Thus, it is likely to have greater efficacy in patients with neuropathic pain (281,282) and has been used to relieve chronic pain for over 50 years (283). A Cochrane review of 30 RCT found that intravenous lidocaine (284), which is more effective than its oral analogue (mexilitine, NNT10-38) and gastrointestinal intolerance most common side effect and major factor limiting its use) (284,285) and is more effective than placebo in decreasing neuropathic pain. It was found to be generally well tolerated with little or no side effects (286). Hence, intravenous lidocaine is a recognized treatment option for patients with severe painful DPN (287), and is included in clinical guidelines (288).

 

Although 5% lidocaine patch is being used in patients with postherpetic neuralgia (289), there is insufficient evidence to recommend its use in those with painful DPN.

 

OPIOIDS

 

Tramadol and NMDA Receptor Antagonists

 

The most examined compounds in painful DPN are tramadol, oxycodone, and tapentadol. Tramadol is a centrally acting weak opioid and SNRI for use in treating moderate to severe pain.  More severe pain requires administration of strong opioids such as oxycodone (µ-opioid agonist) or tapentadol (µ-opioid agonist and SNRI).  There is limited data available on the efficacy of these agents from relatively small-scale studies. Recent Cochrane reviews graded the available evidence as mostly of low or very low quality and likely to overestimate the efficacy of tramadol and oxycodone in the treatment of painful DPN (290,291). Side effects typical of opioids were common including somnolence, headache, and nausea. There is an increased risk of serotonergic syndrome if tramadol and tapentadol are prescribed with other agents with serotonin reuptake inhibitor properties and thus best avoided. Nevertheless, there is role for these agents as 2nd or 3rd line analgesics for painful DPN in carefully selected patients unresponsive to standard treatments. Non-pharmacological and non-opioid analgesic treatments should be optimized and established and/or not tolerated/contraindicated before opioid treatment is considered (292). Regular monitoring/evaluation of efficacy is recommended particularly if treatment is longer than 3 months. Opioids are associated with less pain relief during longer trials possibly due to opioid tolerance or opioid induced hyperalgesia. Moreover, adverse outcomes such as dependence, overdose, depression, and impaired functional status were more common in patients with neuropathic pain (painful DPN 68%) receiving long-term (>90 days) vs short term (<90 days) of treatment (293). Hence, referral to specialist or centers with experience in opioid use is recommended to avoid risks.

 

PSYCHOLOGICAL SUPPORT 

 

A psychological component to pain should not be underestimated. Hence, an explanation to the patient that even severe pain may remit, particularly in poorly controlled patients with acute painful neuropathy or in those painful symptoms precipitated by intensive insulin treatment. Thus, the empathetic approach addressing the concerns and anxieties of patients with neuropathic pain is essential for their successful management (294).

 

PHYSICAL MEASURES

 

The temperature of the painful neuropathic foot may be increased due to arterio-venous shunting. Cold water immersion may reduce shunt flow and relieve pain. Allodynia may be relieved by wearing silk pajamas or the use of a bed cradle. Patients who describe painful symptoms on walking as comparable to walking on pebbles may benefit from the use of comfortable footwear (255).

 

ACUPUNCTURE

 

A 10-week uncontrolled study with a follow-up period of 18-52 weeks in patients with diabetes showed significant pain relief after up to 6 courses of traditional Chinese acupuncture without any side effects (295). A single-blind placebo-controlled randomized trial of acupuncture in 45 subjects with painful DN recently reported an improvement in the outcome measures assessing pain in the acupuncture arm relative to sham treatment (296). However, Chen and colleagues warn that design flaws and lack of robust outcome measures of pain in acupuncture trials make meaningful conclusions difficult (297).  Larger controlled studies are needed to confirm these early findings.

 

ELECTRICAL STIMULATION

 

Transcutaneous electrical nerve stimulation (TENS) influences neuronal afferent transmission and conduction velocity, increases the nociceptive flexion reflex threshold, and changes the somatosensory evoked potentials. In a 4-week study of TENS applied to the lower limbs, each for 30 minutes daily, pain relief was noted in 83% of the patients compared to 38% of a sham-treated group. In patients who only marginally responded to amitriptyline, pain reduction was significantly greater following TENS given for 12 weeks as compared with sham treatment. Thus, TENS may be used as an adjunctive modality combined with pharmacotherapy to augment pain relief  (298).

 

Frequency-modulated electromagnetic nerve stimulation (FREMS) in 2 studies, including a recent double-blind randomized placebo controlled trial with 51 weeks of follow-up, proved to be a safe treatment for symptomatic diabetic neuropathy, with immediate but transient reduction in pain and no effect on nerve conduction velocities (299,300).  Six out of eight trials analyzed in a recent review evaluating the use of electrical stimulation in painful DN found significant pain relief in patients treated with electrical stimulation compared with placebo or sham treatment (301). 

 

Electrical spinal cord stimulation (SCS) was first reported in painful DPN in 1996 (302). With electrodes implanted between T9 and T11, 8 out of 10 patients reported greater than 50% pain relief. Most of these early devices utilized low-frequency stimulation (40-60Hz) with two RCTs demonstrating moderate utility (n=36 to 60) with 6-month to 24-month follow up (303,304,305) with responder attrition within 12 months (306). Modern iterations of SCS employ high-frequency stimulation (10kHz) provides pain relief without generating paresthesia (307,308,309,310). A recent RCT examine the use of 10kHz electrical SCS in patients with refractory painful DPN compared to conventional medical management in 216 randomized patients (311). 50% reduction in pain relief was observed in 5% in the control group compared to 79% in the electrical SCS group with 6 months follow up. The main limitation of this study was the lack of blinding and potential for placebo effects as an important confounding factor. Nevertheless, this is an interesting finding which should open a new area for further research. Overall complications of electrical SCS include wound infection and lead migration requiring reinsertion. Currently, therefore, this invasive treatment option should be reserved for patients who do not respond to analgesic combination pharmacotherapy.

 

SURGICAL DECOMPRESSION

 

Surgical decompression at the site of anatomic narrowing has been promoted as an alternative treatment for patients with symptomatic DPN. A systematic review of the literature revealed only Class IV studies concerning the utility of this therapeutic approach. Given the current evidence available, this treatment alternative should be considered unproven. Prospective randomized controlled trials with standard definitions and outcome measures are necessary to determine the value of this therapeutic intervention (312,313).

 

The odds ratios for efficacy of neuropathic pain medications are given in Figure 15. In addition, Table 5 shows the dosages of the different drugs and the commonly encountered side effects.

Figure 15. Efficacy analysis of drugs used for the treatment of PDN

Guidelines for Pharmacotherapy of Painful Neuropathy

 

Figure 16 is a pharmacotherapy algorithm that we propose for the management of painful neuropathy in diabetes. This presumes that the cause of the pain has been attributed to DPN and that all causes masquerading as DPN have been excluded. The identification of neuropathic pain as being focal or diffuse dictates the initial course of action. Focal neuropathic pain is best treated with splinting, steroid injections, and surgery to release entrapment. Diffuse neuropathies are treated with medical therapy and in a majority of cases, need combination therapy.  Essential to the DPN evaluation is the identification of the patient’s comorbidities, potential adverse events, and drug interactions. When single agents fail, combinations of drugs with different mechanisms of action should be considered. Comorbidities that accompany pain include depression, anxiety, and sleep disturbances, all of which must be addressed for successful management of pain. Treatment of peripheral neuropathic pain conditions can benefit from further understanding of the impact of pain response and QOL, including activities of daily living (ADLs) and sleep. Patients often benefit from participation in pain management groups and psychological intervention to develop/gain better coping strategies and deal with harmful/disruptive pain-related behaviors. There is currently minimal evidence for the use of combination treatment for painful DPN – hence, most guidelines recommend switching to an alternative agent. There are also few head-to-head comparator trials of commonly used agent evaluating efficacy and safety between drugs. We await the outcome of the much-anticipated OPTION-DM study – head-to-head multicenter, RCT will inform clinicians of the most cost effective monotherapy (amitriptyline, pregabalin and duloxetine) followed by combination therapy for painful DPN (314).

Figure 16. Algorithm for the Management of Symptomatic Diabetic Neuropathy. Non-pharmacological, topical or physical therapies can be useful at any time. SNRIs, serotonin and norepinephrine reuptake inhibitors; TCA, tricyclic antidepressants.

AUTONOMIC NEUROPATHY

 

Introduction

 

The autonomic nervous system (ANS) supplies all organs in the body and consists of an afferent and an efferent system, with long efferents in the vagus (cholinergic) and short postganglionic unmyelinated fibers in the sympathetic system (adrenergic). A third component is the neuropeptidergic system with its neurotransmitters substance P (SP), vasoactive intestinal polypeptide (VIP), and calcitonin gene related peptide (CGRP) amongst others. Diabetic autonomic neuropathy (DAN) is a serious and common complication of diabetes but remains among the least recognized and understood. Diabetic autonomic neuropathy (DAN) can cause dysfunction of every part of the body, and has a significant negative impact on survival and quality of life (315). The organ systems that most often exhibit prominent clinical autonomic signs and symptoms in diabetes include the pupils, sweat glands, genitourinary system, gastrointestinal tract, adrenal medullary system, and the cardiovascular system (Table 6). Clinical symptoms generally do not appear until long after the onset of diabetes. However, subclinical autonomic dysfunction can occur within a year of diagnosis in type 2 diabetes patients and within two years in type 1 diabetes patients (316).

 

 

Table 6. Clinical Manifestations of Autonomic Neuropathy

Cardiovascular

Central:

Tachycardia/ Bradycardia

Systolic and diastolic dysfunction

Decreased exercise tolerance

Orthostasis,

Orthostatic tachycardia and bradycardia syndrome

Sleep apnea

Anxiety/ depression

Cardiac denervation syndrome

Paradoxic supine or nocturnal hypertension

Intraoperative and perioperative cardiovascular instability

Peripheral:

Decreased thermoregulation

Decreased sweating

Altered blood flow

Impaired vasomotion

Edema

Gastrointestinal

Esophageal dysmotility

Gastroparesis diabeticorum

Diarrhea

Constipation

Fecal incontinence

Genitourinary

Erectile dysfunction

Retrograde ejaculation

Neurogenic bladder and cystopathy

Female sexual dysfunction (e.g., loss of vaginal lubrication)

Sudomotor

Anhidrosis

Hyperhidrosis

Heat intolerance

Gustatory sweating

Dry skin

Metabolic

Hypoglycemia unawareness

Hypoglycemia unresponsiveness

Pupillary

Pupillomotor function impairment (e.g., decreased diameter of dark-adapted pupil)

Pseudo Argyll-Robertson pupil

 

 

Microvascular flow is under the control of the ANS and is regulated by both the central and peripheral components of the ANS. Defective blood flow in the small capillary circulation is found with decreased responsiveness to mental arithmetic, cold pressor, hand grip, and heating (317). The defect is associated with a reduction in the amplitude of vasomotion (318) and resembles premature aging (277). There are differences in the glabrous and hairy skin (319) and is correctable with antioxidants (320). The clinical counterpart is a dry cold skin, loss of sweating, and development of fissures and cracks that are portals of entry for organisms leading to infectious ulcers and gangrenes. Silent myocardial infarction, respiratory failure, amputations, and sudden death are hazards for diabetes patients with cardiac autonomic neuropathy (321). Therefore, it is vitally important to make this diagnosis early so that appropriate intervention can be instituted (322).

 

Disturbances in the autonomic nervous system may be functional, e.g., gastroparesis with hyperglycemia and ketoacidosis, or organic wherein nerve fibers are actually lost. This creates inordinate difficulties in diagnosing, treating, and prognosticating as well as establishing true prevalence rates. Tests of autonomic function generally stimulate entire reflex pathways. Furthermore, autonomic control for each organ system is usually divided between opposing sympathetic and parasympathetic innervations, so that heart rate acceleration, for example, may reflect either decreased parasympathetic or increased sympathetic nervous system stimulation. Since many conditions affect the autonomic nervous system and autonomic neuropathy (AN) is not unique to diabetes, the diagnosis of DAN rests with establishing the diagnosis and excluding other causes (Table 7 and 8). The best studied diagnostic methods, for which there are large databases and evidence to support their use in clinical practice, relate to the evaluation of cardiovascular reflexes (Figure 17). In addition, the evaluation of orthostasis is fairly straightforward and is readily done in clinical practice (Figure 18), as is the establishment of the cause of gastrointestinal symptoms (Figure 19) and erectile dysfunction. The combination of cardiovascular autonomic tests with sudomotor function tests may allow a more accurate diagnosis of diabetic autonomic neuropathy (323). Tables 9 and 10 below present the diagnostic tests that would be applicable to the diagnosis of cardiovascular autonomic neuropathy. These tests can be used as a surrogate for the diagnosis of AN of any system since it is generally rare to find involvement (although it does occur) of any other division of the ANS in the absence of cardiovascular autonomic dysfunction. For example, if one entertains the possibility that the patient has erectile dysfunction due to AN, then prior to embarking upon a sophisticated and expensive evaluation of erectile status, a measure of heart rate and its variability in response to deep breathing would - if normal - exclude the likelihood that the erectile dysfunction is a consequence of disease of the autonomic nervous system. The cause thereof would have to be sought elsewhere. Similarly, it is extremely unusual to find gastroparesis secondary to AN in a patient with normal cardiovascular autonomic reflexes.

 

Table 7. Differential Diagnosis of Diabetic Autonomic Neuropathy

Clinical Manifestations

Differential Diagnosis

Cardiovascular

Resting tachycardia, Exercise intolerance

Orthostatic tachycardia and bradycardia syndromes

Cardiac denervation, painless myocardial infarction

Orthostatic hypotension

Intraoperative and perioperative cardiovascular instability

Cardiovascular disorders

Idiopathic orthostatic hypotension, multiple system atrophy with Parkinsonism, orthostatic tachycardia, hyperadrenergic hypotension

Shy-Drager syndrome

Panhypopituitarism

Pheochromocytoma

Hypovolemia

Congestive heart disease

Carcinoid syndrome

Gastrointestinal

Esophageal dysfunction

Gastroparesis diabeticorum

Diarrhea

Constipation

Fecal incontinence

Gastrointestinal disorders

Obstruction

Bezoars

Secretory diarrhea (endocrine tumors)

Biliary disease

Psychogenic vomiting

Medications

Genitourinary

Erectile dysfunction

Retrograde ejaculation

Cystopathy

Neurogenic bladder

Genitourinary disorders

Genital and pelvic surgery

Atherosclerotic vascular disease

Medications

Alcohol abuse

Neurovascular

Heat intolerance

Gustatory sweating

Dry skin

Impaired skin blood flow

Other causes of neurovascular dysfunction

Chaga's disease

Amyloidosis

Arsenic

Metabolic

Hypoglycemia unawareness

Hypoglycemia unresponsiveness

Hypoglycemia associated autonomic failure

Metabolic disorders

Other cause of hypoglycemia, intensive glycemic control and drugs that mask hypoglycemia

Pupillary

Decreased diameter of dark- adapted pupil

Argyll-Robertson type pupil

Pupillary disorders

Syphilis

 

Table 8. Diagnosis and Management of Autonomic Nerve Dysfunction

Symptoms

Assessment Modalities

Management

Resting tachycardia, exercise intolerance, early fatigue and weakness with exercise

HRV, respiratory HRV, MUGA thallium scan, 123I MIBG scan

Graded supervised exercise, beta blockers, ACE-inhibitors

Postural hypotension, dizziness, lightheadedness, weakness, fatigue, syncope, tachycardia/bradycardia

HRV, blood pressure measurement lying and standing

Mechanical measures, clonidine, midodrine, octreotide, erythropoietin, pyridostigmine

Hyperhidrosis

Sympathetic/parasympathetic balance

Clonidine, amitryptylline, trihexyphenidyl, propantheline, or scopolamine ,botox, Glycopyrrolate

 

Table 9.  Diagnostic Tests of Cardiovascular Autonomic Neuropathy

TEST

METHOD/ PARAMETERS

Resting heart rate Beat-to-beat heart rate Variation*

>100 beats/min is abnormal. With the patient at rest and supine (no overnight coffee or hypoglycemic episodes), breathing 6 breaths/min, heart rate monitored by EKG or ANSCORE device, a difference in heart rate of >15 beats/min is normal and <10 beats/min is abnormal, R-R inspiration/R-R expiration >1.17. All indices of HRV are age-dependent**.

Heart rate response to Standing*

During continuous EKG monitoring, the R-R interval is measured at beats 15 and 30 after standing. Normally, a tachycardia is followed by reflex bradycardia. The 30:15 ratio is normally >1.03.

Heart rate response to Valsalva maneuver*

The subject forcibly exhales into the mouthpiece of a manometer to 40 mmHg for 15 s during EKG monitoring. Healthy subjects develop tachycardia and peripheral vasoconstriction during strain and an overshoot bradycardia and rise in blood pressure with release. The ratio of longest R-R shortest R-R should be >1.2.

Spectral analysis of heart rate variation, very low frequency power (VLFP 0.003-0.04) and high frequency power (HFP 0.15-0.40 Hz)

Series of sequential R-R intervals into its various frequent components. It defines two fixed spectral regions for the low-frequency and high-frequency measure.

Systolic blood pressure response to standing 

Systolic blood pressure is measured in the supine subject. The patient stands and the systolic blood pressure is measured after 2 min. Normal response is a fall of <10 mmHg, borderline is a fall of 10-29 mmHg, and abnormal is a fall of >30 mmHg with symptoms.

Diastolic blood pressure response to isometric exercise

The subject squeezes a handgrip dynamometer to establish a maximum. Grip is then squeezed at 30% maximum for 5 min. The normal response for diastolic blood pressure is a rise of >16 mmHg in the other arm.

EKG QT/QTc intervals Spectral analysis with respiratory frequency

The QTc (corrected QT interval on EKG) should be <440 ms. VLF peak (sympathetic dysfunction) LF peak (sympathetic dysfunction) HF peak (parasympathetic dysfunction) LH/HF ratio (sympathetic imbalance)

Neurovascular flow

Using noninvasive laser Doppler measures of peripheral sympathetic responses to nociception.

* These can now be performed quickly (<15 min) in the practitioners' office, with a central reference laboratory providing quality control and normative values. LF, VLF, HF =low, very low and high frequency peaks on spectral analysis. These are now readily available in most cardiologist's practice.** Lowest normal value of E/I ratio: Age 20-24:1.17, 25-29:1.15, 30-34:1.13, 35-30:1.12, 40-44:1.10, 45-49:1.08, 50-54:1.07, 55-59:1.06, 60-64:1.04, 65-69:1.03, 70-75:1.02 .

 

Table 10. Diagnostic Assessment of Cardiovascular Autonomic Function

Parasympathetic

Sympathetic

Resting heart rate

Beat to beat variation with deep breathing (E:I ratio)

30:15 heart rate ratio with standing

Valsalva ratio

Spectral analysis of heart rate variation , high frequency power (HFP 0.15-0.40 Hz)

Spectral Analysis of HRV respiratory frequency

Resting heart rate

Spectral analysis of heart rate variation, very low frequency power (VLFP 0.003-0.04)

Orthostasis BP

Hand grip BP

Cold pressor response

Sympathetic skin galvanic response (cholinergic)

Sudorimetry (cholinergic)

Cutaneous blood flow (peptidergic)

Figure 17. This is a sample power spectrum of the HRV signal from a subject breathing at an average rate of 7.5 breaths per minute (Fundamental Respiratory Frequency, FRF = 0.125 Hz). The method using HRV alone defines two fixed spectral regions for the low-frequency (LF) and high-frequency (HF) measure (dark gray and light gray, respectively). It is clear that the high-frequency (light gray) region includes very little area under the HRV spectral curve, suggesting very little parasympathetic activity. The great majority of the HRV spectral activity is under the low-frequency (dark gray) region suggesting primarily sympathetic activity. These representations are incorrect because the slow-breathing subject should have a large parasympathetic component reflective of the vagal activity. This parasympathetic component is represented correctly by the method using both HRV and respiratory activity which defines the red and blue regions of the spectrum in the graph. The blue region defined by the FRF represents purely parasympathetic activity whereas the remainder of the lower frequency regions (red region) represents purely sympathetic activity.

Figure 18. Evaluation of postural dizziness in patients with diabetes

Figure 19. Evaluation of a patient with suspected gastroparesis

The role of over-activation of the autonomic nervous system is illustrated in Figure 20 (324).

Figure 20. Role of over-activation of autonomic nervous system

There are few data on the longitudinal trends in small fiber dysfunction. Much remains to be learned of the natural history of diabetic autonomic neuropathy. Karamitsos et al (325) reported that the progression of diabetic autonomic neuropathy is significant during the 2 years subsequent to its discovery.

 

The mortality for diabetic autonomic neuropathy has been estimated to be 44% within 2.5 years of diagnosing symptomatic autonomic neuropathy (29).  In a meta-analysis, the Mantel-Haenszel estimates for the pooled prevalence rate risk for silent myocardial ischemia was 1.96, with 95% confidence interval of 1.53 to 2.51 (p<0.001; n = 1,468 total subjects). Thus, a consistent association between CAN and the presence of silent myocardial ischemia was shown (284) (Figure 21).

