ABSTRACT

In evaluating a patient with dyslipidemia, the initial step is to decide which particular lipid/lipoprotein abnormalities need to be evaluated and whether they need treatment. These disorders can be divided into elevations of LDL-C, TGs, non-HDL-C, and Lp(a) and decreases in plasma HDL-C. Frequently a patient can have multiple lipid/lipoprotein abnormalities. The next step is to rule out secondary causes that could account for the abnormal lipid/lipoprotein levels. These secondary causes can be due to diet, various disease states, or drug therapy. One should be suspicious of a secondary cause if a patient suddenly develops a lipid/lipoprotein abnormality or the lipid/lipoprotein profile suddenly worsens. Next one should consider the possibility of a genetic disorder and therefore ask whether relatives have either premature cardiovascular disease, lipid disorders, or are receiving lipid lowering medications. If the TG levels are markedly elevated one should inquire about a family history of pancreatitis. When the lipid/lipoprotein abnormality is markedly abnormal or begins at a young age, the likelihood of a genetic disorder is increased, and the family history assumes even greater importance. In most circumstances a routine lipid panel consisting of plasma TGs, total cholesterol, HDL-C, and calculated LDL-C and non-HDL-C provides sufficient information to appropriately decide on who to treat and the best treatment approach. However, it should be recognized that there are certain situations where more sophisticated and detailed laboratory studies can be helpful. The purpose of treating lipid disorders is to prevent the development of other diseases, particularly cardiovascular disease. Thus, the decision to treat should be based on the risk of hyperlipidemia leading to those medical problems. Several guidelines have been published that discuss cardiovascular risk assessment in detail and provide recommendations on treatment strategies. Additionally, calculators are available on-line to determine an individual patient’s risk of developing cardiovascular disease in the next 10 years or their lifetime risk. In the prevention of cardiovascular disease, the main priority is to lower the LDL-C levels. Reductions in other apolipoprotein B containing lipoproteins may be instituted if LDL-C levels are at goal. Depending on the specific guideline the percent reduction in LDL-C and/or the goal LDL-C will vary depending upon the patient profile. When LDL-C levels are at goal but TG and non-HDL-C levels are still elevated a recent study suggests further treatment with icosapent ethyl may be beneficial. Whether decreasing Lp(a) is beneficial in preventing cardiovascular disease is uncertain and further studies are in progress. Lifestyle changes are the initial treatment but in most patients’ drug therapy will be necessary.

INTRODUCTION

The initial step is to decide which particular lipid/lipoprotein abnormalities need to be evaluated and whether they need treatment. These disorders can be divided into elevations of LDL-C, triglycerides (TGs), non-HDL-C, and Lp(a), and decreases in HDL-C. An increase in non-HDL-C accompanies an increase in LDL-C and/or TGs levels. Often a patient can have multiple lipid/lipoprotein abnormalities. For example, it is not uncommon for a patient to have high TGs with low HDL-C levels or high LDL-C and high Lp(a) levels.

From a clinical point of view, one is not usually concerned if the LDL-C, Lp(a), or TG levels are low or if the HDL-C level is high. Very low levels of LDL-C and/or TGs suggest the presence of other medical issues such as hyperthyroidism, malabsorption, liver disease, chronic infections, cancer, etc. On rare occasions very low LDL-C levels or TG levels can be due to genetic disorders (1). Very high HDL-C levels can also be due to genetic causes (2).

RULE OUT SECONDARY CAUSES

The next step is to rule out secondary causes that could account for the abnormal lipid/lipoprotein levels. These secondary causes can be due to diet, various disease states, or medications. One should be suspicious of a secondary cause if a patient suddenly develops a lipid/lipoprotein abnormality or the lipid/lipoprotein profile suddenly worsens. Patients with genetic abnormalities causing dyslipidemia can have their disorder worsen if they develop secondary causes that further adversely affect lipid/lipoprotein levels.

The key is that if one corrects the secondary cause the lipid/lipoprotein abnormality can often markedly improve or even disappear. For example, hypothyroidism can be accompanied by striking increases in LDL-C levels and the treatment of hypothyroidism can result in a large decrease in LDL-C, often to normal levels (3). Likewise, an improvement in glycemic control in a patient with poorly controlled diabetes may result in a large decrease in serum TG levels (4). Occasionally, the presence of dyslipidemia leads to the discovery of an unrecognized secondary disorder that requires treatment.

Similarly stopping certain drugs can greatly improve the lipid profile (5). For example, in some postmenopausal women with hypertriglyceridemia stopping oral estrogen therapy can result in a marked decrease in TG levels (3). The disorders and drugs that cause lipid/lipoprotein abnormalities are shown in tables 1-7. It should be noted that many disorders and drugs can cause multiple lipid abnormalities. The effects of disorders and drugs in an individual patient can vary depending on genetic background and the presence of other disorders and drugs that effect lipid/lipoprotein levels. For an extensive discussion of the secondary disorders that alter lipid and lipoprotein metabolism please refer to the individual Endotext chapters on these disorders. For additional information on the effect of drugs on lipid and lipoprotein metabolism please see the Endotext chapter on this topic (5).

In a patient with an elevated LDL-C level, one should take a diet history, review the medication list, and check a TSH level to rule out hypothyroidism. Most of the disorders that cause elevations in LDL-C levels, other than hypothyroidism, should be obvious on routine history, physical examination, and laboratory screening. In a patient with an elevated TG level, one should take a diet history and in particular focus on the ingestion of simple sugars and ethanol. One should review the medication list and recognize that many common disease states can adversely impact TG levels including obesity, poorly controlled diabetes, chronic renal failure, HIV, and inflammatory disorders (4,6-9). Weight loss, improvements in glycemic control in patients with diabetes, and a reduction of inflammation can all result in a decrease in TG levels  (4,7,8). In a patient with a low HDL-C level one should review the medication list and diet, recognizing that diets very low in fat can result in low HDL-C levels, which are often accompanied by low LDL-C and TG levels (10). In young or very fit males with very low HDL-C levels a careful history directed at anabolic steroid use is essential (3).

THINK ABOUT GENETIC CAUSES

One should always consider the possibility of a genetic disorder and therefore ask whether relatives have either premature cardiovascular disease, lipid disorders, or are taking lipid lowering medications (11). If the TG levels are markedly elevated one should inquire about a family history of pancreatitis. When the lipid/lipoprotein abnormality is markedly abnormal or begins at a young age, the likelihood of a genetic disorder is increased, and the family history assumes even greater importance. It is essential to think about the possibility of a genetic disorder because many of the common lipid disorders, such as familial hypercholesterolemia and elevations in Lp(a), have an autosomal codominant genetic transmission and therefore will be present in approximately 50% of family members (12-16). The recognition of the possibility of a genetic disorder will lead to screening family members and if abnormalities are found early treatment can be initiated, which may prevent the adverse consequences of hyperlipidemia. The monogenetic disorders that cause elevations in LDL-C and TGs levels and low HDL-C levels are shown in tables 8-11.

In autosomal codominant disorders heterozygotes have lipid abnormalities approximately half as severe as homozygotes

In autosomal codominant disorders heterozygotes have lipid abnormalities approximately half as severe as homozygotes

Very frequently hypertriglyceridemia and/or hypercholesterolemia are due to polygenic inheritance secondary to combinations of common small effect genes that regulate the production or catabolism of lipoproteins (17). Additionally, some individuals who are heterozygotes for the gene abnormalities described in table 9 will have elevated TG levels. In addition, lifestyle, other disease states, and medications can interact with genetic susceptibilities to result in marked dyslipidemia and therefore even when a genetic disorder is present one should not ignore reversible factors where appropriate treatment can have marked effects on lipid levels. Often secondary factors facilitate the expression of genetic variations to result in an abnormal lipid phenotype. One of the best examples of the interaction of secondary factors and genetic variants is familial dysbetalipoproteinemia (18-20). The apolipoprotein E2/E2 polymorphism occurs in approximately 1% of individuals whereas the clinical disorder only occurs in 1-5/5000 and is frequently associated with other disorders, such as obesity, hypothyroidism, and diabetes, which also perturb lipid metabolism. A detailed discussion of the genetic disorders that affect plasma lipid and lipoprotein levels can be found in the individual Endotext chapters that focus on these disorders.

ORDERING SPECIAL LABORATORY STUDIES

In most circumstances a routine lipid panel consisting of TGs, total cholesterol, HDL-C, and calculated LDL-C and non-HDL-C provides sufficient information to appropriately decide on who to treat and the best treatment approach. In a patient with high fasting TGs (>200-400mg/dl) where the LDL-C cannot be accurately calculated measurement of direct LDL-C may be helpful. However, it should be recognized that there are certain situations where more sophisticated and detailed laboratory studies can be helpful (21). Indications for measuring Lp(a) are shown in Table 12 (21,22). Note, it is the opinion of many experts and recommended by some guidelines that Lp(a) should be measured once in all individuals. The various specialized lipid and lipoprotein studies and their appropriate use are discussed in detail in the Endotext chapter “Utility of Advanced Lipoprotein Testing in Clinical Practice” (21). 

Note: It is the opinion of some experts that Lp(a) should be measured once in all individuals

DECIDING WHO TO TREAT

The purpose of treating lipid disorders is to prevent the development of other diseases, particularly cardiovascular disease. Thus, the decision to treat should be based on the risk of the hyperlipidemia leading to those medical problems. These issues are discussed in detail in the chapters on Risk Assessment and Guidelines for the Management of High Blood Cholesterol and TGs  (23-25). In addition to cardiovascular complications, marked elevations in TGs can lead to pancreatitis (23,26). The National Lipid Association recommends treating TG levels greater than 500mg/dl while the Endocrine Society recommends treating TGs if they are greater than 1000mg/dl to lower the risk of pancreatitis (27,28).

GOALS OF THERAPY

The current American College of Cardiology/American Heart Association (ACC/AHA) guidelines do not emphasize specific lipid/lipoprotein goals of therapy but rather to just treat with the statins to lower LDL-C by a certain percentage (29). An exception is that they do recommend in patients with very high-risk ASCVD, to use an LDL-C threshold of 70 mg/dL to consider addition of non-statins to statin therapy. In contrast, other groups, such as the National Lipid Association, International Atherosclerosis Society, European Society of Cardiology/European Atherosclerosis Society, and AACE, do recommend lowering the LDL and non-HDL cholesterol levels to below certain levels depending upon the cardiovascular risk in a particular patient but the recommendations from these organizations are not identical (28,30-33).

A detailed discussion of lipid/lipoprotein goals is provided in the chapter on Risk Assessment and Guidelines for the Management of High Blood Cholesterol (25). It should be noted that many lipid experts would recommend trying to achieve an LDL-C levels less than 70mg/dl and non-HDL-C levels less than 100mg/dl in patients with cardiovascular disease or patients at very high risk for the development of cardiovascular disease. In other patients, an LDL-C level less than 100mg/dl and non-HDL-C level less than 130mg/dl is a reasonable goal. AACE and European Society of Cardiology/European Atherosclerosis Society have recommended LDL-C levels less than 55mg/dl in patients at very high risk (30,31,33). With the results of the IMPROVE-IT trial and PCKS9 inhibitor studies, which showed that adding ezetimibe or a PCSK9 inhibitor to statin therapy resulted in an additional decrease in LDL-C levels and a further reduction in cardiovascular events, the arguments in favor of trying to reach lower lipid/lipoprotein goals has been greatly strengthened  (34-36). Moreover, the results of these and other studies provide strong support that the lower the LDL-C level the greater the reduction in cardiovascular events (37,38).     

TREATMENT TO REDUCE COMPLICATIONS OF DYSLIPIDEMIA

The first priority in treating lipid disorders is to lower the LDL-C levels to goal, unless TGs are markedly elevated (> 500-1000mg/dl), which increases the risk of pancreatitis. LDL-C is the usual first priority because the data linking lowering LDL-C with reducing cardiovascular disease are extremely strong and we now have the ability to markedly decrease LDL-C levels. Dietary therapy is the initial step but in the majority of patients’ dietary modifications 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 (10). Additionally, the dietary changes need to be sustained for a long period of time to be effective and many patients while able to follow an LDL-C lowering diet in the short term are unable to follow the diet for an extended period of time.

Primary Prevention Patients

The first step is determining the risk for developing atherosclerotic cardiovascular disease. There are a number of different calculators for determining risk. In the US the most popular is the ACC/AHA risk calculator) (29) or the PREVENT risk calculator (39) whereas in Europe the SCORE (Systematic Coronary Risk Estimation) is popular (31,40). The ACC/AHA recommendations are shown in Figure 1 and the European Society of Cardiology/European Atherosclerosis Society recommendations are shown in Figure 2.

Figure 1. ACC/AHA Recommendations for Patients without ASCVD, Diabetes, or LDL-C greater than 190mg/dl (29). Risk enhancers are listed in table 13. (Note the risk is for MI and stroke, both fatal and nonfatal).

Figure 2. European Society of Cardiology/European Atherosclerosis Society Recommendations for Primary Prevention Patients (31). Risk categories are shown in table 14 and goals of therapy in Table 15 and 16. (Note that the SCORE risk is for a fatal event). There are different tables for different European countries.

A few caveats are worth noting. First, in patients less than 60 years of age it is very helpful to calculate the life-time risk of ASCVD events. Often one will find that the 10-year risk is modest, but the life-time risk is high and this information should be included in the risk discussion to help in the decision process. Second, patients should be made aware of the natural history of ASCVD i.e., that it begins early in life and slowly progresses overtime with high LDL-C levels accelerating the rate of development of atherosclerosis and low LDL-C leading to a slower progression of atherosclerosis (38,41). Third, patients should be made aware of genetic studies demonstrating that variants in genes that lead to lifetime decreases in LDL-C levels (for example the HMG-CoA reductase gene, NPC1L1 gene, PCSK9 gene, ATP citrate lyase gene, and LDL receptor gene) result in a decreased risk of cardiovascular events. In a recent study it was reported that a 10mg/dL lifetime decrease in LDL-C with any of these genetic variants was associated with a 16-18% decrease in cardiovascular events whereas a 10mg/dl reduction in LDL-C with lipid lowering therapy later in life results in only approximately a 5% decrease in cardiovascular events (37,42,43). The combination of the natural history and the results observed with genetic variants strongly suggests that early therapy to lower LDL-C levels will have greater effects on reducing the risk of ASCVD events than starting therapy later in life. This information needs to be discussed with the patient. Fourth, if the patient or health care provider are uncertain of the best course of action obtaining a cardiac calcium scan can be very helpful in the decision-making process, particularly in older individuals. A score of 0, particularly in an older patient would indicate that statin therapy is not needed whereas a score > 100 would indicate a need for statin therapy (29). A score of 1-99 favors the use of a statin (29).

In most primary prevention patients, statin therapy is sufficient to lower LDL-C levels to goal (< 100mg/dL or < 70mg/dL depending upon patient’s risk). One can usually start with moderate statin therapy (for example atorvastatin 10-20mg or rosuvastatin 5-10mg) and increase the statin dose, if necessary, to achieve LDL-C goals. Statins are available as generic drugs and therefore are relatively inexpensive. If a patient does not achieve their LDL-C goal on intensive statin therapy, cannot tolerate statin therapy, or is able to take only a low dose of a statin one can use ezetimibe (generic drug), bempedoic acid, bile acid sequestrants, or PCSK9 inhibitors to further lower LDL-C levels (for detailed discussion of cholesterol lowering drugs see (44)). It should be noted that the addition of ezetimibe or a PCSK9 inhibitor to statin therapy has been shown to reduce cardiovascular events (34-36). In most situations, ezetimibe is the drug of choice given its low cost, ability to reduce ASCVD events, and long-term safety record. If LDL-C is not close to goal PCSK9 inhibitors can be used. In patients intolerant of statin therapy bempedoic acid has been shown to reduce cardiovascular disease (45). Once LDL-C is at goal if the non-HDL-C remains high one can consider the approaches described in the section describing the approach to patients with LDL-C at goal with elevated TGs.

Patients with LDL Cholesterol Greater than 190mg/dl

When the LDL-C is greater than 190mg/dl the patient should be started on intensive statin therapy (atorvastatin 40-80mg per day or rosuvastatin 20-40mg per day). If the LDL-C goal is not achieved (usually < 100mg/dL but if patient is high risk < 70mg/dL) additional lipid lowering medications should be added. If the LDL-C is relatively close to goal one can use ezetimibe but if the LDL-C is far from the goal the use of a PCSK9 inhibitor should be employed. Because of the potential for a genetic disorder, either monogenic or polygenic, one should check family members for lipid abnormalities. If possible genetic testing for monogenic disorders causing hypercholesterolemia is recommended (46).

Patients with Diabetes

Most patients with diabetes (age 40-75) without risk factors should be started on moderate statin therapy (for example atorvastatin 10-20mg or rosuvastatin 5-10mg). In young individuals (< age 40) and older individuals (> age 75) one needs to use clinical judgment. Patients with diabetes with ASCVD or risk factors should be started on intensive statin therapy. In my opinion reasonable goals are shown in table 17 (similar to AACE and ADA guidelines) (30,47). If intensive statin therapy does not achieve LDL-C goals additional drugs can be added. If reasonably close to the LDL-C goal the initial drug added should be ezetimibe. If far from goal one could add a PCSK9 inhibitor. Once LDL-C is at goal if the non-HDL-C remains high one can consider the approaches described in the section describing the approach to patients with LDL-C at goal with elevated TGs.

Secondary Prevention Patients

Patients with ASCVD (secondary prevention patients) should be started on intensive statin therapy (atorvastatin 40-80mg per day or rosuvastatin 20-40mg per day). Given the extensive data showing that the lower the LDL-C the greater the reduction in ASCVD events most secondary prevention patients would benefit from the addition of ezetimibe to maximize LDL-C lowering without markedly increasing costs (37,38). The goal LDL-C in this patient population at a minimum is an LDL<70mg/dL but many experts and some guidelines would prefer an LDL-C<55mg/dL if possible. If on intensive statin therapy and ezetimibe treatment the LDL-C is far above goal one could consider adding a PCSK9 inhibitor (this is particularly necessary if the LDL-C is greater than 100mg/dL or the patient is at very high risk due to other factors (diabetes, cerebral vascular disease, peripheral vascular disease, recent MI, history of multiple MIs) (37,38).

Patients with LDL Cholesterol at Goal but High TGs (>150mg/dL to <500mg/dL)

Patients with an LDL-C at goal but high TG levels (>150mg/dL to <500mg/dL) will often have increased non-HDL-C levels. Numerous studies have shown that the risk of ASCVD events is increased in this patient population (48). The initial step should be to improve lifestyle, treat secondary disorders that may be contributing to the increase in TGs, and if possible, discontinue medications that increase TG levels. In the era of statin therapy, it is uncertain whether lowering TG levels in patients on statin therapy will further reduce cardiovascular events. Studies have not demonstrated a reduction in cardiovascular events when niacin is added to statin therapy and given the side effects of niacin enthusiasm for using niacin in combination with statins to reduce ASCVD is limited (49,50). Additionally, the ACCORD-LIPID trial failed to demonstrate that adding fenofibrate to statin therapy (51) and the PROMINENT trial failed to demonstrate that adding pemafibrate to statin therapy (52) reduces cardiovascular disease. Thus, there is little evidence that adding either niacin or a fibrate to statin therapy will be beneficial in reducing cardiovascular events.

The REDUCE-IT trial demonstrated that adding the omega-3-fatty acid icosapent ethyl (EPA; Vascepa) to statin therapy in patients with elevated TG levels reduced the risk of ASCVD events by 25% while decreasing TG levels by 18% (53). Similar results were seen in the JELIS and RESPECT-EPA trials (54,55). In these trials the reduction in TG levels was relatively modest and would not have been expected to result in the magnitude of the decrease in cardiovascular disease observed. Other actions of EPA, such as decreasing platelet function, anti-inflammation, decreasing lipid oxidation, stabilizing membranes, etc. could account for or contribute to the reduction in cardiovascular events (56). It should be recognized that the STRENGTH and OMEMI trials using EPA and DHA failed to reduce cardiovascular events despite reducing TG levels to a similar degree as in the REDUCE-IT trial (57,58). Whether EPA has special properties that resulted in the reduction in cardiovascular events in the REDUCE-IT, JELIS, and RESPECT-EPA trials or there were flaws in these trials is debated (56,59). Clinicians will need to balance the potential benefits vs. potential side effects and decide for the individual patient whether to treat with EPA (icosapent ethyl). For a detailed discussion of TG lowering drugs see the Endotext chapter on this topic (60).

Patients with Very High TG Levels (>500-1000mg/dL)

The main aim is to keep TG levels below 500 mg/dL to prevent TG-induced pancreatitis (26,61).

FAMILIAL HYPERCHYLOMICRONEMIA (FCS)

FCS is a rare autosomal recessive disorder due to an abnormality in the genes listed in table 9 that result in the absence of functional lipoprotein lipase (LPL) activity (61-63). Patients with FCS respond poorly to most TG lowering drugs (fibrates, omega-3-fatty acids, niacin) (61-63). A very low-fat diet (5-10% of total calories) is the most effective treatment but can be difficult for many patients to comply with (61-63). Orlistat has been effective in lowering TG levels (63). Apo C-III inhibitors are approved in the US and Europe and lower Apo C-III levels and are very effective in lowering TG levels in patients with FCS (60,63). Additionally, they also reduce episodes of pancreatitis (60).

MULTIFACTORIAL CHYLOMICRONEMIA SYNDROME (MCS)

MCS is due to the coexistence of a genetic predisposition (polygenic or heterozygous for genes that cause FCS) for hypertriglyceridemia with 1 or more secondary causes of hypertriglyceridemia (see tables 3 and 4) (18,26,61,62). Initial treatment is a very low-fat diet to reduce TG levels into a safe range (<1000mg/dL). Treating secondary disorders that raise TG levels and when possible, stopping drugs that increase TG levels is essential (18,26,61,62). If the TG levels remain above 500mg/dL the addition of fenofibrate or omega-3-fatty acids is indicated. Many patients with MCS are at high risk for ASCVD and therefore after TG levels are controlled the patient should be evaluated for cardiovascular disease risk and if indicated statin therapy initiated.   

Patients with High Lp(a) Levels

Life style changes do not significantly lower Lp(a) levels (64). The effect of lipid lowering drugs on Lp(a) levels is shown in Table 18. In patients with elevations in Lp(a) the initial therapy is to aggressively control the other cardiovascular disease risk factors. In some instances, one can use niacin, PCSK9 inhibitors, or in postmenopausal women estrogen to lower Lp(a) levels but the effect of these drugs on preventing cardiovascular events by lowering Lp(a) levels is uncertain (16,65). Studies of an antisense oligonucleotide or small interfering RNA (both not yet approved) directed at apo(a) have shown that these drugs can lower Lp(a) by >75% without effecting other lipoprotein levels (66,67). Lipoprotein apheresis can be employed to lower Lp(a) in patients with very high Lp(a) levels who continue to have cardiovascular events despite optimal medical management (68).  

