ABSTRACT

The effective treatment of obesity is challenging. This in part reflects the complexity of the underlying disease process. However, there are a growing number of effective surgical, endoscopic, and pharmacologic treatments which are available. Although there has long been a preference on lifestyle modification such as diet and exercise, there is a relative paucity of evidence to support these interventions as effective long-term treatments for obesity, in producing sustained weight loss and resultant improvements in obesity related disease and mortality. Conversely, bariatric procedures which include sleeve gastrectomy, roux en Y gastric bypass, single anastomosis gastric bypass, biliopancreatic diversion, and several less frequently performed operations have been shown to produce substantial and durable weight loss with significant improvements in obesity related disease, quality of life, and mortality. The mechanisms by which these operations work vary depending on the procedure however they primarily act via alterations in the gut-brain axis and alterations in neurohormonal signaling. These changes produce sustained changes in appetite and hunger and unlike weight loss mediated by diet are not followed by a rebound weight regain in the long term. In addition, there appear to be modifications in bile acid metabolism and the gut microbiome which also play a contributory role in weight loss following bariatric surgery. 

The criteria for consideration of bariatric surgery have recently been updated to reflect advances in knowledge, surgical technique, and safety. According to the 2022 guidelines produced by the International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO), people with a BMI >35kg/m² should be recommended surgery and those with BMI 30-34.9kg/m² with metabolic disease should be considered. It is important to involve the multidisciplinary team in determining suitability for surgery as well as for long-term follow up (1). The multidisciplinary team typically includes a dietician, psychologist, physician, and surgeon. The decision on which procedure should be used is based on patient or surgeon preference, availability of appropriate aftercare and the patient’s tolerance of risk and permanent anatomical change.

BACKGROUND

The hallmark of an effective treatment of obesity is not one which can produce clinically weight loss, rather one which can produce weight loss which is sustained in the long term such that there is an improvement in obesity related disease and mortality. Although diet and lifestyle modification has long been the cornerstone of many obesity treatment programs, the primary concern with such approaches including very low energy diets (VLED) is the durability of weight loss. Randomized controlled trials have shown that weight loss of up to 15% is possible in people living with obesity however less than 10% will maintain this over one year and the majority will return to their pre-diet weight within 3-5 years (2). Conversely, bariatric surgery has been demonstrated to produce weight loss of 20-30% which critically is not only sustained in the long-term but has the effect of modifying the underlying disease process and resetting of the homeostatic weight ‘set point’, primarily through neurohormonal changes (3, 4).

The concept of the set point suggests that in the majority of adults, there is a pre-determined inherent weight around which each individual will maintain their weight over the long-term with a gradual increase seen over time. Following a period of volitional weight loss with dietary changes, there is a decrease in the overall weight followed by several homeostatic adaptations which see a return to the original baseline weight. Following bariatric surgery, irrespective of the procedure performed, there tends to be an initial period of rapid weight loss for the first 18 months followed by a period of weight stability and a subsequent very gradual weight regain. In spite of the recognized weight regain, what is critical is that overall, following surgery, there is a new, lower set point with a similar weight gain trajectory as to what is seen in the general population.

It was initially felt that bariatric procedures could be classified according to the mechanism by which they were thought to act, resulting in the description of ‘restrictive’ and ‘malabsorptive’ procedures however subsequent mechanistic studies have demonstrated this to be incorrect as they were recognized to act via alterations in neurohormonal signaling, bile acid metabolism, and changes in the microbiome (5). 

The longest-term data establishing the role of bariatric surgery as a treatment for obesity compared to traditional lifestyle interventions comes from the landmark Swedish Obese Subjects (SOS) study (3). With more than 25 years of follow up, this case-control series demonstrated that irrespective of the procedure performed, bariatric surgery produces sustained weight loss which is maintained long term and supports a reduction in all-cause mortality due to cardiovascular causes and cancer compared to matched controls receiving standard care at the time (6). Critically, in addition to producing sustained weight loss, evidence from randomized controlled trials (RCTs) have consistently supported the efficacy of bariatric surgery in the treatment of obesity related disease, specifically type 2 diabetes mellitus (T2DM) compared to medical treatment (7-18).

In light of improvements in glycemic control and even remission of diabetes in a subset of people with obesity, bariatric surgery forms a central element in the treatment algorithm as endorsed by the American Diabetes Association (ADA) and International Diabetes Federation (IDF) for those with obesity and T2DM. Early views of gastrointestinal surgery as a means of permanently curing diabetes have been replaced by a more realistic view that it is more likely a means of inducing remission and improving long term glycemic control. Longer-term data from studies has now demonstrated that one in four people  who initially go into remission will experience a relapse of T2DM (7). Despite this, it is essential to recognize that although some of the metabolic improvements associated with surgery dissipate with time, glycemic control is still very good compared to those treated with medication alone. As demonstrated by the UK Prospective Diabetes Study (UKPDS), there is a legacy effect of even a short period of improved glycemic control on the development of diabetes-related complications, cardiovascular endpoints and mortality (19). Thus, even individuals who do not meet the ADA criteria for diabetes remission, these improvements in glycemic control should not be dismissed as they may have important implications for morbidity and mortality.