Figure 21. Relative risks and 95% CIs for studies of cardiovascular neuropathy (CAN) and mortality. Pooled relative risk for 10 studies with CAN define by two or more measures: 3.45 (95% CI 2.66–4.47). Pooled relative risk for 4 studies with CAN defined by a single measure: 1.20 (1.02–1.41). REF: Maser, R. E., Mitchell, B. D., Vinik, A. I., and Freeman, R. Diabetes Care. 2003;26(6):1895-1901.

Prevention and Reversibility of Autonomic Neuropathy

 

It has now become clear that strict glycemic control (37) and a stepwise progressive management of hyperglycemia, lipids, and blood pressure as well as the use of antioxidants (326) and ACE inhibitors (327) reduce the odds ratio for autonomic neuropathy to 0.32 (328). It has also been shown that early mortality is a function of loss of beat-to-beat variability with MI. This can be reduced by 33% with acute administration of insulin (329). Kendall et al (330) reported that successful pancreas transplantation improves epinephrine response and normalizes hypoglycemia symptom recognition in patients with long standing diabetes and established autonomic neuropathy. Burger et al (331) showed that a reversible metabolic component of CAN exists in patients with early CAN.

 

Management of Autonomic Neuropathy

 

POSTURAL HYPOTENSION

 

The syndrome of postural hypotension is posture-related dizziness and syncope. Patients who have Type 2 diabetes mellitus and orthostatic hypotension are hypovolemic and have sympathoadrenal insufficiency; both factors contribute to the pathogenesis of orthostatic hypotension (332). Postural hypotension in the patient with diabetic autonomic neuropathy can present a difficult management problem. Elevating the blood pressure in the standing position must be balanced against preventing hypertension in the supine position.

 

Supportive Garments: Whenever possible, attempts should be made to increase venous return from the periphery using total body stockings. But leg compression alone is less effective, presumably reflecting the large capacity of the abdomen relative to the legs (333). Patients should be instructed to put them on while lying down and to not remove them until returning to the supine position.

 

Drug Therapy: Some patients with postural hypotension may benefit from treatment with 9-flurohydrocortisone. Unfortunately, symptoms do not improve until edema occurs, and there is a significant risk of developing congestive heart failure and hypertension. If fluorohydrocortisone does not work satisfactorily, various adrenergic agonists and antagonists may be used (Table 11). Enhancement of ganglionic transmission via the use of pyridostigmine (inhibitor of acetylcholinesterase) improved symptoms and orthostatic hypotension with only modest effects in supine BP for patients with POTS. Similarly, the use of b-adrenergic blockers may benefit the tachycardia, and anticholinergics, the orthostatic bradycardia. Pyridostigmine has also been shown to improve HRV in healthy young adults.  If the adrenergic receptor status is known, then therapy can be guided to the appropriate agent.  Metoclopramide may be helpful in patients with dopamine excess or increased sensitivity to dopaminergic stimulation. Patients with α2-adrenergic receptor excess may respond to the α2-antagonist yohimbine. Those few patients in whom ß-receptors are increased may be helped with propranolol. α2-adrenergic receptor deficiency can be treated with the α2-agonist clonidine, which in this setting may paradoxically increase blood pressure. One should start with small doses and gradually increase the dose. If the preceding measures fail, midodrine, an α1-adrenergic agonist, or dihydroergotamine in combination with caffeine may help. A particularly refractory form of postural hypotension occurs in some patients post-prandially and may respond to therapy with octreotide given subcutaneously in the mornings.

 

 

Table 11. Pharmacologic Treatment of Autonomic Neuropathy

Clinical status

Drug

Dosage

Side effects

Orthostatic hypotension

 

9α flouro hydrocortisone, mineralocorticoid

0.5-2 mg/day

Congestive heart failure, hypertension

 

Clonidine, α2 adrenergic agonist

0,1-0,5 mg, at bedtime

Orthostatic Hypotension, sedation, dry mouth, constipation, dizziness, bradycardia.

 

Octreotide, somatostatin analogue

0.1-0.5 mg/kg/day

Injection site pain, diarrhea

Orthostatic tachycardia and bradycardia syndrome

 

Clonidine, α2 adrenergic agonist

0.1-0.5 mg, at bedtime

Orthostatic Hypotension, sedation, dry mouth, constipation, dizziness, bradycardia.

 

Octreotide, somatostatin analogue

0.1-0.5 μg/kg/day

Injection site pain, diarrhea

Gastroparesis diabeticorum

 

Domperidone, D2-receptor antagonist

10-20 mg, 30-60 min before meal and bedtime

Galactorrhea

 

Erythromycin, motilin receptor agonist

250 mg, 30 minutes before meals

Abdominal cramps, nausea, diarrhea, rash

 

Levosulphide, D2-receptor antagonist

25 mg, 3 times/day

Galactorrhea

Diabetic diarrhea

 

Metronidazole, broad spectrum antibiotics

250 mg, 3 times/day, minimum 3 weeks

Anorexia, rash, GI upset, urine discoloration, dizziness, disulfiram like reaction.

 

Clonidine, α2 adrenergic agonist

0.1 mg, 2-3 times/day

Orthostatic Hypotension, sedation, dry mouth, constipation, dizziness, bradycardia.

 

Cholestyramine, bile acid sequestrant

4 g, 1-6 times/day

Constipation

 

Loperamide, opiate-receptor agonist

2 mg, four times/day

Toxic megacolon

 

Octreotide, somatostatin analogue

50 μg, 3 times/day

Aggravate nutrient malabsorption (at higher doses)

Cystopathy

 

Bethanechol, acetylcholine receptor agonist

10 mg, 4 times/day

Blurred vision, abdominal cramps, diarrhea, salivation, and hypotension.

 

Doxazosin, α1 adrenergic antagonist

1-2 mg, 2-3 times/day

Hypotension, headache, palpitation

Exercise Intolerance

 

Graded supervised exercise

20 minutes, 3 times/week

Foot injury, angina.

Hyperhidrosis

 

Clonidine, α2 adrenergic agonist

0.1-0.5 mg, at bedtime and divided doses above 0.2 mg

Orthostatic Hypotension, sedation, dry mouth, constipation, dizziness, bradycardia.

 

Amitryptiline, Norepinephrine & serotonin reuptake inhibitor

150 mg/ day

Tachycardia, palpitation

 

Propantheline, Anti-muscarinic.

15 mg/ day PO

Dry mouth, blurred vision

 

Trihexyphenidyl,

2-5 mg PO

Dry mouth, blurred vision, constipation, tachycardia, photosensitivity, arrhythmias.

 

Botox,

 

 

 

Scopolamine, anti-cholinergic

1.5 mg patch/ 3 days; 0.4 to 0.8mg PO

Dry mouth, blurred vision, constipation, drowsiness, and tachycardia.

 

Glycopyrrolate, anti-cholinergic

1-2 mg, 2-3 times daily.

Constipation, tachycardia, dry mouth.

Erectile dysfunction

 

 

 

 

Sildenafil (Viagra), GMP type-5 phosphodiesterase inhibitor

50 mg before sexual activity, only once per day

Hypotension and fatal cardiac event (with nitrate-containing drugs), headache, flushing, nasal congestion, dyspepsia, musculoskeletal pain, blurred vision

 

Tadalafil (Cialis), GMP type-5 phosphodiesterase inhibitor

10 mg PO before sexual activity only once per day.

Headache, flushing, dyspepsia, rhinitis, myalgia, back pain.

 

Verdenafil (Levitra), GMP type-5 phosphodiesterase inhibitor

10 mg PO, 60 minutes before sexual activity.

Hypotension, headache, dyspepsia, priapism.

 

 

SLEEP APNEA

 

During sleep, increased sympathetic drive is a result of repetitive episodes of hypoxia, hypercapnia, and obstructive apnea (OSA) acting through chemoreceptor reflexes. Increased sympathetic drive has been implicated in increased blood pressure variability with repetitive sympathetic activation and blood pressure surges impairing baroreflex and cardiovascular reflex functions (284). A direct relationship between the severity of OSA and the increase in blood pressure has been noted. Furthermore, the use of continuous positive airway pressure (CPAP) for the treatment of OSA has been shown to lower blood pressure and improve cardiovascular autonomic nerve fiber function for individuals with OSA. Withdrawal of CPAP for even a short period (i.e., 1 week) has been shown to result in a marked increase in sympathetic activity (284).

 

GASTROPATHY

 

Gastrointestinal motor disorders are frequent and widespread in patients with type 2 diabetes, regardless of symptoms (334) and there is a poor correlation between symptoms and objective evidence of a functional or organic defect. The first step in management of diabetic gastroparesis consists of multiple, small feedings; decreased fat intake as it tends to delay gastric emptying; maintenance of glycemic control (335,336); and a low-fiber diet to avoid bezoar formation. Metoclopramide may be used. Domperidone (337,338) has been shown to be effective in some patients, although probably no more so than metoclopramide. Erythromycin given as either a liquid or suppository also may be helpful. Erythromycin acts on the motilin receptor, "the sweeper of the gut," and shortens gastric emptying time (339). Several novel drugs, including the ghrelin (orexigenic hormone) and ghrelin receptor agonists, motilin agonist (mitemcinal), 5-HT4-receptor agonists and the muscarinic antagonist are being investigated for their prokinetic effects (340,341).  If medications fail and severe gastroparesis persists, jejunostomy placement into normally functioning bowel may be needed. Different treatment modalities for gastroparesis include dietary modifications, prokinetic and antiemetic medications, measures to control pain and address psychological issues, and endoscopic or surgical options in selected instances (342).

 

For additional information see the Endotext chapter entitled “Gastrointestinal Disorders in Diabetes”.

 

ENTEROPATHY     

 

Enteropathy involving the small bowel and colon can produce both chronic constipation and explosive diabetic diarrhea, making treatment of this complication difficult.

 

Antibiotics: Stasis of bowel contents with bacterial overgrowth may contribute to the diarrhea. Treatment with broad-spectrum antibiotics is the mainstay of therapy, including tetracycline or trimethoprim and sulfamethoxazole. Metronidazole appears to be the most effective and should be continued for at least 3 weeks.

 

Cholestyramine: Retention of bile may occur and can be highly irritating to the gut. Chelation of bile salts with cholestyramine 4g tid mixed with fluid may offer relief of symptoms.

 

Diphenoxylate plus atropine: Diphenoxylate plus atropine may help to control the diarrhea; however, toxic megacolon can occur, and extreme care should be used.

 

Diet: Patients with poor digestion may benefit from a gluten-free diet, while constipation may respond to a high-soluble-fiber diet supplemented with daily hydrophilic colloid. Beware of certain fibers in the neuropathic patient that can lead to bezoar formation because of bowel stasis in gastroparetic or constipated patients.

 

For additional information see the Endotext chapter entitled “Gastrointestinal Disorders in Diabetes”.

 

SEXUAL DYSFUNCTION

 

Erectile dysfunction (ED) occurs in 50-75% of men with diabetes, and it tends to occur at an earlier age than in the general population. The incidence of ED in men with diabetes aged 20-29 years is 9% and increases to 95% by age 70. It may be the presenting symptom of diabetes. More than 50% notice the onset of ED within 10 years of the diagnosis, but it may precede the other complications of diabetes. The etiology of ED in diabetes is multifactorial. Neuropathy, vascular disease, diabetes control, nutrition, endocrine disorders, psychogenic factors as well as drugs used in the treatment of diabetes and its complications play a role (343,344). The diagnosis of the cause of ED is made by a logical stepwise progression in all instances. An approach to therapy has been presented to which the reader is referred; Figure 22 below shows a flow chart modified from Vinik et. al., 1998 (302).

Figure 22. Evaluation of patients with diabetes with erectile dysfunction

A thorough work-up for impotence will include: medical and sexual history; physical and psychological evaluations; blood tests for diabetes and levels of testosterone, prolactin, and thyroid hormones; tests for nocturnal erections; tests to assess penile, pelvic, and spinal nerve function; and a test to assess penile blood supply and blood pressure. The flow chart provided is intended as a guide to assist in defining the problem. The healthcare provider should initiate questions that will help distinguish the various forms of organic erectile dysfunction from those that are psychogenic in origin. Physical examination must include an evaluation of the autonomic nervous system, vascular supply, and the hypothalamic-pituitary-gonadal axis.

 

Autonomic neuropathy causing ED is almost always accompanied by loss of ankle jerks and absence or reduction of vibration sense over the large toes. More direct evidence of impairment of penile autonomic function can be obtained by (1) demonstrating normal perianal sensation, (2) assessing the tone of the anal sphincter during a rectal exam, and (3) ascertaining the presence of an anal wink when the area of the skin adjacent to the anus is stroked or contraction of the anus when the glans penis is squeezed, i.e., the bulbo-cavernosus reflex. These measurements are easily and quickly done at the bedside and reflect the integrity of sacral parasympathetic divisions.

 

Vascular disease is usually manifested by buttock claudication but may be due to stenosis of the internal pudendal artery. A penile/brachial index of <0.7 indicates diminished blood supply. A venous leak manifests as unresponsiveness to vasodilators and needs to be evaluated by penile Doppler sonography.

 

In order to distinguish psychogenic from organic erectile dysfunction, nocturnal penile tumescence (NPT) measurement can be done. Normal NPT defines psychogenic ED, and a negative response to vasodilators implies vascular insufficiency. Application of NPT is not so simple. It is much like having a sphygmomanometer cuff inflate over the penis many times during the night while one is trying to have a normal night's sleep and the REM sleep associated with erections. The individual may have to take home the device and become familiar with it over several nights before one has a reliable estimate of the failure of NPT.

 

Treatment of Erectile Dysfunction

 

A number of treatment modalities are available and each treatment has positive and negative effects; therefore, patients must be made aware of both aspects before a therapeutic decision is made. Before considering any form of treatment, every effort should be made to have the patient withdraw from alcohol and eliminate smoking. If possible, drugs that are known to cause erectile dysfunction should be removed. Additionally, metabolic control should be optimized.

 

Relaxation of the corpus cavernous smooth muscle cells is caused by NO and cGMP, and the ability to have and maintain an erection depends on NO and cGMP. The peripherally acting oral phosphodiesterase type 5 (PDE5) inhibitors block the action of PDE5, and cGMP accumulates, enhancing blood flow to the corpora cavernosum with sexual stimulation. This class of agents consists of sildenafil, vardenafil, and tadalafil. They have been evaluated in patients with diabetes with similar levels of efficacy of about 70%. A 50 mg tablet of sildenafil taken orally is the usual starting dose, 60 minutes before sexual activity. Lower doses should be considered in patients with renal failure and hepatic dysfunction. The duration of the drug effect is 4 hours. Generally, patients with diabetes require the maximum dose of each agent, sildenafil 100 mg, tadalafil 20 mg, and vardenafil 20 mg. Before prescribing a PDE5 inhibitor, it is important to exclude ischemic heart disease. These are absolutely contraindicated in patients being treated with nitroglycerine or other nitrate-containing drugs. Severe hypotension and fatal cardiac events can occur (345). Side-effects include headache, flushing, dyspepsia, and muscle pain (346). Direct injection of prostacyclin into the corpus cavernosum will induce satisfactory erections in a significant number of men. Also, surgical implantation of a penile prosthesis may be appropriate. The less expensive type of prosthesis is a semirigid, permanently erect type that may be embarrassing and uncomfortable for some patients. The inflatable type is three times more expensive and subject to mechanical failure, but it avoids the embarrassment caused by other devices.

 

Female Sexual Dysfunction

 

Women with diabetes mellitus may experience decreased sexual desire and more pain on sexual intercourse, and they are at risk of decreased sexual arousal, with inadequate lubrication (347). Diagnosis of female sexual dysfunction using vaginal plethysmography to measure lubrication and vaginal flushing has not been well established.

 

For additional information on this topic see the Endotext chapter entitled “Sexual Dysfunction in Diabetes”.

 

CYSTOPATHY

 

In diabetic autonomic neuropathy, the motor function of the bladder is unimpaired, but afferent fiber damage results in diminished bladder sensation. The urinary bladder can be enlarged to more than three times its normal size. Patients are seen with bladders filled to their umbilicus, yet they feel no discomfort. Loss of bladder sensation occurs with diminished voiding frequency, and the patient is no longer able to void completely. Consequently, dribbling and overflow incontinence are common complaints. A post-void residual of greater than 150cc is diagnostic of cystopathy. Cystopathy may put the patients at risk for urinary infections.

 

Treatment of Cystopathy

 

Patients with cystopathy should be instructed to palpate their bladder and, if they are unable to initiate micturition when their bladders are full, use Crede's maneuver (massage or pressure on the lower portion of abdomen just above the pubic bone) to start the flow of urine. The principal aim of the treatment should be to improve bladder emptying and to reduce the risk of urinary tract infection. Parasympathomimetics such as bethanechol are sometimes helpful, although frequently they do not help to fully empty the bladder. Extended sphincter relaxation can be achieved with an alpha-1-blocker, such as doxazosin. Self-catheterization can be particularly useful in this setting, with the risk of infection generally being low.

 

SWEATING DYSFUNCTION

 

Hyperhidrosis of the upper body, often related to eating (gustatory sweating), and anhidrosis of the lower body, are a characteristic feature of autonomic neuropathy. Gustatory sweating accompanies the ingestion of certain foods, particularly spicy foods, and cheeses. There is a suggestion that application of glycopyrrolate (an antimuscarinic compound) might benefit diabetes patients with gustatory sweating (348). Low-dose oral glycopyrrolate in the range of 1 mg to 2 mg once daily can be tolerated without problematic adverse effects to alleviate the symptoms of diabetic gustatory sweating. Although more long-term data are needed, the use of glycopyrrolate for diabetic gustatory sweating may be a viable option (349). Symptomatic relief can be obtained by avoiding the specific inciting food. Loss of lower body sweating can cause dry, brittle skin that cracks easily, predisposing one to ulcer formation that can lead to loss of the limb. Special attention must be paid to foot care.

 

METABOLIC DYSFUNCTION

 

Hypoglycemia Unawareness

 

Blood glucose concentration is normally maintained during starvation or increased insulin action by an asymptomatic parasympathetic response with bradycardia and mild hypotension, followed by a sympathetic response with glucagon and epinephrine secretion for short-term glucose counter regulation, and growth hormone and cortisol secretion for long-term regulation. The release of catecholamine alerts the patient to take the required measures to prevent coma due to low blood glucose. The absence of warning signs of impending neuroglycopenia is known as "hypoglycemic unawareness". The failure of glucose counter regulation can be confirmed by the absence of glucagon and epinephrine responses to hypoglycemia induced by a standard, controlled dose of insulin (350).

 

In patients with type 1 diabetes mellitus, the glucagon response is impaired with diabetes duration of 1-5 years; after 14-31 years of diabetes, the glucagon response is almost undetectable. Absence of the glucagon response is not present in those with autonomic neuropathy. However, a syndrome of hypoglycemic autonomic failure occurs with intensification of diabetes control and repeated episodes of hypoglycemia. The exact mechanism is not understood, but it does represent a real barrier to physiologic glycemic control. In the absence of severe autonomic dysfunction, hypoglycemia unawareness is at least in part reversible.

 

Patients with hypoglycemia unawareness and unresponsiveness pose a significant management problem for the physician. Although autonomic neuropathy may improve with intensive therapy and normalization of blood glucose, there is a risk to the patient, who may become hypoglycemic without being aware of it and who cannot mount a counterregulatory response. It is our recommendation that if a pump is used, boluses of smaller than calculated amounts should be used and, if intensive conventional therapy is used, long-acting insulin with very small boluses should be given. In general, normal glucose and HbA1 levels should not be goals in these patients to avoid the possibility of hypoglycemia. The use of continuous glucose monitoring with hypoglycemic alarms can be very helpful in warning patients of hypoglycemia and in preventing severe hypoglycemic reactions.

 

Further complicating management of some patients with diabetes is the development of a functional autonomic insufficiency associated with intensive insulin treatment, which resembles autonomic neuropathy in all relevant aspects. In these instances, it is prudent to relax therapy, as for the patient with bona fide autonomic neuropathy. If hypoglycemia occurs in these patients at a certain glucose level, it will take a lower glucose level to trigger the same symptoms in the next 24-48 hours. Avoidance of hypoglycemia for a few days will result in recovery of the adrenergic response.

 

For additional information on this topic see the Endotext chapter entitled “Hypoglycemia During Therapy of Diabetes”.

 

DIABETIC NEUROPATHIES: PROSPECTS FOR THE FUTURE

 

Management of DN encompasses a wide variety of therapies. Treatment must be individualized in a manner that addresses the particular manifestation and underlying pathogenesis of each patient's unique clinical presentation, without subjecting the patient to untoward medication effects. An increased understanding of the pathogenesis of DN will lead to more effective approaches to diagnose and treat this condition.  Refinements and adoption of new approaches to measure quantitatively and diagnose DN early is crucial, so that appropriate therapies (risk factor modification or pathogenic) can be commenced before nerve damage is established. These tests must be validated and standardized to allow comparability between studies and a more meaningful interpretation of study results. Our ability to manage successfully the many different manifestations of DN depends ultimately on our success in uncovering the pathogenic processes underlying this disorder.