*only approved for the treatment of Homozygous FH; **not currently available

Decreased HDL Cholesterol Levels

Despite epidemiologic studies consistently showing that high HDL-C levels are associated with a decreased risk of cardiovascular disease there are no studies demonstrating that increasing HDL-C levels reduces cardiovascular disease (69). It should be recognized that the crucial issue with HDL may not be the HDL-C levels per se but rather the function of the HDL particles (69). Assays have been developed to determine the ability of HDL to facilitate cholesterol efflux from macrophages and these studies have shown that the levels of HDL-C do not necessarily indicate the ability to mediate cholesterol efflux (70). Similarly, the ability of HDL to protect LDL from oxidation may also play an important role in the ability of HDL to reduce ASCVD (71). Thus, the functional capability of HDL may be more important than HDL-C levels (69-71).

CONCLUSION

In summary, modern therapy demands that we aggressively evaluate and when indicated treat lipid disorders to reduce the risk of atherosclerotic cardiovascular disease and in those with very high TGs to reduce the risk of pancreatitis.

ACKNOWKEDGEMENTS

This work was supported by grants from the Northern California Institute for Research and Education.

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ABSTRACT 

The two major goals of the treatment of hypertriglyceridemia are the prevention of cardiovascular disease and pancreatitis. Here we discuss the drugs used for the treatment of hypertriglyceridemia: (niacin, fibrates, omega-3-fatty acids, and apo CIII inhibitors. Niacin decreases total cholesterol, TGs (20-50% decrease), LDL-C, and Lp(a). Additionally, niacin decreases small dense LDL resulting in a shift to large, buoyant LDL particles. Moreover, niacin increases HDL-C. Skin flushing, insulin resistance, and other side effects have limited the use of niacin. The enthusiasm for niacin has greatly decreased with the failure of AIM-HIGH and HPS-2 Thrive to decrease cardiovascular events when niacin was added to statin therapy. The omega-3-fatty acids eicosapentaenoic acid (C20:5n-3) (EPA) and docosahexaenoic acid (C22:6n-3) (DHA) lower TGs by 10-50% but do not affect total cholesterol, HDL-C, or Lp(a). LDL-C may increase with EPA + DHA when the TG levels are markedly elevated (>500mg/dL). EPA alone does not increase LDL-C. Omega-3-fatty acids have few side effects, drug interactions, or contraindications. Numerous studies of low dose omega-3-fatty acids on cardiovascular outcomes have failed to demonstrate a benefit. However, in the JELIS, REDUCE-IT, and RESPECT-EPA trials high doses of EPA alone reduced cardiovascular events while in the STRENGTH and OMEMI trials high doses of EPA+DHA did not reduce cardiovascular events. Fibrates reduce TG levels by 25-50% and increase HDL-C by 5-20%. The effect on LDL-C is variable. If the TG levels are very high (>500mg/dL), fibrate therapy may result in an increase in LDL-C, whereas if TGs are not markedly elevated fibrates decrease LDL-C by 10-30%. Fibrates also reduce apolipoprotein B, LDL particle number, and non-HDL-C and there may be a shift from small dense LDL towards large LDL particles. Fibrates do not have any major effects on Lp(a). Monotherapy with fibrates appears to reduce cardiovascular events particularly in patients with high TG and low HDL-C levels. In contrast, in the ACCORD LIPID and PROMINENT trials the addition of fibrates to statin therapy did not reduce cardiovascular disease, which has reduced the enthusiasm for using fibrates to reduce cardiovascular disease. In patients with diabetes fibrates appear to slow the progression of microvascular disease (retinopathy, nephropathy, and amputations, ulcers, and gangrene. Antisense oligonucleotides, volanesorsen and olezarsen, inhibit the production of apolipoprotein C-III and decrease TG levels in patients with severe hypertriglyceridemia including patients with the familial chylomicronemia syndrome (FCS). Studies also suggest that apo CIII inhibitors reduce episodes of pancreatitis in patients with severe hypertriglyceridemia. Patients with FCS have also reported that apo C-III inhibitors improved symptoms and reduced interference of FCS with work/school responsibilities. Of concern has been decreases in platelet levels with 47% of patients treated with volanesorsen developing platelet counts below100 x 109/L, a side effect that is not observed with olezarsen. Thus, a number of drugs are available for the treatment of hypertriglyceridemia and may be employed when lifestyle changes are not sufficient. 

INTRODUCTION

The two primary goals of the treatment of hypertriglyceridemia are the prevention of cardiovascular disease and the prevention of pancreatitis. The evaluation and guidelines for the management of hypertriglyceridemia are discussed in detail in the Endotext chapters “Risk of Fasting and Non-Fasting Hypertriglyceridemia in Coronary Vascular Disease and Pancreatitis” (1) and Pancreatitis Secondary to Hypertriglyceridemia (2), and the approach to evaluating a patient with hypertriglyceridemia is discussed in the Endotext chapter “Approach to the Patient with Dyslipidemia” (3). The treatment of hypertriglyceridemia by diet and weight loss are discussed in detail in the Endotext chapters “The Effect of Diet on Cardiovascular Disease and Lipid and Lipoprotein Levels” and “Obesity and Dyslipidemia” (4,5). Lifestyle changes are recommended as the first line for hypertriglyceridemia therapy, but drug therapy is often required. In this chapter we will discuss the drugs used for the treatment of elevated plasma TG levels. Statins, ezetimibe, PCSK9 inhibitors, bempedoic acid, lomitapide, mipomersen, and evinacumab, which are primarily used to lower LDL-C, are discussed in the chapter “Cholesterol Lowering Drugs” (6).  

NIACIN

Introduction

Niacin was the first drug approved to treat dyslipidemia. In 1955, Altschul et al showed that pharmacologic doses of niacin decreased plasma cholesterol levels (7). Several forms of niacin are available for clinical use. Immediate release niacin has a short duration of action and is typically given two or three times per day with meals, whereas sustained release niacin and extended-release niacin are once a day drugs usually given at bedtime. The extended release form of niacin exhibits release rates that are intermediate between immediate release niacin and sustained release niacin (8). While the effects of the various forms of niacin on plasma lipid levels are similar, the side effect profiles are different. Because of an increased risk of serious liver toxicity with sustained release niacin this preparation is no longer widely used to treat dyslipidemia. Over-the- counter “No flush” niacin is also available but is generally ineffective as a lipid-modifying agent because most of these preparations do not contain active nicotinic acid.    

Effect of Niacin on Lipid and Lipoprotein Levels

Niacin decreases all the pro-atherogenic lipid and lipoprotein particles including total cholesterol, TG, LDL-C, and Lp(a) levels (Table 1) (9,10). Additionally, niacin has been shown to decrease small dense LDL resulting in a shift to large, buoyant LDL particles (11). Moreover, niacin increases HDL-C levels (9,10).

In a meta-analysis of 30 trials with 4,749 subjects treatment with immediate release, sustained release, or extended release niacin decreased total cholesterol by 10%, decreased TGs by 20%, decreased LDL-C by 14%, and increased HDL-C by 16% (12). All three niacin preparations were effective in decreasing total cholesterol, TG, and LDL-C levels and increasing HDL-C levels (12). At a dose of 1.5 grams per day, immediate release niacin and extended release niacin produced similar decreases in total cholesterol, TGs, and LDL-C and a similar increase in HDL-C (13). A meta-analysis of 14 studies with 9,013 subjects reported a 23% decrease in Lp(a) with extended release niacin treatment (14).

A small meta-analysis of 5 trials in 432 subjects compared the response to extended release niacin in men and women (15). The effect of niacin on LDL-C was greater in women than men at all niacin doses (1,000mg 6.8% decrease in women vs 0.2% in men, p = 0.006; 1,500mg 11.3% decrease vs 5.6% decrease, p = 0.013; 2,000 mg 14.8% decrease vs 6.9% decrease, p = 0.010; 3,000mg 28.7% decrease vs 17.7% decrease, p = 0.006). The effect of niacin on plasma TG levels also tended to be greater in women but the difference only reached statistical significance at the 1,500mg dose (28.6% vs 20.4%, p = 0.040). The mechanism for the more robust decrease in LDL-C and TGs in women is unknown but might be due to a smaller body mass in women leading to increased circulating niacin levels and hence a greater response. However, the effect of niacin on HDL-C and Lp(a) levels were similar in males and females. Not unexpectedly the effect of niacin is dose dependent with higher doses having a greater effect on plasma lipid and lipoprotein levels (Table 2) (15).

Numerous studies have examined the effect of the addition of niacin to statin therapy. Combination therapy typically results in further reductions in atherogenic lipoprotein particles and an increase in HDL-C levels. An example of such a study is shown in Table 3 (16).

While a literature search did not find any studies comparing the combination of ezetimibe + niacin vs. monotherapy there is a large trial that has examined the effect of adding 2 grams niacin to ezetimibe/simvastatin 10/20 (17). In this study the addition of niacin improved the lipid profile with a marked decrease in TGs and an increase in HDL-C levels (table 4).

In patients with marked hypertriglyceridemia combining niacin with other drugs that also lower plasma TGs can be considered. Sixty patients with the metabolic syndrome were randomized to 16 weeks of treatment with placebo, omega-3-fatty acids (Lovaza 4 g/day), extended release niacin (2 g/day), or both drugs in combination (18). In the niacin group TGs decreased by 30%, in the omega-3-fatty acids group by 22%, and in the combination group by 42% compared to the placebo group. Of note, the beneficial effects of niacin on decreasing LDL-C and non-HDL-C levels were blunted by omega-3-fatty acids, which are known to raise LDL-C levels in patients with marked hypertriglyceridemia (see below). These results show that the combination of niacin and fish oil will lower TG levels more than either drug individually but at the expense of diminishing the effect of niacin on LDL and non-HDL-C levels.   

Surprisingly there are few large, randomized trials examining the effect of combination therapy with niacin + fibrate vs. monotherapy. One very small trial reported that while both niacin monotherapy and bezafibrate monotherapy were effective in lowering serum TGs there was no statistically significant added benefit of combination therapy in reducing serum TG levels (19). However, a larger trial in HIV+ patients reported that the combination of niacin and fenofibrate was better at lowering TGs and non-HDL-C and increasing HDL-C levels than monotherapy with either niacin or fenofibrate (20). It would be informative if additional trials of combination therapy were carried out in patients with marked hypertriglyceridemia that can often be difficult to control with lifestyle changes and monotherapy.

Mechanisms Accounting for the Niacin Induced Lipid Effects

TRIGLYCERIDES

Early studies demonstrated that niacin inhibited the release of free fatty acids from cultured adipocytes and decreased circulating free fatty acid levels (21-23). The ability of niacin to inhibit adipose tissue lipolysis is mediated by the activation of GPR109A (hydroxycarboxylic acid 2 receptor), a G protein-coupled receptor that is highly expressed in adipose tissue (23-25). It was initially thought that the decrease in plasma TGs induced by niacin therapy was due to niacin inhibiting lipolysis in adipose tissue resulting in a decrease in the transport of fatty acids to the liver leading to the decreased availability of fatty acids for hepatic TG synthesis. However, studies have shown that while niacin acutely decreases plasma free fatty acid levels this inhibition is not sustained (26). Additionally, studies in mice lacking GPR109A have shown that niacin does not inhibit lipolysis but still decreases plasma TG and LDL-C levels (27). Moreover, studies in humans using GPR109A agonists lowered plasma free fatty acid levels but did not cause the expected effects on plasma TGs and LDL-C (27). Thus, the effects of niacin on adipose tissue lipolysis are no longer thought to mediate the niacin induced decrease in plasma TG levels.

Niacin has been shown to inhibit diglycerol acyltransferase 2 (DGAT2) activity in the liver (23,28). DGAT2 is the key enzyme that catalyzes the final step in TG synthesis. Inhibition of DGAT2 will reduce hepatic TG synthesis and the availability of TG for VLDL assembly and secretion (23). A decrease in TG will result in an increase in apolipoprotein B degradation in the liver. Kinetic studies in humans have shown that treatment with niacin decreases VLDL TG production (29,30).

In addition, in animal models, niacin reduces the hepatic expression of apolipoprotein C-III, which could result in the accelerated clearance of TG rich lipoproteins (31). Whether this plays a significant role in mediating the decrease in plasma TG levels induced by niacin therapy remains to be determined.

LOW DENSITY LIPOPROTEIN

The decrease in plasma LDL-C with niacin therapy is thought to be secondary to a reduction in VLDL and LDL formation and secretion by the liver (23).

HIGH DENSITY LIPOPROTEIN

There are multiple potential mechanisms by which niacin may increase HDL-C levels. Some of these changes may be anti-atherogenic while others may be pro-atherogenic. One hypothesis for the increase in HDL induced by niacin therapy is a decrease in the surface expression of hepatocyte beta chain ATP synthase, a receptor that has been proposed to be involved in the uptake of HDL particles by the liver (32). Studies have further shown that niacin inhibits HDL protein degradation by cultured hepatocytes but does not inhibit the selective uptake of cholesterol esters carried in HDL (23,33).

Some kinetic studies have shown that niacin decreases HDL and apolipoprotein A1 fractional catabolic rate (34,35). In contrast, other kinetic studies have shown that niacin increase apolipoprotein AI production (36).

In addition, in monocytes, niacin also increased the expression of ABCA1 and CD36 resulting in an increase in cholesterol efflux to HDL, which would increase HDL-C levels and likely have anti-atherogenic effects (37). Similarly, in vitro studies suggest that niacin may increase the transport of cholesterol and phospholipids via ABCA1 from the liver to lipid poor apolipoprotein A1 particles thereby decreasing the clearance of apolipoprotein A1, which might not be anti-atherogenic (23,38).

Finally, decreasing plasma TG levels may result in a reduction in CETP mediated exchange of TGs on VLDL for cholesterol on HDL leading to an increase in HDL-C levels. Additionally, studies have shown that niacin decreases the expression of CETP (39).

LIPOPROTEIN(a)

Niacin decreases the synthetic rate of Lp(a) but does not increase Lp(a) catabolism (40,41). In cell culture and animal studies niacin has been shown to decrease the expression of apo (a) (42).

Pharmacokinetics  

Oral niacin is well absorbed with immediate release niacin resulting in a rapid increase in plasma levels while extended release and sustained release niacin result in a delayed peak in plasma levels. Niacin undergoes metabolism in the liver by two primary pathways; conjugation or amidation (8,43). The conjugative pathway is low affinity and high capacity that metabolizes niacin to nicotinuric acid while the amidation pathway is high affinity and low capacity that converts niacin into several oxidative-reductive intermediates, which can induce hepatic toxicity (8,43) (Figure 1). The clinical importance is that immediate release niacin results in high levels of niacin and therefore is primarily metabolized by the conjugative pathway (low affinity, high capacity), which does not result in toxic intermediates that can cause liver damage. In contrast, sustained release niacin results in lower levels of niacin for a longer period and therefore metabolism via the amidation pathway (high affinity, low capacity) is dominant leading to an increase in the formation of toxic intermediates that can induce hepatic injury (8,43). Extended-release niacin would be metabolized midway between immediate release and sustained release

niacin (43).

Figure 1. Pathways of Niacin Metabolism.

Effect of Niacin on Cardiovascular Outcomes 

MONOTHERAPY

The Coronary Drug Project, conducted between 1966 and 1975, was the first large randomized, double-blind clinical trial to show that lowering lipids reduced cardiovascular disease (44). This trial determined the effect of clofibrate (1.8g/day), dextrothyroxine (6mg/day), two doses of oral estrogen (2.5 or 5mg per day), or immediate release niacin (3 grams/day) vs. placebo in 8,341 men 30 to 64 years of age with an electrocardiogram documented myocardial infarction. The mean baseline total cholesterol level was 251mg/dL and the TG level was 183mg/dL. The two estrogen regimens and dextrothyroxine treatment groups were discontinued early because of increased adverse effects. Clofibrate treatment did not demonstrate clinical benefit. In the niacin treated patients there was an average 10% decrease in serum cholesterol and 26% decrease in serum TGs despite modest compliance with the study medication. Moreover, niacin treatment (n=1,119) decreased recurrent myocardial infarctions by 26%, stroke by 24%, and revascularization by 67% compared to placebo (n=2,789) but did not decrease total mortality, which was the primary endpoint. Long term follow-up (6.2 years during the study and 8.8 years post study after niacin was discontinued in most participants) demonstrated an 11% decrease in mortality in the niacin group vs. the placebo group (52.0 versus 58.2%; p = 0.0004) (45). The majority of this difference in mortality was accounted for by a decrease in coronary heart disease mortality (36.5% vs. 41.3%; p=0.005). Further analysis revealed that niacin reduced the risk of 6-year recurrent myocardial infarction and coronary heart disease death and 15-year total mortality similarly in patients at all levels of baseline fasting plasma glucose, including those with glucose levels ≥126mg/dL (i.e. patients with diabetes) (46). Additionally, the beneficial effect of niacin on cardiovascular events and total mortality was not diminished, even among those with one hour plasma glucose levels > 220mg/dL (46). Moreover, the beneficial effects of niacin on recurrent myocardial infarction and total mortality were similar in patients with or without the metabolic syndrome at baseline (47). These results demonstrate that immediate release niacin monotherapy decreases recurrent atherosclerotic cardiovascular events in a broad spectrum of patients with pre-existing cardiovascular disease (secondary prevention).

COMBINATION WITH FIBRATES

In the Stockholm Ischemic Heart Disease Secondary Prevention Study survivors of a myocardial infarction below 70 years of age were randomized to a control group (n = 276) (no placebo) and a group treated with clofibrate (2 grams) and immediate release nicotinic acid (up to 3 grams) (n = 279) (48). Serum cholesterol and TG were lowered by 13% and 19%, respectively, in the treatment group compared to the control group. Recurrent myocardial infarction was reduced by 50% within one year (49). Total mortality was decreased by 26% in the group treated with clofibrate + niacin (p< 0.05) while ischemic heart disease mortality was decreased by 36% (p< 0.01). Notably, the benefit of clofibrate + niacin was only observed in patients with a baseline TG level > 143mg/dL. In the age of statins, the clinical implications of this early study are unclear. 

COMBINATION WITH STATINS

The AIM-HIGH trial was designed to determine if the addition of Niaspan, an extended-release form of niacin, to aggressive statin therapy would result in a further reduction in cardiovascular events in patients with pre-existing cardiovascular disease (50). In this trial 3,314 patients were randomized to extended-release Niaspan (1500-2000mg/day) vs. placebo that contained 100-150mg of immediate release niacin. On trial, LDL-C levels were in the 60-70mg/dL range in both groups. As expected, HDL-C levels were increased in the Niaspan treated group (approximately 44mg/dL vs. 38mg/dL), while TGs were decreased (approximately 121mg/dL vs. 155mg/dL). However, there were no differences in the primary endpoint between the control and Niaspan treated groups (Primary endpoint consisted of the first event of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization). There were also no differences in secondary endpoints except for a possible increase in strokes in the Niaspan treated group. The addition of Niaspan to statin therapy did not result in a significant increase in either muscle or liver toxicity. Thus, this study does not provide support for the addition of niacin to statins. However, most of the patients included in this study did not have a lipid profile that one would typically consider treating with niacin therapy. In the subset of patients with TG > 198mg/dL and HDL-C < 33mg/dL Niaspan treatment showed a trend towards benefit (hazard ratio 0.74; p=0.073), suggesting that if the appropriate patient population was studied the results may have been different (51).

HPS 2 Thrive also studied the effect of niacin added to statin therapy (52). This trial utilized extended-release niacin (2000mg/day) combined with laropiprant, a prostaglandin D₂ receptor antagonist, which reduces the flushing side effect of niacin treatment. HPS 2 Thrive was a very large trial with over 25,000 patients randomized to either niacin therapy or placebo. As in the AIM HIGH study, the baseline LDL-C levels were low at 63mg/dL, the HDL-C levels were 44mg/dL, and the TGs were 125mg/dL at baseline. As expected, niacin therapy resulted in a modest reduction in LDL-C (10mg/dL), a modest increase in HDL-C (6mg/dL), and a marked reduction in TGs (33mg/dL) compared to placebo. However, despite these lipid changes there were no significant differences in major cardiovascular events between the niacin and control group (risk ratio 0.96 CI 0.90- 1.03). It is unknown whether laropiprant, the prostaglandin D₂ receptor antagonist, might have effects that worsen atherosclerosis and increase event rates. Mice deficient in the prostaglandin D2 receptor have been noted to have an increase in atherogenesis in response to angiotensin II (53). Similar to the AIM-HIGH study, the group of patients included in the HPS 2 Thrive trial may not have been the ideal patient population to study for the beneficial effects of niacin treatment added to statin therapy. Ideally, patients with high TGs and high non-HDL-C levels coupled with low HDL-C levels should be studied.

Thus, these two studies have failed to demonstrate that adding niacin to statin therapy results in a decrease in cardiovascular events. It should be recognized that both the AIM-HIGH study and the HPS-2 Thrive study had limitations. First, the patient populations that were included in these studies were not ideal as the TG and non-HDL-C levels were not elevated in a range that one would usually consider adding niacin therapy. Second, in both trials a significant percentage of patients stopped niacin therapy (AIM-HIGH 25.4% discontinued niacin; HPS-2 Thrive 25.4% discontinued niacin). Third, the duration of these studies was relatively short, and it is possible that the beneficial effects of niacin take longer to occur (AIM-HIGH 3 years; HPS-2 Thrive 3.9 years). Fourth, in the HPS-2 Thrive it is possible, as noted earlier, that laropiprant had adverse effects that increased the risk of cardiovascular events. Fifth, in the AIM-HIGH study the placebo contained a low dose of niacin, which may have resulted in beneficial effects. Finally, both of these trials used extended-release niacin, whereas the Coronary Drug Project and the Stockholm Ischemic Heart Disease Secondary Prevention Study used immediate release niacin. It is possible that these different formulations of niacin have different effects on cardiovascular events. Additional studies are required to definitively determine the effect of niacin added to a statin therapy on cardiovascular events.

Effect of Niacin on Atherosclerosis

Many of the initial niacin therapy imaging studies combined niacin with other drugs and compared these combinations vs. placebo. These studies showed that niacin in combination with other drugs reduced the progression and/or increased the regression of atherosclerosis. However, because of the use of other drugs it is impossible to determine if niacin therapy per se was beneficial (Table 5).

However, there are studies that compared niacin to placebo or other drugs added to standard statin therapy that do provide useful insights (Table 6).

The ARBITER 2 Trial was a double-blind randomized study of extended-release niacin (1000mg) vs. placebo added to background statin therapy in 167 patients with coronary heart disease and low HDL-C levels (<45mg/dL) (61). At the initiation of the study mean LDL-C levels were < 100mg/dL. The primary end point was the change in common carotid intima-media thickness (CIMT). As expected, plasma TGs decreased and HDL-C levels increased with niacin therapy. LDL-C levels were unchanged. After 12 months, the mean CIMT increased significantly in the placebo group (P<0.001) and was unchanged in the niacin group (P=0.23). The overall difference in CIMT progression between the niacin and placebo groups was almost statistically significant (P=0.08). Cardiovascular events occurred in 3 patients treated with niacin (3.8%) and 7 patients treated with placebo (9.6%; P=0.20). ARBITER 3 was a 12-month extension and in the 57 patients that continued on niacin therapy there was an additional regression of CIMT (p = 0.001 vs. placebo) (60).

In ARBITER 6, patients with coronary heart disease or a coronary heart disease risk equivalent on long-term statin therapy with LDL-C level < 100mg/dL and an HDL-C level < 50mg/dL for men or <55mg/dL for women were randomly assigned to receive either extended-release niacin (target dose, 2000mg per day) or ezetimibe (10mg per day) (62). The primary end point was the change from baseline in the mean CIMT. LDL-C levels decreased in the ezetimibe group by −18mg/dL (~ 20%) and by −10.0mgdL (~ 12%) in the niacin group (P=0.01) while HDL-C levels were slightly decreased in the ezetimibe group −2.8mg/dL and increased by 7.5mg/dL (~18%) in the niacin group (P<0.001). TG levels were not markedly altered in the ezetimibe group but decreased by ~ 15-20% in the niacin group.  Notably niacin therapy resulted in a significant reduction of both mean (P = 0.001) and maximal CIMT (P < 0.001) while ezetimibe therapy significantly increased CIMT (P < 0.001). The incidence of major cardiovascular events was lower in the niacin group than in the ezetimibe group (1% vs. 5%, P = 0.04).

In a trial by Thoenes and colleagues fifty patients with the metabolic syndrome not on statin therapy were randomized to either extended-release niacin (1000mg/day) or placebo (63). Treatment with niacin decreased LDL-C by 17% and TGs by 23% and increased HDL-C levels by 24% without significant changes in the placebo group. After 52 weeks of treatment, there was an increase in CIMT of +0.009 +/- 0.003 mm in the placebo group and a decrease in CIMT of -0.005 +/- 0.002 mm in the niacin group (p = 0.021 between groups).

Finally, Lee and colleagues performed a double-blind, randomized study of 2 g daily modified-release niacin or placebo added to statin therapy in 71 patients with low HDL-C (<40mg/dL) and either: 1) type 2 diabetes with coronary heart disease; or 2) carotid/peripheral atherosclerosis (64). The primary end point was the change in carotid artery wall area, quantified by magnetic resonance imaging, after 1 year. Treatment with niacin increased HDL-C by 23% and decreased LDL-C by 19% and TGs by 11%. At 12 months, niacin significantly reduced carotid wall area compared with placebo (Mean change in carotid wall area was -1.1 +/- 2.6 mm² for niacin vs +1.2 +/- 3.0 mm² for placebo).

While these imaging studies provide data suggesting that niacin therapy when added to statin therapy may reduce atherosclerotic cardiovascular disease, one must recognize that the studies described above were relatively small studies and that decreases or the lack of progression in CIMT or carotid wall area are surrogate markers, which may not necessarily indicate that cardiovascular events will be decreased.  

Side Effects

Treatment with niacin frequently results in side effects and these side effects are a major limitation of niacin therapy.

SKIN FLUSHING

This is a very common side effect and is characterized by redness and warmth due to vasodilation of the blood vessels in the skin (9,65). It is often most apparent in the head and neck region. Itching can occur and a tingling and burning sensation may also be noted. Niacin induced flushing is usually not accompanied by diaphoresis. The cutaneous flushing usually lasts for approximately one hour and in some patients it is extremely annoying. In a review of 30 studies, it was noted that flushing occurred in 85% of participants treated with immediate release niacin, 66% of participants treated with extended release niacin, and 26% of participants treated with slow release niacin (12).  The occurrence of flushing is related to a rapid increase in plasma nicotinic acid levels, which differs depending upon the niacin preparation. Flushing was the primary reason that subjects discontinued niacin therapy during studies and with either immediate release or extended release niacin approximately 20% of study participants discontinue niacin, which is twice the rate of discontinuation observed in the placebo groups (12). Continuous administration of niacin for approximately one- week results in tachyphylaxis and flushing decreases. Unfortunately, if a patient skips taking niacin for a few days this tachyphylaxis is lost and the flushing returns.

The mechanism for the niacin induced skin flushing has been partially elucidated (9,65). Niacin activates GPR109A in dermal Langerhan cells (macrophages in the skin), which leads to the increased production of prostaglandin D_2.  Additionally, niacin activates GPR 109A in keratinocytes, which leads to the production of prostaglandin E_2.  The prostaglandins then interact with prostaglandin receptors on blood vessels resulting in vasodilation and the flushing phenomena. Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDS) taken prior to niacin administration can decrease flushing by inhibiting the synthesis of prostaglandins (9,66). Laropiprant decreases flushing by blocking the D prostanoid receptor (9). Since flushing is related to rapid increases in plasma nicotinamide levels taking immediate release niacin with food slows absorption and thereby reduces flushing. Extended-release niacin is typically taken at bedtime so that the flushing will occur when the patient is asleep. Conditions that predispose to cutaneous vasodilatation such as alcohol intake, hot liquids, spicy foods, or hot showers should be avoided. One should increase the dose of niacin slowly to reduce the severity of flushing reactions and allow tolerance to develop.

HEPATIC TOXICITY

Sustained release niacin has a much greater propensity to induce hepatic toxicity than other niacin preparations and therefore is no longer widely used (8,43,67). The explanation for this difference is due to the increased metabolism of sustained release niacin by the amidation pathway described in the pharmacokinetics section, which results in toxic compounds that injure the liver (8,43). Patients who have developed signs of liver toxicity on sustained release niacin can often be treated with immediate release niacin without developing liver problems (68). Extended-release niacin can induce liver dysfunction but the rate is much lower than sustained release niacin. Because of the potential for liver disease, serum transaminase levels (SGOT and SGPT) should be monitored before treatment begins, every 6 to 12 weeks for the first year, and periodically thereafter (e.g., at approximately 6-month intervals).

It should be noted that there is some evidence that niacin may be beneficial for non-alcoholic fatty liver disease (NAFLD) but further studies are required (69).

MUSCLE SYMPTOMS

Myalgias and myopathy have not been a significant adverse effect with niacin monotherapy (12). In combination with statins, an increased risk of muscle symptoms has been observed in some studies. In the HPS-2 Thrive study the combination of simvastatin and extended-release niacin increased the risk of myopathy four-fold (1.2% of patients on combined therapy) (52). Of note, this increase occurred predominantly in Chinese participants. In contrast, in the AIM-HIGH trial muscle related symptoms were not increased with the simvastatin + niacin combination (50,70).

HYPERGLYCEMIA

It has been recognized for many years that niacin induces insulin resistance (71). The mechanisms by which niacin induces insulin resistance are unknown but possible mechanisms include a rebound increase in free fatty acids with niacin therapy or the accumulation of diacylglycerol (30,72). A recent analysis of the AIM-HIGH trial demonstrated that in subjects with normal glucose metabolism, subjects with impaired fasting glucose, and subjects with diabetes, treatment with extended release niacin resulted in only small increases in fasting glucose levels but increased serum insulin levels due to an increase in insulin resistance (73). Additionally, there was an increased risk of progressing from normal to impaired fasting glucose in subjects treated with niacin in the AIM-HIGH trial (niacin 58.6% vs placebo 41.5%; P < .001) (73).

A meta-analysis examined the effect of niacin therapy on the development of new onset diabetes (74). In 11 trials with 26,340 non-diabetic participants, niacin therapy was associated with a 34% increased risk of developing diabetes (RR of 1.34; 95% CIs 1.21 to 1.49). This increased risk results in one additional case of diabetes per 43 initially non-diabetic individuals who are treated with niacin for 5 years (0.47% ten-year risk or 4.7 per 1000 patient years). Results were similar in patients who were receiving niacin therapy in combination with statin therapy.

Studies have shown that niacin is usually well tolerated in diabetic subjects who are in good glycemic control (75,76). In patients with poor glycemic control, niacin is more likely to adversely impact glucose levels. A meta-analysis of 7 studies with 838 patients with diabetes found that niacin therapy did not result in a significant increase in fasting glucose levels in short term studies but in long term studies there was a very small increase in fasting glucose levels (1.5mg/dL) that was not clinically significant (77). An important caveat is that in most of these trials adjustments in diabetes therapy were permitted, which could blunt worsening of glycemic control. In contrast to these findings, the HPS-2 Thrive Trial reported that in the 8,299 participants who had diabetes at the time of randomization, treatment with niacin–laropiprant was associated with a 55% increase in serious disturbances in diabetes control, most of which led to hospitalization (11.1% vs. 7.5%, P<0.001) (52). The extent to which the latter was due to laropiprant is unknown. Thus, care must be used in treating patients with diabetes with niacin. In patients in whom adjustments in diabetic therapy can easily be carried out the risk of adverse effects will likely be limited whereas in patients in whom adjustments in diabetic therapy will be difficult the risks of niacin therapy are likely to be increased. Careful patient selection and education are important steps to reduce the risks of niacin therapy in patients with diabetes.

Thus, while niacin therapy may adversely affect glucose homeostasis one needs to balance these adverse effects with the potential benefits of niacin therapy. One should note that in the Coronary Drug Project participants with abnormal glucose metabolism also demonstrated a decrease in cardiovascular events with niacin therapy (46).  

URIC ACID  

Niacin may increase uric acid levels by inhibiting the secretion of uric acid (9,78). In susceptible patients niacin therapy can precipitate gouty attacks (9).   

GASTROINTESTINAL SYMPTOMS  

Niacin therapy can induce heartburn, indigestion, nausea, diarrhea, and abdominal discomfort (9). High dose niacin is more likely to cause these gastrointestinal disturbances. The mechanism for these symptoms is not clear. 

MISCELLANEOUS  

Recent trials have reported an increased incidence of infections with niacin therapy (52,70). A trial of niacin in combination with laropiprant found increased bleeding (52). The increased bleeding could be due to the approximately 10% decrease in platelet levels that can occur with niacin (see Niaspan Package Insert). However, a very large observational study that compared rates of major gastrointestinal bleeding and intracranial hemorrhage in patients treated with niacin (>200,000 subjects) to propensity matched subjects on fenofibrate did not observe an increase in bleeding (79). Niacin has been reported to induce cystoid macular edema, which resolves when the drug is stopped (80).

Contraindications

There are a number of contraindications to niacin therapy (Table 7).

Summary

The enthusiasm for the use of niacin has greatly decreased with the failure of AIM-HIGH and HPS-2 Thrive to show a decrease in cardiovascular events when niacin was added to statin therapy. In the absence of definitive data showing benefits from niacin therapy when added to a statin it is hard to justify the use of this drug given the frequent side effects. The availability of ezetimibe, bempedoic acid, and PCSK9 inhibitors has greatly reduced the need to use niacin to lower LDL-C levels. Additionally, in patients with markedly elevated TG levels (>500mg/dL), niacin can be employed in combination with other drugs to reduce the risk of pancreatitis, but fibrates and omega-3-fatty acids are the initial choices.

OMEGA-3-FATTY ACIDS (FISH OIL) 

Introduction 

The lipid lowering effects of fish oil are mediated by two omega-3-fatty acids; eicosapentaenoic acid (C20:5n-3) (EPA) and docosahexaenoic acid (C22:6n-3) (DHA). There are four prescription products approved by the FDA which contain various amounts of EPA and DHA (Table 8). Lovaza (generic is available) and Omacor (Omacor is currently not available in the US but is available in other countries) contain a mixture of EPA and DHA fatty acid esters (ethyl esters), Vascepa contains only EPA fatty acid esters (ethyl esters), and Epanova contains a mixture of EPA and DHA free fatty acids (Epanova is currently not available in the US).

1-gram capsules of Epanova contain at least 850mg of fish oil derived fatty acids including multiple omega-3-fatty acids with EPA and DHA being the most abundant

Fish oil is also sold as a food supplement. It should be recognized that dietary fish oil supplements are not approved by the FDA and quality control will not meet the same rigorous standards as prescription or over the counter drugs. The amount of EPA and DHA can vary greatly in these supplements and one needs to read the labels carefully, as products can contain less than 100mg of EPA/DHA per 1 gram capsule (81). It is helpful to have the patient bring their fish oil supplements to the clinic for verification of the actual amount of EPA and DHA in the product. Moreover, the amount of EPA and DHA indicated on the label may not be accurate (82). One needs to take a sufficient number of capsules to provide 2-4 grams of EPA/DHA per day to effectively lower plasma TG levels. Depending upon the fish oil supplement, the patient may be required to take a large number of capsules to obtain 2-4 grams of EPA/DHA per day. Furthermore, these supplements may contain other compounds in addition to omega-3-fatty acids, such as cholesterol, oxidized lipids, and saturated fatty acids. The major advantage of fish oil supplements is that they are much less expensive than prescription omega-3-fatty acid drugs. If one elects to use fish oil supplements, one should have the patient use a single brand to try to ensure as much consistency as possible.

Some omega-3 supplements contain alpha linolenic acid (C18:3n-3) (ALA), a plant omega-3-fatty acid rather than EPA/DHA. ALA can be converted to EPA and DHA but the conversion is limited and hence it is ineffective in lowering plasma TG levels or altering other lipid or lipoprotein levels (83).

Effect of Omega-3-Fatty Acids on Lipid and Lipoprotein Levels 

Several meta-analyses have examined the effect of fish oil supplements on lipid and lipoprotein levels. A meta-analysis by Eslick and colleagues of 47 studies with 16,511 participants found that fish oil supplements significantly decreased plasma TG levels by approximately 14% without resulting in clinically significant changes in total, LDL-C, or HDL-C levels (84). These authors also reported that the reduction in plasma TG levels was directly related to baseline plasma TG levels (i.e., the higher the baseline TG level the greater the reduction in TGs with fish oil). Additionally, the higher the dose of EPA/DHA, the greater the reduction in plasma TGs, with clinically significant reductions occurring with approximately 3.25 grams per day. A meta-analysis by Balk and colleagues of 21 studies also found minimal effects of fish oil supplements on total, LDL-C, and HDL-C levels (< 5% change) with significant decreases in plasma TG levels (most of the studies in this meta-analysis had at least a 15% decrease) (85). Similar to the meta-analysis by Eslick et al, the higher the baseline TG levels the greater the reduction in TG levels. 

Several meta-analyses have focused on specific patient populations. In a meta-analysis of patients with diabetes, twenty three trials with1075 participants were analyzed and similar to patients without diabetes the major effect of fish oil supplements was a reduction in plasma TG levels with no change in total cholesterol or HDL-C (86). A small increase in LDL-C was observed (4.3mg/dL). Of note, fish oil supplementation did not alter fasting glucose or glycated hemoglobin levels indicating that fish oil supplementation does not adversely affect glycemic control. In a meta-analysis that included patients with type 2 diabetes or impaired glucose metabolism a decrease in TGs was observed without significant changes in total cholesterol, LDL-C, or HDL-C levels (87). Again, no adverse effects on glycemic control were observed.

In patients with end stage renal disease several meta-analyses have consistently shown a decrease in plasma TGs with fish oil administration but the effect on total, LDL-C, and HDL-C has been variable (88-90). This variability was likely due to the small changes that were observed. In patients with nephrotic syndrome a study has shown a reduction in plasma TGs and an increase in LDL-C levels without a change in total cholesterol or HDL-C levels (91). In patients with non-alcoholic fatty liver disease, omega-3-fatty acids have also been shown to decrease plasma TG levels (92). Finally, In HIV infected subjects, fish oil supplementation was also effective in lowering plasma TG levels (93,94).

Thus, fish oil supplementation in a variety of different patient populations lowers plasma TG levels. In patients with elevated TG levels treated with 3-4 grams of EPA/DHA one can expect an approximate 15-25% decrease. Total plasma cholesterol levels are usually not altered by fish oil supplementation. The exceptions are patients with high chylomicron and/or VLDL levels where a substantial portion of the plasma cholesterol is carried on these TG rich lipoproteins. Fish oil supplementation will decrease the levels of these TG rich lipoproteins and thereby result in a decrease in total plasma cholesterol levels. LDL-C levels are not markedly affected by fish oil supplementation except in patients with very high TG levels (>500mg/dL) where increases in LDL-C levels have been observed (95-97). If there are sufficient reductions in plasma TG levels a shift from small dense LDL to large buoyant LDL may be observed (98,99). The effect of fish oil supplements on HDL-C levels is minimal except if the patient has very high TG levels where significant elevations (>10%) have been reported (95-97). Finally, some but not all studies have shown that the administration of fish oil modestly lowers Lp(a) levels (100-104)

During the development of pharmacological omega-3-fatty acid drugs for approval by the FDA, extensive clinical trials were carried out and will be reviewed below (Tables 10 and 11). It should be noted that these studies are not directly comparable as they studied different patient populations at different times.

EPA + DHA FATTY ACID ESTERS (LOVAZA)  

In patients with marked elevations in plasma TG levels (500-2000mg/dL) a 6 week trial of EPA + DHA esters resulted in a 31% decrease in plasma TGs, a 21% increase in LDL-C levels, and a 12% increase in HDL-C levels compared to the placebo group (97). In a 16 week trial TG concentrations were decreased by 45% and LDL-C and HDL-C were increased by 31% and 13%, respectively (95). Studies have also been carried out in patients with moderate hypertriglyceridemia (200-500mg/dL) who were on statin therapy (105). EPA + DHA esters resulted in a 23% decrease in plasma TGs and a 7% decrease in non-HDL-C levels, and a 4.6% increase in HDL-C levels (105).

EPA FATTY ACID ESTER ALONE (VASCEPA)  

In patients with marked elevations in plasma TGs (500-2000mg/dL), 4 grams of EPA ester alone significantly decreased TG levels by 33.1% and non-HDL-C levels by 17.7% (106). In contrast to EPA and DHA fatty acid esters, LDL-C and HDL-C levels were not significantly altered by EPA fatty acid esters alone (106). Studies have also been carried out in patients with moderate hypertriglyceridemia (200-500mg/dL) who were on statin therapy. EPA esters resulted in a 21.5% decrease in plasma TGs, 13.6% decrease in non-HDL-C, 6.2% decrease in LDL-C, and a 4.5% decrease in HDL-C levels (107)

EPA + DHA FATTY ACIDS (EPANOVA)  

In patients with marked elevations in plasma TGs (500-2000mg/dL), 4 grams of EPA + DHA fatty acids decreased plasma TGs by 31% and non-HDL-C by 9.6% and increased LDL-C by 19% and HDL-C by 5.8% (108). Studies have also been carried out in patients with moderate hypertriglyceridemia (200-500mg/dL) who were on statin therapy. EPA + DHA fatty acids resulted in a 20.6% decrease in plasma TGs, 6.9% decrease in non-HDL-C with no significant changes in LDL-C or HDL-C levels (96).

These studies demonstrate that in patients on statin therapy with moderate elevations in plasma TG levels the effects of these three pharmaceutical products on lipids and lipoprotein levels are similar (table 11). However, in patients with marked elevations in plasma TG levels EPA ethyl esters alone do not increase LDL-C levels whereas products containing EPA and DHA result in a substantial increase in LDL-C levels (table 10). It should also be noted that the ability of omega-3-fatty acids to reduce plasma TGs and increase HDL-C levels is enhanced if baseline TG levels are markedly elevated.

ND- not determined; NS- no significant change

NS- no significant change

HEAD-TO-HEAD COMPARISONS  

A meta-analysis of six studies has compared the effect of EPA alone vs. DHA alone on plasma lipids and lipoproteins (109). Administration of DHA increased LDL-C by 4.6mg/dL compared to EPA (95% CI 2.2- 7.1). In contrast, DHA reduced plasma TG levels to a greater extent than EPA (6.1mg/dL; 95% CI 2.5- 9.8). Finally, DHA increased HDL-C levels more than EPA (3.7mg/dL; 95% CI: 2.4- 5.1). Whether these very modest differences are clinically significant is unknown.

Tatsuno et al compared the effect of DHA + EPA ethyl esters vs. EPA ethyl esters alone on lipid and lipoprotein levels in patients with mean baseline plasma TG of 250-270mg/dL and mean LDL-C levels of 125-135mg/dL (110,111). These authors found that at equivalent doses there were no differences in effect on plasma TG, LDL-C, or HDL-C levels between DHA + EPA ethyl ester or EPA ethyl ester treatment.

These head-to-head studies indicate that in subjects with moderate hypertriglyceridemia the effects of EPA and DHA on lipid and lipoprotein levels are similar. Perhaps if the baseline TGs were markedly elevated differences in response might have been observed.

IN COMBINATION WITH FENOFIBRATE  

In patients with marked hypertriglyceridemia a single drug is often not sufficient to lower TGs into the desired range. In patients with TG levels > 500mg/dL the combination of fenofibrate 130mg per day and 4 grams of Lovaza reduced TG levels to a greater extent than monotherapy with fenofibrate alone (7% decrease; P = 0.059) (112). Not unexpectedly, LDL-C levels were increased to a greater extent with combination therapy (9% increase; p= 0.03). When subjects who had received 8 weeks of fenofibrate monotherapy were treated with Lovaza during the 8-week, open-label extension study, TG levels were reduced by an additional 17.5% (P = 0.003). These results indicate that the addition of omega-3-fatty acids to fenofibrate will further decrease TG levels.

IN COMBINATION WITH NIACIN

Sixty patients with the metabolic syndrome were randomized to 16 weeks of treatment with placebo, Lovaza (4 g/day), extended release niacin (2 g/day), or both drugs in combination (18). In the niacin group TGs decreased by 30%, in the omega-3-fatty acids group by 22%, and in the combination group by 42% compared to the placebo group. Of note, the beneficial effects of niacin on decreasing LDL and non-HDL-C were blunted by omega-3-fatty acids. These results show that the combination of niacin and fish oil will lower TG levels more than either drug individually but at the expense of diminishing the effect of niacin on LDL and non-HDL-C levels.    

Mechanism Accounting for the Omega-3-Fatty Acid Induced Lipid Effects

As noted above, the major effect of fish oil is to lower plasma TG levels. The predominant cause of the reduction in plasma TG levels is a decrease in the hepatic production and secretion of TG rich lipoproteins (113-116). In cultured hepatocytes, omega-3-fatty acids inhibit the assembly and secretion of VLDL and apolipoprotein B 100 (114,116-118).  The incorporation of TGs into VLDL is a key regulatory step in determining the rate of formation and secretion of VLDL and there are a number of mechanisms by which omega-3 fatty acids reduce the level of hepatic TGs available for VLDL formation (113,114,116). Studies in animal models have demonstrated that omega-3-fatty acids inhibit fatty acid synthesis and stimulate fatty acid oxidation in the liver, which would reduce the availability of fatty acids for TG synthesis (113-116). The increase in fatty acid oxidation is due to omega-3-fatty acids activating PPAR alpha, which stimulates fatty acid oxidation in the liver and other tissues (113,115,116,119). The decrease in fatty acid synthesis is due to omega-3-fatty acids inhibiting the expression of SREBP-1c, a key transcription factor that regulates fatty acid synthesis (115,116,119). In addition, omega-3-fatty acids decrease TG synthesis, which may be due to the decreased availability of fatty acids and an inhibition of the activity of DGAT, a key enzyme required for TG synthesis (113,115,116). Finally, omega-3-fatty acids also decrease the flux of free fatty acids from adipose tissue to the liver, which will lead to a decreased quantity of fatty acids available for TG synthesis in the liver (113). This decrease in flux of free fatty acids is due to omega-3-fatty acids reducing hormone sensitive lipase mediated intracellular lipolysis in adipose tissue (113). It is likely that these and perhaps other factors will lead to the decreased availability of TGs resulting in a reduction in VLDL formation and secretion. In addition, the peroxidation of omega-3-fatty acids may stimulate the degradation of apolipoprotein B-100, which would provide another pathway that could contribute to a decrease in VLDL formation and secretion (116).