 

ACKNOWLEDGEMENTS

 

This chapter updates the original Endotext chapter on this topic written by Aaron Vinik, Carolina Casellini, and Marie-Laure Nevoret.

 

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The Effect of Inflammation and Infection on Lipids and Lipoproteins

ABSTRACT

 

Chronic inflammatory diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriasis and infections, such as periodontal disease and HIV, are associated with an increased risk of cardiovascular disease. Patients with these disorders also have an increase in coronary artery calcium measured by CT and carotid intima media thickness measured by ultrasound. Inflammation and infections induce a variety of alterations in lipid metabolism that may initially dampen inflammation or fight infection, but if chronic could contribute to the increased risk of atherosclerosis. The most common changes are decreases in serum HDL and increases in triglycerides. The increase in serum triglycerides is due to both an increase in hepatic VLDL production and secretion and a decrease in the clearance of triglyceride rich lipoproteins. The mechanisms by which inflammation and infection decrease HDL levels are uncertain. With inflammation there is also a consistent increase in lipoprotein (a) levels due to increased apolipoprotein (a) synthesis. LDL levels are frequently decreased but the prevalence of small dense LDL is increased due to exchange of triglycerides from triglyceride rich lipoproteins to LDL followed by triglyceride hydrolysis. In addition to affecting serum lipid levels, inflammation also adversely effects lipoprotein function. LDL is more easily oxidized as the ability of HDL to prevent the oxidation of LDL is diminished. Moreover, there are a number of steps in the reverse cholesterol transport pathway that are adversely affected during inflammation.  The greater the severity of the underlying inflammatory disease, the more consistently these abnormalities in lipids and lipoproteins are observed. Treatment of the underlying disease leading to a reduction in inflammation results in the return of the lipid profile towards normal. The changes in lipids and lipoproteins that occur during inflammation and infection are part of the innate immune response and therefore are likely to play an important role in protecting the host. The standard risk calculators for predicting cardiovascular disease (ACC/AHA, Framingham, SCORE, etc.) underestimate the risk in patients with inflammation. It has been recommended to increase the calculated risk by approximately 50% in patients with severe inflammatory disorders. The treatment of lipid disorders in patients with inflammatory disorders is similar to patients without inflammatory disorders. Of note statins, fibrates, and fish oil have anti-inflammatory properties and have been reported to have beneficial effects on some of these inflammatory disorders.

 

INTRODUCTION

 

A number of chronic inflammatory diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), ankylosing spondylitis, Sjögren's syndrome, polymyalgia rheumatica, inflammatory bowel disease, and psoriasis are associated with an increased risk of cardiovascular disease (1-9). For example, in a meta-analysis of twenty-four studies comprising 111,758 patients with 22,927 cardiovascular events it was observed that there was a 50% increased risk of CVD death in patients with RA (10). In some studies patients with RA have a similar risk for a cardiovascular event as patients with diabetes (11). Similarly, women with SLE in the 35- to 44-year age group were over 50 times more likely to have a myocardial infarction than were women of similar age in the Framingham Offspring Study (12). As a final example, a meta-analysis of 14 studies reported that in individuals with severe psoriasis the risk for cardiovascular mortality was 1.37, the risk for myocardial infarction was 3.04, and the risk for stroke was 1.59 times higher than the general population (13). It should be noted that the pathology in psoriasis is localized to the skin but nevertheless even this disorder, by inducing systemic inflammation, is associated with an increased risk of cardiovascular disease.

 

Further, supporting the link of RA, SLE, and psoriasis with atherosclerosis are studies showing that patients with these disorders have an increase in coronary artery calcium measured by CT and carotid intima media thickness measured by ultrasound (14-20). Finally, even children and adolescents with SLE have an increase in carotid intimal-medial thickness (21). Thus, it is clear that patients with a number of different chronic inflammatory diseases have an increased risk of atherosclerotic cardiovascular complications.

 

In addition, chronic infections are also associated with an increased risk of atherosclerosis (22-24). Since the development of effective anti-viral agents, it has been widely recognized that a major cause of morbidity and mortality in HIV infected patients is due to cardiovascular disease (25,26). Moreover, numerous studies have demonstrated an association of periodontal infections with an increased risk of atherosclerotic vascular disease (27). Additionally, carotid intima-media thickness is increased in patients with periodontal disease (28-31). The link between various chronic infections, such as HIV, dental infections, Helicobacter pylori, chronic bronchitis, and urinary tract infections with cardiovascular disease is presumably due to the chronic inflammation that accompanies these infections (32). For certain infections such as chlamydia pneumonia and cytomegalovirus it is possible that the association with cardiovascular disease is due to a direct role in the vessel wall.

 

To definitively link inflammation with cardiovascular disease studies determining the effect of anti-inflammatory drugs on cardiovascular events have been carried out. The Cantos study has provided data supporting a link between inflammation and cardiovascular disease (33). In this trial 10,061 patients with a previous myocardial infarction and a hsCRP level of 2 mg/L or more were randomized to canakinumab, a monoclonal antibody targeting interleukin-1β, or placebo. At 48 months canakinumab did not reduce lipid levels from baseline but did reduce hsCRP levels by approximately 30-40% indicating a decrease in inflammation. Most importantly, canakinumab administration led to a significantly lower rate of recurrent cardiovascular events than placebo. In addition, several randomized trials have demonstrated that colchicine reduces cardiovascular events in patients with chronic cardiovascular disease (34-36). These results support the hypothesis that inflammation increases the risk of cardiovascular events and that reducing inflammation will decrease events. In contrast to the positive trials described above, a trial using methotrexate to inhibit inflammation failed to reduce cardiovascular event (37). However, in this trial methotrexate did not reduce levels of interleukin-1β, interleukin-6, or C-reactive protein raising the possibility that methotrexate did not effectively inhibit inflammation and therefore did not reduce cardiovascular events. Clearly further studies determining the effect of drugs that reduce inflammation on cardiovascular events are required.

 

The mechanisms by which chronic inflammation and infection increase the risk of atherosclerotic cardiovascular disease are likely multifactorial. As will be discussed below inflammation and infection induce a variety of alterations in lipid and lipoprotein metabolism that could contribute to the increased risk of atherosclerosis.     

 

LIPID AND LIPOPROTEIN ABNORMALITIES IN PATIENTS WITH INFLAMMATORY DISORDERS AND INFECTIONS

 

Rheumatoid Arthritis

 

The most consistent abnormality in patients with RA is a decrease in HDL-C and apolipoprotein A-I levels (9,38-41). In particular, small HDL particles are decreased in patients with RA (42). Patients with more severe RA have the greatest reductions in HDL-C levels (38-41,43). There is an inverse correlation of CRP levels with HDL-C levels (i.e., higher CRP levels are associated with lower HDL-C levels). With regards to total cholesterol and LDL-C, there is more variability with many studies showing a decrease, other studies showing no change, and some studies showing an increase in patients with RA (38-41,43). The more severe the RA the greater the likelihood that the LDL-C levels will be decreased. Small dense LDL levels are increased in RA (44,45). Serum triglyceride levels tend to be increased in patients with RA (38-41,43,46). Levels of lipoprotein (a) are characteristically elevated in patients with RA and correlate with CRP levels (47-49).  

 

Systemic Lupus Erythematosus

 

The changes in serum lipids and lipoproteins seen in patients with SLE are very similar to those observed in patients with RA (50-52). Specifically, there is a decrease in HDL-C levels and an increase in serum triglyceride levels. LDL-C levels are variable and maybe increased, normal, or low but small dense LDL levels tend to be increased. Lipoprotein (a) levels are also increased (53). Similar to RA the more severe the disease state the greater the alterations in serum lipid levels.

 

Psoriasis

 

A large number of studies have compared serum lipid levels in controls and patients with psoriasis (54). However, many of these studies included only a small number of subjects and the results have therefore been extremely variable with some studies showing alterations in serum lipid levels in patients with psoriasis and other studies showing no changes. In general, there is a tendency for an increase in serum triglycerides and a decrease in HDL-C levels in patients with psoriasis (55-59). Additionally, a number of studies showed an increase in LDL-C and lipoprotein (a) levels in patients with psoriasis (55,56,58). Small dense LDL levels and oxidized Lp(a) are also increased in psoriasis (46) (60). This variability between studies is most likely due to differences in the severity of the psoriasis with more severe disease demonstrating more robust alterations in lipid levels. The prevalence of other abnormalities that affect lipid metabolism such as obesity and abnormalities in glucose metabolism could also account for the variability in results.

 

Other Inflammatory Disease

 

Decreased HDL-C levels have also been observed in patients with inflammatory bowel disease, Sjögren's syndrome, and ankylosing spondylitis (61-64). LDL-C and triglyceride levels varied but LDL-C levels tended to be decreased and triglyceride levels increased.

 

Periodontal Disease

 

Differences exist between studies but in general patients with periodontitis tend to have increased LDL-C and triglyceride levels and decreased HDL-C levels (65-69). Additionally, the prevalence of small dense LDL is increased in patients with periodontitis (68,70). The severity of the periodontitis correlated with the changes in the in the lipid profile with patients with increased periodontal disease having higher triglyceride levels, lower HDL-C levels, and smaller LDL particle size (71). Moreover, treatment of periodontitis improved the dyslipidemia, with the HDL-C levels increasing and the LDL-C levels decreasing (68,72,73).  

 

Acute Infections

 

Patients with a variety of different infections (gram positive bacterial, gram negative bacterial, viral, tuberculosis, parasitic) have similar alterations in plasma lipid levels. Specifically, total cholesterol, LDL-C, and HDL-C levels are decreased while plasma triglyceride levels are elevated or inappropriately normal for the poor nutritional status (32,74-81). As expected apolipoprotein A-I, A-II, and B levels are reduced (74,79,80). While LDL-C levels were decreased, the concentration of small dense LDL has been found to be increased during infections (82-84).That plasma cholesterol levels decrease during infection has been known for many years as it was described by Denis in 1919 in the Journal of Biological Chemistry (JBC 29: 93, 1919). The alterations in lipids correlate with the severity of the underlying infection i.e., the more severe the infection the more severe the alterations in lipid and lipoprotein levels (85,86). The decreases in plasma cholesterol levels can be quite profound and a case report described HDL-C levels < 10mg/dl and LDL-C levels < 3mg/dl in sepsis (87).

 

Of note studies have demonstrated that the degree of reduction in total cholesterol, HDL-C, and apolipoprotein A-I are predictive of mortality in patients with severe sepsis (81,88-92). Moreover, epidemiologic studies have suggested that low cholesterol, LDL-C, and HDL levels increase the chance of developing an infection (93-96). Additionally, a genetic approach, which reduces the risk of confounding variables, has suggested a causal relationship between low HDL-C levels and an increased risk of infections (97,98). During recovery from the infection plasma lipid and lipoprotein abnormalities return towards normal. The changes in lipid and lipoproteins that occur during infection can be experimentally reproduced in humans and animals by the administration of endotoxin and lipoteichoic acid (32,99).   

 

Summary  

 

Thus, in these different inflammatory disorders and infectious diseases, the alterations in plasma lipid and lipoprotein levels are very similar with decreases in plasma HDL being consistently observed. Also of note is the consistent increase in small dense LDL and Lp(a) level (the increase in Lp(a) occurs in inflammatory diseases but not infections) (32,100). There is also a tendency for plasma triglyceride levels to be elevated and LDL-C levels decreased. The greater the severity of the underlying disease the more consistently these abnormalities in lipids are observed. Additionally, treatment of the underlying disease leading to a reduction in inflammation results in a return of the lipid profile towards normal. This is best illustrated in periodontal disease where intensive dental hygiene can reverse the abnormalities in the lipid profile (72,73).

 

Table 1. Effect of Inflammation and Infection on Lipid and Lipoprotein Levels

Triglycerides- Tend to be increased

HDL-C- Decreased

LDL-C- Variable but with more severe inflammation or infection they are decreased

Small dense LDL- Increased

Lp(a)- Increased with inflammation; may decrease with certain infections

 

EFFECT OF ANTI-INFLAMMATORY DRUGS ON LIPID LEVELS

 

Treatments that reduce inflammation will return the lipid profile towards normal resulting in an increase in plasm HDL levels and a decrease in triglyceride levels. If LDL levels were reduced at baseline, treatment that reduces inflammation will also result in an increase in LDL levels (i.e., a return towards “normal” levels) (101-103). Many of the drugs used for the treatment of RA, SLE, and psoriasis decrease inflammation and have been shown to increase both HDL and LDL levels (9,101,102,104). The increase in HDL tends to be more robust. In a few instances, drugs used to treat inflammatory disorders have effects on lipid metabolism that are independent of the reduction in inflammation. For example, high dose glucocorticoid treatment results in an increase in serum triglyceride and LDL levels due to the increased production and secretion of VLDL by the liver (105-107) and hydroxychloroquine has been reported to lower total cholesterol, LDL, and triglycerides in patients with RA and SLE (108-110).

 

PATHOPHYSIOLOGY OF THE DYSLIPIDEMIA OF INFLAMMATION AND INFECTION

 

Inflammation and infections increase the production of a variety of cytokines, including TNF, IL-1, and IL-6, which have been shown to alter lipid metabolism (32). Many of the changes in plasma lipids and lipoproteins that are seen during chronic inflammation and infections are also observed following the acute administration of cytokines (32).

 

Increased Triglyceride Levels

 

Multiple cytokines increase serum triglyceride and VLDL levels (TNF, IL-1, IL-2, IL-6, etc.) (32). Following a single administration of a cytokine or LPS (a model of gram-negative infections), which stimulates cytokine production, an increase in serum triglyceride and VLDL levels can be seen within 2 hours and this effect is sustained for at least 24 hours. The increase in serum triglycerides is due to both an increase in hepatic VLDL production and secretion and a decrease in the clearance of triglyceride rich lipoproteins (figure 1) (32). The increase in VLDL production and secretion is a result of increased hepatic fatty acid synthesis, an increase in adipose tissue lipolysis with the increased transport of fatty acids to the liver, and a decrease in fatty acid oxidation in the liver. Together these changes provide an increased supply of fatty acids in the liver that stimulate an increase in hepatic triglyceride synthesis (32). The increased availability of triglycerides leads to the increased formation and secretion of VLDL. The decrease in the clearance of triglyceride rich lipoproteins is due to a decrease in lipoprotein lipase, the key enzyme that metabolizes triglycerides in the circulation (32). A variety of cytokines have been shown to decrease the synthesis of lipoprotein lipase in adipose and muscle tissue (32). Studies have also shown that inflammation also increases angiopoietin like protein 4, an inhibitor of lipoprotein lipase activity, which would further block the metabolism of triglyceride rich lipoproteins (111). In SLE, antibodies to lipoprotein lipase have been reported and are associated with increased triglyceride levels (112,113).

Figure 1. Pathogenesis of Hypertriglyceridemia

Production of Small Dense LDL

 

The elevation in triglyceride rich lipoproteins in turn has effects on other lipoproteins (32). Specifically, cholesterol ester transfer protein (CETP) mediates the exchange of triglycerides from triglyceride rich VLDL and chylomicrons to LDL. The increase in triglyceride rich lipoproteins per se leads to an increase in CETP mediated exchange, increasing the triglyceride content of LDL. The triglyceride on LDL is then hydrolyzed by hepatic lipase leading to the increased production of small dense LDL.

 

Decreased HDL Levels

 

In addition to a decrease in HDL, inflammation can also lead to structural changes in this lipoprotein (32). During inflammation HDL particles tend to be larger with a decrease in cholesterol ester and an increase in free cholesterol, triglycerides, and free fatty acids. Furthermore, there are marked changes in HDL associated proteins and the enzymes and transfer proteins involved in HDL metabolism and function (figure 2 and 3).

Figure 2. Changes in HDL Protein Composition During Inflammation

Figure 3. Changes in Enzymes and Transfer Proteins During Inflammation

The precise mechanism by which inflammation and infection decrease HDL levels is uncertain and is likely to involve multiple mechanisms (32). Decreases in apolipoprotein A-I synthesis in the liver occur during inflammation and would result in the decreased formation of HDL. However, in acute infection and inflammation HDL decreases faster than would be predicted from decreased synthesis of apolipoprotein A-I. Increased serum amyloid A (SAA) production by the liver and other tissues occurs during inflammation and infection and the SAA binds to HDL displacing apolipoprotein A-I, which can accelerate the clearance of HDL. However, the overexpression in SAA in the absence of the acute phase response does not result in a decrease in HDL levels (114). Inflammation results in a decrease in LCAT leading to decreased cholesterol ester formation, which would prevent the formation of normal HDL, leading to decreased cholesterol carried in HDL. Elevations in triglyceride rich lipoproteins that accompany inflammation and infection can lead to the enrichment of HDL with triglycerides that can accelerate the clearance of HDL. Finally, cytokine induced increases in enzymes such as secretory phospholipase A2 (sPLA2) and endothelial cell lipase, which metabolize key constituents of HDL, could alter the stability and metabolism of HDL. Given the complexity of HDL metabolism it is not surprising that multiple pathways could be affected by inflammation, which together may account for the decrease in HDL levels.

 

Increased Lipoprotein (a)

 

The mechanism accounting for the increase in lipoprotein (a) (Lp(a)) during inflammation is likely due to increased apolipoprotein (a) synthesis, as apolipoprotein (a) is a positive acute phase protein whose expression is up-regulated during inflammation (32,115). The apolipoprotein (a) gene contains several IL-6 responsive elements that enhance transcription (116). Tocilizumab an antibody against IL-6, that is used to treat RA, has been shown to decrease Lp(a) levels (117) .

 

FUNCTIONAL CHANGES IN LIPOPROTEINS THAT INCREASE THE RISK OF ATHEROSCLEROSIS

 

LDL

 

While the levels of LDL do not consistently increase and may even decrease with inflammation and infection, many studies have indicated that inflammation and infection are associated with small dense LDL (32). These small dense LDL particles are believed to be more pro-atherogenic for a number of reasons (118). Small dense LDL particles have a decreased affinity for the LDL receptor resulting in a prolonged period of time in the circulation. Additionally, they more easily enter the arterial wall and bind more avidly to intra-arterial proteoglycans, which traps them in the arterial wall. Finally, small dense LDL particles are more susceptible to oxidation, which could result in an enhanced uptake by macrophages (119).

 

Several markers of lipid peroxidation, including conjugated dienes, thiobarbituric acid-reactive substances, malondialdehyde, and lipid hydroperoxides are increased in serum and/or circulating LDL during inflammation and infection (32,71,120-123). Moreover, LDL isolated from LPS-treated animals is more susceptible to oxidation in vitro (32). Oxidized LDL is taken up very efficiently by macrophages and is thought to play a major role in foam cell formation in the arterial wall (124). Additionally, antibodies to oxidized LDL are present in patients with SLE and could facilitate the uptake of an antibody LDL complex via the Fc-receptor in macrophages (120). Finally, studies have shown that LDL isolated from patients with periodontal disease leads to enhanced uptake of cholesterol esters by macrophages (71)

 

HDL

 

In addition to a decrease in serum HDL, inflammation and infection affects the anti-atherogenic properties of HDL (32,125,126). Reverse cholesterol transport plays a key role in preventing cholesterol accumulation in macrophages thereby reducing atherosclerosis. Many steps in the reverse cholesterol transport pathway are adversely affected during inflammation and infection (figure 4 and 5)  (43,127). First, cytokines induced by inflammation and infection decrease the production of Apo A-I, the main protein constituent of HDL. Second, pro-inflammatory cytokines decrease the expression of ABCA1, ABCG1, SR-B1, and apolipoprotein E in macrophages, which will lead to a decrease in the efflux of phospholipids and cholesterol from the macrophage to HDL. Third, the structurally altered HDL formed during inflammation is a poor acceptor of cellular cholesterol and in fact may actually deliver cholesterol to the macrophage (43,61,127-134). HDL isolated from patients with RA, SLE, inflammatory bowel disease, psoriasis, ankylosing spondylitis, periodontal disease, and acute sepsis are poor facilitators of cholesterol efflux (61,128-133,135). Similarly, the experimental administration of endotoxin to humans also results in the formation of HDL that is a poor facilitator of the efflux of cholesterol from macrophages (136). Of note treatments that reduce inflammation in patients with RA, psoriasis, or periodontitis can restore towards normal the ability of HDL to remove cholesterol from cells (133,137-139). Fourth, pro-inflammatory cytokines decrease the production and activity of LCAT, which will limit the conversion of cholesterol to cholesteryl esters in HDL. This step is required for the formation of a normal spherical HDL particle and facilitates the ability of HDL to transport cholesterol. Fifth, pro-inflammatory cytokines decrease CETP levels, which will decrease the movement of cholesterol from HDL to Apo B containing lipoproteins, an important step in the delivery of cholesterol to the liver. Sixth, pro-inflammatory cytokines decrease the expression of SR-B1 in the liver. SR-B1 plays a key role in the uptake of cholesterol from HDL particles into hepatocytes. Finally, inflammation and infection decrease both the conversion of cholesterol to bile acids and the secretion of cholesterol into the bile, the two mechanisms by which cholesterol is disposed of by the liver.

Figure 4. Effect of Inflammation on Reverse Cholesterol Transport (from reference (127))

Figure 5. Effect of Inflammation on the Factors Involved in Reverse Cholesterol Transport (from reference (127))

Another important function of HDL is to prevent the oxidation of LDL. Oxidized LDL is more easily taken up by macrophages and is pro-atherogenic (124). Paraoxonase is an enzyme that is associated with HDL and plays a key role in preventing the oxidation of LDL. Inflammation and infection decrease the expression of paraoxonase 1 in the liver resulting in a decrease in circulating paraoxonase activity (32). Plasma paraoxonase levels are decreased in patients with RA, SLE, psoriasis, and infections (140-148) Studies have shown that HDL isolated from patients with RA and SLE have a diminished ability to protect LDL from oxidation and in fact may facilitate LDL oxidation (125). Moreover, in patients with RA, reducing inflammation and disease activity with methotrexate treatment restored HDL function towards normal (149). Additionally, treatment with atorvastatin 80mg improved the function of HDL in patients with RA (150). 

 

Thus, it should be recognized that in patients with inflammatory disorders and infections the absolute levels of lipids and lipoproteins may not be the only factor increasing the risk of atherosclerosis (32,54,121,125-127). Rather functional changes in LDL and HDL maybe pro-atherogenic and thereby contribute to the increased risk of atherosclerosis in inflammatory disorders and infections. Additionally, the increase in lipoprotein (a) may also play a role.

 

Table 2. Pro-Atherogenic Changes During Inflammation

Increased triglycerides

Decreased HDL

Increased small dense LDL

Increased Lp(a)

Oxidized LDL

Dysfunctional HDL

 

BENEFICIAL EFFECTS OF LIPIDS DURING INFECTIONS AND INFLAMMATION

 

The changes in lipids and lipoproteins that occur during inflammation and infection are part of the innate immune response and therefore are likely to play an important role in protecting from the detrimental effects of infection and inflammatory stimuli (32,151-153). Some of the potential beneficial effects are listed in Table 3. Thus, the changes in lipid and lipoprotein metabolism that occur during inflammation may initially be protective but if chronic can increase the risk of atherosclerosis.

 

Table 3. Beneficial Effects of Lipoproteins

Redistribution of nutrients to immune cells that are important in host defense

Lipoproteins bind endotoxin, lipoteichoic acid, viruses and other biological agents and prevent their toxic effects

Lipoproteins bind urate crystals

Lipoproteins bind and target parasites for destruction

Apolipoproteins neutralize viruses

Apolipoproteins lyse parasites

 

LIPID MANAGEMENT IN A PATIENT WITH AN INFLAMMATORY DISEASE

 

Deciding When to Treat

 

As noted earlier, patients with inflammatory disorders are at an increased risk for atherosclerosis and this is not totally accounted for by standard lipid profile measurements and other risk factors (1-3,9). Some authors have advocated considering inflammatory disorders as a cardiovascular risk equivalent similar to diabetes; risk calculators (ACC/AHA, Framingham,  and SCORE) commonly used for deciding on lipid lowering therapy do not take into account this increased risk in patients with inflammatory disorders (3,154,155). It should be noted that the QRISK calculator (http://qrisk.org/) does factor in the presence of RA when calculating risk (156). Not surprisingly, the standard risk calculators for predicting cardiovascular disease (ACC/AHA and Framingham) underestimate the risk in this population (157-162). Even the Reynolds Risk Calculator (http://www.reynoldsriskscore.org/Default.aspx), which uses measurements of hsCRP levels, a marker of inflammation, underestimates the risk of cardiovascular events in patients with inflammatory disorders (157-161). Thus, using these calculators will underestimate cardiovascular risk in patients with inflammatory disorders. However, in both the 2018 American College of Cardiology/American Heart Association and 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guideline recommendations, the presence of inflammatory disease is included as a risk factor, which can influence decisions on whether to initiate treatment (163,164).

 

A reasonable approach is to use the standard approach and calculators but increase the calculated risk by approximately 50% in patients with severe inflammatory disorders. For example, if a patient with severe RA has a 5% ten-year risk and 40% lifetime risk one might increase the ten-year risk to 7.5% and lifetime risk to 60%. This approach has been recommended by an expert committee who advocated introducing a 1.5 multiplication factor (i.e., 50% increase) in patients with RA (9). Alternatively, one could carry out imaging studies such as obtaining a coronary artery calcium score to better define risk. Whatever the approach taken, it is crucial to recognize that patients with inflammatory diseases have an increased risk of cardiovascular disease and therefore one needs to be more aggressive.

 

Guidelines from the American College of Cardiology (ACC)/American Heart Association (AHA) and European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) are briefly summarized in table 4, 5,and 6 (163,164) and are discussed in detail in the Endotext chapter “Guidelines for the Management of High Blood Cholesterol” (165).

 

Table 4. ACC/AHA Guidelines

In patients with clinical ASCVD initiate high intensity statin therapy or maximally tolerated statin therapy. High intensity statin therapy is atorvastatin 40-80mg per day or rosuvastatin 20-40mg per day.

In very high-risk ASCVD, use an LDL-C > 70 mg/dL (1.8 mmol/L) to consider addition of non-statins (ezetimibe or PCSK9 inhibitors). Very high-risk includes a history of multiple major ASCVD events or 1 major ASCVD event and multiple high-risk conditions.

In patients with LDL-C ≥190 mg/dL [≥4.9 mmol/L]) begin high-intensity statin therapy. If the LDL-C level remains ≥100 mg/dL (≥2.6 mmol/L), adding ezetimibe is reasonable.

In patients with diabetes aged 40-75 years with an LDL > 70mg/dL begin moderate intensity statin therapy. For patients > 50 year consider high intensity statin to achieve a 50% reduction in LDL-C.

In adults 40 to 75 years of age without diabetes mellitus and with LDL-C levels ≥70 mg/dL (≥1.8 mmol/L) start a moderate-intensity statin if the 10-year ASCVD risk is ≥7.5%. Moderate intensity therapy is atorvastatin 10-20mg, rosuvastatin 5-10mg, simvastatin 20-40mg, pravastatin 40mg.

 

Table 5. ESC/EAS Cardiovascular Risk Categories

Very High-Risk

ASCVD, either clinical or unequivocal on imaging

DM with target organ damage or at least three major risk factors or T1DM of long duration (>20 years)

Severe CKD (eGFR <30 mL/min/1.73 m2)

A calculated SCORE >10% for 10-year risk of fatal CVD.

FH with ASCVD or with another major risk factor

High Risk

Markedly elevated single risk factors, in particular total cholesterol >8 mmol/L (>310mg/dL), LDL-C >4.9 mmol/L (>190 mg/dL), or BP >180/110 mmHg.

Patients with FH without other major risk factors.

Patients with DM without target organ damage, a with DM duration >_10 years or another additional risk factor.

Moderate CKD (eGFR 30-59 mL/min/1.73 m2).

A calculated SCORE >5% and <10% for 10-year risk of fatal CVD.

Moderate Risk

Young patients (T1DM <35 years; T2DM <50 years) with DM duration <10 years, without other risk factors.

Calculated SCORE >1 % and <5% for 10-year risk of fatal CVD.

Low Risk

Calculated SCORE <1% for 10-year risk of fatal CVD

 

Table 6. ESC/EAS LDL Cholesterol Goals

Very High Risk

LDL-C reduction of >50% from baseline and an LDL-C goal of <1.4 mmol/L (<55 mg/dL) is recommended

High Risk

LDL-C reduction of >50% from baseline and an LDL-C goal of <1.8 mmol/L (<70 mg/dL) is recommended

Moderate Risk

LDL-C goal of <2.6 mmol/L (<100 mg/dL) should be considered

Low Risk

LDL-C goal <3.0 mmol/L (<116 mg/dL) may be considered.

 

Treatment Approach

 

As in all patients with lipid abnormalities the initial approach is lifestyle changes. Dietary recommendations are not unique in patients with inflammatory disorders. Exercise is recommended but depending upon the clinical situation the ability of patients with certain inflammatory disorders to participate in an exercise regimen may be limited. Exercise programs will need to be tailored for each patient’s capabilities. Treatment of the underlying disease to decrease inflammation is likely to be beneficial (9,166). Studies have shown that increased disease activity is associated with a greater risk of cardiovascular disease while lower disease activity is associated with a lower risk (9,167-173). Moreover, treatments that reduce disease activity can decrease cardiovascular risk (9,166).

 

Drug Therapy

 

This section on drug therapy will focus solely on the studies that are unique to patients with inflammatory diseases. Detailed information on the use of these drugs can be found in the Endotext chapters on cholesterol lowering drugs and triglyceride lowering drugs (174,175).

 

STATIN THERAPY

 

As expected, studies have demonstrated that statins lower LDL-C levels in patients with inflammatory disorders to a similar degree as patients without inflammatory disorders. For example, in a randomized trial in 116 patients with RA with a mean LDL-C level of 125mg/dl, the effect of atorvastatin 40mg was compared to placebo (176). Atorvastatin reduced LDL-C by 54mgdl vs. 3mg/dl in the placebo group (176). Similarly in the IDEAL trial there was a small subgroup of patients with RA (177). The IDEAL trial compared the ability of atorvastatin 80mg vs. simvastatin 20-40mg to reduce cardiovascular events. The lowering of LDL-C with either simvastatin or atorvastatin was similar in the patients with and without RA (177). Finally, a combined analysis of the IDEAL, Treat to New Target (TNT), and CARDS trials reported that the decrease in LDL-C levels with statin therapy was similar in patients with or without psoriasis (178). Studies have shown similar reductions in LDL-C levels with statin therapy in patients with SLE (179-181). The effects of statin treatment on other lipid parameters were also similar in patients with and without inflammatory diseases. Thus, as expected statins improve the lipid profile in patients with inflammatory disorders. In some studies, the incidence of statin associated side effects have been increased in the patients with inflammatory disorders. Specifically, in the IDEAL trial RA patients reported myalgia more frequently than patients without RA (10.4% and 7.7% in RA patients vs 1.1% and 2.2% in non-RA patients receiving simvastatin and atorvastatin respectively) (177). Note that this does not necessarily indicate that statins induce myalgias more frequently in patients with RA as there was not a placebo group in the IDEAL trial. Rather it is likely that patients with RA have an increased prevalence of myalgias.

 

A key question is whether statin therapy will reduce cardiovascular events in patients with inflammatory diseases. A number of studies have looked at surrogate markers for events such as changes in carotid intima-media thickness or changes in cardiac calcium scores in patients treated with statins. The results have varied with some studies showing benefits and other studies showing no effects. Rollefstad et al measured changes in carotid plaque size in 86 patients with inflammatory joint disease treated with rosuvastatin for 18 months (182). The LDL-C levels decreased from 155mg/dl to 66mg/dl and plaque height was significantly reduced (182). Similarly, Mok et al treated 72 patients with SLE with rosuvastatin 10mg or placebo for 12 months and reported that carotid intima-media thickness appeared to decrease (179). Moreover, Plazak et al treated 60 patients with SLE with atorvastatin 40mg or placebo for 1 year and measured changes in coronary calcium score (180). They observed an increase in coronary calcium in the placebo group while there was no change in the patients treated with statin therapy (180).  In contrast, Petri et al treated 200 patients with SLE with atorvastatin 40mg or placebo for 2 years and measured both carotid intima-media thickness and coronary calcium score (183). In this study no beneficial effects of statin therapy were observed (183). Similarly, Schanberg et al treated 221 children with SLE with atorvastatin 10-20mg or placebo for 36 months and did not observe a beneficial effect of statin treatment on carotid intima-media thickness (181). Additionally, Tam et al also failed to find a decrease in carotid intima-media thickness with rosuvastatin treatment in patients with RA (184). Thus, the effect of statin therapy in patients with inflammatory disorders on these surrogate markers of atherosclerosis is uncertain.

 

There are no large randomized controlled trials evaluating the impact of statin therapy on cardiovascular disease outcomes in patients with inflammatory disease. A subgroup analysis of a small number of patients with SLE in the ALERT study has been reported (185). The ALERT study was a randomized placebo-controlled trial examining the effect of fluvastatin 40-80mg on cardiovascular events after kidney transplantation. In this trial fluvastatin therapy reduced the risk of cardiovascular events by 74% in the patients with SLE (185). Additionally, a post hoc analysis of patients with inflammatory arthritis in the IDEAL and TNT trial has been reported (186). The IDEAL trial compared atorvastatin 80mg vs simvastatin 20-40mg and the TNT compared atorvastatin 80mg vs. atorvastatin 10mg. In these trials, statin therapy resulted in a decrease in lipid levels in the patients with inflammatory arthritis to a similar degree as patients without inflammatory arthritis (186). Moreover, there was an approximate 20% reduction in the risk of cardiovascular events in patients treated with atorvastatin 80mg compared to moderate dose statin therapy in patients with and without inflammatory arthritis (186). Similarly, a post hoc analysis of the IDEAL and TNT trials reported a similar reduction in cardiovascular events with high dose statin therapy compared to low dose statin therapy in patients with psoriasis (178). A trial that focused solely on patients with RA was initiated but stopped early due to a lower than expected event rate (187). In this trial 3,002 patients with RA were randomized to atorvastatin 40mg/day vs. placebo for a median of 2.51 years.  As expected, the reduction in LDL-C levels was significantly greater in the atorvastatin group compared to placebo (-30mg/dL, p<0.001). There was a 34% risk reduction for major cardiovascular events in the atorvastatin group compared to placebo that was not statistically significant due to the small number of events. Of note, the decrease in events was actually greater than expected based on the Cholesterol Treatment Trialists’ Collaboration meta-analysis of the effect of statins in other populations (42% decrease per 39mg/dL in this trial whereas in the large collaboration meta-analysis there was a 21% decrease per 39mg/dL). The number and type of adverse events were similar in the atorvastatin and placebo groups. Taken together these results strongly suggest that patients with inflammatory diseases will have a reduction in cardiovascular events with statin theapy.

 

It is well recognized that statins have anti-inflammatory properties and studies have consistently demonstrated a decrease in CRP levels in patients treated with statins (175). Two meta-analyses have explored the effect of statin therapy on disease activity in patients with RA. A meta-analysis by Ly et al included 15 studies with 992 patients and reported that statin therapy decreased erythrocyte sedimentation rate, CRP, tender joint count, swollen joint count, and morning stiffness (188). Similarly, a meta-analysis by Xing et al included 13 studies with 737 patients (189). They reported that statin therapy decreased erythrocyte sedimentation rate, CRP, tender joint count, and swollen joint count (189). Additionally, the disease activity score 28 (DAS28), which focuses on joint pathology, decreased significantly in the patients treated with statin therapy and the patients with the most active disease benefited the most (189,190).

 

In contrast to the beneficial effects seen in patients with RA, in randomized placebo controlled trials in patients with SLE studies by Plazak et al and Petri et al failed to show a decrease in disease activity with statin therapy (180,183). In psoriasis treatment with statins has produced mixed results with some studies showing a decrease in skin abnormalities and others showing no significant effect or even an increase in disease activity (191). A meta-analysis of 5 randomized trials with 223 patients found that statins may improve psoriasis, particularly in patients with severe disease (192). Finally, treatment with statins has been shown to improve periodontal disease and reduce inflammation (193-195). Thus, statins can decrease the clinical manifestations of RA, periodontitis, and perhaps psoriasis but has no effect on the clinical manifestations of SLE. These differences could be due to the relative severity of the inflammatory response and/or the specific pathways that induce inflammation in these different disorders.

 

The effect of statins on outcomes in patients with sepsis has been extensively studied. Numerous observational studies have shown that patients treated with statins have a marked reduction in morbidity and mortality (196,197). For example, in a meta-analysis by Wan et al of 27 observational studies with 337,648 patients, statins were associated with a relative mortality risk of 0.65 (CI 0.57-0.75) (197). However, in randomized placebo controlled clinical trials statin administration has not been shown to reduce mortality or improve outcomes (196-198). For example in a meta-analysis by Wan et al of 5 randomized controlled trials with 867 patients the relative risk was 0.98 (197). Similarly, a meta-analysis by Pertzov et al of fourteen randomized trials evaluating 2628 patients also did not observe any benefits of statin therapy in patients with sepsis (199). Additionally, a recent study examining the effect of rosuvastatin on sepsis associated acute respiratory distress also failed to demonstrate a benefit of statin therapy (200). Finally, meta-analyses of observational studies have found that statins in patients with COVID-19 infections are beneficial (201,202) but a randomized trial failed to demonstrate that statin treatment was beneficial (203). Thus, while observational data suggested that statins may be beneficial the more rigorous randomized placebo-controlled trials have not provided evidence of benefit. 

 

FIBRATE THERAPY

 

Fibrates, gemfibrozil and fenofibrate, are used to lower triglycerides and raise HDL-C levels. However, fibrates, by activating PPAR alpha, are well known to have anti-inflammatory effects. Several studies have shown that fibrate therapy improves the clinical manifestations in patients with RA. For example, Shirinsky et al treated 27 patients with RA with fenofibrate and reported a significant reduction in disease activity score (DAS28) (204). A recent review described 4 randomized trials and 2 observation trials of fibrates in patients with RA and in general these studies showed that fibrate therapy decreased disease activity in patients with RA (205). The authors are not aware of clinical trials of fibrate therapy in patients with sepsis, psoriasis, SLE, and periodontal disease. Thus, there is a suggestion that the anti-inflammatory properties of fibrates may beneficially impact disease activity, but clearly further studies are required.

 

BILE ACID SEQUESTRANT THERAPY

 

Bile acid binders are used to lower LDL-C levels. While there are no studies of the effect of bile acid binders in patients with either RA, SLE, or periodontal disease, there are two studies in patients with psoriasis. Both Roe and Skinner et al reported that the treatment of patients with psoriasis with bile acid binders improved the skin condition (206,207). The mechanism for this beneficial effect is unknown.

 

EZETIMIBE THERAPY

 

Ezetimibe is used to lower LDL-C levels. There is a single six-week trial in 20 patients with RA that demonstrated that ezetimibe treatment decreased total cholesterol, LDL-C, and CRP levels (208). Moreover, ezetimibe treatment reduced disease activity (208). The mechanism for this beneficial effect is unclear.

 

FISH OIL THERAPY

 

Fish oil (omega-3-fatty acids) is widely used to reduce serum triglyceride levels and is recognized to have anti-inflammatory properties. There are numerous studies examining the effect of fish oil therapy on inflammatory diseases. A meta-analysis of 17 randomized controlled trials by Goldberg and Katz of the effect of omega-3-fatty acids in patients with RA reported that treatment with omega-3-fatty acids reduced joint pain intensity, morning stiffness, number of painful and/or tender joints, and the use of non-steroidal anti-inflammatory medications (209). Similarly, a meta-analyses by Lee et al and Gioxari et al also demonstrated that fish oil had beneficial effects in patients with RA (210,211). In psoriasis, a recent review of 15 trials reported that overall, there was a moderate benefit of fish oil supplements with 12 trials showing clinical benefit and 3 trials showing no benefit (212). In contrast, Gamret et al evaluated fish oil treatment in patients with psoriasis in 20 studies (12 randomized controlled trials, 1 open-label nonrandomized controlled trial, and 7 uncontrolled studies) (213). They reported that most of the randomized controlled trials showed no significant improvement in psoriasis, whereas most of the uncontrolled studies showed benefit when fish oil was used daily. In a meta-analysis of eighteen randomized controlled trials involving 927 study participants reached the conclusion that fish oil as monotherapy for psoriasis had not affect but when combined with conventional treatments appeared to be beneficial (214). In SLE four randomized trials have demonstrated clinical benefit with fish oil therapy, while three trials failed to show disease improvement (215-221). Finally, there are data suggesting that treatment with fish oil reduces periodontal disease (222-224). A major limitation of the studies in patients with periodontal disease is that in these trials the experimental group treated with fish oil also was simultaneously treated with aspirin making it difficult to be sure that the beneficial effects were solely due to fish oil supplementation (222,223). A meta-analysis of 20 randomized trials involving 1514 patients with sepsis reported that parenteral or enteral omega-3 fatty acid supplementation was associated with a decrease in mortality and length of stay in the intensive care unit (225). Taken together these studies indicate that in addition to lowering serum triglyceride levels, fish oil therapy may have beneficial effects on the underlying inflammatory disorder in some instances.

 

NIACIN THERAPY

 

Niacin is used to lower LDL-C levels and triglycerides and raise HDL-C levels.  The authors are not aware of clinical trials of niacin in patients with RA, SLE, psoriasis, or periodontal disease.

 

PCSK9 INHIBITORS

 

PCSK9 inhibitors are used to lower LDL-C level. In addition, PCSK9 inhibitors also lower Lp(a) levels. The authors are not aware of clinical trials of PCSK9 inhibitors in patients with RA, SLE, psoriasis, or periodontal disease.

 

BEMPEDOIC ACID

 

Bempedoic acid is used to lower LDL-C levels. The authors are not aware of clinical trials of bempedoic acid in patients with inflammatory diseases or infections.