While not the primary mechanism for the decrease in plasma TGs, studies have shown that omega-3-fatty acids may increase the clearance of TG rich lipoproteins (113,120). Post heparin lipoprotein lipase activity is not increased by omega-3-fatty acid administration but the lipolytic activity of non-stimulated plasma is enhanced (113,120).  Additionally, apolipoprotein C-III levels are decreased with omega-3-fatty acid administration which could also contribute to an increase in the clearance of TG rich lipoproteins (121-124).

The increase in LDL-C levels that occurs in patients with marked hypertriglyceridemia treated with omega-3-fatty acids is thought to be due to the enhanced conversion of VLDL to LDL (115). The increase in HDL-C observed in studies in patients with very high TG levels may be due to the increased clearance of TG rich lipoproteins.    

Pharmacokinetics and Drug Interactions

Omega-3 ethyl esters and fatty acids are absorbed by the GI tract similar to other dietary lipids. It is worth noting that omega-3-free fatty acids (Epanova) are directly absorbed by the small intestine and are not dependent on pancreatic lipases for absorption. Thus, absorption of omega-3-fatty acids is not decreased in patients with pancreatic insufficiency and therefore may be preferred in patients with pancreatic disease. Additionally, the bioavailability of omega-3-fatty acids with a low fat diet was greater than omega-3-ethyl esters while there was little difference between these different formulations with a high fat diet (125,126).

Drug interactions have not been seen with omega-3-fatty acids (Package Inserts for Lovaza, Vascepa, and Epanova).

Effect of Low Dose Omega-3-Fatty Acids on Cardiovascular Outcomes

Initial studies of the effect of low dose fish oil administration on cardiovascular outcomes were favorable, demonstrating a reduction in events including all-cause mortality. However, more recent studies have failed to confirm these favorable results. In these more recent studies the use of other drugs, such as statins, that reduce cardiovascular disease were more intensively utilized. The outcomes studies that will be described below were carried out with doses of EPA and DHA that are lower than the doses used to lower plasma TGs. We will limit our discussion to the administration of fish oil as a drug and not discuss diet studies, such as DART, which had patients increase fatty fish intake (127,128).

• GISSI-Prevenzione trial was a randomized trial of 850-882mg of EPA and DHA ethyl esters per day in 11,323 participants with a recent myocardial infarction (< 3 months) for 3.5 years (129). The primary endpoint was death, non-fatal myocardial infarction, and stroke. No change in total cholesterol, LDL-C, or HDL-C was observed but plasma TG levels were decreased by 5%. Patients treated with EPA/DHA had a significant decreased risk of major cardiovascular events (RR 0.90), cardiac death (RR 0.78), and sudden death (RR 0.74). The decrease in sudden death occurred very quickly and was noted as early as 4 months after initiation of therapy. Interestingly, non-fatal cardiovascular events were not affected by EPA/DHA treatment (RR 0.98). The decrease in total mortality was driven by a reduction in sudden death suggesting an anti-arrhythmic effect of EPA/DHA.

• GISSI-Heart Failure (GISSI-HF) trial was a randomized, double-blind, placebo-controlled trial in patients with chronic heart failure who were randomly assigned to 850-882mg of EPA and DHA ethyl esters per day (n=3,494) or placebo (n=3,481) (130). Patients were followed for a median of 3.9 years. Primary endpoints were time to death, and time to death or admission to the hospital for cardiovascular reasons. Omega-3-fatty acid treatment at these low doses resulted in a slight decrease in plasma TG levels with no change in total, LDL-C or HDL-C levels. In the omega-3-fatty acid group 27% patients died from any cause vs. 29% in the placebo group (HR 0.91; p=0.041). In the omega-3-fatty acid group 57% of patients died or were admitted to hospital for cardiovascular reasons vs. 59% in the placebo group (HR 0.92; p=0.009). No significant differences were observed in fatal or non-fatal myocardial infarctions or strokes. In this trial, similar to the GISSI-Prevenzione trial, the benefit was primarily due to a reduction in arrhythmic events and little benefit on atherothrombotic events was noted.

• OMEGA was a randomized, placebo-controlled, double-blind, trial in 3,851 survivors of an acute myocardial infarction (131). Patients were randomized 3 to 14 days after an acute myocardial infarction to omega-3-acid ethyl esters, 1 gram/day (460mg EPA and 380mg DHA) or placebo capsules containing 1 gram of olive oil and followed for one year. The primary endpoint was rate of sudden death and secondary end points were total mortality and nonfatal clinical events. No significant differences were seen in the primary or secondary endpoints.

• Alpha Omega was a double-blind, placebo-controlled trial in 4,837 patients between 60 and 80 years of age (78% men) who had had a myocardial infarction (132). Patients were randomized to receive for 40 months one of four trial margarines: a margarine supplemented with a combination of EPA and DHA (with a targeted additional daily intake of 400mg of EPA-DHA; actual intake 226mg EPA and 150mg DHA), a margarine supplemented with alpha-linolenic acid (ALA) (with a targeted additional daily intake of 2g of ALA), a margarine supplemented with EPA-DHA and ALA, or a placebo margarine. The primary end point was the rate of major cardiovascular events, which comprised fatal and nonfatal cardiovascular events and cardiac interventions. Neither low dose EPA-DHA, ALA, nor the combination of EPA/DHA and ALA significantly reduced the rate of major cardiovascular events or cardiac interventions.

• FOL.OM3 Study was a double blind, randomized, placebo-controlled trial in 2,501 patients with a history of a myocardial infarction, unstable angina, or ischemic stroke in the past 12 months (133). Patients were randomized to a daily dietary supplement containing 5-methyltetrahydrofolate (560μg), vitamin B-6 (3mg), and vitamin B-12 (20μg) or placebo; and a dietary supplement containing omega 3 fatty acids (600mg of EPA and DHA) or placebo. The median duration of treatment was 4.7 years. The primary outcome was a composite of non-fatal myocardial infarction, stroke, or death from cardiovascular disease. Treatment with B vitamins or omega 3 fatty acids had no significant effect on major vascular events.

• Origin was a double-blind study in 12,536 patients at high risk for cardiovascular disease who had impaired fasting glucose, impaired glucose tolerance, or diabetes (134). Patients were randomized to receive a 1-gram capsule containing at least 900mg of ethyl esters of omega-3 fatty acids (EPA 465mg and DHA 375mg) or placebo for approximately 6 years. The primary outcome was death from cardiovascular causes. TG levels were reduced by 14.5mg/dL in the group receiving omega-3-fatty acids compared to the placebo group (P<0.001), without a significant effect on other lipids. The incidence of the primary outcome was not significantly decreased among patients receiving omega-3-fatty acids as compared with those receiving placebo. The use of omega-3-fatty acids also had no significant effect on the rates of major vascular events, death from any cause, or death from arrhythmia.

• Risk and Prevention Study was a double-blind, placebo-controlled trial in 12,513 men and women with multiple cardiovascular risk factors or atherosclerotic vascular disease but not myocardial infarctions (135). Patients were randomly assigned to 1-gram daily omega-3 fatty acids (EPA and DHA content not <85 %,) or placebo (olive oil) for 5 years. The initially specified primary end point was the rate of death, nonfatal myocardial infarction, and nonfatal stroke. At 1 year, after the event rate was found to be lower than anticipated, the primary end point was revised as time to death from cardiovascular causes or admission to the hospital for cardiovascular causes. Plasma TG levels decreased slightly more in the omega−3-fatty acid group than in those who received placebo (−28.2±1.3mg/dL vs. −20.1±1.3mg/dL; P<0.001). Total, LDL, and HDL-C levels were similar in the omega-3-fatty acid and placebo groups. No significant differences were observed between the omega-3-fatty acid group and placebo group for the primary endpoint or any of the secondary endpoints.

• A Study of Cardiovascular Events in Diabetes (ASCEND) was a randomized, placebo controlled, double blind trial of 1-gram omega-3-fattys acids (400mg EPA and 300mg DHA ethyl esters) vs. olive oil placebo in 15,480 patients with diabetes without a history of cardiovascular disease (primary prevention trial) (136). The primary end point was serious vascular events (non-fatal myocardial infarction, non-fatal stroke, transient ischemic attack, or vascular death). Total cholesterol, HDL-C, and non-HDL-C levels were not significantly altered by omega-3-fatty acid treatment (changes in TG levels were not reported). After a mean follow-up of 7.4 years the composite outcome of a serious vascular event or revascularization occurred in 882 patients (11.4%) on omega-3-fatty acids and 887 patients (11.5%) on placebo (rate ratio, 1.00; 95% CI, 0.91 to 1.09). Serious adverse events were similar in placebo and omega-3-fatty acid treated groups.

• The Vitamin D and Omega-3 Trial (Vital) was a randomized, double blind, placebo-controlled trial of 1-gram omega-3 fatty acids (465mg EPA and 375mg DHA ethyl esters) vs. placebo in 25,875 men (>50 years of age) and women (>55 years of age) that were not selected on the basis of an elevated risk (primary prevention) (137). Changes in lipid levels were not reported. The primary end point was major cardiovascular events, a composite of myocardial infarction, stroke, or death from cardiovascular causes. After a median follow-up of 5.3 years, major cardiovascular events occurred in 386 participants in the omega-3 fatty acid group and in 419 in the placebo group (hazard ratio, 0.92; 95% confidence interval (CI), 0.80 to 1.06; P=0.24). Serious adverse events were similar in placebo and omega-3-fatty acid treated groups.

• Summary: The above results indicate that low dose fish oil (doses that do not greatly affect lipid levels) does not consistently reduce the risk of cardiovascular disease.

Effect of High Dose Omega-3-Fatty Acids on Cardiovascular Outcomes

• Japan EPA Lipid Intervention Study (JELIS) was an open label study without a placebo in patients with total cholesterol levels > 254mg/dL with (n= 3,664) or without cardiovascular disease (n=14,981) who were randomly assigned to be treated with 1800 mg of EPA (Vascepa) + statin (n=9,326) or statin alone (n= 9,319) with a 5-year follow-up (130). The primary endpoint was any major coronary event, including sudden cardiac death, fatal and non-fatal myocardial infarction, and other non-fatal events including unstable angina pectoris, angioplasty, stenting, or coronary artery bypass grafting. Total, LDL-C, and HDL-C levels were similar in the two groups but plasma TGs were modestly decreased in the EPA treated group (5% decrease in EPA group compared to controls; p = 0.0001). In the EPA group the primary endpoint occurred in 2.8% of the patients vs. 3.5% of the patients in the statin alone group (19% decrease; p = 0.011). Unstable angina and non-fatal coronary events were also significantly reduced in the EPA group but in this study sudden cardiac death and coronary death did not differ between groups. Unstable angina was the main component contributing to the primary endpoint and this is a more subjective endpoint than other endpoints such as a myocardial infarction, stroke, or cardiovascular death. In patients with high TG levels (>150 mg/dL) and low HDL-C levels (<40 mg/dL EPA treatment decreased the risk of CAD by 53% (HR: 0.47; P=0.043) (138). A subjective endpoint has the potential to be an unreliable endpoint in an open label study and is a limitation of the JELIS Study.

• The Reduction of Cardiovascular Events with EPA – Intervention Trial (REDUCE-IT) was a randomized, double blind trial of 2 grams twice per day of EPA ethyl ester (icosapent ethyl) (Vascepa) vs. mineral oil placebo in 8,179 patients with hypertriglyceridemia (135mg/dL to 499mg/dL) and established cardiovascular disease or high cardiovascular disease risk (diabetes plus one risk factor) who were on stable statin therapy (139). The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. The key secondary end point was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. At baseline, the median LDL-C level was 75.0 mg/dL, HDL-C level was 40.0 mg/dL, and TG level was 216.0 mg/dL. The median change in TG level from baseline to 1 year was a decrease of 18.3% (−39.0 mg/dL) in the EPA group and an increase of 2.2% (4.5 mg/dL) in the placebo group. After a median of 4.9 years the primary endpoint occurred in 17.2% of the patients in the EPA group vs. 22.0% of the patients in the placebo group (hazard ratio, 0.75; P<0.001), indicating a 25% decrease in events. The number needed to treat to avoid one primary end-point event was 21. The reduction in cardiovascular events was noted after approximately 2 years of EPA treatment. Additionally, the rate of cardiovascular death was decreased by 20% in the EPA group (4.3% vs. 5.2%; hazard ratio, 0.80; P=0.03). The cardiovascular benefits of EPA were similar across baseline levels of TGs (<150, ≥150 to <200, and ≥200 mg per deciliter). Moreover, the cardiovascular benefits of EPA appeared to occur irrespective of the attained TG level at 1 year (≥150 or <150 mg/dL), suggesting that the cardiovascular risk reduction was not associated with attainment of a normal TG level. Additionally, icosapent ethyl reduced cardiovascular events regardless of baseline LDL-C levels including in patients with LDL-C levels < 55mg/dL (140). An increase in hospitalization for atrial fibrillation or flutter (3.1% vs. 2.1%, P=0.004) occurred in the EPA group. In addition, serious bleeding events occurred in 2.7% of the patients in the EPA group and in 2.1% in the placebo group (P=0.06). There were no fatal bleeding events in either group and the rates of hemorrhagic stroke, serious central nervous system bleeding, and serious gastrointestinal bleeding were not significantly higher in the EPA group than in the placebo group.

It should be noted that in this trial mineral oil was used as the placebo. In the placebo group the LDL-C, non-HDL-C, and CRP levels were increased compared to the EPA group during the trial (LDL-C 96mg/dL vs 85mg/dL; non-HDL-C 130mg/dL vs. 113mg/dL; hsCRP 2.8mg/L vs. 1.8mg/L). Increases in other biomarkers of atherosclerosis (oxidized LDL-C, IL-6, IL-1 beta, and lipoprotein-associated phospholipase A2) also occurred in the mineral oil group (141). The impact of these adverse changes on clinical outcomes is uncertain and whether they contributed to the apparent beneficial effects observed in the individuals treated with EPA is unknown.

• The STRENGTH Trial was a double-blind, randomized, trial comparing 4 grams per day of a carboxylic acid formulation of omega-3 fatty acids (EPA and DHA; Epanova) (n = 6,539)) vs. corn oil placebo (n = 6539) in statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of HDL-C (142). Approximately 55% of patients had established cardiovascular disease and approximately 70% had diabetes. Median LDL-C level was 75.0 mg/dL, median TG level was 240 mg/dL, and median HDL-C level was 36 mg/dL. There were minimal differences in the change in LDL-C and HDL-C levels between the treated and placebo groups after treatment for 12 months but as expected there was a greater reduction in TG levels in the group treated with omega-3-fatty acids (−19.0% vs −0.9%). The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization which occurred in 12.0% of individuals treated with omega-3 CA vs. 12.2% treated with corn oil (hazard ratio, 0.99; P = .84). There were no significant differences between the treatment groups with regards to the risk of the individual components of the primary end point over the 3-4 years of the study. Similar to the REDUCE-IT trial atrial fibrillation was increased with EPA + DHA treatment (HR 1.69 CI 1.29- 2.21). Thus, in contrast to the JELIS and REDUCE-IT trials the STRENGTH trial did not demonstrate a benefit of treatment with a mixture of omega-3-fatty acids (EPA + DHA).

• The OMEMI trial was a randomized trial of 1.8 grams per day of omega-3-fatty acids (930 mg EPA and 660 mg DHA) (n= 505) vs. corn oil placebo (509) in patients aged 70 to 82 years with a recent myocardial infarction (2-8 weeks) (143). Baseline LDL-C was approximately 76mg/dL, HDL-C was 49mg/dL, and TGs 110mg/dL. The primary endpoint was a composite of nonfatal myocardial infarction, unscheduled revascularization, stroke, all-cause death, and heart failure hospitalization after 2 years of follow-up. The primary endpoint occurred in 21.4% of patients on omega-3-fatty acids vs. 20.0% on placebo (hazard ratio, 1.08; P=0.60). TGs levels decreased 8.1% in the omega-3-fatty acid group and increased 5.1% in the placebo group (between group difference 13.2%; P<0.001) while changes in LDL-C were minimal in both groups. Thus, similar to the STRENGTH trial no benefits on cardiovascular disease were observed with EPA + DHA treatment. An increase in atrial fibrillation was observed in the EPA + DHA treatment group (144).

• The RESPECT-EPA trial was a randomized, open-label, blinded end-point study of 8 grams icosapent ethyl(EPA) per day or usual care in patients with stable coronary artery disease on statin therapy (145) . 3884 patients were enrolled and followed for 5 years. Baseline LDL-C levels were 80mg/dL, TG levels approximately 120mg/dL, and HDL-C levels 49mg/dL. The primary end point (cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, unstable angina pectoris, and coronary revascularization) occurred in 9.1% of the patients in the EPA group and 12.6% of the patients in the control group (HR 0.79; 95% CI 0.62-1.00; P=0.055). Of the primary endpoints only coronary revascularization was significantly reduced in the EPA group (4.2% versus 6.7%; HR 0.68; 95% CI 0.48–0.96); hard outcomes did not differ between groups. While this trial did not result in a statistically significant decrease in cardiovascular events it provides suggestive evidence that icosapent ethyl reduces cardiovascular events. As seen in other trials new-onset atrial fibrillation was significantly higher in the EPA group (3.1% versus 1.6%; P=0.017).

Summary of Omega-3-Fatty Acid Clinical Outcome Trials

• Low dose omega-3-fatty acids are not effective at decreasing cardiovascular outcomes.
• High dose EPA (JELIS, REDUCE-IT, and RESPECT-EPA) reduced cardiovascular outcomes while high dose EPA+DHA (STENGTH and OMEMI) did not decrease cardiovascular outcomes.
• The decrease in TG levels is not a major contributor to the beneficial effect of high dose EPA as the combination of high EPA+DHA lowers TG levels to the same degree as EPA alone without benefit. Additionally, the JELIS trial and RESPECT-EPA only lowered TG levels by 5-7% but nevertheless reduced cardiovascular events. It is likely that the beneficial effects of EPA seen in the JELIS, REDUCE-IT, and RESPECT-EPA trials are multifactorial with TG lowering making only a small contribution to the decrease in cardiovascular disease. Other actions of EPA, such as decreasing platelet function, anti-inflammation, decreasing lipid oxidation, stabilizing membranes, etc. could account for or contribute to the reduction in cardiovascular events (146). A large meta-analysis, excluding the REDUCE-IT trial, demonstrated that a 40mg/dL decrease in triglyceride levels resulted in a relative risk reduction of only 0.96 (4% decrease) indicating that one needs to markedly lower triglyceride levels to reduce cardiovascular events (147).
• Whether EPA has special properties that resulted in the reduction in cardiovascular events in the REDUCE-IT trial or there were flaws in the trial design (the use of mineral oil as the placebo) is uncertain and debated. It should be noted that in the REDUCE-IT trial LDL-C and non-HDL-C levels were increased by approximately 10% in the mineral oil placebo group (139). Additionally, Apo B levels were increased by 7% (6mg/dL) by mineral oil (139). Finally, an increase in hsCRP (20-30%) and other biomarkers of atherosclerosis (oxidized LDL-C, IL-6, IL-1 beta, and lipoprotein-associated phospholipase A2) were noted in the mineral oil group (139,141). In the STRENGTH trial there were no differences in LDL-C, Non-HDL-C, HDL-C, Apo B, or hsCRP levels between the treated vs. placebo groups (142). Whether EPA has special properties compared to DHA leading to a reduction in cardiovascular events or the mineral oil placebo resulted in adverse changes increasing ASCVD in the placebo resulting in an artifactual decrease in the EPA group is debated (148,149). Ideally, another large randomized cardiovascular trial with EPA ethyl ester (icosapent ethyl) (Vascepa) using a placebo other than mineral oil would help resolve this controversy. In the meantime, clinicians will need to use their clinical judgement on whether to treat patients with modest elevations in TG levels with EPA (icosapent ethyl; Vascepa) balancing the potential benefits of treatment vs. the potential side effects.
• The JELIS and RESPECT-EPA trials were carried out in Japan and did not include a placebo control. Whether the results seen in these trials would occur in other patient populations is unknown. Additionally, the absence of a placebo group is not ideal.

Side Effects

Gastrointestinal side effects such as diarrhea, nausea, dyspepsia, abdominal discomfort, and eructation have been observed with fish oil therapy (Package Inserts for Lovaza, Vascepa, and Epanova).

At very high doses, omega-3-fatty acids can inhibit platelets and prolong bleeding time. However, at the recommended doses this has not been a major clinical problem but nevertheless when patients are on anti-platelet drugs one should be alert for the possibility of bleeding problems (Package Inserts for Lovaza, Vascepa, and Epanova). Increased bleeding was noted in the REDUCE-IT trial in the patients treated with icosapent ethyl 4 grams/day (EPA) (see above discussion of this trial). A recent review found no evidence for discontinuing the use of omega-3 fatty acid treatment before invasive procedures or when given in combination with other agents that affect bleeding (150).

As noted above an increase in atrial fibrillation was observed in the REDUCE-IT trial and RESPECT-EPA in the patients treated with icosapent ethyl (EPA) and in the STRENGTH trial and the OMEMI trial in the patients treated with EPA + DHA.

Contraindications 

There are no contraindications to the use of omega-3-fatty acids. Lovaza, Omacor, and Vascepa are pregnancy category C drugs and they should only be used if the benefits to the mother outweigh the potential risks to the fetus.

Conclusions 

Omega-3-fatty acids are effective drugs in reducing TG levels with few significant side effects (atrial fibrillation and bleeding), drug interactions, or contraindications.  High dose EPA (4 grams/day) reduced cardiovascular disease events in the REDUCE-IT trial and a moderate dose of EPA (1.8 grams/day) reduced cardiovascular events in the JELIS and RESPECT-EPA trials but trials of EPA and DHA have not produced cardiovascular benefits. The basis for these differences is debated and discussed in the “Summary of Omega-3-Fatty Acid Clinical Outcome Trials” section above. Finally, omega-3-fatty acids are effective in lowering TGs in patients with marked hypertriglyceridemia and while not proven, it will likely reduce the risk of development of pancreatitis.