 

Treatment Strategy

 

The first priority in treating lipid disorders is to lower the LDL-C levels to goal, unless triglycerides are markedly elevated (> 500-1000mg/dl), which increases the risk of pancreatitis. LDL-C is the first priority because the database linking lowering LDL-C with reducing cardiovascular disease is extremely strong and we now have the ability to markedly decrease LDL-C levels in the vast majority of patients. Dietary therapy is the initial step but, in many patients, will not be sufficient to achieve the LDL-C goals. If patients are willing and able to make major changes in their diet it is possible to achieve remarkable reductions in LDL-C levels but this seldom occurs in clinical practice (for details see the Endotext chapter on the effect of lifestyle changes on lipids and lipoproteins) (226).

 

Statins are the first-choice drugs to lower LDL-C levels and many patients with inflammatory disorders will require statin therapy. Statins are available as generic drugs and are relatively inexpensive. The choice of statin will depend on the magnitude of LDL-C lowering required and whether other drugs that the patient is taking might alter statin metabolism thereby increasing the risk of statin toxicity. For example, cyclosporine affects the metabolism of many of the statins and in patients taking cyclosporine fluvastatin appears to be the safest statin (227).

 

If a patient is unable to tolerate statins or statins as monotherapy are not sufficient to lower LDL-C to goal the second-choice drug is either ezetimibe or a PCSK9 inhibitor. Ezetimibe is a generic drug and relatively inexpensive and can be added to any statin. PCSK9 inhibitors can also be added to any statin and are the drugs of choice if a large decrease in LDL-C is required to reach goal (PCSK9 inhibitors will lower LDL-C levels by 50-60% when added to a statin, whereas ezetimibe will only lower LDL-C by approximately 20%).  Bile acid sequestrants are an alternative particularly if a reduction in A1c level is also needed. Bempedoic acid also lowers LDL-C by approximately 20% and is another alternative. Ezetimibe, PCSK9 inhibitors, bempedoic acid, and bile acid sequestrants additively lower LDL-C levels when used in combination with a statin, because these drugs increase hepatic LDL receptor levels by different mechanisms, thereby resulting in a reduction in serum LDL-C levels. Niacin and the fibrates also lower LDL-C levels but are not usually employed to lower LDL-C levels

 

The second priority should be non-HDL-C (non-HDL-C = total cholesterol – HDL-C), which is particularly important in patients with elevated triglyceride levels (>150mg/dl). Non-HDL-C is a measure of all the pro-atherogenic apolipoprotein B containing particles. Numerous studies have shown that non-HDL-C is a strong risk factor for the development of cardiovascular disease. The non-HDL-C goals are 30mg/dl greater than the LDL-C goals. For example, if the LDL goal is <100mg/dl then the non-HDL-C goal would be <130mg/dl. Drugs that reduce either LDL-C or triglyceride levels will reduce non-HDL-C levels. If LDL-C is only slightly below goal increasing drug dose or adding drugs to further lower LDL-C is a reasonable approach. If the LDL-C is significantly below goal lowering TG levels is reasonable.

 

The third priority in treating lipid disorders is to decrease triglyceride levels. Initial therapy should focus on lifestyle changes including a decrease in simple sugars and ethanol intake and initiating and exercise program. Fibrates, niacin, statins, and omega-3-fatty acids all reduce serum triglyceride levels. Typically, one will target triglyceride levels when one is trying to lower non-HDL-C levels to goal. Patients with very high triglyceride levels (> 500-1000 mg/dl) are at risk of pancreatitis and therefore lifestyle and triglyceride lowering drug therapy should be initiated early. Note that there is limited evidence demonstrating that lowering triglyceride levels reduces cardiovascular events with fibrates, niacin, and most omega-3-fatty acid preparations. A study has shown that adding the omega-3-fatty acid icosapent ethyl (EPA) to statins in patients with elevated triglyceride levels reduces cardiovascular events (228). In addition, the potential beneficial effects of fish oil on disease activity in many patients with inflammatory diseases make the use of omega-3-fatty acids an attractive choice in patients with inflammatory diseases and elevated triglyceride levels/non-HDL-C levels.

 

The fourth priority in treating lipid disorders is to increase HDL-C levels. There is strong epidemiologic data linking low HDL-C levels with cardiovascular disease, but whether increasing HDL levels with drugs reduces cardiovascular disease is unknown and studies have not been encouraging (229). Life style changes are the initial step and include increased exercise, weight loss, and stopping cigarette smoking. The role of recommending ethanol, which increases HDL levels, is controversial but in patients who already drink moderately there is no reason to recommend that they stop. The most effective drug for increasing HDL levels is niacin, but studies have not demonstrated a reduction in cardiovascular events when niacin is added to statin therapy (230,231). Fibrates and statins also raise HDL-C levels but the increases are modest (usually less than 15%). Additionally, the ACCORD-LIPID trial failed to demonstrate that adding fenofibrate to statin therapy reduces cardiovascular disease (232). Unfortunately, given the currently available drugs, it is very difficult to significantly increase HDL-C levels and in many of our patients we are unable to achieve HDL-C levels in the recommended range. Furthermore, whether this will result in a reduction in cardiovascular events is unknown.

 

Note that there is very limited evidence that adding fibrates or niacin to lower triglyceride levels and/or increase HDL-C levels will reduce cardiovascular events. However, the studies of fibrates or niacin in combination with statins did not specifically target patients with high triglycerides, high non-HDL-C, and low HDL-C levels. The only drugs in combination with statin therapy that has been shown to further reduce cardiovascular events when added to statin therapy are ezetimibe, PCSK9 inhibitors, and icosapent ethyl (EPA), an omega-3-fatty acid (175).

 

In summary, modern therapy of patients with inflammatory diseases demands that we aggressively treat lipids to reduce the high risk of cardiovascular disease in this susceptible population. Furthermore, treatment with lipid lowering drugs in some instances may improve the underlying inflammatory disorder.

 

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Prediabetes

ABSTRACT

 

The global epidemic of type 2 diabetes remains one of the greatest health challenges of our time. The collective human and economic costs are staggering and rising. Widespread initiatives now exist to prevent diabetes wherever possible. These initiatives are singularly focused on preventing diabetes in the very highest risk group: people with prediabetes. Plasma glucose concentrations can exist over a continuum with normoglycemia on one side and diabetes mellitus on the other. Nevertheless, the concept of “prediabetes” – a state of neither normoglycemia or bonafide diabetes – has been in the clinical purview since the first formal diagnostic criteria of diabetes itself. Most can agree that prediabetes represents a high-risk state for diabetes (and for the sake of this review, high-risk for type 2 diabetes, specifically), but consensus is lacking for much else, including the diagnostic thresholds, if, when, or what to initiate as to pharmacotherapy for diabetes prevention, and whether prediabetes is actually just an earlier form of diabetes warranting similarly aggressive risk factor modification for diabetes-related complications. In this chapter, PREDIABETES, we will review the recommendations for screening, diagnosis, and intervention, largely according to the American Diabetes Association (ADA).  We will also look at the pathogenesis of this highly heterogeneous dysglycemic state as well as an increasing body of evidence that treatment of prediabetes back to normoglycemia should be the goal for people with prediabetes. Lastly, the scientific evidence reviewed will be distilled into an example of a conversation intended to engage patients in this process.

 

INTRODUCTION

 

In 1979-1980, the National Diabetes Data Group and World Health Organization introduced the first formal diagnostic criteria for diabetes (1,2). Cross sectional observations that the presence of both microvascular disease (MVD) (3-6)and cardiovascular disease (CVD) (7,8) were higher when fasting plasma glucose (FPG) was >140 mg/dl and/or 2-hour post-challenge glucose (2h-PG) was >200 mg/dl were confirmed in longitudinal population studies, providing rationale for these cut points (9-11). Nevertheless, clear evidence that lowering plasma glucose could prevent diabetic complications was not available until the 1993 publication of the Diabetes Complications and Control Trial (DCCT) (12). The DCCT noted an inflection point between A1c 6.5-7.0% (48-53 mmol/mol) and risk for retinopathy, as well as a 76% reduction in retinopathy, in participants with type 1 diabetes randomized to intensive treatment (12). Hence, the A1c goal of <6.5-7.0% soon became – and has remained – the major benchmark of care for people with diabetes (type 1 and 2) (13).  

 

Diagnostic criteria for diabetes have evolved over the years, lowering plasma glucose thresholds (14) and even advocating use of the A1c for diagnosis (15), while continuing to calibrate these thresholds against risk for retinopathy. Far less well known than the landmark publication of the DCCT is the re-analysis of the original data demonstrating a flaw in the models with no inflection point in A1c and risk for retinopathy noted (16). Instead, reduction in retinopathy was appreciated across the A1c range, including what is now considered the pre-diabetic A1c range. The first formal diagnostic criteria for “pre”-diabetes (i.e. impaired glucose tolerance) were introduced concurrently with those for diabetes itself (1). Diagnostic thresholds for prediabetes have been more moveable (14,15,17) and more controversial. Despite evidence demonstrating higher MVD and CVD in people with prediabetes compared to their normoglycemic peers (18-21), treatment of people with prediabetes is uncommon (22,23) as the notion of a “pre” disease presents a clinical and regulatory conundrum. 

 

SCREENING

 

Much ado has been made about the cost-effectiveness of screening for prediabetes.  Nevertheless, because roughly one-quarter of people with diabetes in the U.S. remain undiagnosed (24), numerous guidelines do advocate screening for dysglycemia (e.g. diabetes and prediabetes). According to the American Diabetes Association (ADA) together with the European Association for the Study of Diabetes (EASD), an informal assessment of risk factors or use of a risk assessment tool (e.g. www.diabetes.org/socrisktest) can guide who should undergo blood testing (25). Children >10 years old or who have gone through puberty (whichever occurs first) who are >85th% weight for height, with one or more risk factors (Table 1), should be screened. Non-pregnant adults >35 years without risk factors, or adults of any age who are overweight (BMI>25 kg/m2 or BMI >23 kg/m2, if Asian ethnicity) and have one or more risk factors (Table 1), should be screened. The screening test should be A1c, fasting glucose, or 2-hour glucose, and repeated at least at 3-year intervals for those whose screening reveals normoglycemia and once yearly in those diagnosed with prediabetes (26).

 

Table 1.  Risk Factors for Prediabetes and Diabetes

First-degree relative with type 2 diabetes

Non-Caucasian ethnicity

History of cardiovascular disease

Hypertension (blood pressure >140/90 or use of anti-hypertensive medication)

HDL cholesterol <35 mg/dl and/or triglyceride concentration >250 mg/dl

Women with polycystic ovary syndrome

Physical inactivity (<90 min/wk aerobic activity)

Presence of severe obesity, acanthosis nigricans and/or skin tags

 

DIAGNOSIS

 

According to the ADA and EASD, the diagnosis of prediabetes is made when the fasting plasma glucose (FPG) is 100-125 mg/dl (5.6-6.9 mmol/l; “impaired fasting glucose” (IFG)), plasma glucose concentration is 140-199 mg/dl (7.8-11.1 mmol/l; “impaired glucose tolerance” (IGT)) 2 hours after a 75 g oral glucose tolerance test (OGTT), and/or A1c 5.7-6.4% (26) (Table 2).  Unlike diagnostic criteria for diabetes that are based on their predictive value for retinopathy (14), diagnostic thresholds for prediabetes are based on the likelihood of developing overt diabetes (27-30).  However, discussion regarding the existing cut points is ongoing. Longitudinal data from a cohort of Israeli soldiers suggest that a fasting glucose above 87 mg/dl (4.8 mmol/l) is associated with an increased risk of future diabetes (31). Further, misclassification is common given the day-to-day variability in the fasting (15%) and 2-hour (46%) glucose concentrations (32). A1c can be confounded by a number of comorbid conditions like renal disease, anemia, and hemoglobinopathies (see www.ngsp.org/interf.asp)  and must be done using a method certified by the National Glycohemoglobin Standardization Program (NGSP).  Use of the 1-hour glucose value (i.e., >155 mg/dl post-OGTT), fructosamine, 5-androhydroglucitol among others have also been proposed, but none are standardized hence none currently recommended (33,34). Despite the fact that A1c-defined prediabetes appears to confer worse outcomes than prediabetes defined by fasting or 2-hour glucose criteria (35), the use of the A1c is not supported by the World Health Organization (WHO) for the diagnosis of prediabetes (36).

 

Table 2.  Current Diagnostic Criteria for Prediabetes (ADA & EASD)

Fasting plasma glucose 100-125 mg/dl

and/or

Glucose 140-199 mg/dl 2-hours post 75 g OGTT

and/or

A1c 5.7-6.4%

 

PREVALENCE

 

The changes in diagnostic criteria over the past years make it difficult to estimate exact trends in the global burden of prediabetes. However, by combining recent data from diverse sources, the prevalence of prediabetes can roughly be approximated. In 2021, the Centers for Disease Control (CDC) estimated that 96 million Americans – 38% of the adult population – had prediabetes demonstrating an increase in the percent of the population that has prediabetes that had previously been stable (24). Discordance in the diagnostic criteria for prediabetes, regional differences in surveillance and reporting for chronic diseases, and other cultural nuances pose challenges in estimating the global burden of prediabetes. To this point, the literature is currently devoid of any estimate of global prevalence of IFG, specifically. In 2017, the International Diabetes Federation (IDF) estimated the worldwide prevalence of IGT at 318 million - a number expected to increase to 482 million by 2040 (www.diabetesatlas.org) – with no further update in 2021. Data from the National Health and Nutrition Examination Survey (NHANES) would contend that the prevalence of IFG is twice that of IGT (37) (using ADA criteria), suggesting that the worldwide prevalence of prediabetes (IFG and/or IGT) may exceed 1 billion. Most alarming is that roughly one- third of people with IGT (and possibly IFG) are between 20 and 39 years old, thus are expected to spend many years at risk for or with diabetes (www.diabetesatlas.org).

 

RISK FOR DIABETES

 

Screening for and diagnosis of prediabetes is advocated as it represents a high-risk state for the development of overt type 2 diabetes. A recent meta-analysis showed that the yearly progression rate to diabetes in individuals with prediabetes is 3.5-7.0% (vs. 2%/year in their normoglycemic counterparts) (28), with highest rates in those with combined IFG and IGT and the lowest in those with IFG by ADA (vs. WHO) definition (38). Increasing A1c is also associated with increased risk of diabetes with yearly incidence rates approximating 5% for those with an A1c of 5.7-6.0% and up to 10% for those with an A1c of 6.1-6.4% (39).  Adding non-glycemic risk factors (Table 1) to the diagnosis of prediabetes markedly increases risk for diabetes, approaching 30% per year (40).  Decompensation from prediabetes to diabetes appears rapid in the later stages (41) and may warrant closer monitoring for people close to the thresholds for diabetes as well as earlier risk factor modification.

 

A recent study looked at the prevalence of prediabetes and risk of developing diabetes in 3412 individuals between 71 and 90 years of age (42). The prevalence of diabetes in this population was very high with 44% meeting the criteria based on A1C, 59% based on fasting glucose, 73% based on either A1c or fasting glucose, and 29% based on both A1c and fasting glucose. After a median 5-year follow-up only 9% of individuals with prediabetes based on A1c developed diabetes and only 8% of individuals with prediabetes based on fasting glucose developed diabetes. In individuals with prediabetes based on both A1c and fasting glucose levels 12% developed diabetes during the 5-year follow-up period. Many of the individuals with prediabetes regressed to normal glycemia. Thus, in the elderly the risk of progressing from prediabetes to diabetes appears to be lower than in middle aged individuals.  

 

SUBTYPES & PATHOGENESIS

 

Not long ago, the universal teaching was that post-prandial hyperglycemia always preceded fasting hyperglycemia in the evolution of diabetes (Figure 1).  The past decade has ushered in compelling evidence that this is not always the case. IFG can be isolated or precede IGT, IGT can be isolated or precede IFG, or they can be concurrent in the prediabetic state (27,29,43) (Figure 1).  This realization has sparked rigorous investigations into the pathogenesis of the subtypes - IFG, IGT and IFG/IGT - as discreet prediabetic states. Early studies used the homeostasis model assessment (HOMA) to delineate IFG from IGT, concluding that IFG was more insulin resistant than IGT (43).  Most noteworthy is the fact that this conclusion is inherently flawed since HOMA relies on FPG (i.e., HOMA-IR = FPG x FPI / 22.5) and IFG is defined by FPG.  Fortunately, more rigorous investigations have followed.

Figure 1. A) Former concept as to the pathophysiology of prediabetes and diabetes >10 years ago; B) Current knowledge as to the pathophysiology of prediabetes and diabetes <10 years

In some individuals, type 2 diabetes seems to develop as a consequence of inherent beta cell dysfunction (44). In others, development of insulin resistance precedes defects in the pancreatic beta cells (44,45). These findings underscore that prediabetes (like type 2 diabetes) is not a single disease entity, but rather multiple diseases with different pathologies (Table 3) and trajectories for disease development. This notion is supported by longitudinal data from the Whitehall II Study illustrating that the underlying disease mechanisms for individuals developing type 2 diabetes differ depending on whether diabetes is diagnosed by increased fasting or 2-hour plasma glucose levels (44). Further, this heterogeneity in the disease process is present decades before the clinical onset of diabetes.  Defects unique to IFG and IGT may be collective or unique when IFG and IGT exist in combination (46).

 

Table 3. Overview of the Distinguishing Features of IFG vs. IGT

 

IFG

IGT

 

 

 

Demographics

Men > women

Women > men

 

Younger

Older

 

 

 

Lipids

High plasma triglycerides

---

 

Low HDL cholesterol

---

 

 

 

Site of insulin resistance

Liver

Skeletal muscle

 

 

 

Type of beta cell defect

1st phase insulin secretion

2nd phase insulin secretion

 

 

 

 

Impaired Fasting Glucose (IFG)

 

THE ROLE OF THE LIVER

 

In healthy humans, circulating plasma glucose concentration is maintained in a narrow range by the liver’s ability to regulate its direction of glucose flux (47).  By virtue of hepatic insulin resistance (48), decreased hepatic glucose clearance (49), or lower glucose effectiveness (50), endogenous glucose production (EGP) becomes abnormal in the development of isolated IFG (48,51-54).  EGP, as measured by glucose rate of appearance (Ra), has been reported as 8-25% higher in people with IFG vs. normal glucose tolerant (NGT) controls in some studies (46,54), or “inappropriately” comparable to NGT (given the higher circulating glucose and insulin levels in IFG) in others (48,55). It is clear that the liver, rather than muscle, plays a distinctive role in the pathogenesis of IFG.

 

THE ROLE OF THE BETA CELL

 

Unique defects in beta cell function are seen in concert with the defects in the liver in people with isolated IFG. Collective data suggest that beta cell function may be intrinsically impaired, vs. acquired, in IFG. This notion is supported by epidemiologic studies showing diminished insulin response to glucose in normoglycemic individuals who later develop isolated IFG (56) and that this defect may be seen as long as 18 years before they are diagnosed with diabetes (44).  Furthermore, beta cell dysfunction has been demonstrated in individuals with isolated IFG and normal peripheral insulin sensitivity (48,51). 

 

The exact manner of beta cell dysfunction in IFG appears specific to 1st vs. 2nd phase insulin secretion (55,57).  It should be pointed out, however, that 1st phase insulin secretion is only appreciated in response to an intravenous glucose challenge bringing its physiologic relevance into question. Studies carefully examining insulin secretion in IFG (vs. NGT or IGT) have uniformly noted decrements in response to intravenous, but not oral, glucose challenges (46,48,51,54,55). Collectively, these data imply a dependence on the incretin hormones to maintain normal insulin secretion in IFG that may diverge from the role of the incretin hormones to facilitate insulin secretion in IGT.

 

OTHER DISTINGUISHING AND NON-DISTINGUISHING FEATURES OF IFG

 

Despite the implication of different roles for the incretin hormones in conferring IFG vs. IGT, existing data are conflicting (51,58). Likewise, plasma glucagon concentrations (51), adipose tissue mass and function (59) do not appear different, and other pathogenic features such as intramuscular lipids have not been compared between the subtypes of prediabetes. Of note, people with IFG tend to be male and younger – whereas those with IGT female and older - and have slight differences in their risk factors for CVD (43,60,61).

 

Impaired Glucose Tolerance (IGT)

 

THE ROLE OF SKELETAL MUSCLE

 

Despite reports of greater hepatic fat in people with IGT vs. IFG (62), skeletal muscle, rather than liver, has been implicated as the site of insulin resistance in isolated IGT. Glucose rate of disappearance (Rd; a measure of muscle insulin sensitivity) has been shown to be 42-48% lower in IGT vs. NGT (48,55) with only minimal impairments seen in IFG (54).  Because of the larger contribution of muscle (vs. liver) to whole-body insulin sensitivity, people with isolated IGT demonstrate on average 15-30% lower whole body insulin sensitivity compared to those with isolated IFG(51,52,57).

 

THE ROLE OF THE BETA CELL

 

In contrast to IFG, beta cell dysfunction appears to be acquired rather than intrinsic in IGT. For example, long-term population studies have not noted early defects in people destined to develop isolated IGT (56).  Nevertheless, beta cell dysfunction has been repeatedly observed in people with established IGT, particularly when significant whole body and skeletal muscle insulin resistance co-exists (51,56,63,64).  The exact manner of beta cell dysfunction in IGT appears specific to 2nd vs. 1st phase insulin secretion (55,57) and is observed whether or not the incretin-axis is invoked during the assessment. 

 

A1c-Defined Prediabetes

 

Recent trends in medical practice have seen the 2-hour OGTT fall from grace and be replaced by the A1c, even for the diagnosis and surveillance of prediabetes. Being that A1c is a composite of fasting and post-prandial glucose concentrations, it cannot delineate IFG from IGT nor any of the pathology unique to either. Alpha-hydroxybuytric acid, linoleoyl-glycerophosphocholine, and oleic acid have been shown predictive of 2-hour glucose values in three European cohort studies (65), hence may hold value if the pathophysiologic differences between IFG and IGT are to guide clinical decision-making in the future.  Currently, the strategies for diabetes prevention do not discriminate between the subtypes of prediabetes.

 

CLINICAL TRIALS AIMED AT PREVENTING OR DELAYING DIABETES

 

With the global surge in the prevalence of type 2 diabetes, focus on its prevention has intensified. Clinical trials for diabetes prevention around the globe have universally enrolled participants with untreated prediabetes (mostly IGT) due to their high risk for acquiring overt diabetes (28). Approaches for the prevention of diabetes have included intensive lifestyle modification (66-68) (Figure 2) or drug therapy using glucose-lowering medications (69-76)  (Figure 3) or anti-obesity medications (77-81) (Figure 4). Lifestyle interventions have utilized a low fat (<30% calories from fat; <10% from saturated fat) hypocaloric diet and moderate intensity exercise ~150 minutes per week for the purpose of 5-7% weight reduction. With the exception of the NAVIGATOR Trial (75), collective results demonstrate that diabetes incidence can be reduced by 20-89% over 2.4-6 years in a wide range of ethnic groups. 

Figure 2. Major trials using intensive lifestyle interventions for diabetes prevention

Figure 3. Major trials using glucose-lowering medications for diabetes prevention

Figure 4. Major trials using anti-obesity medications for diabetes prevention

Despite success amongst the various strategies employed, only intensive lifestyle modification has been universally advocated. The lifestyle curriculum designed for the U.S. Diabetes Prevention Program (DPP) serves as the foundation for the National DPP (NDPP) – the translational effort of bringing clinical trial results to the real world (www.cdc.gov/diabetes/prevention). A recent meta-analysis of 63 publications stemming from international real-world translations of clinical trial lifestyle curriculum demonstrated a 3% reduction in absolute risk and 29% reduction in relative risk for active participants, even when weight loss was modest (82). Likewise, the National Health Service Diabetes Prevention Programme (NHS DPP) began implementation across the United Kingdom in 2016 (83).  Evaluation of the program showed a consistent ~40% reduction in onset of diabetes over 13.4 months, including when the curriculum was delivered by lay volunteers (84). Initiation of metformin in people with pre-diabetes is recommended for those younger than 65 years old with a body mass index (BMI) >25 kg/m2 (85). To date, only ~0.7% of people with prediabetes in the U.S. are treated with metformin (23). It should be noted that no medication is approved by the U.S. Food and Drug Administration (FDA) for the treatment of prediabetes – not even metformin – as the FDA does not recognize prediabetes as a disease. In fact, the mere notion of a “pre” disease creates a clinical and regulatory conundrum. In 2008, the FDA issued guidance for industry developing drugs for the treatment or prevention of diabetes stating that it would consider approving pharmacotherapy for prediabetes if the drug could show “clinical benefit” (e.g. a delay or lessening in micro- or macrovascular complications) (https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071624.pdf).  Increasing evidence shows this may be possible.

 

COMPLICATIONS OF PREDIABETES

 

It is alluring to imagine an A1c threshold below which patients are fully protected from diabetic complications (86). This quest has proven less straightforward than is widely acknowledged.  People with prediabetes can suffer the same micro-, macrovascular, and non-vascular complications as people with diabetes, just at a lower incidence rate. Further, data exist and studies ongoing to show clear benefit from early intervention for people with prediabetes (www.clinicaltrials.gov/prediabetes).

 

Microvascular

 

Diabetes remains a leading cause of blindness, kidney failure, and amputations around the world. Benchmarks for diabetes care are explicitly based on the prevention of such microvascular complications (13). Nonetheless, complications of diabetes increase with increasing glycemia, even in the prediabetic glucose range. For example, nearly 10% of DPP participants had diabetic retinopathy, without diabetes, in a cross sectional analysis (19).  Moreover, data from NHANES suggests the steepest increase in risk for retinopathy occurs at an A1c of 5.5% (18), which would be considered normoglycemia by current ADA and WHO criteria. Polyneuropathy has also been reported as more prevalent in prediabetes, affecting 13% of people with IGT and 11.3% with IFG compared to 7.4% with NGT (21). Lastly, microalbuminuria doubles in prevalence with the onset of IFG or IGT, whereas its progression appears slower at the diagnostic threshold for overt diabetes (87). Recent trends reveal chronic kidney disease (defined as a glomerular filtration rate (GFR) < 60 ml/min/1.73 m2) is now as prevalent in people with prediabetes as diabetes itself (88). 

 

Perhaps more surprising than the incidence and prevalence of microvascular disease in people with prediabetes are data showing benefit from early interventions.  For example, the DPP Outcomes Study (DPPOS) demonstrated a 21% lower prevalence of the composite microvascular endpoint (retinopathy, nephropathy and/or neuropathy) in women who had been randomized to the intensive lifestyle intervention and followed 15 years post-randomization and a 28% lower prevalence across the treatment groups when diabetes was prevented (89).  In the roughly 600 participants with prediabetes that entered the Swedish Obesity Study (SOS), the composite microvascular endpoint was 82% lower in those who underwent bariatric surgery a median of 19 years after their procedure – an effect size that was much greater than for those who entered the study with either diabetes or normoglycemia (90).  Lastly, retinopathy was shown reduced by 40% in the 30-year follow-up of the Da Qing Study – a study that rendered a meager average of 1.8 kg weight loss during the intervention period (91).  Altogether, there is increasing evidence that people with prediabetes are at risk for classic complications of diabetes and these can be prevented with early intervention (Figure 5).

Figure 5. Trials demonstrating a reduction in microvascular disease in people with prediabetes

Macrovascular

 

In 2010, a meta-analysis by Ford et al. illustrated an approximate 20% increased risk of cardiovascular disease (CVD) in people with prediabetes, irrespective of type (IFG or IGT), criteria used to define it, or the development of diabetes (20). As a continuous variable, however, CVD risk appears more closely related to 2-hour than fasting glucose (92).  In 2018, serial cross sectional data from NHANES showed surprising similarity in the prevalence of myocardial infarction and stroke in people with prediabetes vs. diabetes (88) likely due to the dramatic fall in incident myocardial infarction and stroke in people with diabetes (93).  This finding implies that CVD may now be as common in people with prediabetes as with diabetes (recently reviewed by (94)). It should be recognized that whether the elevated glucose is causing the increased risk of CVD in individuals with prediabetes is uncertain as prediabetes is associated with other factors such as obesity, insulin resistance, dyslipidemia, hypertension, hypercoagulation, and inflammation that could be playing important roles in increasing the risk of CVD.

 

As with microvascular disease, data do exist that early intervention also prevents macrovascular disease in people with prediabetes (Figure 6).  The first study to contend that this may be the case came from a post-hoc analysis of STOP-NIDDM – a trial that used acarbose to prevent or delay diabetes in people with prediabetes.  This analysis showed a highly unexpected 49% lower probability of any CV event in the group randomized to acarbose (95).  Interestingly, the trial was repeated, powered with benefit as the a priori hypothesis and did not succeed at recapitulating the prior findings (73). Differences in medication dosage and ethnic admixture may or may not explain the discrepancy. Nevertheless, pioglitazone has been shown to reduce CV events over 4.8 years in insulin-resistant people 6 months post-stroke with an average A1c of 5.8% (96).  Likewise, the Da Qing Study revealed a 33% lower CV mortality and 26% lower all-cause mortality, whilst still preventing diabetes, 30 years into the post-randomization follow-up (91).  CV data from the DPPOS is expected shortly with great anticipation that prediabetes may finally be recognized as an earlier form of diabetes warranting intervention. While the effect of lowering glucose levels in individuals with prediabetes is uncertain given the high risk of CVD in this population aggressive treatment of dyslipidemia and hypertension is indicated given the large number of studies showing benefits.

Figure 6. Trials demonstrating a reduction in macrovascular disease in people with prediabetes

Not Necessarily Vascular

 

Although risk factor modification largely focuses on preventing the classic complications of diabetes, greater attention is being paid to a much larger scope of possible comorbidities.  A recent study elaborated on structural brain abnormalities in people with prediabetes that are linked to dementia, stroke, and depression and hypothesized that glucose-lowering may reverse the abnormalities (97).  Functionally, these brain changes lead to slower processing speeds and cognitive deficits (98).  Mild cognitive impairments are accelerated by the presence of prediabetes leading to frank dementia (99). Unequivocally, cognitive impairments and dementia dramatically reduce quality of life for both patients and their care-takers.  Fortunately, patient-reported outcomes are becoming increasing revered as a scientific endpoint and may provide additional rationale for treating prediabetes. The much-anticipated long term outcomes from the DPPOS (expected 2020-2025) also include examining treatment effect on cognition, aspects of aging, quality of life, health care utilization and cancer.

 

RESTORATION OF NORMOGLYCEMIA

 

In clinical trials to date, interventions were deemed successful if diabetes was prevented or delayed, yet many participants remained with prediabetes. Arguably, prevention of diabetes and its complications lies in the restoration of normoglycemia rather than in the maintenance of prediabetes.  This was confirmed by a post-hoc analysis from the Diabetes Prevention Program Outcomes Study (DPPOS) (100). This analysis demonstrated a 56% lower risk of diabetes 10 years from randomization among those who were able to achieve normoglycemia during DPP vs. those who remained with prediabetes. Additionally, restoration of normoglycemia reduced prevalence of microvascular disease (101) and CV risk factors despite less use of medication to lower lipids and blood pressure (102).  The concept that diabetes and CV risk can be significantly reduced over the long-term through the pursuit of normoglycemia represents a major shift in our current thinking and has quickly gained consensus as the goal for people with prediabetes (103,104). Clinical predictors (105) and calculators as to the likelihood of regression (106)can be used to select and activate patients. Importantly, restoration of normoglycemia – as opposed to “diabetes prevention” – is clinically actionable. 

 

Exactly how normoglycemia should be achieved is far less clear. Data from the DPP would contend that only lifestyle modification, not metformin, is useful in achieving normoglycemia in people with prediabetes (105) (Figure 7). Of note, lifestyle modification has been shown particularly effective in women (107) and the elderly (108). The thiazolidinediones (TZD’s) have also demonstrated their ability to restore normoglycemia in people with prediabetes (71,72,109) and may gain greater acceptance in this population now that their CV safety has been established.  An increasing number of trials are focused on the ability of medication or lifestyle to not only prevent or delay onset of diabetes, but restore normoglycemia (79,110,111).

 

TRANSLATING INFORMATION INTO CONVERSATION

 

As we follow the recommended steps for screening and diagnosis of prediabetes outlined above, the next step in beginning the conversation with a patient with prediabetes is educating them about what the diagnosis means.  An A1c of 5.7-6.0% carries up to a 25%/5-year risk, whereas an A1c 6.0-6.4% carries up to a 50%/5-year risk, and prediabetes period carries up to a 70% lifetime risk of diabetes.  Further, people with prediabetes can suffer complications of diabetes even if they never convert. Early intervention can prevent diabetes by more than 50% if normoglycemia can be attained – even if transiently. Intensive lifestyle modification and a number of glucose-lowering and anti-obesity medications have been shown as capable to achieve this.  Metformin is recommended for younger, overweight people with prediabetes even though it may not achieve normoglycemia as readily. Micro- and macrovascular risk factor modification is critical.  Plasma glucose concentrations should be followed and re-screening for diabetes done annually.

 

CONCLUSION

 

In the light of the global burden of prediabetes affecting close to one billion people, the high progression rates to type 2 diabetes, and the increased risk of both micro- and macrovascular complications and death (112), efforts focused on preventing progression to diabetes and its complications are crucial. Although both intensive lifestyle intervention and various medications have proven to be effective for prevention or delay of diabetes in people with prediabetes, their uptake has been slow. This is true even in light of emerging data showing the vast benefits of early interventions.  Our best bet to recognize prediabetes as a disease is probably by calling it what it is: early diabetes (94) and treat it as such, eradicating the term “prediabetes” for good.

 

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Platelets, Coagulation, and Antithrombotic Therapy in Diabetes

ABSTRACT

 

Diabetes mellitus is a strong, independent risk factor for the development of atherosclerotic cardiovascular disease (ASCVD) and therefore for atherothrombotic events. Compared to those without diabetes, individuals with diabetes are also at increased risk of cardioembolic stroke in the presence of atrial fibrillation (AF) and of venous thromboembolism. Activation of platelets and the coagulation cascade are the central mechanisms of thrombosis. A range of antiplatelet and anticoagulant drugs are now available. Antithrombotic therapy should be considered in all those with diabetes and established ASCVD or AF. Intensification of antithrombotic therapy is typically indicated during the acute phase of an atherothrombotic event or in those with chronic coronary syndromes who are at high ischemic risk, provided this outweighs bleeding risk. Clinical decisions regarding antithrombotic therapy should be made by assessing an individual’s ischemic and bleeding risks, in consultation with the recipient and reviewed upon any change in circumstances.

 

LIST OF ABBREVIATIONS

 

5HT

5-hydroxytryptamine

ACS

acute coronary syndrome

ADP

adenosine diphosphate

AF

atrial fibrillation

ALI

acute limb ischemia

APT

antiplatelet therapy

ASCVD

atherosclerotic cardiovascular disease

ATP

adenosine triphosphate

ATT

antithrombotic therapy

CAD

coronary artery disease

CCS

chronic coronary syndromes

CI

confidence interval

COX

cyclo-oxygenase

DAPT

dual antiplatelet therapy

DATT

dual antithrombotic therapy

DM

diabetes mellitus

DVT

deep vein thrombosis

GP

glycoprotein

HR

hazard ratio

LEAD

lower extremity artery disease

MACE

major adverse cardiovascular event

MI

myocardial infarction

miR

microribonucleic acid

NOAC

non-vitamin K antagonist oral anticoagulant

OAC

oral anticoagulant

PAD

peripheral artery disease

PAR

protease-activated receptor

PCI

percutaneous coronary intervention

PGI2

prostacyclin

RCTs

randomized controlled trials

RRR

relative risk reduction

SAPT

single antiplatelet therapy

TIMI

thrombolysis in myocardial infarction

TP

thromboprostanoid

TXA2

thromboxane A2

UA

unstable angina

VKA

vitamin K antagonist

vWF

von Willebrand factor

 

INTRODUCTION

 

Despite a century of advances in understanding and management of diabetes mellitus (DM), it continues to increase in prevalence and, furthermore, remains an independent risk factor for atherosclerotic cardiovascular disease (ASCVD), leading to a significant burden of premature mortality and morbidity (1).

 

ASCVD includes a spectrum of clinical syndromes. This can include acute presentations such as acute coronary syndromes (ACS, including myocardial infarction [MI] or unstable angina [UA]), thrombotic stroke, or acute limb ischemia (ALI) (Figure 1). Similarly, ASCVD can lead to chronic conditions such as chronic coronary syndromes (CCS, for example those with stable angina or a history of MI >1 year previously) or chronic lower extremity arterial disease (LEAD) (2).

 

Most acute events in ASCVD are caused by thrombosis. The hemostatic response has an important physiological role in the response to trauma but, if it becomes activated inappropriately, thrombosis can be triggered (3). The clinical effects of thrombosis arise primarily from its location, such as in the coronary arteries leading to acute coronary syndrome (ACS, including myocardial infarction [MI] and unstable angina [UA]), cerebral arteries leading to thrombotic stroke, peripheral arteries leading to acute limb ischemia or deep limb veins leading to deep vein thrombosis (DVT). Alternatively, a thrombus formed at a site can embolize, leading to presentations such as acute pulmonary embolism (typically embolism of a DVT to the pulmonary arteries) or embolic stroke (typically left atrial thrombus to the cerebral arteries) (2,4). In addition to atherosclerotic diseases, individuals with DM who have atrial fibrillation are at higher risk of stroke, secondary to atrial thrombosis and subsequent cardioembolic events (5).

 

There are clear links between pathological processes associated with DM and those responsible for atherogenesis and thrombosis, including inflammation, platelet activation, and coagulation (6,7). Alongside control of glucose levels and optimization of other risk factors, such as dyslipidemia, hypertension, and smoking cessation, antithrombotic therapy (ATT), including antiplatelet therapy (APT) and oral anticoagulation (OAC), has become a key component of the treatment and prevention of atherothrombotic and cardioembolic events. ATT has evolved greatly in the last decades, both in terms of the range of drugs available but also our understanding of how best to deploy them (8).

 

Whilst ATT reduces thrombotic risk, in particular reducing the composite of major adverse cardiovascular events (MACE, typically defined as cardiovascular death, stroke or MI), it also leads to an increased risk of bleeding. Balancing these risks is central to interpretation of clinical trial data and development of treatment recommendations, including in those with DM (9).

 

In this chapter, we will review the underlying pathophysiological mechanisms of thrombosis and the pharmacology of commonly prescribed drugs during ATT. With specific reference to individuals with DM, we will appraise evidence for ATT in a broad range of clinical settings, highlighting current treatment recommendations and particular areas in which more data are needed.

Figure 1. The spectrum of acute cardiovascular events relating to thrombosis and hemostasis in DM.

THE THROMBOTIC RESPONSE AND ITS PHARMACOLOGY

 

As described in Virchow’s triad, prothrombotic changes in the blood flow, constituents and/or vessel wall can trigger thrombosis (10). Broadly, thrombosis involves the activation of platelets and the coagulation cascade (Figure 2). Understanding these processes provides insights into how pharmacological modulation may improve ischemic risk and increase bleeding risk as well as how the individual components of combination ATT interact, including in those with DM.

 

Platelet Activation

 

Platelet activation typically occurs upon endothelial injury and atherosclerotic plaque rupture or erosion, resulting in exposure of blood constituents to prothrombotic substances such as collagen. Collagen exposure leads to platelets adhering to the vessel wall via the glycoprotein (GP) Ia receptor and activation via GPVI (11,12). GPIb forms a complex with clotting factors IX, V and von Willebrand Factor (vWF), strengthening adhesion (13).

 

Platelet activation involves several key processes. Alterations in the cytoskeleton lead to shape change with the formation of filopodia, which increase surface area to volume ratio and may facilitate mechanical adhesion to the vessel wall, other platelets and fibrin strands (14). Platelet activation also involves the release of arachidonic acid from the cell membrane, which is then locally converted to thromboxane A2 (TXA2) by cyclo-oxygenase (COX) 1 and TXA2synthase. TXA2, via the platelet TP-α receptor, contributes further to platelet activation (15). Aspirin (acetylsalicylic acid) irreversibly inhibits COX1, thereby blocking the downstream release of TXA2 for the platelet’s lifespan (around 8-10 days in healthy individuals) as, unlike nucleated cells, platelets cannot regenerate the enzyme (8). Endothelial COX1 and 2 generate the antiplatelet and vasodilatory substance prostacyclin (PGI2). The facts that aspirin is short-lived in the systemic circulation, that platelets are exposed to higher levels of aspirin than endothelium, due to travel through the portal circulation, and that aspirin has relative selectivity for COX1 over COX2 leads to aspirin’s net antiplatelet effect at low doses (16).

 

Platelets also undergo degranulation on activation; a granules contain procoagulant and proinflammatory factors, including platelet P-selectin (also known as CD62P), the surface expression of which is therefore increased. P-selectin mediates platelet-leukocyte aggregation and therefore contributes to an associated inflammatory response (17). Dense granules contain adenosine triphosphate (ATP), adenosine diphosphate (ADP) and 5-hydroxytryptamine (5HT, also known as serotonin). In particular, ADP stimulates platelet activation via P2Y1 and, most significantly, P2Y12 receptors (18,19).

 

Stimulation of the P2Y12 receptor leads to central amplification of the response to a range of agonists and contributes significantly to activation of platelet surface GPIIb/IIIa receptors, the final pathway of platelet aggregation (20). Via vWF and fibrinogen bridges, GPIIb/IIIa mediates platelet-platelet interaction (21).