FIBRATES

Introduction 

The fibrate drug class includes clofibrate, gemfibrozil, fenofibrate, bezafibrate, ciprofibrate, and pemafibrate. Clofibrate was developed in the 1960s and was the first member of this class. Clofibrate is no longer available because of an increased risk of adverse effects. Gemfibrozil and fenofibrate are available in the United States while gemfibrozil, fenofibrate, bezafibrate, and ciprofibrate are available in Europe. Pemafibrate is available in Japan. All of the fibrates work via activation of the nuclear hormone receptor PPAR alpha.

Effect of Fibrates on Lipid and Lipoprotein Levels

Fibrates reduce fasting TG levels by 25-50% (151-153). The magnitude of the reduction in TGs is dependent on the baseline TG levels. Patients with marked elevations in TGs have a greater reduction in TG levels (151,153,154). In addition, fibrates increase HDL-C levels by 5-20% (152,153). The increase in HDL-C levels is more robust if the TG levels are elevated and/or if the HDL-C levels are low (154). The effect on LDL-C is more variable (153). If the TG levels are very high (>400-500mg/dL), fibrate therapy may result in an increase in LDL-C levels whereas if TGs are not elevated fibrates decrease LDL-C by 10-30% (151). Given the decrease in plasma TGs and LDL-C levels, fibrates also reduce apolipoprotein B, LDL particle number, and non-HDL-C levels (153). Depending upon the TG level there may be a shift from small dense LDL towards large LDL particles (153). Fibrates do not have any major or consistent effects on Lp(a) levels (155). Table 13 below shows the effect of fenofibrate on lipid and lipoprotein levels in patients with different lipid profiles and illustrates some of the principles outlined above.

The values are adjusted for changes in the placebo group. Data modified from Tricor Package Insert.

In large, randomized, fibrate outcome trials similar changes in lipid and lipoprotein levels were noted (Table 14). These trials are discussed in detail in the effect of fibrates on cardiovascular outcomes section presented below.

*The values are adjusted for changes in the placebo group.

The different fibrates in general cause similar changes in lipid and lipoprotein levels. There are only a few comparative trials of fibrates comparing their effects on lipid and lipoprotein levels and these trials have been very small. Comparisons of ciprofibrate and gemfibrozil have not shown any major differences between these two fibrates (161,162). In contrast, two very small trials have compared gemfibrozil vs. fenofibrate and reported that fenofibrate was more efficacious in lowering LDL levels than gemfibrozil (163,164).

In very rare instances fibrates can cause a paradoxical marked decrease in HDL-C levels (165-168). This rare paradoxical decrease in HDL-C typically occurs when fibrates are used in combination with a thiazolidinedione (rosiglitazone and pioglitazone) but can occur when fibrates are used alone or with ezetimibe (165-169). The decrease in HDL-C can be extreme with decreases of 50% to 88% reported and recovery to normal can take weeks after the fibrate is discontinued (166). The mechanism for this paradoxical effect is unknown.

Effect of Fibrates in Combination with Other Lipid Lowering Drugs on Lipid and Lipoprotein Levels 

STATINS

Statins are the primary drugs used to treat most patients with dyslipidemia. Statins are very effective in lowering LDL-C levels but have only modest effects on TG and HDL-C levels. Therefore, it is appealing to add a fibrate to patients who on statin therapy have LDL-C levels at goal but still have elevated non-HDL-C and TG levels and decreased HDL-C levels. Therefore, there have been numerous studies examining the effect of the combination of statins and fibrates on lipid and lipoprotein levels. An example is the Safari Trial which compared the effect of simvastatin only (n=207) vs. simvastatin + fenofibrate (n=411) in patients with combined hyperlipidemia (170). The results of this trial are shown in table 15. As anticipated, adding a fibrate results in a further lowering of LDL-C, non-HDL-C, and TG levels with a further increase in HDL-C.

A meta-analysis of 9 studies with over 1,200 participants compared the effect of statin alone vs. statin + fibrate on lipid and lipoprotein levels (171). The combination of statins and fibrates provided significantly greater reductions in total cholesterol, LDL-C, and TGs, and a significantly greater increase in HDL-C than treatment with statins alone. A larger meta-analysis of 13 randomized controlled trials, involving 7,712 patients, similarly demonstrated significant decreases in LDL-C (8.8mg/dL), TGs (58mg/dL), and total cholesterol (11.2mg/dL), and increases in HDL-C (4.65mg/dL) in patients receiving the combination of statins + fibrates compared with statin therapy alone (172). The combination of statins + fibrates also result in a shift of LDL particles from small dense particles to large buoyant particles whereas no change in LDL particle size was observed with statin monotherapy (173).  

EZETIMIBE

In patients unable to tolerate statin therapy one needs to use other drugs to treat dyslipidemia. In a study comparing the effect of ezetimibe 10mg alone, fenofibrate 145mg alone, or ezetimibe + fenofibrate the combination had a better effect on the lipid profile resulting in a greater decrease in LDL-C levels and increase in HDL-C levels than either drug alone (Table 16) (174).

Similar results were observed in another randomized trial of ezetimibe 10mg and fenofibrate 160mg (175). Moreover, both fibrate therapy and the combination of ezetimibe and fenofibrate results in a shift of LDL particles from small dense LDL particles to large buoyant particles (175).

EZETIMIBE + STATIN

A large, randomized trial has compared the effect of ezetimibe /simvastatin 10mg/20mg, fenofibrate 160mg, or ezetimibe/simvastatin + fenofibrate on lipid and lipoprotein levels. As one would expect triple drug therapy had a better effect on the lipid profile (Table 17) (176). While ezetimibe/simvastatin was very effective in lowering LDL-C levels and fenofibrate was very effective in lowering TGs and raising HDL-C levels the combination resulted in more favorable changes in TGs. In a similar study the addition of fenofibrate 135mg to atorvastatin 40 mg + ezetimibe 10 mg resulted in a greater reduction in TGs (-57% vs. -40%; p<0.001) and a greater increase in HDL (13% vs. 4.2%; p<0.001) than placebo (177).  Fibrate therapy and ezetimibe/simvastatin + fenofibrate also resulted in a shift of LDL particles from small dense LDL particles to large buoyant particles (176).

BILE ACID SEQUESTRANT  

Studies have also examined the effect of fibrates in combination with bile acid sequestrants. Participants receiving fenofibrate 160 mg/day were randomized to receive either colesevelam HCl 3.75 g/day or placebo (178). No significant differences in TG or HDL-C levels were observed between the two groups. However, LDL-C levels decreased in the fenofibrate + colesevelam group compared to the fenofibrate + placebo group (12.4% greater decrease: p<0.001). A study of the combination of fenofibrate and colestipol also demonstrated a more marked decrease in LDL-C with that combination compared to either drug alone (colestipol -18%; fenofibrate -17%, colestipol + fenofibrate 37%) (179). The combination of both drugs did not blunt the effects of fenofibrate on VLDL and HDL. Other studies of the combination of a fibrate with a bile acid sequestrant have also demonstrated an enhanced effect in lowering LDL-C levels (180-182).

NIACIN

Surprisingly there are few large, randomized trials examining the effect of combination therapy with niacin + fibrate vs. monotherapy. One very small trial reported that while both niacin monotherapy and bezafibrate monotherapy were effective in lowering serum TGs there was no added benefit of combination therapy in reducing serum TG level although a large variance may have reduced the ability to detect statistically significant results (16). A larger trial in HIV+ patients reported that the combination of niacin and fenofibrate was better at lowering TGs and non-HDL-C and increasing HDL-C levels than monotherapy with either niacin or fenofibrate (17). It would be informative if additional trials of fibrate + niacin combination therapy were carried out in patients with marked hypertriglyceridemia that can often be difficult to control with lifestyle changes and monotherapy.

FISH OIL  

In patients with TG levels > 500mg/dL the combination of fenofibrate 130mg per day and 4 grams of Lovaza (DHA and EPA) reduced TG levels to a greater extent than monotherapy with fenofibrate alone (7% decrease; P = 0.059) (103). Not unexpectedly, LDL levels were increased to a greater extent with combination therapy (9% increase; p= 0.03). When subjects who had received 8 weeks of fenofibrate monotherapy were treated with Lovaza (DHA and EPA) during the 8-week, open-label extension study TG levels were reduced by an additional 17.5% (P = 0.003). These results indicate that the addition of omega-3-fatty acids to fenofibrate will further decrease TG levels.

Mechanisms Accounting for the Fibrate Induced Lipid Effects

Fibrates are ligands that bind and activate PPAR alpha, a member of the family of nuclear hormone receptors that are activated by lipids (183,184). PPAR alpha is highly expressed in the liver and other tissues important in fatty acid metabolism. PPAR alpha forms a heterodimer with RXR and together the PPAR alpha:RXR complex when activated binds to the PPAR response elements in a large number of genes and regulates the expression of these genes (183,184). The natural ligands of PPAR alpha are fatty acid derivatives formed during lipolysis, lipogenesis, or fatty acid catabolism (183,184).

TRIGLYCERIDES  

Fibrates lower plasma TG levels by decreasing VLDL production and by increasing the clearance of TG rich lipoproteins (185,186). The decrease in VLDL production is primarily due to PPAR alpha activation of the beta oxidation of fatty acids, which reduces the substrate available for the synthesis of TGs and the formation of VLDL (183,186). Additionally, a decrease in hepatic fatty acid synthesis may also contribute to the decrease in fatty acids (183,186). The increased clearance of TG rich lipoproteins is due to PPAR alpha stimulating the transcription of lipoprotein lipase, the key enzyme that catabolizes the TGs carried by VLDL and chylomicrons (183,186). In addition, activation of PPAR alpha also inhibits the transcription of APO C-III, which inhibits lipoprotein lipase activity (183,186). A decrease in Apo C-III enhances the clearance of TG rich lipoproteins by increasing lipoprotein lipase activity. Notably, a decrease in Apo C-III also decreases TG levels in patients deficient in lipoprotein lipase indicating that there are multiple mechanisms for its effects on TG metabolism (187). Recent studies suggest that Apo C-III inhibits the uptake of TG rich lipoproteins into the liver by the LDL receptors/ LDLR-related protein 1 axis (188). PPAR alpha activation also increases the transcription of Apo A-V, which would also facilitate the activity of lipoprotein lipase (183).

HIGH DENSITY LIPOPROTEINS

The increase in HDL induced by fibrates is due to PPAR alpha activation stimulating Apo A-I and A-II transcription (183,186). This leads to the increased production of HDL (185). In addition, a decrease in TG rich lipoproteins may result in a reduction in CETP mediated transfer of cholesterol from HDL to VLDL and of TG from VLDL to HDL (186). This would lead to less TG enrichment of HDL and a decrease in the opportunity of hepatic lipase to remove TG leading to small HDL particles that may be rapidly catabolized.

LOW DENSITY LIPOPROTEINS

As noted above, the effect of fibrates on LDL-C levels is variable with increases in LDL seen in patients with high TG levels (>400mg/dL) and decreases in LDL-C levels in patients with lower TG levels. In patients with modest elevations in plasma TG levels the clearance of LDL is enhanced (185). The mechanism for this enhanced clearance could be due to a decrease in Apo C-III, as increased levels of this protein inhibits LDL receptor activity (188,189). Additionally, the shift from small dense LDL to large buoyant LDL would enhance the uptake of LDL by the LDL receptor (190). In patients with TG levels > 400mg/dL fibrate therapy decreases LDL clearance (185). Prior to treatment, patients with marked hypertriglyceridemia have hypercatabolism of LDL, which is likely due to increased uptake by the reticuloendothelial system (185). This increased clearance is LDL receptor independent. Treatment with fibrates lowers the plasma TGs leading to normalization of reticuloendothelial cell function and a decrease in LDL clearance resulting in an increase in LDL-C levels with fibrate therapy (185). In addition, the metabolism of VLDL to LDL may be enhanced by fibrates when the TG levels are markedly elevated.

Effect of Monotherapy with Fibrates on Cardiovascular Outcomes 

There have been a number of studies that have examined the effect of monotherapy with a variety of different fibrates on cardiovascular disease. We will describe the major studies below.

• Coronary Drug Project (CDP): CDP conducted between 1966 and 1975, was a randomized, double-blind clinical trial that determined the effect of clofibrate (1.8g/day), dextrothyroxine (6mg/day), two doses of oral estrogen (2.5 or 5mg per day), or immediate release niacin (3 grams/day) vs. placebo in 8,341 men aged 30 to 64 years of age with an electrocardiogram documented myocardial infarction on cardiovascular events and mortality (44). The mean baseline total cholesterol level was 251mg/dL and TG level was 183mg/dL. The two estrogen regimens and dextrothyroxine treatment groups were discontinued early because of increased adverse effects. Clofibrate treatment (n= 1,051) compared to placebo (n= 2,680) also did not demonstrate clinical benefit. The five-year mortality in subjects treated with clofibrate was 20.0% as compared with 20.9% in subjects on placebo therapy (P = 0.55). The results with niacin are discussed above in the section on niacin and cardiovascular outcomes.

• WHO: WHO was a double-blind trial in middle-aged men, age 30-59 years of age, without evidence of heart or other major disease, who were treated with 1.6 grams/day clofibrate (n=5,000) or placebo (n=5,000) for an average of 5.3 years (191). Average serum cholesterol levels were approximately 248mg/dL and a mean reduction of approximately 9 per cent occurred in the clofibrate group. The incidence of ischemic heart disease was decreased by 20% in the clofibrate group compared to the control group (P <0.05). This decrease was confined to non-fatal myocardial infarcts which were reduced by 25% while the incidence of fatal heart attacks and angina was similar in the clofibrate and placebo groups. Importantly, the numbers of deaths and crude mortality rates from all causes were increased in the clofibrate-treated group compared to the control group (P < 0.05). The excess deaths were partially accounted for by increased deaths due to liver, biliary tract, and intestinal disease. There was also an increase in cholecystectomies in subjects treated with clofibrate. Because of increased toxicity clofibrate is no longer available.

• Helsinki Heart Study (HHS): HSS was a randomized double-blind trial in middle aged men age 40-55 years of age without cardiovascular who had non-HDL-C levels greater than or equal to 200mg/dL (156). Subjects were randomized to receive 600mg gemfibrozil twice a day (n=2,051) or placebo (n=2,030) for five years. At initiation of the study total cholesterol was 289mg/dL, HDL-C 47mg/dL, non-HDL-C 242mg/dL, and TGs 176mg/dL. Gemfibrozil caused an increase in HDL-C (approximately 10%) and reductions in total (~10%), LDL-C (~11%), non-HDL-C (~14%), and TG levels (~35%). There were minimal changes in serum lipid levels in the placebo group. Fatal and non-fatal myocardial infarctions and cardiac death were the principal end points, and the cumulative rate of these cardiac end points were reduced 34% in the gemfibrozil group (27.3 per 1,000 in the gemfibrozil group vs. 41.4 per 1,000 in the placebo group; P< 0.02). The decrease in cardiovascular disease in the gemfibrozil group became evident in the second year and continued throughout the remainder of the study. There was no difference in mortality between the gemfibrozil and placebo groups. The benefit of gemfibrozil therapy was greatest in participants with elevated TGs and decreased HDL-C levels (192,193). Risk reduction with gemfibrozil was 78% (P = .002) among those with BMI > 26 kg/m² and dyslipidemia (TGs > ~200mg/dL and HDL-C < 42mg/dL) suggesting that certain types of patients are likely to derive greater benefit from fibrate treatment (194).

• Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT): VA-HIT was a double-blind trial in men with coronary heart disease who had an HDL-C level <40mg/dL and LDL-C level <140mg/dL (157). Subjects were randomized to gemfibrozil 1200mg per day (n=1,264) or placebo (n=1,267) for 5.1 years. Mean lipid levels at study initiation were HDL-C 32mg/dL, LDL-C 111mg/dL, total cholesterol 175mg/dL, and TGs 160mg/dL. At one year, the mean HDL-C level was 6 percent higher, the mean TG level was 31 percent lower, and the mean total cholesterol level was 4 percent lower in the gemfibrozil group than in the placebo group. LDL-C levels did not differ significantly between the groups. The primary study outcome was nonfatal myocardial infarction or death from coronary causes. The primary outcome occurred in 21.7% of patients in the placebo group and 17.3% of patients in the gemfibrozil group (22 percent decrease; P=0.006). A 24% reduction in the combined outcome of death from coronary heart disease, nonfatal myocardial infarction, and stroke was observed in the gemfibrozil group (P< 0.001). There were no significant differences in the rates of coronary revascularization, hospitalization for unstable angina, death from any cause, and cancer. Similar to HHS the beneficial effect of gemfibrozil did not become apparent until approximately two years after treatment. A low HDL-C (<33.5mg/dL) and high TGs (>180mg/dL) at baseline predicted a beneficial response to gemfibrozil therapy (195).

• Bezafibrate Infarction Prevention Study (BIP): BIP was a double-blind study in male and female patients aged 45-74 with a previous myocardial infarction or stable angina (158). Patients were randomized to receive either 400 mg of bezafibrate per day (n=1,548) or a placebo (n=1,542) and were followed for 6.2 years. At the initiation of the study total cholesterol was 212mg/dL, LDL-C was 148mg/dL, HDL-C was 34.6mg/dL, and TGs were145mg/dL. Bezafibrate increased HDL-C by 18% and reduced TGs by 21%. There was a small 7% decrease in LDL-C. The primary end point was fatal or nonfatal myocardial infarction or sudden death. The primary end point occurred in 13. 6% of the bezafibrate group vs. 15.0% of the placebo (9.4% reduction; P=0.26). Total and non-cardiac mortality rates were similar. In a post hoc analysis in the subgroup with high baseline TGs (> or =200 mg/dL), the reduction in the primary end point in the bezafibrate group was 39.5% (P=0.02). Additionally, bezafibrate reduced cardiovascular events in patients with the metabolic syndrome (196). These results again suggest that patients with high TGs are likely to derive benefit from fibrate therapy.

• Leader Trial: The Leader trial was a double blind placebo controlled randomized trial in men age 35 to 92 with lower extremity arterial disease (197,198). Subjects were randomized to bezafibrate 400mg per day (n=783) or placebo (n=785). At baseline total cholesterol levels were 218mg/dL, LDL-C levels 132mg/dL, HDL-C levels 44mg/dL, and TGs 187mg/dL. Bezafibrate therapy reduced total cholesterol levels by 7.6%, LDL-C by 8.1%, and TGs by 23% and increased HDL-C levels by 8%. The primary endpoint of coronary heart disease and strokes was not reduced by bezafibrate treatment. Neither major coronary events nor strokes were significantly reduced.

 .

• Fenofibrate Intervention and Event Lowering in Diabetes Trial (FIELD): In the FIELD Trial patients with Type 2 diabetes between the ages of 50 and 75 with or without pre-existing cardiovascular disease not taking statin therapy were randomized to fenofibrate 200 mg daily (n=4,895) or placebo (n=4,900) and followed for approximately 5 years (160). At initiation of the study total cholesterol was 196mg/dL, LDL-C was 120mg/dL, HDL-C was 43mg/dL, and TGs were 152mg/dL. Fenofibrate therapy resulted in an 11% decrease in total cholesterol, a 12% decrease in LDL-C, a 29% decrease in TGs, and a 5% increase in HDL-C levels. The primary outcome was coronary events (coronary heart disease death and non-fatal MI), which were reduced by 11% in the fenofibrate group but this difference did not reach statistical significance (p= 0.16). However, there was a 24% decrease in non-fatal MI in the fenofibrate treated group (p=0.01) and a non-significant increase in coronary heart disease mortality. Total cardiovascular disease events (coronary events plus stroke and coronary or carotid revascularization) were reduced 11% (p=0.035). These beneficial effects of fenofibrate therapy on cardiovascular disease were observed in patients without a previous history of cardiovascular disease. In patients with a previous history of cardiovascular disease no benefits were observed. Additionally, the beneficial effect of fenofibrate therapy was seen only in those subjects less than 65 years of age. The beneficial effects of fenofibrate in this study may have been blunted by the increased use of statins in the placebo group, which reduced the differences in lipid levels between the placebo and fenofibrate groups. If one adjusted for the addition of lipid-lowering therapy, fenofibrate reduced the risk of coronary heart disease events by 19% (p=0.01) and of total cardiovascular disease events by 15% (p=0.004). Additionally, many patients in the Field trial did not have elevations in TGs and decreased HDL-C levels. In a post hoc analysis, patients with high TGs 200mg/dL) and low HDL levels (<40mg for men and <50mg/dL for women) derived greater benefit from fenofibrate therapy (199).

• Summary: While the above monotherapy fibrate studies suggest that fibrates reduce cardiovascular event, particularly in patients with high TG and low HDL levels, the results are not as robust or consistent as the beneficial effects of statins on cardiovascular outcomes (6).

Effect of Combination Therapy of Fibrates and Statins on Cardiovascular Outcomes

Given the marked benefits of statin therapy, it is essential to know if adding fibrates to statin therapy further reduces cardiovascular events. Two large trials described below have addressed this key question.

• ACCORD LIPID Trial: The ACCORD-LIPID Trial was designed to determine if the addition of fenofibrate to aggressive statin therapy would result in a further reduction in cardiovascular disease in patients with Type 2 diabetes (200). In this trial, 5,518 patients on statin therapy were randomized to placebo or fenofibrate therapy. The patients had diabetes for approximately 10 years and either had pre-existing cardiovascular disease or were at high risk for developing cardiovascular disease. During the trial, LDL-C levels were approximately 80mg/dL. There was only a small difference in HDL-C with the fenofibrate groups having a mean HDL-C of 41.2mg/dL while the control group had an HDL-C of 40.5mg/dL. Differences in TG levels were somewhat more impressive with the fenofibrate group having a mean TG level of 122mg/dL while the control group had a TG level of 144mg/dL. First occurrence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes was the primary outcome and there was no statistical difference between the fenofibrate treated group and the placebo group. Additionally, there were also no statistically significant differences between the groups with regards to any of the secondary outcome measures of cardiovascular disease. Of note, the addition of fenofibrate to statin therapy did not result in an increase in either muscle or liver side effects. On further analysis there was a suggestion of benefit with fenofibrate therapy in the patients in whom the baseline TG levels were elevated (>204mg/dL) and HDL-C levels decreased (<34mg/dL). While this was a negative study, it must be recognized that most of the patients included in this study did not have the lipid profile that would typically lead to treatment with fibrates.

• PROMINENT Trial: The PROMINENT trial studied the effect of pemafibrate, a new selective PPAR-alpha activator, in reducing cardiovascular outcomes in 10,497 patients (66.9% with previous ASCVD) with diabetes (201). This was a double-blind, randomized, controlled trial, in patients with Type 2 diabetes, with mild-to-moderate hypertriglyceridemia (TG level, 200 to 499 mg/dL), LDL-C < 100mg/dL, and HDL-C levels < 40 mg/dL who received either pemafibrate (0.2-mg tablets twice daily) or placebo in addition to statin therapy (96% on statins). The primary end point was a composite of nonfatal MI, ischemic stroke, coronary revascularization, or death from cardiovascular causes. Baseline fasting TG was 271 mg/dL, HDL-C 33 mg/dL, and LDL-C 78 mg/dL. Compared with placebo, pemafibrate decreased TG by 26.2%, while HDL-C increased 5.1% and LDL-C increased 12.3%. Notably non-HDL-C levels were unchanged and Apo B levels increased 4.8%. The primary endpoint was similar in the pemafibrate and placebo group (HR 1.03; 95% CI 0.91 to 1.15). The increase in LDL-C and Apo B levels may have accounted for the failure to reduce cardiovascular events.