Figure 2. Pathophysiology of the thrombotic response showing targets for antithrombotic drugs discussed in this chapter. 5HT, 5-hydroxytryptamine (serotonin); AA, arachidonic acid; ADP, adenosine diphosphate; ATP, adenosine triphosphate; Ca2+, calcium; COX1, cyclo-oxygenase 1; GP, glycoprotein; IXa, activated factor IX; P2X1, platelet ATP receptor; P2Y1/P2Y12, platelet ADP receptors; PAR, protease activated receptor; PLA2, phospholipase A2; PSGL1, P-selectin glycoprotein ligand 1; TF, tissue factor; TPα, thromboxane receptor α; TXA2, thromboxane A2; TXA2s, thromboxane A2 synthase; Va, activated factor V; VIIa, activated factor VII; VIIIa, activated factor VIII; VASP, vasodilator-stimulated phosphoprotein; vWF, von Willebrand factor; Xa, activated factor X; XIa, activated factor XI; XIIa, activated factor XII; XIIIa, activated factor XII. Modified from (22).

Several oral platelet P2Y12 receptor antagonists (‘P2Y12 inhibitors’) are currently available (23). Clopidogrel and prasugrel are irreversibly-binding thienopyridines (8). As pro-drugs, they require hepatic metabolism to be activated. In the case of prasugrel this pathway is reliable, whereas there is interindividual variation in the metabolism of clopidogrel meaning around one-third of recipients have poor response when assessed using aggregometry (22). Ticagrelor is a reversibly-binding cyclopentyl-triazolopyrimidine that does not require metabolism to be active. Prasugrel or ticagrelor provide more potent and reliable platelet inhibition compared with clopidogrel (24).

 

Parenterally administered P2Y12 inhibitors have also been developed. Cangrelor is a reversibly-binding ATP analogue that is potent and has rapid onset and offset (25). Selatogrel is a novel, parenterally-active, reversibly-binding P2Y12 inhibitor formulated for subcutaneous administration, but has not yet completed phase III trials and is yet to be marketed (26).

 

Activation of the Coagulation Cascade

 

Although likely an oversimplification of the in vivo state, the coagulation cascade can be summarized as two key pathways made up of factors that converge on a final pathway (27).

 

Loss of endothelium leads to exposure of subendothelial extracellular matrix and contact activation of factor XII, triggering the chain of clotting factor activation known as the intrinsic pathway (28). Tissue factor, expressed on subendothelial cells and released in microparticles from atheromatous plaques, can activate factor IX when in a complex with factor VII: this is the extrinsic pathway (29).

 

Initiation of either pathway can lead to activation of factor X, which associates with activated factor V, calcium (released from damaged tissue) and phospholipids to form the prothrombinase complex (30). Prothrombin (II) is thus broken down to thrombin (IIa), which completes the process through cleavage of fibrinogen to fibrin, the latter being insoluble and forming strands. Tissue factor pathway inhibitor and antithrombin limit this response, but, as recruitment of activated platelets contributes to higher levels of thrombin generation, this endogenous inhibition is quickly overwhelmed (31). Once fibrin is formed, factor XIIIa, activated by thrombin, stabilizes the structure of clot by forming crosslinks between strands and by crosslinking anti-fibrinolytic proteins into the clot (32).

 

Fibrin is lysed by plasmin, a proteolytic enzyme that degrades into variously termed fragments (33). Plasmin is cleaved from its precursor, plasminogen, by tissue plasminogen activator, and is endogenously inhibited by antiplasmin.

 

A number of drugs target the coagulation cascade. During chronic administration, vitamin K antagonists (VKA) such as warfarin reduce the biological activity of prothrombotic vitamin-K-dependent factors (II, VII, IX, X) more than antithrombotic factors (e.g., proteins C and S) (34). Non-vitamin K antagonist oral anticoagulants (NOACs) include the Xa inhibitors apixaban, edoxaban and rivaroxaban and the thrombin inhibitor dabigatran (35).

 

Crosstalk Between Platelets and the Coagulation Cascade

 

Despite the fact that platelets and coagulation are often considered separately when discussing physiology and pharmacology, there is significant crosstalk between the two. Thrombin is generated upon activation of coagulation, and is able to stimulate platelet activation via action on protease-activated receptor (PAR) 1 and, at higher concentrations, PAR4 (36). Conversely platelets can contribute to thrombin generation, increasing coagulability, via scramblase activity that leads to greater surface expression of phosphatidylserine, supporting the assembly of prothrombinase complex on the activated platelet surface, which potentiates thrombin generation (37).

 

SPECIAL PATHOPHYSIOLOGICAL CONSIDERATIONS IN DIABETES

 

DM is an independent risk factor for atherothrombosis and also thrombosis after vascular interventions (38).  Individuals with DM have greater average atherosclerotic plaque burden than those without (39), and onset is at an earlier age (40). There is also some evidence that atherosclerosis in people with DM is more likely to involve distal vessels than those without DM (41). The reasons for this are not completely understood and are likely multifactorial, but a number of relevant pathological processes such as hyperglycemia, chronic inflammation, and oxidative stress are prominent in DM. These contribute to both endothelial injury/dysfunction and increased platelet reactivity, resulting in a prothrombotic milieu (42-44).

 

Platelet activation markers are enhanced in people with DM (45). Effects of hyperglycemia on platelets include increased expression of GPIba, GPIIb/IIIa, and P2Y12, and reduced platelet membrane fluidity (46,47).Hyperglycemia-induced changes in intracellular magnesium and calcium signaling increase sensitivity of platelets to agonists such as ADP, epinephrine and thrombin (48). TXA2 and F2-isoprostane synthesis is increased, the latter via oxidative stress, leading to increased TPa receptor stimulation (49). Reduced sensitivity to PGI2, nitric oxide and insulin, which inhibit platelet activation, also contributes to hyper-reactivity (50,51).

 

Platelet turnover is accelerated in those with DM compared to those without (52). This increased activity in the creation and destruction of circulating platelets means a higher proportion of immature platelets, which are hyper-reactive, are present at any time (53). As well as increasing baseline platelet reactivity, the more frequent appearance of aspirin-naïve platelets in the circulation means more have uninhibited COX1 between doses (54).

 

There is also evidence that DM affects expression of platelet-associated microRNAs (miR-223, miR-26b, miR-126, miR-140), which play a role in the expression in a wide range of genes including those encoding the P2Y12 receptor and P-selectin, though the significance of this remains to be fully established (55,56).

 

As well as platelet activation, DM may affect coagulation and fibrinolysis (57). Changes include increased levels of tissue factor, prothrombin, factor VII and fibrinogen leading to impaired anticoagulant and fibrinolytic activity (58). Increased levels of fibrinogen and its levels of glycation and oxidation lead to more compact, densely-packed fibrin networks and reduced fibrinolysis (59). Hyperglycemia inhibits the fibrinolytic activity of plasminogen through inducing qualitative changes (60). Fibrinolysis is further impaired by elevated levels of plasminogen activator inhibitor 1 and thrombin-activatable fibrinolysis inhibitor as well as incorporation into clot of complement C3 and plasmin inhibitor (59,61).

 

DM also appears to enhance the crosstalk between platelets and clotting factors, leading to tendency to more externalization of phosphatidylserine in the outer platelet membrane, promoting clotting factor assembly and tissue factor activation (62).

 

Finally, individuals with DM frequently have other metabolic conditions such as obesity, dyslipidemia, and increased systemic inflammation. These may interact with diabetes to further enhance platelet reactivity and impair fibrinolysis (59).

 

CURRENT EVIDENCE AND TREATMENT RECOMMENDATIONS FOR ANTITHROMBOTIC THERAPY IN DIABETES

 

The Need for Therapeutic Oral Anticoagulation

 

Broadly, when considering the need for antithrombotic therapy (ATT), including in people with DM, it is helpful to make first a distinction between those with an indication for therapeutic anticoagulation and those without. The most common indication is for prevention of cardioembolic stroke in those with current or previous atrial fibrillation (AF). Individuals with atrial flutter are typically regarded as having similar thrombotic risk to those with AF so similar recommendations are followed (63).

 

DM increases the risk of developing AF by around 40% (64,65). Whilst difficult to completely exclude the effects of confounders such as obesity and hypertension, epidemiological data suggest a causal association between DM and AF, including that poor glycemic control and longer diabetes duration increase AF risk (66). A raised level of HbA1c is also associated with a higher chance of AF recurrence after catheter ablation (67). Hyperglycemia and glycemic fluctuations may contribute to the development of AF though exact mechanisms remain to be determined. Disappointingly, however, there is no clear evidence that intensive glycemic control reduces AF risk, though prospective trials are lacking (66). Treatment with metformin, thiazolidinediones, or dapagliflozin is associated with lower AF risk, suggesting that hypoglycemia avoidance may play a role but adequately designed studies to investigate this possibility are lacking (68-71). AF is often clinically silent and screening with simple pulse checking or using wearable devices should be considered in those over 65 years old (72).

 

Presence of DM is incorporated into the CHA2DS2VASc score used to assess stroke risk when determining whether to recommend oral anticoagulation in people with AF (Table 1 and 2) (73). Long-term oral anticoagulation is strongly recommended in those with AF/atrial flutter and a CHA2DS2VASc score of ³2 (if male) or ³3 (if female), and should be considered when the score is 1 (male) or 2 (female). Individuals with DM, technically defined for the purposes of calculating the score as treatment with oral hypoglycemic drugs and/or insulin or fasting blood glucose >7.0 mmol/L (126 mg/dL), will have a score of at least 1 (males) or 2 (females), therefore OAC should be considered in all people with DM and concurrent AF (63). Bleeding risk should also be considered when weighing the benefits and risks of OAC, but there is no concrete evidence that DM itself increases this, including in those with complications such as retinopathy (74). For people with non-valvular AF (i.e., those without at least moderate mitral valve stenosis or a mechanical valve prothesis), there is now good evidence that, unless contraindicated, a NOAC should be preferred over a VKA, offering better stroke prevention whilst leading to less bleeding, including in individuals with DM (75).

 

Components of the CHA2DS2VASc score are shown in Table 1 and the relation of the score with stroke risk is shown in table 2 (76-78).

 

Table 1. Components of the CHA2DS2VASc Score

Abbreviation

Criterion

Contribution to score

Details

C

Congestive heart failure

1

LVEF £40%

H

Hypertension

1

Includes patients receiving antihypertensive medication

A

Age ³75 years

2

 

D

Diabetes

1

Treatment with oral hypoglycemic drugs and/or insulin or fasting blood glucose >7.0 mmol/L (126 mg/dL)

S

Stroke/TIA/thromboembolism

2

 

V

Vascular disease

1

Atherosclerotic disease e.g., prior MI, PAD or aortic plaque

A

Age 65-74

1

 

Sc

Sex category female

1

 

LVEF, left ventricular ejection fraction; MI, myocardial infarction; PAD, peripheral artery disease; TIA, transient ischemic attack.

 

Table 2. Relation of CHA2DS2VASc Score with Stroke Risk

Total CHA2DS2VASc score

Adjusted stroke risk (% per year)

0

<1

1

1.3

2

2.2

3

3.2

4

4.0

5

6.7

6

9.8

7

9.6

8

6.7

9

15.2

 

When choosing between individual non-vitamin K antagonist oral anticoagulants (NOACs), beyond considering specific drug interactions, there is little evidence to support the use of one agent over another as these have never undergone head-to-head clinical outcome-driven randomized controlled trials (RCTs), although observational data have emerged to provide some insights. In a large retrospective observational study of 434,046 participants with non-valvular AF comparing treatment with apixaban, dabigatran, rivaroxaban and warfarin, apixaban led to a lower risk of stroke against both dabigatran (HR 0.72 [ 95% CI 0.60-0.85]) and rivaroxaban (0.80 [0.73-0.89]), whilst also leading to less bleeding (major bleeding: vs. dabigatran 0.78 [0.70-0.87]; vs. rivaroxaban 0.80 [0.55-0.59]) (79). These findings remain hypothesis-generating, however, and prospective trials would clarify this issue more definitively.

 

Although not discussed in detail in this chapter, OAC may also be indicated for the treatment and prevention of venous thromboembolism. Whilst DM is regarded as a weak risk factor for VTE, beyond this there are no particular considerations relating to DM and usual clinical guidelines as for non-DM individuals should generally be followed (4). Of specific note, however, is that people with DM who are experiencing hyperosmolar states such as ketoacidosis or hyperosmolar hyperglycemic syndrome are at particular risk of VTE. There is ongoing debate around the intensity of anticoagulation that is appropriate for thromboprophylaxis in this group. Consensus is that at least prophylactic doses of low molecular weight heparin, for example, are warranted, with others advocate therapeutic doses (80,81). A robustly-powered clinical outcomes-driven RCT would be welcome to definitively address this issue.

 

Where indications for both anti-platelet therapy (APT) and therapeutic levels of oral anticoagulant therapy (OAC) exist, the general principle is to prioritize continuation of OAC. Co-prescription of APT and OAC should in general be reserved for those with acute coronary syndrome (ACS), recent percutaneous coronary intervention (PCI) or indication for long-term therapy in selected individuals with chronic coronary syndromes (CCS) where ischemic risk is felt to significantly outweigh bleeding risk (22).

 

Treating Acute Atherothrombotic Events

 

ACUTE CORONARY SYNDROMES (ACS)

 

Current guidelines recommend 12 months of dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor, including in those with DM, as the default antithrombotic strategy for ACS (72,82-84).

 

There is robust evidence for aspirin therapy in ACS. For example, ISIS-2 demonstrated that aspirin led to an odds reduction in 30-day vascular mortality of 23% in those with acute MI (85). Current recommendations advise a loading dose of around 300 mg followed by maintenance therapy with 75 mg once daily, including in those with DM. However, because of higher platelet turnover in people with DM, 24-hour platelet inhibition is greater with twice-daily compared with once-daily aspirin administration (86-88). Any effects of clinical outcomes are yet to be determined, but are being studied in the ANDAMAN trial that aims to recruit 2573 participants (NCT02520921) and is estimated to finish in December 2023.

 

In ACS, the newer P2Y12 inhibitors prasugrel and ticagrelor are recommended in preference to clopidogrel due to their greater pharmacodynamic and clinical efficacy (83,84). Post-hoc analysis of the TRITON-TIMI trial suggested an impressive benefit of prasugrel over clopidogrel in people with DM (89). Similar findings were noted with regards to ticagrelor over clopidogrel in the PLATO trial, for which post-hoc analysis showing that the absolute benefit of was greatest in individuals with both DM and chronic kidney disease (90).

 

Table 3. Key Double-Blinded Randomized Controlled Trials of Dual Antiplatelet Therapy in Acute Coronary Syndrome, Including in People with Diabetes.

 

Trial

 

n

ACS group included

Group 1

Group 2

Primary efficacy endpoint – whole trial population

Number with DM

Primary efficacy endpoint – DM subgroup

CURE

(91)

12,562

 

NSTE-ACUTE CORONARY SYNDROME

Aspirin + Clopidogrel

Aspirin + Placebo

CV death/MI/stroke:11.4% vs. 9.3%, HR 0.80 [95% CI 0.72-0.90], p<0.001), ARR 2.1%.

2840 (23%)

CV death/MI/stroke:14.2% vs. 16.7%. RR 0.85. ARR 2.5%.

 

CLARITY

(92)

3491

STEMI

Aspirin + Clopidogrel

Aspirin + Placebo

Occluded infarct-related artery/death/recurrent MI: 15.0% vs. 21.7%, odds reduction 36% [95% CI 24-47], p<0.001, ARR 6.7%.

575 (16%)

NR

COMMIT

(93)

45,852

 

STEMI

Aspirin + Clopidogrel

Aspirin + Placebo

Death/reinfarction/stroke: 9.2% vs. 10.1%, OR 0.91 [95% CI 0.86-0.97], p=0.002, ARR 0.9%.

NR

NR

TRITON-THROMBOLYSIS IN MYOCARDIAL INFARCTION 38

(94)

13,608

ACUTE CORONARY SYNDROME with scheduled PCI

Aspirin + Prasugrel

Aspirin + Clopidogrel

CV death/MI/stroke: 9.9% vs. 12.1%, HR 0.81 [95% CI 0.73-0.90], p<0.001, ARR 2.2%.

3146 (23%)

CV death/MI/stroke: 12.2% vs. 17.0%, HR 0.70, ARR 4.8%.

TRILOGY ACUTE CORONARY SYNDROME

(95)

7243

NSTE-ACUTE CORONARY SYNDROME

with medical management

Aspirin + Prasugrel

Aspirin + Clopidogrel

CV death/MI/stroke: 13.9% vs. 16.0%, HR 0.91 [95% CI 0.79-1.05], p=0.21, ARR 2.1%.

2811 (39%)

CV death/MI/stroke: 17.8% vs. 20.4%, HR 0.90 [95% CI 0.73 to 1.09]), ARR=2.6%, interaction-p for DM status 0.71, ARR 2.6%.

PLATO

(96)

18,624

All ACUTE CORONARY SYNDROME (STEMI

patients included only if for PPCI)

Aspirin + Ticagrelor

Aspirin + Clopidogrel

CV death/MI/stroke: 9.8% vs. 11.7%, HR 0.84 [95% CI 0.77-0.92], p<0.001, ARR 1.9%.

 

 

4662 (25%)

CV death/MI/stroke: 14.1% vs. 16.2, HR 0.88 [95% CI 0.76-1.03], interaction-p for DM status 0.49, ARR 2.1%.

ACS, acute coronary syndrome; ARR, absolute risk reduction; CV, cardiovascular; DM, diabetes mellitus; HR, hazard ratio; MI, myocardial infarction; NR, not reported; NSTE-ACS, non-ST elevation ACS; OR, odds ratio; PCI, percutaneous coronary intervention; PPCI, primary PCI; PPM, permanent pacemaker; RR, relative risk; STEMI, ST elevation MI; NR, not recorded

 

The recent ISAR-REACT-5 study demonstrated superiority of a prasugrel-based strategy over a ticagrelor-based strategy in reducing cardiovascular events in ACS patients but was an open-label trial with limited power (97,98). Furthermore, data from the pre-specified subgroup with DM suggested there was no difference between the drugs (99).

 

Early de-escalation from dual antiplatelet therapy (DAPT) to ticagrelor monotherapy after PCI, including for ACS, has recently been trialed as an alternative strategy. In the TWILIGHT study, de-escalation from aspirin and ticagrelor to ticagrelor monotherapy at 3 months after PCI for ACS or stable coronary artery disease (CAD) was compared with continued DAPT in 7,119 participants (100). De-escalating to ticagrelor monotherapy led to a lower incidence at 12 months of the primary end point of Bleeding Academic Research Consortium type 2, 3, or 5 bleeding compared with DAPT (4.0% vs 7.1%, HR 0.56 [95% 0.45-0.68], p<0.001). This finding appeared similar regardless of DM status. There was no evidence of an increase in the secondary combined endpoint of death, MI or stroke. Conversely, 1 month of DAPT followed by ticagrelor alone for 23 months was not superior to 12 months of standard DAPT followed by 12 months of aspirin alone in reducing the primary endpoint of all-cause mortality or new Q-wave MI following PCI in the GLOBAL LEADERS trial, in which 47% of participants had ACS (101). Antiplatelet strategy had no significant effect on BARC type 3 or 5 bleeding in those with and without DM (102). Currently, de-escalation of DAPT may be an option for individuals with high bleeding risk and relatively low risk of vascular re-occlusion but guidelines are yet to recommend more widespread adoption.

 

In summary, following ACS in individuals with diabetes, DAPT for 12 months with aspirin and prasugrel or aspirin and ticagrelor is recommended by the majority of guidelines/experts and early de-escalation should be reserved to those at high bleeding risk. Longer term DAPT should be considered in those at high thrombosis/low bleeding risk, which is further detailed below. 

 

ACUTE ISCHEMIC STROKE

 

If no contraindications exist, the first-line treatment for significant acute ischemic stroke is thrombolysis with an intravenous tissue plasminogen activator, or percutaneous mechanical thrombectomy (103). Antiplatelet therapy (APT), typically aspirin monotherapy, is then administered from 24 hours later (104,105).

 

In those with minor stroke (National Institutes of Health Stroke Score <3), high-risk transient ischemic attack (TIA) (Age, blood pressure, clinical feature, duration and presence of diabetes score>4) or TIA not requiring thrombolysis or thrombectomy, APT can be initiated as soon as hemorrhagic stroke is excluded. The current regimen of choice may be dual antiplatelet therapy (DAPT) with aspirin 75-100 mg once daily and clopidogrel 75 mg once daily, based on findings from the CHANCE and POINT trials (106,107). After 21 days, DAPT should be de-escalated to clopidogrel monotherapy (105).

 

Both ticagrelor monotherapy and aspirin plus ticagrelor have also been compared to aspirin alone after acute non-severe ischemic stroke or high-risk TIA. The SOCRATES trial narrowly failed to demonstrate statistically-significant difference in the primary endpoint of stroke, MI or death (6.7% vs. 7.5%, HR 0.89 [95% CI 0.78-1.01], p=0.07) between participants receiving ticagrelor vs. aspirin (108). However, exploratory analysis suggested those who received both aspirin and ticagrelor in the peri-event period appeared to gain more benefit compared to individuals not having aspirin pre-randomization (HR 0.76 [95% CI 0.61-0.95], p=0.02; vs. 0.96 [0.82-1.12]). This was explored further in the THALES trial, which demonstrated a significant reduction in the primary composite endpoint of stroke or death at 30 days (5.5% vs. 6.6%, HR 0.83 [95% CI 0.71-0.96, p=0.02) when receiving aspirin plus ticagrelor compared to aspirin alone, but at the expense of more frequent severe bleeding (0.5% vs. 0.1%, HR 3.99 [95% CI 1.74-9.14], p=0.001), defined using the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries trial criteria (109). Findings from SOCRATES appeared similar in the subgroups with and without DM, whereas in THALES there was less signal of benefit of DAPT in those with DM vs. those without (HR 0.93 [95% CI 0.72-1.20] vs. 0.78 [0.64-0.94]).