• Summary: The results of the ACCORD and PROMINENT trials were very disappointing and have greatly decreased the enthusiasm for adding fibrates to statin therapy to reduce cardiovascular events.

Effect of Fibrates on Non-Cardiovascular Outcomes

DIABETIC RETINOPATHY

Small studies in the 1960’s presented suggestive evidence that treatment with clofibrate improved diabetic retinopathy (202,203). Randomized trials have confirmed these observations.

The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a randomized trial in patients with Type 2 diabetes mellitus. Patients were randomly assigned to receive either fenofibrate 200 mg/day (n=4,895) or placebo (n=4,900). Laser treatment for retinopathy was significantly lower in the fenofibrate group than in the placebo group (3.4% patients on fenofibrate vs 4.9% on placebo; p=0.0002) (204). Fenofibrate therapy reduced the need for laser therapy to a similar extent for maculopathy (31% decrease) and for proliferative retinopathy (30% decrease). In the ophthalmology sub-study (n=1,012), the primary endpoint of 2-step progression of retinopathy grade did not differ significantly between the fenofibrate and control groups (9.6% patients on fenofibrate vs 12.3% on placebo; p=0.19). In patients without pre-existing retinopathy there was no difference in progression (11.4% vs 11.7%; p=0.87). However, in patients with pre-existing retinopathy, significantly fewer patients on fenofibrate had a 2-step progression than did those on placebo (3.1% patients vs 14.6%; p=0.004). A composite endpoint of 2-step progression of retinopathy grade, macular edema, or laser treatments was significantly reduced in the fenofibrate group (HR 0.66, 95% CI 0.47-0.94; p=0.022).

In the ACCORD Lipids Study a subgroup of participants were evaluated for the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study Severity Scale or the development of diabetic retinopathy necessitating laser photocoagulation or vitrectomy over a four-year period (205). At 4 years, the rates of progression of diabetic retinopathy were 6.5% with fenofibrate therapy (n=806) vs. 10.2% with placebo (n=787) (adjusted odds ratio, 0.60; 95% CI, 0.42 to 0.87; P = 0.006). Of note, this reduction in the progression of diabetic retinopathy was of a similar magnitude as intensive glycemic treatment vs. standard therapy.

A double-blind, randomized, placebo-controlled study in 296 patients with type 2 diabetes mellitus evaluated the effect of placebo or etofibrate on diabetic retinopathy (206). After 12 months an improvement in ocular pathology was more frequent in the etofibrate group vs the placebo group ((46% versus 32%; p< 0.001).

The MacuFen study was a small double-blind, randomized, placebo-controlled study in 110 subjects with diabetic macular edema who did not require immediate photocoagulation or intraocular treatment (207). Patients were randomized to fenofibric acid or placebo for 1 year. Patients treated with fenofibric acid had a modest improvement in total macular volume that was not statistically significant compared to the placebo group.

Based on these trials a large trial specifically designed to investigate the ocular effects of fenofibrate was carried out (The Lowering Events in Non-proliferative retinopathy in Scotland (LENS) trial) (208). In this trial 1151 patients with diabetic retinopathy or maculopathy were randomized to fenofibrate 145mg (n= 576) or placebo (n= 575) for a median of 4.0 years. Progression of diabetic retinopathy or maculopathy requiring referral or treatment (primary endpoint) occurred in 22.7% of patients in the fenofibrate group and 29.2% of patients in the placebo group (HR 0.73; 95% CI 0.58 to 0.91; P=0.006). Any progression of retinopathy or maculopathy was reduced by 26%, the development of macular edema by 50%, and the need for treatment with intravitreal injection, retinal laser, or vitrectomy by 42% in the fenofibrate group.

Taken together these results indicate that fibrates have beneficial effects on the progression of diabetic retinopathy (209). The mechanisms by which fibrates decrease diabetic retinopathy are unknown, and whether decreases in serum TG levels play an important role is uncertain. Fibrates activate PPAR alpha, which is expressed in the retina (210). Diabetic PPARα KO mice developed more severe DR while overexpression of PPARα in the retina of diabetic rats significantly alleviated diabetes-induced retinal vascular leakage and retinal inflammation, suggesting that fibrates could have direct effects on the retina to reduce diabetic retinopathy (210).

DIABETIC KIDNEY DISEASE

The Diabetes Atherosclerosis Intervention Study (DAIS) evaluated the effect of fenofibrate therapy (n= 155) vs. placebo (n=159) on changes in urinary albumin excretion in patients with Type 2 diabetes (211). Fenofibrate significantly reduced the worsening of albumin excretion (fenofibrate 8% vs. placebo 18%; P < 0.05). This effect was primarily due to reduced progression from normal albumin excretion to microalbuminuria (fenofibrate 3% vs. 18% placebo; P < 0.001).

 In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial, Type 2 diabetic patients aged 50 to 75 years were randomly assigned to fenofibrate (n = 4,895) or placebo (n = 4,900) for 5 years (212). Fenofibrate reduced urine albumin/creatinine ratio by 24% vs 11% in placebo group (p < 0.001), with 14% less progression and 18% more albuminuria regression (p < 0.001) in the fenofibrate group than in participants on placebo. As expected, fenofibrate therapy acutely increased plasma creatinine levels and decreased eGFR (213). However, over the long-term, the increase in plasma creatinine was lower in the fenofibrate group compared to the placebo group (14% decrease; p=0.01). Similarly, there was a slower annual decrease in eGFR in the fenofibrate group (1.19 vs 2.03 ml/min/1.73 m²annually, p < 0.001). End-stage renal disease, dialysis, renal transplant, and renal death were similar in the fenofibrate and placebo groups, likely due to the small number of events.

In the ACCORD-LIPID trial, 5,518 patients on statin therapy were randomized to placebo or fenofibrate therapy (200). The patients had diabetes for approximately 10 years and either had pre-existing cardiovascular disease or were at high risk for developing cardiovascular disease. The post-randomization incidence of microalbuminuria was 38.2% in the fenofibrate group and 41.6% in the placebo group (p=0.01) and post-randomization incidence of macroalbumuria was 10.5% in the fibrate group and 12.3% in the placebo group (p=0.04) indicating a modest reduction in the development of proteinuria in patients treated with fenofibrate (200). There was no significant difference in the incidence of end-stage renal disease or need for dialysis between the fenofibrate group and the placebo group, likely due to the small number of events.

A small randomized study in patients with Type 2 diabetes and hypertriglyceridemia compared the effect of fenofibrate (200mg/day) (n=28) vs. no treatment (n=28) on urinary albumin excretion (214). After 180 days urinary albumin/creatine ratio was decreased in the fenofibrate group vs. controls (control -8.15 vs fenofibrate -44.05 mg/g; P<0.05).

These studies suggest that fibrates may have a beneficial effect on diabetic kidney disease (215). One should recognize that reducing proteinuria is a surrogate marker and may not indicate a reduction in the development of end stage renal disease. The mechanisms accounting for the decrease in proteinuria are unknown.

LOWER EXTREMITY COMPLICATIONS (AMPUTATIONS, ULCERATION, GANGRENE) IN PATIENTS WITH DIABETES

In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, patients aged 50-75 years with Type 2 diabetes were randomly assigned to receive fenofibrate 200 mg per day (n=4,895) or matching placebo (n=4,900) for 5 years' duration (216). The risk of first amputation was decreased by 36% (p=0.02) and minor amputation events without known large-vessel disease by 47% (p=0.027) in the fenofibrate treated group (216). The reduction in amputations was independent of glucose control or dyslipidemia. No difference between the risks of major amputations was seen in the placebo and fenofibrate groups. The basis for this reduction in amputations is unknown.

In the PROMINENT trial 10,497 participants with type 2 diabetes, mild to moderate hypertriglyceridemia (triglyceride level 200-499 mg/dL), and high-density lipoprotein cholesterol levels ≤40 mg/dL were randomized to pemafibrate, a selective PPARα activator, or placebo. During a median follow-up of 3.4 years pemafibrate reduced diabetic lower extremity ulceration and gangrene by 37% (HR 0.63; 95% CI: 0.41-0.96; P = 0.03) (217).

GOUT

In the Field trial treatment with fenofibrate reduced uric acid levels by 20% and reduced episodes of gout by approximately 50% compared to placebo (HR 0·48, 95% CI 0·37-0·60; p<0·0001) (218). Interestingly, a meta-analysis of fibrate trials found that fenofibrate but not bezafibrate reduced serum uric acid levels suggesting that the reduction in uric acid levels is not a class effect (219).

SUMMARY

The above studies provide substantial evidence that fibrates have a favorable effect on diabetic microvascular disease (159). While fibrates are not approved specifically for the prevention or treatment of diabetic microvascular disease one should consider these potential beneficial effects when deciding on treatment choices. For example, in a patient with diabetes and microvascular disease and hypertriglyceridemia needing therapy one might elect to use fibrates to lower plasma TGs given their potential beneficial effects on slowing the progression of microvascular disease. 

Side Effects

RENAL

Fibrate therapy leads to an increase in serum creatinine and cystatin C levels (220-222). For example, in the Field Trial serum creatinine levels increased from 0.88mg/dL to 0.99mg/dL, a 12% increase (160). This increase in creatinine has been seen with all fibrates but appears to be less profound with gemfibrozil (220). The increase in cystatin C occurs with fenofibrate but not with other fibrates (221). It must be recognized that this increase in creatinine is reversible on stopping fibrate therapy and does not reflect kidney damage (220). In fact, careful measurements of renal function have not demonstrated a decrease in glomerular filtration rate despite the increase in serum creatinine (213,223,224). As discussed above, studies of renal function in patients with diabetes actually suggests that treatment with fibrates may be protective. The precise mechanism by which fibrates increase serum creatinine levels is unknown.

In patients with chronic renal disease fibrates should be used with caution and at lower doses (220). Fibrates are all excreted by the kidneys and thus the excretion of fibrates is decreased in patients with renal dysfunction (220). Therefore, one needs to adjust the fibrate dose depending upon renal function. The National Kidney Foundation recommends the dose adjustments shown in Table 18 (225).

GALLBLADDER DISEASE

It is clear that clofibrate increases the risk of gallbladder disease. In both the WHO trial and the Coronary Drug Project, cholecystectomies occurred two to three times more often in the patients treated with clofibrate compared to placebo (44,191,226). Whether gemfibrozil, fenofibrate, or other fibrates increases the risk of gallbladder disease is uncertain. In the large, randomized outcome studies presented earlier (Effect of fibrates on cardiovascular outcomes section) a statistically significant increase in either gallbladder disease or cholecystectomies were not observed. However, in a sub-study of 450 Helsinki Heart Study participants a trend toward a greater prevalence of gallstones during the study in the gemfibrozil group was observed (7.5% versus 4.9% for the placebo group, a 55% excess for the gemfibrozil group) (Lopid Package Insert). A trend toward a greater incidence of gallbladder surgery was also observed in the gemfibrozil group (17 versus 11 subjects, a 54% excess) (Lopid Package Insert). In a single epidemiological trial fibrate treatment independently correlated with the presence of gallstones with a relative risk of 1.7 (p=0.04) (227).

All fibrates alter the composition of bile resulting in an increase in the concentration of cholesterol, which will predispose to the formation of cholesterol gallstones (220). In a comparison of clofibrate and gemfibrozil it was observed that clofibrate resulted in changes in bile composition that would be more lithogenic than gemfibrozil (228).

The effect of combining fibrates with statins on the risk of gallbladder disease is unknown.  An increased risk of gallbladder disease or cholecystectomies was not reported in the ACCORD-LIPID trial where fenofibrate was added to statin therapy or the PROMINENT trial where pemafibrate was added to statin therapy (200,201).

While it is clear that clofibrate increases the risk of gallbladder disease the effect of other fibrates either as monotherapy or in combination with other drugs is less well defined.

PANCREATITIS  

In a meta-analysis of 7 fibrate trials involving 40,162 participants conducted over 5.3 years, 144 participants developed pancreatitis (84 assigned to fibrate therapy, 60 assigned to placebo) (RR, 1.39 (95% CI, 1.00-1.95; P = .053) (229). These observations raise the possibility that fibrates may increase the risk of pancreatitis.

CANCER

A large meta-analysis of 17 randomized controlled trials, involving 44,929 participants, with an average follow-up of 5.2 years has examined if fibrates lead to an increased risk of cancer. No increase in either cancer incidence (RR = 1.02, 95% CI 0.92-1.12) or cancer death (RR = 1.06, 95% CI: 0.92-1.22) was noted with fibrate treatment (230).

LIVER DISEASE

Fenofibrate has rarely been associated with idiosyncratic hepatotoxicity manifesting as hepatocellular to cholestatic disorders (231). The hepatitis may be acute self-limited or persistent chronic hepatitis. Liver abnormalities are very rare and in large trials such as the FIELD trial described above liver function test abnormalities were similar in the fenofibrate and placebo groups (160).   

GLYCEMIC PARAMETERS

A meta-analysis of 22 randomized placebo-controlled trials involving a total of 11,402 subjects demonstrated that fibrate therapy significantly decreased fasting plasma glucose, insulin levels, and insulin resistance measured by HOMA-IR, but did not affect HbA1c levels (232).

MUSCLE DISORDERS

Fibrate monotherapy has been reported to cause myopathy (220). In a large epidemiological study the incidence of hospitalization for rhabdomyolysis per 10,000 person-years for monotherapy with a fibrate was 2.82 (95% CI, 0.58-8.24) while in patients not exposed to lipid lowering drugs the incidence was 0 (95% CI, 0-0.48) (233). The risk of rhabdomyolysis was greater with gemfibrozil therapy than with fenofibrate. Interestingly the incidence of rhabdomyolysis was greater for patients treated with fibrate monotherapy than for patients treated with statin monotherapy (incidence for atorvastatin, pravastatin, or simvastatin was only 0.44 per 10,000 person-years). In an epidemiological study focusing on myopathy similar results were observed (234). The relative risks of myopathy in current users of fibrates and statins compared with nonusers were 42.4 (95% CI = 11.6-170.5) and 7.6 (95% CI = 1.4-41.3), respectively. It should be recognized though that in large randomized clinical trials the risk of muscle symptoms was low in patients treated with fibrates and not dissimilar to that seen in the patients treated with placebo (220). For example, in the Helsinki Heart Study over 2,000 patients were treated and in the VA-HIT over 1,000 patients were treated with gemfibrozil for five years and no cases of  myopathy were reported in either trial (156,157). In the Bezafibrate Infarction Prevention Study, seven patients in the placebo group and five patients in the bezafibrate group reported muscle pain, while CPK levels greater than 2x the upper range of normal was seen in four patients in the bezafibrate group and one patient in the placebo group (158). Finally, in the Field Trial, patients with diabetes were treated with fenofibrate (n=4,895) or placebo (n=4,900) (160). Myositis was observed in one patient treated with placebo and two patients treated with fenofibrate while rhabdomyolysis was observed in one patient treated with placebo and three patients treated with fenofibrate. Elevations in CPK levels values > 10x the upper range of normal were seen in three patients on placebo and 4 patients treated with fenofibrate. Thus, while fibrates can lead to significant muscle dysfunction this is a rare event and appears to occur only slightly more often in patients treated with a fibrate than in patients treated with a placebo. The risk of serious muscle disease appears to be increased in patients with renal failure, hypothyroidism, and in the elderly (220). The mechanism by which fibrates predispose to muscle disorders is unknown.

The effect of fibrates in combination with statins on muscle disorders will be discussed in detail in the section on drug interactions below.

Drug Interactions

STATINS

The combination a fibrate and a statin may increase the risk of developing muscle symptoms (220). The degree of risk is dependent on both the specific statin and the specific fibrate that is being used in combination (220). For example, the average incidence per 10,000 person-years for hospitalization for rhabdomyolysis with monotherapy with atorvastatin, pravastatin, or simvastatin was 0.44 (95 % CI, 0.20-0.84); with fibrate alone was 2.82 (95% CI, 0.58-8.24); and with combined therapy of atorvastatin, pravastatin, or simvastatin with a fibrate was 5.98 (95% CI, 0.72-216.0) (233). Of note, the average incidence per 10,000 person-years for hospitalization for rhabdomyolysis with the combination of cerivastatin with a fibrate was 1035 (95% CI, 389-2117), clearly demonstrating an increased risk of the cerivastatin-fibrate combination compared to other statin-fibrate combinations (233). A study by Alsheikh-Ali and colleagues looking at cases of rhabdomyolysis reported to the FDA relative to the total number of prescriptions reached the conclusion that the combination of cerivastatin with a fibrate markedly increased the risk of this complication (235). Additionally, it was noted that the risk of rhabdomyolysis was greater with gemfibrozil compared to fenofibrate and that the combination of cerivastatin and gemfibrozil was particularly toxic (235). Other studies have also noted a marked risk with the combination of cerivastatin and gemfibrozil (236). Cerivastatin is no longer available.

Studies comparing the risk of rhabdomyolysis with gemfibrozil-statin combination therapy compared to fenofibrate-statin combination therapy have shown an increased risk with gemfibrozil (220). For example, the number of cases of rhabdomyolysis reported with fenofibrate and statins other than cerivastatin was 0.58 per million prescriptions whereas with gemfibrozil and statins other than cerivastatin was 8.6 per million prescriptions (237). Reviews of the FDA’s adverse events reporting system database have estimated that the risk of myopathy for the combination of gemfibrozil with a statin was much greater than the risk with the combination of fenofibrate with a statin (235,237).  Additionally, studies that employed the combination of gemfibrozil and statins have reported a significant occurrence of muscle related symptoms whereas studies of fenofibrate in combination with statins have not shown an increase in muscle related symptoms (220). For example, the rate of myopathy in over 4,000 patients taking lovastatin was only 0.4% but in patients on the combination of lovastatin and gemfibrozil the frequency increased to 5% (238). In contrast, in the ACCORD-LIPID Trial over 5,000 patients on statin therapy were randomized to fenofibrate or placebo for 4.7 years and no increase in the incidence of muscle related symptoms was observed with fenofibrate therapy (200). Similarly, in the Field Trial approximately 1,000 patients were taking fenofibrate and a statin and with 5 years of follow-up no cases of rhabdomyolysis were reported (160). Finally, a meta-analysis by Geng and colleagues identified 13 randomized trials with 7,712 patients receiving combination fenofibrate-statin therapy compared with statin therapy alone (172). The incidence of elevated creatine kinase levels, muscle-associated adverse events, or withdrawals attributed to muscle dysfunction did not differ significantly between the fenofibrate + statin patients vs. the statin alone patients (172). The American College of Cardiology and American Heart Association Guidelines recommend against using the combination of a statin and gemfibrozil but recognize that the use of a statin and fenofibrate is appropriate under certain circumstances (239).

The increased risk of combining gemfibrozil with statins is due to alterations in statin metabolism leading to increases in the serum levels of statins and hence an increased risk of myopathy (220,240). In contrast, fenofibrate does not alter statin metabolism and therefore can be safely combined with statins (Table 19) (240).   

The explanation for the difference between gemfibrozil and fenofibrate is that gemfibrozil uses the same family of glucuronidation enzymes as the statins thereby inhibiting statin metabolism (220,242). In contrast, fenofibrate uses a different family of glucuronidation enzymes and does not inhibit statin metabolism (220).

COUMADIN ANTI-COAGULANTS

Gemfibrozil and fenofibrate can potentiate the effect of coumadin anti-coagulants leading to a prolongation of prothrombin time and an increased risk of bleeding. When starting a fibrate in patients on coumadin therapy the dose of coumadin should be decreased and prothrombin times should be closely monitored (Lopid and Tricor Package Inserts).    

REPAGLINIDE

Gemfibrozil in combination with rapaglinide increases blood levels of rapaglinide and therefore this combination should not be used because of the increased risk of hypoglycemia (Lopid Package Insert).

Contraindications

Fibrates are contraindicated in patients with severe hepatic dysfunction. Additionally, patients with pre-existing gallstones should not be treated with fibrates. Fenofibrate and gemfibrozil are pregnancy category C drugs and should only be used if the potential benefit justifies the potential risk to the fetus. The combination of gemfibrozil and a statin should be avoided.

Conclusions

Fibrates are effective drugs in reducing TG levels and modestly increase HDL-C levels. Additionally, they also reduce LDL-C and non-HDL-C levels. Fibrates have a number of side effects, and one should avoid using gemfibrozil in combination with statins. In contrast, fenofibrate can be used in combination with statins. Studies have not consistently demonstrated that fibrate monotherapy therapy reduces cardiovascular events and the combination of fibrates and statins in two studies has not been shown to be beneficial. Therefore, enthusiasm to use fibrates to reduce cardiovascular events has markedly diminished. In patients with diabetes fibrates appear to slow the progression of microvascular disease. Finally, fibrates are effective in lowering TGs in patients with marked hypertriglyceridemia and while not proven it will likely reduce the risk of the development of pancreatitis.

APOLIPOPROTEIN C-III INHIBITORS

Volanesorsen

INTRODUCTION  

Volanesorsen (Waylivra) is an antisense oligonucleotide inhibitor of apolipoprotein C-III (apo C-III) mRNA that is approved in Europe for the treatment of familial chylomicronemia syndrome (FCS). This drug has not been approved by the FDA for use in the United States. FCS is a rare metabolic disorder involving the impaired function of lipoprotein lipase (LPL) due to mutations in LPL, Apo C-II, Apo A-V, lipase maturation factor 1, and glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) (243,244). For a detailed discussion of the diagnosis and treatment of FCS see the following references (243-245).

EFFECT OF VOLANESORSEN ON LIPID AND LIPOPROTEIN LEVELS      

Familial Chylomicronemia Syndrome

A double-blind, randomized 52-week trial (APPROACH study) evaluated the ability of volanesorsen (300 mg subcutaneously once weekly) vs. placebo to decrease TG levels in 66 patients with FCS (baseline TGs 2,209mg/dL) (246). The primary end point was the percentage change in fasting TG levels at 3 months. As expected, there was a marked reduction in Apo C-III levels (84% decrease) in the volanesorsen group and a small increase (6%) in the placebo group. Most importantly patients treated with volanesorsen had a 77% decrease at 3 months in TG levels (mean decrease of 1,712 mg/dL) whereas patients receiving placebo had an 18% increase in TG levels. The decrease in TGs in patients treated with volanesorsen persisted for 24 months (247). Significantly, 77% of the patients in the volanesorsen group vs. only 10% of patients in the placebo group had TG levels of less than 750 mg/dL, a level that would greatly reduce the risk of pancreatitis. In addition, patients who received volanesorsen had decreases in levels of chylomicron TG by 83%, apolipoprotein B-48 by 76%, non–HDL-C by 46%, and VLDL-C by 58% and increases in levels of HDL-C by 46%, apolipoprotein A1 by 14%, LDL-C by 136% (note LDL-C increased from 28 to 61 mg/dL), and total apolipoprotein B by 20%.

While the APPROACH study was not powered to examine the effect of volanesorsen on pancreatitis, during the study three patients in the placebo group had four episodes of acute pancreatitis, whereas one patient in the volanesorsen group had one episode. In patients with a history of recurrent pancreatitis events (≥ 2 events in the 5 years prior to study, n = 11), a reduction in pancreatitis attacks was seen in patients treated with volanesorsen compared with placebo (none of the 7 patients in the volanesorsen group and 3 of the 4 patients in the placebo group experienced a pancreatitis attack over the 52-week study period).

In a retrospective global web-based survey open to all patients with the FCS who received volanesorsen for ≥3 months, 22 patients responded and reported reductions in steatorrhea, pancreatic pain, and constant worry about an attack of pain/ acute pancreatitis (248). The patients also reported that volanesorsen improved overall management of symptoms and reduced interference of FCS with work/school responsibilities. Decreases in the negative impact of FCS on personal, social, and professional life were also reported.

Hypertriglyceridemia

A randomized, double-blind, placebo-controlled, study evaluated volanesorsen in patients with hypertriglyceridemia (249). Patients who were not receiving TG-lowering therapy (n=57) were eligible if they had fasting TG level between 350 mg/dL and 2000 mg/dL and were assigned to volanesorsen 100, 200, or 300 mg or placebo. Patients who were receiving a fibrate (n=28) were eligible if they had a fasting TG level between 225 mg/dL and 2000 mg/dL and were randomly assigned to volanesorsen 200 or 300 mg or placebo. The study drug was administered as a single subcutaneous injection once a week for 13 weeks. Baseline TG levels were 581±291 mg/dL in patients not on fibrates and 376±188 mg/dL in patients on fibrates. In patients not on fibrates volanesorsen 300 mg decreased Apo C-III levels by 79.6% vs. an increase of 4.2% in the placebo group (P<0.001) and decreased TG levels by 70.9% compared with an increase of 20.1% in the placebo group (P<0.001). Additionally, HDL-C levels increased by 45.7% from baseline in the 300 mg group, as compared with an increase of 0.7% in the placebo group (P<0.001). LDL-C levels increased from 79.5±29.9 mg/dL to 127.8±44.9 mg/dL with 300 mg of volanesorsen and was associated with an increase in LDL particle size. However, non-HDL-C and total apo B levels remained relatively unchanged and similar to those in the placebo group. Similar changes in Apo C-III, TGs, HDL-C, non-HDL-C, VLDL-C, and total apo B levels were observed in the patients on fibrates treated with volanesorsen. Of note, LDL-C levels did not increase in the patients on fibrates treated with volanesorsen perhaps due to the lower baseline TG levels. 

The COMPASS study randomized 113 patients with fasting TGs ≥500 mg/dL (mean TG 1,261mg/dL) to receive either volanesorsen 300 mg or placebo subcutaneously once weekly for 26 weeks (250). Most of these patients had the multifactorial chylomicronemia syndrome but a small number had FCS. A 71% reduction in TGs from baseline after 3 months was observed in patients treated with volanesorsen vs. a 0.9% reduction in placebo-treated patients (P<0.0001). LDL-C levels increased 96% (64 to 111mg/dL), HDL-C increased 61% (25 to 39mg/dL) and non-HDL-C decreased 27% (232 to 158mg/dL) Notably pancreatitis episodes were reduced with 5 events in 3 patients occurring in the placebo group vs. none with volanesorsen treatment (P=0.036). 

Diabetes

A randomized, double-blind, placebo-controlled trial of volanesorsen 300 mg weekly or placebo was performed in 15 adult patients with type 2 diabetes (HbA1c >7.5%) and hypertriglyceridemia (TG >200 and <500 mg/dL) (251). Treatment with volanesorsen significantly reduced plasma apo C-III (-88%, P = 0.02) and TG (-69%, P = 0.02) levels and raised HDL-C (42%, P = 0.03) without altering LDL-C levels compared with placebo. These changes were accompanied by a 57% improvement in whole-body insulin sensitivity (P < 0.001) and decreases in HbA1c (-0.44%, P = 0.025) 3 months postdosing. The improvement in insulin sensitivity was strongly related to the decrease in plasma apo C-III and TGs.

Familial Partial Lipodystropy (FPL)

Patients with FPL were randomized to volanesorsen 300mg weekly (n=21) or placebo (n=19) (252). Median TG level was 781mg/dL in the placebo group and 749mg/dL in the volanesorsen group. Volanesorsen treatment at 3 months resulted in an 88% decrease in TG levels while in the placebo group TG levels decreased by 22% (net difference of −67%; P=0.0009). Non-HDL-HDL-C levels decreased while LDL-C and HDL-C levels increased. A smaller study in 5 patients with FPL also demonstrated decreases in TG levels (253).

MECHANISMS ACCOUNTING FOR THE VOLANESORSEN INDUCED LIPID EFFECTS           

Volanesorsen binds to apo C-III mRNA leading to increased degradation and thereby inhibits the hepatic synthesis of apo C-III protein resulting in a reduction in plasma apo C-III levels (254,255). Apo C-III has a number of important effects on the metabolism of TG rich lipoproteins (256). Apo C-III is an inhibitor of LPL and therefore decreasing apo C-III levels will enhance LPL activity. In patients with FCS this will not be important because patients with this disorder have defects in components of the LPL complex that result in the inability to increase LPL activity. However, in patients with increased TG levels not due FCS this would accelerate the clearance of TG rich lipoproteins. Studies have also shown that apo C-III stimulates the production and secretion of VLDL by the liver. This effect is also not likely to be of primary importance in patients with FCS as the very high TG levels are primarily due to chylomicrons and not VLDL. However, in other situations increased hepatic secretion of VLDL may be an important contributor to hypertriglyceridemia. Whether apo C-III regulates chylomicron secretion by the intestine is unknown. Finally, Apo C-III inhibits the binding of TG rich lipoproteins to hepatic LDL receptors and LDL receptor–related protein 1 decreasing the clearance of TG rich lipoprotein particles. A decrease in apo C-III will accelerate the clearance of TG rich lipoproteins, which likely accounts for the ability of volanesorsen to decrease TG levels in patients with FCS.

DRUG ADMINISTRATION AND PHARMACOKINETICS

The recommended starting dose is 285 mg injected subcutaneously once weekly for 3 months after which the dose should be reduced to 285 mg every 2 weeks. If serum TGs decrease by less than 25% or are not below 2000 mg/dL (22.6 mmol/L) after 3 months on volanesorsen 285 mg weekly, treatment should be discontinued (package insert;https://www.ema.europa.eu/en/documents/product-information/waylivra-epar-product-information_en.pdf).

After 6 months of treatment one can consider increasing the dose frequency back to 285 mg weekly if the serum TG response has been inadequate and the platelet counts are in the normal range. Patients should return to 285 mg every 2 weeks if the higher 285 mg once weekly dose does not provide a significant additional TG reduction after 9 months (package insert).

EFFECT ON CLINICAL OUTCOMES

As described above in the description of the effect of volanesorsen on lipid/lipoprotein levels in patients with FCS and marked hypertriglyceridemia there is suggestive evidence that lowering the very high TG levels with volanesorsen treatment will reduce the risk of pancreatitis and improve the quality of life. An analysis of 3 randomized trials in  patients with severe hypertriglyceridemia reported that acute pancreatitis occurred in 2 patients (2%) in the volanesorsen group and in 9 patients (10%) in the placebo group (odds ratio, 0.18; 95% confidence interval, 0.04 to 0.82) (257).

Volanesorsen treatment reduced hepatic fat assessed by MRI in patients with FCS, severe hypertriglyceridemia, and familial partial lipodystrophy (258). The greater the hepatic fat the greater the decrease induced by volanesorsen.

The effect of volanesorsen on cardiovascular disease has not been determined. However, epidemiologic studies have demonstrated that increased Apo C-III levels are associated with an increased risk of cardiovascular events (259-261)and coronary artery calcification (262). Moreover, carriers of rare heterozygous loss-of-function mutations in Apo C-III have reduced TG levels and reduced cardiovascular disease risk (263-265). One can speculate that lowering Apo C-III and TG levels with volanesorsen will have beneficial effects on the development of cardiovascular disease.

SIDE EFFECTS 

Treatment with volanesorsen is very commonly associated with reductions in platelet count in patients with the FCS and may result in thrombocytopenia (package insert; https://www.ema.europa.eu/en/documents/product-information/waylivra-epar-product-information_en.pdf). Platelet counts below 140 x 10⁹/L were observed in 75% of patients treated with volanesorsen vs. 24% of placebo patients. Reductions to below 100 x 10⁹/L were observed in 47% of patients treated with volanesorsen compared with none of the patients in the placebo group. Bleeding secondary to low platelets may occur. Careful monitoring for thrombocytopenia is important during treatment and recommendations for adjustments to monitoring frequency and dosing are shown in table 20 (package insert). Platelet counts recover following drug discontinuation and administration of glucocorticoids where medically indicated.

Renal toxicity has been observed after administration of volanesorsen. Monitoring for evidence of nephrotoxicity by routine urine dipstick is recommended on a quarterly basis. In the case of a positive assessment, one should measure serum creatinine and collect a 24-hour urine collection to quantify the proteinuria and assess creatinine clearance. Treatment should be discontinued if proteinuria ≥ 500 mg/24 hours is present, or an increase in serum creatinine ≥ 0.3 mg/dL that is >ULN occurs, or the creatinine clearance estimated by the CKD-EPI equation is ≤ 30 mL/min/1.73m²(package insert).

Elevations of liver enzymes have been observed after the administration of volanesorsen. Serum liver enzymes and bilirubin should be monitored every 3 months. Treatment should be discontinued if there is a single increase in ALT or AST > 8 x ULN, or an increase > 5 x ULN, which persists for ≥ 2 weeks, or lesser increases in ALT or AST that are associated with total bilirubin > 2 x ULN or INR > 1.5 (package insert).

As expected, injection site reactions are frequently observed and were reported in 82% of patients (erythema, pain, pruritus, or local swelling) (package insert).

CONTRAINDICATIONS

Treatment should not be initiated in patients with thrombocytopenia (platelet count <140 x 10⁹/L). Safety and efficacy have not been established in patients with severe renal disease or patients with hepatic impairment (package insert). There are no data on the use of volanesorsen in pregnant women and it is preferable to avoid the use of volanesorsen during pregnancy (package insert). However, there have been 2 instances where volanesorsen was used during pregnancy in patients with familial chylomicronemia syndrome and “In both case, fetal health was maintained throughout pregnancy, fetal scans revealed no anomalies, and planned C-sections delivered healthy babies without congenital issues” (266).

DRUG INTERACTIONS 

Discontinuation of antiplatelet drugs/NSAIDs/anticoagulants should be considered for

platelet levels < 75 x 10⁹/L. Treatment with these products must be discontinued at platelet levels < 50 x 10⁹/L. No other drug interactions have been described (package insert)

CONCLUSIONS 

Volanesorsen is a useful drug in patients with the FCS, particularly in patients who have repeated episodes of acute pancreatitis. Whether volanesorsen will be useful for the treatment of less severe hypertriglyceridemia remains to be determined, particularly given its potential side effects. It is likely that the use of this drug will be very limited as olezarsen is a very similar drug without the side effect of thrombocytopenia (see below).

Olezarsen

INTRODUCTION 

Olezarsen (Tryngolza) is an antisense oligonucleotide that reduces apo C-III production by binding to Apo C-3 mRNA and inducing its degradation. Olezarsen has the same nucleotide sequence and backbone chemical composition as volanesorsen and differs from it only through conjugation with GalNAc3, which facilitates uptake by the liver allowing for the administration of lower doses. It is approved in the US for the treatment of patients with Familial Chylomicronemia Syndrome (FCS).

EFFECT OF OLEZARSEN ON LIPID AND LIPOPROTEIN LEVELS  

Familial Chylomicronemia Syndrome 

Patients were randomized to placebo (n=23), olezarsen 50mg (n=21), or olezarsen 80mg (n=22) every 4 weeks (267). The mean TG levels were approximately 2600mg/dL. As expected, the Apo C-III level in the 80mg group decreased by 73.7% and in the 50mg group by 65.5%. At 6 months TG levels compared to placebo decreased by 43.5% with the 80mg dose (95% CI −69.1 to −17.9; P<0.001) and by 22.4% with the 40mg dose (95% CI −47.2 to 2.5; P = 0.08). At 12 months TG levels compared to placebo were decreased by 59% in the 80mg olezarsen group (95% CI, −90.7 to −28.1) and 44% in the 50mg olezarsen group (95% CI, −73.9 to −13.7). In the 80mg dose LDL-C increased from 22.8mg/dL to 37.6mg/dL and the Apo B increased from 58mg/dL to 69mg/dL while non-HDL-C decreased by 24%. By 53 weeks, 11 episodes of acute pancreatitis had occurred in the placebo group and 1 episode in the olezarsen group (RR 0.12; 95% CI, 0.02 to 0.66).

Hypertriglyceridemia

Patients with either moderate hypertriglyceridemia (TG 150-499mg/dL plus elevated cardiovascular risk or severe hypertriglyceridemia (TG> 500mg/dL) were randomized to placebo (n=39), 50mg olezarsen (n= 58), or 80mg olezarsen (n= 57) monthly (268). The median TG level was between 230-250mg/dL. After 6 months TG levels compared to placebo were decreased by 49% by the 50mg dose and 53% by the 80mg dose. Additionally, non-HDL-C levels were decreased by 23% and Apo B levels by 19% in patients treated with olezarsen 80mg with no significant change in LDL-C levels. Notably, HDL-C levels increased by 39% in patients treated with olezarsen 80mg.

In a study of patients with TG levels between 200-500mg/dL the effect of 50mg olezarsen every 4 weeks on NMR-derived lipoprotein particle size and concentration was determined (269). TG rich lipoprotein particles decreased (51%) with the greatest decrease in large and medium size TG rich lipoprotein particles (approx. 60-70% decrease). The total number of LDL particles was unchanged but there was an increase in large LDL particles and a decrease in small LDL particles. Total HDL particles increased due to an increase in small HDL.

 MECHANISMS ACCOUNTING FOR THE OLEZARSEN INDUCED LIPID EFFECTS   

See the section on the Mechanisms Accounting for the Volanesorsen  Induced Lipid Effects described above.

DRUG ADMINISTRATION

The recommended dosage of olezarsen is 80mg administered subcutaneously monthly into the abdomen or front of the thigh.

 EFFECT ON CLINICAL OUTCOMES

The clinical trial with olezarsen in patients with FCS described above observed a decrease in episodes of pancreatitis. This is similar to the results seen with volanesorsen (described above in the volanesorsen section) and together these results indicate that decreasing TG levels via reducing Apo C-III levels is an effective treatment for preventing pancreatitis in FCS patients.  

The effect of olezarsen on cardiovascular disease has not been determined. However, epidemiologic studies have demonstrated that increased Apo C-III levels are associated with an increased risk of cardiovascular events (259-261)and coronary artery calcification (262). Moreover, carriers of rare heterozygous loss-of-function mutations in Apo C-III have reduced TG levels and reduced cardiovascular disease risk (263-265). One can speculate that lowering Apo C-III and TG levels with olezarsen will have beneficial effects on the development of cardiovascular disease.

SIDE EFFECTS

Hypersensitivity reactions, including symptoms of bronchospasm, diffuse erythema, facial swelling, urticaria, chills, and myalgias, requiring medical treatment have occurred (package insert). As expected, injection site reactions may occur. Additionally, arthralgias were noted in 9% of olezarsen treated patients and 0% of placebo treated patients (package insert).

Similar to volanesorsen there is a decrease in platelet levels, but the decrease is much less. The mean percent change in platelet count was -10% and no patients with FCS treated with olezarsen had a platelet count <50,000/mm3 (package insert). There was no major bleeding events associated with a low platelet count and the patients experiencing a bleeding adverse event was similar in the olezarsen and placebo groups (package insert).

Small increases in average fasting glucose (≤17 mg/dL) and HbA1c (<0.2%) were observed over time with olezarsen treatment in the FCS population. The incidence of hyperglycemia (defined as adverse events, new antidiabetic medication, or laboratory values) was higher in olezarsen-treated patients without a medical history of diabetes at baseline (52%) compared to placebo-treated patients (35%) (package insert).

CONTRAINDICATIONS

There is no data on the use of olezarsen during pregnancy and lactation.

While not discussed in the package insert it is the author’s opinion that in patients with a low platelet count (<75,000/mm3) one should either avoid the use of olezarsen or very closely monitor platelet levels.  

DRUG INTERACTIONS

There are no described drug interactions.

CONCLUSIONS

Olezarsen is a useful drug to lower TG levels in patients with the FCS, particularly in patients who have repeated episodes of acute pancreatitis. Because it doesn’t have a major adverse effect on platelets it will replace volanesorsen for lowering TG levels in patients with FCS. The drug is not currently approved for the treatment of multifactorial chylomicronemia syndrome (MFCS) but one would anticipate that it would be useful in patients with MFCS with recurrent pancreatitis refractory to the usual treatments. Whether olezarsen will be useful for the treatment of patients with less severe hypertriglyceridemia, who are not at high risk for pancreatitis, will depend on whether studies demonstrate that olezarsen reduces cardiovascular events.  

ALIPOGENE TIPARVOVEC (GLYBERA)

Introduction

Alipogene tiparvovec is a gene therapy that was approved in Europe for adult patients with FCS due to lipoprotein lipase deficiency and a history of multiple or severe episodes of pancreatitis who have failed dietary therapy (270). The diagnosis of FCS with loss of function mutations in lipoprotein lipase must be confirmed by genetic testing but patients need to have detectable levels of lipoprotein lipase protein (to avoid immunological reactions) (270). Alipogene tiparvovec is an adeno-associated virus gene therapy that results in the expression of the naturally occurring S447X variant of the human lipoprotein lipase gene that has increased lipoprotein lipase activity compared to “normal” lipoprotein lipase (270). Approximately 20% of Caucasians express this gene variant and these individuals have lower plasma TG levels and an increase in HDL-C levels (271,272). Because of the lack of long-term efficacy alipogene tiparvovec is no longer clinically available.

Effect of Alipogene Tiparvovec on Lipid and Lipoprotein Levels 

In patients with lipoprotein lipase deficiency and plasma TG levels > 880mg/d, treatment with alipogene tiparvovec resulted in an approximately 40% decrease in fasting plasma TGs with half of the patients having > 40% decrease in fasting plasma TG levels at 3-12 weeks post treatment (273). By week 16-26, fasting TG levels returned to baseline values but chylomicron levels were reduced (273). While fasting TG levels returned to baseline, postprandial TG levels were reduced by approximately 60% suggesting that there are long term effects that are not reflected by fasting TG levels (274). In fact, in some patients treated with alipogene tiparvovec, lipoprotein lipase expression was demonstrated in muscle biopsies at 26 weeks (273).

Mechanisms Accounting for the Alipogene Tiparvovec Induced Lipid Effects 

Gene therapy with alipogene tiparvovec results in the expression of lipoprotein lipase in muscle, which accelerates the clearance of chylomicrons (270,273). Studies have demonstrated a reduced peak level and a reduced area under the curve for postprandial chylomicrons (274).

Drug Administration and Pharmacokinetics 

Alipogene tiparvovec is administered by multiple intramuscularly injections in the legs given at a single visit (270). The number of injections is > 40 and therefore the injections are given under spinal anesthesia (273). From 3 days before administration until 12 weeks after administration patients may be treated with cyclosporine (3mg/kg/day) and mycophenolate (2g/day) and on the day of administration methylprednisolone 1mg/kg) may be administered IV (270,273).

Effect on Clinical Outcomes

In patients with FCS and lipoprotein lipase deficiency the outcome of interest is pancreatitis. In a retrospective study of 19 patients treated with alipogene tiparvovec an approximate 50% decrease in pancreatitis was observed (275). In addition, patients treated with alipogene tiparvovec have reported benefits including discontinuing lipoprotein apheresis, increased energy, and the ability to liberalize their diet, which is difficult to comply with due to the marked limitation in dietary fat (273,276).

Conclusions 

Alipogene tiparvovec may be a useful treatment for the rare patient with FCS due to lipoprotein lipase deficiency but the lack of long-term efficacy and the difficulty of giving the required injections led to this drug being removed from the market. Additionally, the development of inhibitors of Apo CIII described above has diminished the usefulness of alipogene tiparvovec for the treatment of patients with FCS due to lipoprotein lipase deficiency.

EVINACUMAB (EVKEEZA

Introduction

Evinacumab is a human monoclonal antibody against angiopoietin-like protein 3 (ANGPTL3). It is approved for the treatment of Homozygous Familial Hypercholesterolemia (see Endotext chapter on Cholesterol Lowering Drugs (6)). Evinacumab decreases LDL-C levels by mechanisms independent of LDL receptor activity. The recommended dose of evinacumab is 15 mg/kg administered by intravenous infusion over 60 minutes every 4 weeks. While it is not approved for TG lowering it is effective in lowering TG levels.

Effect on Evinacumab on TG Levels

For information on the effect of evinacumab on LDL-C levels see the Endotext chapter on “Cholesterol Lowering Drugs (6). Because of the difficulty in treating severe hypertriglyceridemia, I have focused on evinacumab in this group of patients. Phase 1 studies have shown that various doses of evinacumab lower TG levels in individuals with TG levels between 150-450mg/dL with maximal effects of approximately 80% reductions (277). Additionally. In patients treated with evinacumab to lower LDL-C, TG levels were reduced even though the baseline TG levels were < 150mg/dL (278).  As one would expect LDL-C and HDL-C levels also decreased in these individuals with normal or modestly elevated TG levels.

A phase 2 study evaluated evinacumab in three groups of patients with severe hypertriglyceridemia; FCS patients with bi-allelic loss-of-function mutations in the lipoprotein lipase (LPL) pathway (n = 17), multifactorial chylomicronemia syndrome (MFCS) with heterozygous loss-of-function LPL pathway mutations (n = 15), and MFCS without LPL pathway mutations (n = 19) (279). Patients were randomized to evinacumab 15 mg/kg IV or placebo every 4 weeks over 12-weeks. The effect on TG and non-HDL-C levels are shown in table 21. Despite the very small number of patients the results suggest that evinacumab can lower TG levels in patients with MFCS but not in patients with FCS. This result Is not surprising based on the proposed mechanism of action of inhibiting ANGPTL3 (see below).

*p= 0.0076, **p= 0.0418, ^p= 0.0074, ^^p= 0.0677, ^^^p= 0.1016.