 

In summary, following major stroke requiring thrombolysis or thrombectomy, aspirin monotherapy should be administered 24 hours later. In minor stroke or high-risk TIA, DAPT should be initiated as soon as intracerebral bleeding is ruled out and continued for 21 days with aspirin then withdrawn and individuals treated with long-term clopidogrel monotherapy.

 

Preventing Atherothrombotic Events in Individuals with Diabetes and Established Cardiovascular Disease

 

CORONARY ARTERY DISEASE

 

In those with established CAD, even without an ACS event in the last 12 months, the benefits of antiplatelet therapy (APT) are well-established. Robust evidence for vs. against use of APT in patients with ASCVD, including CAD comes, for example, from the Antithrombotic Trialists Collaboration, who performed a meta-analysis including 135,000 individuals (110). This demonstrated clear benefit, mainly with aspirin as single-antiplatelet therapy (SAPT), in reducing MACE by around a quarter (110).  The incidence of diabetes in these studies, many of which are now several decades old, was relatively low, however.

 

There is evidence from trials with both pharmacodynamic and clinical outcomes that increasing daily aspirin dose beyond 75-100 mg in patients with DM leads to neither greater platelet inhibition nor improved outcomes (111,112).

 

Daily doses of aspirin in the range 75-100 mg and no higher are recommended for use as APT. Recent data on clinical outcomes relating to aspirin dosing comes from the ADAPTABLE trial, in which the regimens 81 mg OD and 325 mg OD were compared in 15,076 patients with ASCVD (113). After a median of 26 months, there was no significant difference in the rates of a composite primary endpoint of all-cause death, hospitalization for myocardial infarction or hospitalization for stroke (7.28% [81 mg] vs. 7.51% [325 mg], HR 1.02, 95% CI 0.91-1.14; p=0.75). Furthermore, this finding appeared replicated in the subgroup (n=5676) with diabetes (HR 0.99 [0.84-1.17]). This is supported by pharmacodynamic data showing that, whilst individuals with DM have reduced response to aspirin 75 mg once daily compared with healthy controls, increasing the dose to 300 mg does not alter the response (111).

 

In the CAPRIE study, clopidogrel 75 mg once daily was compared with aspirin 325 mg once daily (114). There was a slightly lower rate of MI, ischemic stroke or CV death with clopidogrel (5.32% vs. 5.83%, RRR 8.7% [95% CI 0.3-16.5], p=0.043) as well as less gastrointestinal bleeding. A fifth of participants in CAPRIE had diabetes and a retrospective subgroup analysis suggested an amplified benefit of clopidogrel over aspirin compared to those without diabetes. Clopidogrel monotherapy is currently recommended in those people with chronic coronary syndromes (CCS) who are unable to take aspirin, or, based on pre-specified subgroup analyses of CAPRIE suggesting particular benefit, as a first-line agent in those with either concurrent CAD and cerebrovascular disease or PAD.

 

Beyond single antiplatelet therapy (SAPT), there is good evidence for intensification of antithrombotic therapy in select people with CAD who are at high risk of ischemic events but without high risk of bleeding. The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study randomized 19,185 stable aspirin-treated individuals with established atherothrombotic disease or multiple risk factors to receive clopidogrel 75 mg once daily or placebo (115). Though the point estimate of the hazard ratio was below 1, there was no significant reduction in the primary efficacy endpoint of MACE when receiving dual antithrombotic therapy (DAPT) vs. aspirin alone (HR 0.93, [95% CI 0.83-1.05], p=0.22). However, in the subgroup with prior MI, prior stroke or PAD, there was some evidence of benefit (0.77 [0.61-0.98], p=0.031) (116). Around 30% of the participants in CHARISMA had DM and there was in fact a trend towards less benefit of DAPT over SAPT in this group compared to those without DM.

 

The DAPT study similarly showed that 30 vs. 12 months of clopidogrel (65%) or prasugrel (35%) given to aspirin-treated individuals undergoing PCI significantly reduced death, MI or stroke in those with prior MI (HR 0.56 [95% CI 0.42-0.76], p<0.001), but not those without (0.83 [0.68-1.02], p=0.08) (117). Like CAPRIE, there was some evidence that those in the trial with DM gained less benefit in reduction of MACE from continued thienopyridine vs. placebo, when compared to those without DM (6.6% vs. 7.0% in those with DM, p=0.55; 3.3% vs. 5.2% in those without, p<0.001; interaction-p=0.03). Conversely, DM did not appear to be an interacting factor with regards to stent thrombosis or bleeding.

 

There is perhaps more convincing evidence, particularly in those with DM, for use of long-term ticagrelor-based DAPT. In the PEGASUS-TIMI 54 study, DAPT with aspirin plus ticagrelor, either 60 mg or 90 mg twice-daily, reduced MACE vs. aspirin alone (e.g. 60 mg twice-daily vs. placebo: HR 0.84 [95% CI 0.74-0.95], p=0.008) in participants with prior MI (>1 year ago) and an additional risk factor (age ≥65 years, DM, recurrent MI, multivessel CAD or non-end stage CKD) (118). Thrombolysis In Myocardial Infarction (TIMI)-major bleeding was significantly more frequent in ticagrelor-treated individuals, but serious events such as intracranial hemorrhage, hemorrhagic stroke or fatal bleeding showed no increase. In contrast to the thienopyridine trials, the 6806 participants with diabetes demonstrated a significant benefit of DAPT over SAPT in reducing MACE (HR 0.84 [95% CI 0.72-0.99], p=0.035) with a greater absolute risk reduction than in the cohort without diabetes (1.5% vs. 1.1%) (119). Patients without a history of anemia or hospitalization for bleeding, important risk factors for bleeding, appeared to derive greater benefit from long-term DAPT (120).

 

As well as in those with prior MI, ticagrelor-based DAPT has also been tested against aspirin alone in people with type 2 DM and chronic coronary syndromes (CCS) but without prior MI. THEMIS included 19,220 participants randomized to receive ticagrelor (90 mg twice daily, reduced to 60 mg during the trial) or placebo, on a background of aspirin treatment (121). After an average follow-up of 40 months, there was a lower incidence of MACE in those receiving ticagrelor when compared to placebo (HR 0.90 [95% CI 0.81-0.99], p=0.04).  Notably, however, there was a relatively greater increase in TIMI-major bleeding (2.32 [1.82-2.94], p<0.001). Whilst meeting its primary endpoint, the net clinical benefit has not supported adoption in European practice, although subgroup analysis has suggested this may have been more favorable in those patients with prior PCI (122). Furthermore, based on the THEMIS data, the US Food and Drug Administration has recently extended the licensed indication for ticagrelor to include the prevention of a first MI or stroke in people with CCS at high risk of MI or stroke, including in those with DM (123).

 

An alternative to long-term DAPT is low-dose dual antithrombotic therapy (DATT) with aspirin 75-100 mg once daily and rivaroxaban 2.5 mg twice daily.  The COMPASS trial included randomization of 27,395 participants with prior MI or multivessel CAD (38% with DM) or PAD to receive either low-dose DATT, rivaroxaban 5 mg twice daily alone or aspirin alone (124). Compared to aspirin alone, low-dose DATT led to a significantly reduced incidence of MACE [4.1% vs 5.4%, HR 0.76 [95% CI 0.66-0.86], p<0.001], people with DM gaining an even greater absolute net benefit.

 

Current guidelines recommend long-term DAPT or low-dose dual antithrombotic therapy (DATT) in those individuals with CCS without an indication for therapeutic oral anticoagulant (OAC) who are at high ischemic risk but not high bleeding risk (22).

 

In those undergoing PCI for stable CAD, including in those individuals with DM, the standard DATT regimen is DAPT with aspirin and clopidogrel for 6 months (125).

 

In summary, individuals with DM who have CCS should be treated with at least one antiplatelet agent, usually aspirin, although clopidogrel can be used if aspirin is contraindicated. However, more recent evidence indicates that those with a previous MI benefit from long-term DAPT (aspirin and ticagrelor) or a combination of antiplatelet and anticoagulant (DATT with aspirin and rivaroxaban) provided they have a low bleeding risk. Individuals with significant CAD but without a previous MI may also benefit from DAPT or DATT, which is best reserved for people with high vascular risk but low bleeding risk. 

 

CEREBROVASCULAR DISEASE  

 

There is good evidence for use of APT with aspirin, clopidogrel, ticlopidine or aspirin and dipyridamole in combination for secondary prevention in people with cerebrovascular disease, including those who also have DM (126). Aspirin plus dipyridamole offers better long-term protection than aspirin alone, but has a frequent adverse effect of headache that can limit its use (127). Clopidogrel monotherapy, without this side effect, offers similar levels of secondary prevention to aspirin plus dipyridamole and is the current preferred agent. In the first 3 months after an ischemic stroke, if reperfusion therapy has been given, aspirin alone is typically prescribed. In cases where reperfusion therapy has not been given, there is good evidence for using either aspirin and clopidogrel or aspirin and ticagrelor over aspirin alone (128,129).  After 3 months, typically clopidogrel monotherapy is then given long-term, though aspirin and dipyridamole or aspirin alone are used instead at some centers (127,130,131).

 

PERIPHERAL ARTERY DISEASE

 

The effectiveness of APT for secondary prevention of ASCVD, including in those with symptomatic PAD, was established by the Antithrombotic Trialists’ Collaboration as discussed above. Similarly, in the CAPRIE trial, P2Y12inhibitor monotherapy with clopidogrel was compared with aspirin, including in people with PAD (114). Whilst in the overall trial population there was only a modest reduction in MACE, there was evidence of greater efficacy in the subgroup with PAD, meaning clopidogrel may be preferred to aspirin. Current ESC guidelines recommend either aspirin or clopidogrel for patients with symptomatic PAD and/or those who have required revascularization, including in individuals with DM (132).

 

In those with symptomatic PAD, ticagrelor monotherapy has also been compared with clopidogrel in the EUCLID trial (133). There was no significant difference in the primary composite endpoint of MACE during a median follow-up period of 30 months and therefore ticagrelor monotherapy is not licensed for use in PAD. Prasugrel monotherapy has not been well tested in clinical-outcome studies but may offer pharmacodynamic advantages over clopidogrel, including in individuals with DM (134).

 

Comparison of DAPT (aspirin plus clopidogrel) with aspirin alone in people with PAD was included in CHARISMA (n=3,096 with PAD, 36.2% with DM). There was no significant difference in MACE (7.6% vs 8.9%, HR 0.85 [0.66–1.08], p=0.18) (135).

 

Conversely, there is good evidence for intensification of aspirin monotherapy to low-dose DATT with aspirin 75-100 mg once daily and rivaroxaban 2.5 mg twice daily in people with PAD, supported by the analysis of 7,470 participants with PAD in the COMPASS trial (136). The combination of rivaroxaban and aspirin reduced incidence of MACE over a median follow up of 21 months versus aspirin alone [5.1% vs 6.9%, HR 0.72 (0.57-0.90); p=0.0047]. Particularly important benefits observed included a lower incidence of major adverse limb events [1% vs 2%, HR 0·63 [95% CI 0.41–0.96], p=0·032], and lower incidence of major amputation [0.30 [0.11–0.80], p=0.011].

 

Subsequently, the evidence base for low-dose DATT in people PAD has been enhanced by the results of the VOYAGER-PAD trial, which randomized 6564 individuals with PAD treated by revascularization to receive either low-dose DATT or aspirin alone (137). After a median follow-up of 28 months (interquartile range 22-34), the primary composite endpoint of acute limb ischemia, amputation, MI, ischemic stroke or CV death occurred in 17.3% vs. 19.9% (HR 0.85 [0.76-0.96], p=0.009) without a significant increase in the incidence of TIMI major bleeding (2.65% vs. 1.87%, HR 1.43 [0.97-2.10, p=0.07). Forty percent of the trial population had DM with a similar response observed in this group.

 

It should be noted that DM individuals with symptomatic PAD are likely to have extensive vascular pathology and therefore DATT is likely to offer benefit in more than one vascular bed. Discussion of antithrombotic therapy for those people with DM and asymptomatic PAD is included in the next section.

 

Preventing First Atherothrombotic Event in Patients with Diabetes and No Symptomatic Atherosclerotic Cardiovascular Disease

 

It is rational to hypothesize that antithrombotic therapy (ATT) therapy may reduce the chance of a first atherothrombotic event or limit its severity by preventing thrombosis or reducing its impact.  ATT in several distinct groups with DM but without symptomatic ASCVD have been investigated in a number of trials. The largest individual-level meta-analysis was performed in 2009 and included 95,000 participants from 6 trials (138). In individuals with DM, though aspirin led to a 12% proportional reduction in the rate of serious vascular events, this did not reach statistical significance. However, the point estimate was consistent with the statistically significant benefit of aspirin in the non-DM population and the DM population showed an identical trend. Three further trials have been added to the literature since this meta-analysis was performed. Two, JPAD (n=2539) and POPADAD (n=1276) were not adequately powered to draw firm conclusions (139,140). However, most recently ASCEND provided data from 15,480 individuals with DM but without symptomatic ASCVD who were randomized to receive aspirin 100 mg once daily or placebo (141). After a mean follow up of 7.4 years, those randomized to aspirin had a significantly reduced rate of serious vascular events (MI, stroke or TIA, or vascular death excluding intracranial hemorrhage) (RR 0.88 [95 % CI 0.79-0.97], p=0.01). However, major bleeding was significantly more frequent when receiving aspirin (1.24 [1.09-1.52], p=0.003), the majority being gastrointestinal. The investigators concluded that the absolute benefits were largely counterbalanced by the risks, despite a favorable, albeit modest, risk-benefit ratio.

 

Antiplatelet drugs other than aspirin have not been widely studied for primary prevention in individuals with DM and this remains an area for future research.

 

CONCLUSIONS

 

DM leads to a prothrombotic milieu that increases the risk of atherothrombotic and thromboembolic events compared to the non-DM population. Changes in platelets, coagulation, and inflammation appear central to this increased risk. Antithrombotic therapy (ATT) can help treat or prevent thrombotic events but increases bleeding risk. In those with a history of symptomatic ASCVD, long-term antiplatelet therapy (APT) with aspirin or clopidogrel is indicated. Intensification to long-term dual antiplatelet therapy (DAPT) or low-dose dual antithrombotic therapy (DATT) should be considered in those with chronic coronary syndromes (CCS) who have high ischemic risk but not high bleeding risk. Low-dose DATT can also be beneficial to people with symptomatic PAD. Therapeutic levels of oral anticoagulant (OAC) should be considered in all individuals with DM who develop AF. Accurately assessing and balancing a patient’s risk of ischemic and bleeding events is key to making rational treatment recommendations for ATT in DM (Figure 3).

 

Looking to the future, further work to determine more precisely an individual’s thrombotic and bleeding risk would greatly enhance our ability to make the best treatment recommendations for patients with DM. Whether this is achieved by more complex statistical modelling, novel imaging techniques, and/or better appreciation of circulating biomarkers remains to be determined. This would allow a greater move towards personalized strategies in order to more appropriately balance the benefits and risks of ATT. People with DM often have complex co-morbidities meaning choosing the best regimen is difficult, but is at the same time crucial to ensure an optimal outcome.

 

Emerging strategies such as early de-escalation of DAPT are encouraging new tools giving more options for subtle adjustment of ATT intensity, but require definitive proof they lead to no significant ischemic penalty and ratification by guideline committees before wider adoption can be recommended. No doubt further clarity will follow in the coming years.

 

The lack of an ability of ATT to meaningfully improve net clinical outcomes in those with DM without established ASCVD is a source of disappointment and demands future attention. Trials have focused on aspirin but it is clear that people with DM may have a poor response (111). As well as trials exploring novel regimens of aspirin, trials testing P2Y12 inhibitor monotherapy, which may offer pharmacodynamic advantages over aspirin in this group, are warranted (134).

 

Finally, targeting the pathological abnormalities that cause hypofibrinolysis in diabetes, such as inhibition of PAI-1 activity, may offer an alternative management strategy to further reduce vascular occlusive disease in diabetes, while keeping the risk of bleeding to a minimum.

Figure 3. Principles to consider when deciding on the optimal regimen of antithrombotic therapy in a person with diabetes. ACS, acute coronary syndrome; AF, atrial fibrillation; ASCVD, atherosclerotic cardiovascular disease; CAD, coronary artery disease; CI, contraindication; DAPT, dual antiplatelet therapy; DATT, dual antithrombotic therapy; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; GI, gastrointestinal; OAC, oral anticoagulation; PAD, peripheral artery disease; PCI, percutaneous coronary intervention.

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Multiple Endocrine Neoplasia Type 4

ABSTRACT

 

Multiple Endocrine Neoplasia Type 4 (MEN4) (OMIM #610755) has many similarities with MEN1, but is caused by germline mutations in CDKN1B. MEN4 is less common than MEN1. Clinical manifestations of MEN4 encompass: primary hyperparathyroidism, pituitary adenomas. and gastroenteropancreatic neuroendocrine neoplasms. In line with MEN1 other neoplasms may occur.

 

INTRODUCTION

 

Multiple Endocrine Neoplasia Type 4 (MEN4) (OMIM #610755) was initially named MENX and was first described in rats (1-3). MEN4 is caused by germline mutations in CDKN1B (Cdkn1b in rats), a tumor suppression gene encoding for the protein p27Kip1 (commonly referred to as p27 or as KIP1). The CDKN1B gene is located on chromosome 12p13.1 (4). p27 is a member of the cyclin-dependent kinase inhibitor (CDKI) family which regulates the cell cycle (5, 6). Germline mutations in CDKN1B lead to reduced expression of p27, thereby resulting in uncontrolled cell cycle progression. To date, most of the reported human mutations were missense. These mutations were deemed pathogenic due to their in vivo or in vitro effects on the function of p27. In humans, two CDKI families were identified: the INK4a/ARF and Cip/Kip family (7). Natalia Pellegata and colleagues reported in 2006 a three-generation family with apparently MEN1-related tumors, but turned out to become the first reported cases of MEN4 in humans (2). The incidence of CDKN1B mutations in patients with a MEN1-related phenotype is likely to be in the range of 1-4% (8-10). MEN4 screening is recommended for all patients with a MEN1-related phenotype without the presence of a MEN1 gene mutation. All first-degree relatives of patients with MEN4 should be offered genetic testing (11-13).

 

CLINICAL FEATURES OF MEN4

 

Primary Hyperparathyroidism

 

Primary hyperparathyroidism has been reported in up to 80%-90% of cases with MEN4 (3). The indications for parathyroid surgery in MEN4 are the same as for MEN1 and the approach in MEN4-related primary hyperparathyroidism may be similar to that in MEN1 (14, 15). It is suggested that screening for hyperparathyroidism with serum calcium measurements (and parathyroid hormone levels (PTH) if indicated) should start at the age of 15 years in MEN4 mutation carriers (16, 17).

 

Pituitary Adenomas

 

Pituitary involvement in MEN4 is the second most common manifestation of the disease, affecting approximately 1/3 of the reported cases to date. The types of pituitary disorders in MEN4 include: nonfunctional pituitary adenoma, acromegaly and gigantism, prolactinoma, or Cushing’s disease (13, 18-27). Pituitary tumors in MEN4 generally present with less aggressiveness and smaller size compared to those in MEN1 (21). The management of pituitary tumors in MEN4 is similar to other sporadic or familial cases (14). Routine surveillance for the development of pituitary tumors in patients with MEN4 should be performed on a case-by-case basis and following the current guidelines for MEN1 (14, 17).

 

Gastroenteropancreatic Neuroendocrine Neoplasms (GEP NENs)

 

The prevalence of GEP NENs in MEN4 is approximately 25%. These include gastroduodenal or pancreatic NENs (panNENs), which are either nonfunctioning or secreting several peptides and hormones, including gastrin, insulin, adrenocorticotropic hormone (ACTH), or vasoactive intestinal polypeptide (VIP) (10, 15, 18, 28, 29). It appears that there is a decreased penetrance of gastroduodenal NENs or panNENs in MEN4 as compared to MEN1. The clinical syndromes associated with these hormonal overproductions can be found elsewhere (30-33). The diagnosis and management of panNENs in MEN4 is similar to that in MEN1 (14). Screening for gastroduodenal NENs and panNENs should be initiated according to MEN1 screening protocols (14).

 

Other Neoplasms

 

Cervical neuroendocrine carcinoma (NEC), secreting and non-secreting adrenal tumors, testicular cancer, breast cancer, papillary thyroid cancer, colon cancer, carcinoid, and meningioma have been reported in MEN4 cases (2, 8, 10, 12, 16, 27).

 

REFERENCES

 

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