FCS= familial chylomicronemia syndrome, MFCS= multifactorial chylomicronemia syndrome.

Mechanism Accounting for the Evinacumab Induced Decrease in TG

ANGPTL3 inhibits lipoprotein lipase (LPL) activity thereby slowing the clearance of VLDL and chylomicrons resulting in an increase in plasma triglyceride levels (280,281). Mice deficient in ANGPTL3 have lower plasma triglyceride levels while mice overexpressing ANGPTL3 have elevated plasma triglyceride levels (281). Evinacumab by inhibiting the ability of ANGPTL3 to decrease LPL activity results in an increases in LPL activity, which accelerates the clearance of TG rich lipoproteins decreasing plasma triglyceride levels (281). In patients with FCS who lack a functioning lipoprotein lipase clearance system evinacumab will not accelerate the clearance of TG rich lipoproteins. For information on the mechanism by which evinacumab lowers LDL-C and HDL-C see the Endotext chapter on “Cholesterol Lowering Drugs” (6).

Pharmacokinetics and Drug Interactions

There are no significant drug interactions.

Effect of Evinacumab on Clinical Outcomes

There are no cardiovascular outcome studies.

Homozygosity for loss-of-function mutations in ANGPTL3 is associated with significantly lower plasma levels of LDL-C, HDL-C, and triglycerides (familial combined hypolipidemia) (281,282). Heterozygous carriers of loss-of-function mutations in ANGPTL3, which occur at a frequency of about 1:300, have significantly lower total cholesterol, LDL-C, and triglyceride levels than noncarriers (281). Moreover, patients carrying loss-of-function variants in ANGPTL3 have a significantly lower risk of coronary artery disease (283,284). Additionally, in an animal model of atherosclerosis treatment with evinacumab decreased atherosclerotic lesion area and necrotic content (283). Taken together these observations suggest that inhibiting ANGPTL3 with evinacumab will reduce cardiovascular disease.

Side Effects

Serious hypersensitivity reactions have occurred with evinacumab. In clinical trials, 1 (1%) of evinacumab treated patients experienced anaphylaxis vs. 0% of patients who received placebo (package insert).

Contraindications

Based on animal studies, evinacumab may cause fetal harm when administered to pregnant patients (package insert). Patients should be advised of the potential risks to the fetus of pregnancy. Patients who may become pregnant should be advised to use effective contraception during treatment with evinacumab and for at least 5 months following the last dose.

Summary

Evinacumab lowers triglyceride levels in patients with severe hypertriglyceridemia due to multifactorial chylomicronemia syndrome and could be useful in selected patients with hypertriglyceridemia. Note it is not approved to treat severe hypertriglyceridemia and administration intravenously every 4 weeks will limit its use to special circumstances.

CLINICAL USE OF TRIGLYCERIDE LOWERING DRUGS 

Marked Hypertriglyceridemia (>500mg/dL): Prevention of Pancreatitis

In patients with marked elevations in TG levels (>500-1000mg/dL) the major concern is an increased risk of pancreatitis (285,286). Because of this increased risk it is imperative to lower TG levels. The initial steps are to 1) treat any disease states that could be leading to an elevation in plasma TG levels, 2) if possible, discontinue any drugs that could be leading to an elevation in plasma TGs, and 3) initiate lifestyle changes (Table 22) (3,287).

These initial steps are often sufficient to result in marked reductions in plasma TG levels eliminating the need for TG lowering medications. For example, in patients with diabetes in very poor glycemic control, treatment that results in good glycemic control can markedly lower TG levels (288). Similarly, the restoration of euthyroidism in a hypothyroid patient can also markedly lower lipid levels (289). If these initial steps do not result in a lowering of TGs into an acceptable range, then the use of drugs to lower plasma TG levels is indicated. There have been no randomized controlled trials demonstrating that treatment diminishes pancreatitis but most experienced clinicians believe that lowering TG levels to below 500-1000mg/dL reduces the risk of developing pancreatitis (285,286). The addition of either fibrates or omega-3 fatty acids to lifestyle changes are commonly used to lower markedly elevated TG levels. In some patients, combination therapy is required to lower plasma TGs to an acceptable range.

The approach described above is ineffective in most patients with FCS. In patients with FCS dietary fat calories need to be severely restricted to approximately 5-20% of calories, which is difficult for many patients to comply with. Additionally, patients with FCS often respond poorly to the usual drugs (fibrates, omega-3 fatty acids, niacin) used to lower TG levels. The development of Apo CIII inhibitors has resulted in drugs that are effective in lowering TG levels and preventing pancreatitis in patients with FCS.

Moderate Hypertriglyceridemia (150-500mg/dL): Prevention of Cardiovascular Disease  

In the era of statin therapy, it is uncertain whether lowering TG levels in patients on statin therapy will further reduce cardiovascular events. As discussed in detail in the sections on individual drugs, the studies carried out so far have not shown that adding niacin or fibrates to statin therapy is beneficial with regards to cardiovascular disease. As also discussed, some of the available studies have major limitations because many of the patients in these outcome studies did not have substantial elevations in TGs. Nevertheless, at this time there is little enthusiasm for adding either fibrates or niacin to statins to lower the risk of cardiovascular events.

Notably, the REDUCE-IT trial, which tested the effect of high dose EPA (4 grams per day) in patients with elevated TG levels on statin therapy demonstrated a 25% reduction in cardiovascular events. However, the decrease in cardiovascular events was considerably greater than one would expect based on the reduction in TG levels suggesting that the decrease in cardiovascular events was not solely due to lowering TG levels and that other effects of EPA likely played a role. Additionally, as discussed in detail in the section discussing cardiovascular trials in the omega-3-fatty acid section there are concerns that the use of mineral oil as the placebo in the REDUCE-IT trial may have caused harmful effects leading to increased cardiovascular events in the placebo group. Thus, the role of EPA in reducing cardiovascular events is debated with some experts feeling that it is beneficial while others feeling that the evidence for benefit is not definitive. Clearly additional studies are required to resolve this controversy. In the meantime, clinicians will need to use their clinical judgement on whether to treat patients with modest elevations in TG levels with EPA (icosapent ethyl; Vascepa) balancing the potential benefits of treatment vs. the potential side effects.

Some guidelines use non-HDL-C as a therapeutic goal and thus the use of omega-3-fatty acids and fibrates will often be required to lower TG levels to achieve these non-HDL-C goals. In contrast, other guidelines focus on LDL-C levels and the use of statins and thus de-emphasize the use of omega-3-fatty acids and fibrates. Given the absence of definitive data one needs to use clinical judgement. Consideration should also be given to the use of fenofibrate in hypertriglyceridemic patients with diabetes at high risk for microvascular disease given the studies that have shown that fibrates reduce the microvascular complications of diabetes. Because of the side effects of niacin, the use of niacin to lower TG levels has markedly diminished. In the past we used to use niacin to lower both LDL-C levels and TGs but with the availability of ezetimibe, bempedoic acid, and PCSK9 inhibitors the need to use niacin to lower LDL-C levels has markedly decreased.

ACKNOWLEDGEMENTS

This work was supported by grants from the Northern California Institute for Research and Education.

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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 TGs. The increase in serum TGs is due to both an increase in hepatic VLDL production and secretion and a decrease in the clearance of TG rich lipoproteins. The mechanisms by which inflammation and infection decrease HDL levels are uncertain. With inflammation there is also a consistent increase in Lp(a) levels due to increased apo (a) synthesis. LDL levels are frequently decreased but the prevalence of small dense LDL is increased due to the exchange of TGs from TG rich lipoproteins to LDL followed by TG hydrolysis. In addition to affecting serum lipid levels, inflammation also adversely affects 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 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, gout, Sjögren's syndrome, polymyalgia rheumatica, inflammatory bowel disease, pernicious anemia, multiple sclerosis, myasthenia gravis, vitiligo, and psoriasis are associated with an increased risk of cardiovascular disease (1-11). 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 (12). The greater the disease activity the greater the risk of cardiovascular disease (13). In some studies patients with RA have a similar or greater risk for a cardiovascular event than patients with diabetes (14,15). 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 (16). 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 (17). 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 (18-24). Finally, even children and adolescents with SLE have an increase in carotid intimal-medial thickness (25). 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 (26-28). 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 (29,30). Moreover, numerous studies have demonstrated an association of periodontal infections with an increased risk of atherosclerotic vascular disease (31). Additionally, carotid intima-media thickness is increased in patients with periodontal disease (32-35). 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 (36). 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 (37). 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 (38-40). It should be noted that a recent trial where colchicine treatment was initiated very soon after an acute myocardial infarction failed to demonstrate a reduction in cardiovascular events in patients treated with colchicine (41). 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 (42). 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 (9,43-46). In particular, small HDL particles are decreased in patients with RA (47). Patients with more severe RA have the greatest reductions in HDL-C levels (43-46,48). 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 (43-46,48). 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 (49,50). Serum triglyceride (TG) levels tend to be increased in patients with RA (43-46,48,51). Levels of lipoprotein (a) (Lp(a)) are characteristically elevated in patients with RA and correlate with CRP levels (52-54).  

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 (55-57). Specifically, there is a decrease in HDL-C levels and an increase in serum TG levels. LDL-C levels are variable and maybe increased, normal, or low but small dense LDL levels tend to be increased. In a study of 344 patients 36.6% had elevated LDL-C levels (58). Lp(a) levels are also increased (59). 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 (60). 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 TGs and a decrease in HDL-C levels in patients with psoriasis (61-65). Additionally, a number of studies showed an increase in LDL-C and Lp(a) levels in patients with psoriasis (61,62,64). Small dense LDL levels and oxidized Lp(a) are also increased in psoriasis (51) (66). 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 (67-70). LDL-C and TG levels varied but LDL-C levels tended to be decreased and TG levels increased.

Periodontal Disease

Differences exist between studies but in general patients with periodontitis tend to have increased LDL-C and TG levels and decreased HDL-C levels (71-75). Additionally, the prevalence of small dense LDL is increased in patients with periodontitis (74,76). The severity of the periodontitis correlated with the changes in the in the lipid profile with patients with increased periodontal disease having higher TG levels, lower HDL-C levels, and smaller LDL particle size (77). Moreover, treatment of periodontitis improved the dyslipidemia, with the HDL-C levels increasing and the LDL-C levels decreasing (74,78,79).  

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 TG levels are elevated or inappropriately normal for the poor nutritional status (36,80-87). As expected apolipoprotein A-I, A-II, and B levels are reduced (80,85,86). While LDL-C levels were decreased, the concentration of small dense LDL has been found to be increased during infections (88-90).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 (91,92). 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 (93). These changes in lipid and lipoprotein levels were also noted during COVID 19 infections (94,95).

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 (87,96-100). Moreover, epidemiologic studies have suggested that low cholesterol, LDL-C, and HDL levels increase the chance of developing an infection (101-104). 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 (105,106). 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 (36,107).   

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) levels (the increase in Lp(a) occurs in inflammatory diseases but not infections) (36,108). There is also a tendency for plasma TG 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 (78,79).

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 TG 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) (109-111). 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 (9,109,110,112). 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 TG and LDL levels due to the increased production and secretion of VLDL by the liver (113-115) and hydroxychloroquine has been reported to lower total cholesterol, LDL, and TGs in patients with RA and SLE (116-118).

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 (36). 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 (36).

Increased TG Levels

Multiple cytokines increase serum TG and VLDL levels (TNF, IL-1, IL-2, IL-6, etc.) (36). Administration of LPS (a model of gram-negative infections) or lipoteichoic acid (a model of gram-positive infections), both of which stimulate cytokine production, increase serum TG and VLDL levels within 2 hours and this effect is sustained for at least 24 hours. The increase in serum TGs is due to both an increase in hepatic VLDL production and secretion and a decrease in the clearance of TG rich lipoproteins (figure 1) (36). 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 abundant supply of fatty acids in the liver that stimulate an increase in hepatic TG synthesis (36). The increased availability of TGs leads to the increased formation and secretion of VLDL. The decrease in the clearance of TG rich lipoproteins is due to a decrease in lipoprotein lipase, the key enzyme that metabolizes TGs in the circulation (36). A variety of cytokines have been shown to decrease the synthesis of lipoprotein lipase in adipose and muscle tissue (36). Additionally, sepsis decreases apolipoprotein C2, a cofactor for lipoprotein lipase (119). Studies have also shown that inflammation increases angiopoietin like protein 4, an inhibitor of lipoprotein lipase activity, which would further block the metabolism of TG rich lipoproteins (120). In SLE, antibodies to lipoprotein lipase have been reported and are associated with increased TG levels (121,122).

Figure 1. Pathogenesis of Hypertriglyceridemia.

Production of Small Dense LDL

The elevation in TG rich lipoproteins in turn has effects on other lipoproteins (36). Specifically, cholesterol ester transfer protein (CETP) mediates the exchange of TGs from TG rich VLDL and chylomicrons to LDL. The increase in TG rich lipoproteins per se leads to an increase in CETP mediated exchange, increasing the TG content of LDL. The TG 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 (36). During inflammation HDL particles tend to be larger with a decrease in cholesterol ester and an increase in free cholesterol, TGs, 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 (36). 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 (123). 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 TG rich lipoproteins that accompany inflammation and infection can lead to the enrichment of HDL with TGs 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 Lp(a)

The mechanism accounting for the increase in Lp(a) during inflammation is likely due to increased apo (a) synthesis, as apo (a) is a positive acute phase protein whose expression is up-regulated during inflammation (36,124). The apo (a) gene contains several IL-6 responsive elements that enhance transcription (125). Tocilizumab an antibody against IL-6, that is used to treat RA, has been shown to decrease Lp(a) levels (126) .

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 (36). These small dense LDL particles are believed to be more pro-atherogenic for a number of reasons (127). 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 (128).

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 (36,77,129-132). Moreover, LDL isolated from LPS-treated animals is more susceptible to oxidation in vitro (36). 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 (133). 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 (129). Finally, studies have shown that LDL isolated from patients with periodontal disease leads to enhanced uptake of cholesterol esters by macrophages (77)

HDL

In addition to a decrease in serum HDL, inflammation and infection affects the anti-atherogenic properties of HDL (36,134,135). 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)  (48,136). 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 (48,67,136-143). HDL isolated from patients with RA, SLE, inflammatory bowel disease, Helicobacter pylori infection, psoriasis, ankylosing spondylitis, periodontal disease, and acute sepsis are poor facilitators of cholesterol efflux (67,137-142,144,145). 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 (146). 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 (142,147-149). 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 (136)).

Figure 5. Effect of Inflammation on the Factors Involved in Reverse Cholesterol Transport (from reference (136)).\

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 (133). 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 (36). Plasma paraoxonase levels are decreased in patients with RA, SLE, psoriasis, and infections (150-158) 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 (134). Moreover, in patients with RA, reducing inflammation and disease activity with methotrexate treatment restored HDL function towards normal (159). Additionally, treatment with atorvastatin 80mg improved the function of HDL in patients with RA (160). 

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 (36,60,130,134-136). Rather functional changes in LDL and HDL may be pro-atherogenic and thereby contribute to the increased risk of atherosclerosis in inflammatory disorders and infections. Additionally, the increase in Lp(a) may also play an important role. In an analysis of the UK Biobank the combination of autoimmune conditions and elevated Lp(a) had a high risk of cardiovascular disease than either of these conditions alone ((combination of autoimmune conditions and elevated Lp(a) HR 1.77; only elevated Lp(a) HR 1.23; only autoimmune conditions HR, 1.28) (161).

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 (36,162-164). 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 it can increase the risk of atherosclerosis.

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 commonly used for deciding on lipid lowering therapy do not take into account this increased risk in patients with inflammatory disorders (3,165,166). It should be noted that the QRISK calculator (http://qrisk.org/) does factor in the presence of RA when calculating risk (167). Not surprisingly, the standard risk calculators for predicting cardiovascular disease underestimate the risk in this population (168-174). 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 (168-172,175). 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 (176,177).

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 in treating risk factors.

Because Lp(a) levels are increased by inflammation it is important to measure Lp(a) levels in patients with inflammatory disorders. An elevated Lp(a) level would be an indication for more aggressive treatment of lipid levels and other cardiovascular risk factors.

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 (176,177) and are discussed in detail in the Endotext chapter “Guidelines for the Management of High Blood Cholesterol” (178).

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 need to be tailored for each patient’s capabilities. Treatment of the underlying disease to decrease inflammation is likely to be beneficial (9,179). 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 (9,180-186). Moreover, treatments that reduce disease activity can decrease cardiovascular risk (9,179). In patients with RA treatment with tumor necrosis factor inhibitors or methotrexate reduced the risk of cardiovascular disease (187).

Drug Therapy

This section on drug therapy will focus on the drugs widely used to reduce LDL-C levels (statins, ezetimibe, PCSK9 inhibitors, and bempedoic acid) and solely on the studies that are focused on patients with inflammatory diseases. Detailed information on the use of these and other lipid lowering drugs can be found in the Endotext chapters on cholesterol lowering drugs and TG lowering drugs (188,189).

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 (190). Atorvastatin reduced LDL-C by 54mgdl vs. 3mg/dl in the placebo group (190). Similarly in the IDEAL trial there was a small subgroup of patients with RA (191). 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 (191). 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 (192). Studies have shown similar reductions in LDL-C levels with statin therapy in patients with SLE and HIV infections (193-196). 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 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) (191). 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 primary prevention cardiovascular outcome study evaluated the effect of statin therapy in individuals living with HIV (196). In this trial 7769 participants with HIV infection with a low-to-moderate risk of cardiovascular disease were randomized to receive pitavastatin 4 mg or placebo. The incidence of a major adverse cardiovascular event was reduced by 35% in the pitavastatin group (HR 0.65; 95% CI 0.48 to 0.90; P = 0.002). Pitavastatin lowered LDL-C by approximately 30mg/dL and thus the decrease in cardiovascular events was greater than predicted based on the Cholesterol Treatment Trialists meta-analysis (approximately 20% decrease in events per 39mg/dL decrease in LDL-C) (197).   

There are no large randomized controlled trials evaluating the impact of statin therapy on cardiovascular disease outcomes in patients with other inflammatory diseases. A subgroup analysis of a small number of patients with SLE in the ALERT study has been reported (198). 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 (198). Additionally, a post hoc analysis of patients with inflammatory arthritis in the IDEAL and TNT trial has been reported (199). 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 (199). 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 (199). 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 (192). A trial that focused solely on patients with RA was initiated but stopped early due to a lower than expected event rate (200). 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 20% decrease per 39mg/dL) (197). 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 therapy similar to or greater to what is observed in patients without inflammatory disorders.

It is well recognized that statins have anti-inflammatory properties and studies have consistently demonstrated a decrease in hsCRP levels in patients treated with statins (189). 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 (201). Similarly, a meta-analysis by Xing et al included 13 studies with 737 patients (202). They reported that statin therapy decreased erythrocyte sedimentation rate, CRP, tender joint count, and swollen joint count (202). 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 (202,203). A recent meta-analysis by Ren and Li found similar beneficial effects of statin therapy on RA (204).

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 (194,205). 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 (206). A meta-analysis of 5 randomized trials with 223 patients found that statins may improve psoriasis, particularly in patients with severe disease (207). Finally, treatment with statins has been shown to improve periodontal disease and reduce inflammation (208-210). 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 (211,212). 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) (212). However, in randomized placebo controlled clinical trials statin administration has not been shown to reduce mortality or improve outcomes (211-214). For example in a meta-analysis by Wan et al of 5 randomized controlled trials with 867 patients the relative risk was 0.98 (212). 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 (215). Additionally, a recent study examining the effect of rosuvastatin on sepsis associated acute respiratory distress also failed to demonstrate a benefit of statin therapy (216). Finally, meta-analyses of observational studies have found that statins in patients with COVID-19 infections are beneficial (217,218) but randomized trials have not consistently demonstrated that statin treatment was beneficial (219-222). Thus, while observational data suggested that statins may be beneficial the more rigorous randomized placebo-controlled trials have not provided clear evidence of benefit.

EZETIMIBE THERAPY

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 (223). Moreover, ezetimibe treatment reduced disease activity (223). The mechanism for this beneficial effect is unclear.

PCSK9 INHIBITORS

The FOURIER trial was a cardiovascular outcome trial using the PCSK9 inhibitor evolocumab. In this very large trial 889 patients (3.2%) had an autoimmune or inflammatory disease, most commonly rheumatoid arthritis (33.7%) or psoriasis (15.6%) (224). The baseline LDL cholesterol levels in patients with or without an autoimmune or inflammatory disease were very similar and the reduction in LDL-C with a PCSK9 inhibitor was virtually identical in patients with or without an autoimmune or inflammatory disease (approximately 60%). Baseline hsCRP levels were higher in patients with an autoimmune or inflammatory disease and did not change with PCSK9 inhibitor treatment in patients with or without an autoimmune or inflammatory disease. Notably, compared with placebo, treatment with a PCSK9 inhibitor reduced the rate of the primary end point of cardiovascular death, myocardial infarction, stroke, unstable angina, or coronary revascularization by 14% in patients without an autoimmune or inflammatory disease and by 42% in patients with an autoimmune or inflammatory disease. These results demonstrate that in patients with autoimmune or inflammatory diseases PCSK9 inhibitors reduce LDL-C levels and are effective in decreasing cardiovascular events.

BEMPEDOIC ACID

The author is 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 TGs 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, it 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 “The Effect of Diet on Cardiovascular Disease and Lipid and Lipoprotein Levels”) (225).

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 (226).

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, bempedoic acid, 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 and bempedoic acid will only lower LDL-C by approximately 20%).  Ezetimibe, bempedoic acid, and PCSK9 inhibitors 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 TG 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 TG 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 TG levels. Initial therapy should focus on lifestyle changes including a decrease in simple sugars and ethanol intake and initiating an exercise program. Fibrates, niacin, and omega-3-fatty acids all reduce serum TG levels. Typically, one will target TG levels when one is trying to lower non-HDL-C levels to goal. Note that there is limited evidence demonstrating that lowering TG 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 TG levels reduces cardiovascular events (227) but there is controversy regarding these results (see Endotext chapter on Triglyceride Lowering Drugs for detailed information (188)). 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 TG levels/non-HDL-C levels. Patients with very high TG levels (> 500-1000 mg/dl) are at risk of pancreatitis and therefore lifestyle and TG lowering drug therapy should be initiated early to reduce the risk of pancreatitis (228).

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). Lifestyle changes are the initial step and include increased exercise, weight loss, and stopping cigarette smoking. Whether increasing HDL-C levels will result in a reduction in cardiovascular events is unknown and it is likely that HDL function is more important than HDL levels.

Unfortunately, at this time we do not yet have drugs that specifically lower Lp(a) levels and therefore in patients with elevated Lp(a) levels we lower other risk factors for cardiovascular disease aggressively to reduce risk.

In summary, modern therapy of patients with inflammatory diseases demands that we aggressively treat LDL-C to reduce the high risk of cardiovascular disease in this susceptible population.

ACKNOWLEDGEMENTS

This work was supported by grants from the Northern California Institute for Research and Education.

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