A HISTORICAL PERSPECTIVE OF BARIATRIC SURGERY

Surgical procedures involving the upper gastrointestinal tract have long been recognized to result in substantial and sustained reductions in weight, albeit most often to the detriment of the patient. Although the mechanisms producing this weight loss were at the time very poorly understood, it became apparent that this effect could be used within the context of obesity to potentially produce surgically mediated weight loss with an improvement in metabolic disease.

Small Bowel Bypass Procedures (1950-1970)

Surgical management of obesity began with the introduction of the jejunoileal bypass (JIB) in 1954 (20). In this procedure, the proximal jejunum was diverted to distal part of the gut, leaving a long segment of excluded small intestine and a marked reduction in absorptive capacity. Although the JIB offered substantial and sustained weight loss with improvements in lipid metabolism, it was associated with serious side-effects including diarrhea, electrolyte imbalances, oxalate calculi in the kidneys, and progressive hepatic fibrosis with eventual liver failure (21-25). Given the seriousness of these complications, these procedures were generally abandoned by the 1970s in favor of so-called stomach stapling procedures

Stomach Stapling Procedures (1970-1990)

The Roux-en-Y gastric bypass (RYGB) operation was introduced by Edward Mason in 1960 (26) and gastroplasty in 1973 (27). Numerous variations of this procedure have followed, the most significant variant being the vertical banded gastroplasty (VBG) which was first described by Dr Mason in 1982 (28) . It was hoped that this group of operations would provide greater short- and long-term safety and yet retain the power of gastric bypass. Unfortunately, both randomized controlled trials and observational studies have consistently shown that it failed in both aspirations (29-32).

In the meantime, there was a resurgence of hypoabsorptive surgery with Italian surgeon,  Nicola Scopinaro, introducing the biliopancreatic diversion procedure (BPD) in 1976 (33). The basic procedure involves distal gastrectomy leaving a proximal gastric pouch of 200 – 500 ml, a 200 cm length of terminal ileum anastomosed to the gastric pouch, and the biliopancreatic limb entering at 50 cm from the ileocecal valve (34). The most notable remodeling of the procedure has been the so-called duodenal switch variant (BPD-DS) proposed by Picard Marceau’s group in 1993 (35, 36) in which a longitudinal gastrectomy (sleeve gastrectomy) enabled retention of the gastric antrum for controlled gastric emptying, and the ileal limb was anastomosed to the proximal duodenum.

Adoption of the Laparoscopic Approach

One of the most remarkable advances in bariatric surgery came with the near universal adoption of a laparoscopic approach. The reduced invasiveness resulted in major improvements in safety with regard to morbidity and mortality, irrespective of the procedure performed. This contributed to a major rise in the use of bariatric surgery for obesity across the world. According to the most recent IFSO Global Registry Report, 99.7% of all primary bariatric procedures undertaken worldwide are done laparoscopically (37).

One of the first laparoscopic procedures to gain widespread acceptance was the laparoscopic adjustable gastric band (LAGB) which had been specifically designed as a standalone laparoscopic procedure in 1993. Proponents of the LAGB felt the procedure offered two primary benefits; there was an improved safety profile as it did not require the formation of any gastrointestinal anastomoses while also providing the option of a procedure which could be specifically tailored to individual needs; and allowing for band filling and deflation without requiring further surgery. LAGB became the most commonly performed bariatric procedure worldwide throughout the 1990s with only the United States not seeing widespread adoption due to regulatory restrictions which were only resolved in 2001. The adoption of laparoscopic RYGB started within a similar timeframe as LAGB however, the technical challenge associated with the formation of two gastrointestinal anastomoses contributed to a slower uptake. As surgical techniques advanced, in part due to the development of more advanced stapling devices, RYGB became the most commonly performed bariatric procedure worldwide. The adoption of sleeve gastrectomy (SG) has steadily risen in recent years, now accounting for approximately 60% of procedures world-wide, therefore overtaking RYGB which accounted for 29.5% as of 2023 (37).This increase is in part driven by the perception that it is less technically challenging than procedures such as RYGB as no anastomosis is formed.

Although RYGB and SG continue to account for the majority of procedures, the adoption of laparoscopic surgery has not only increased safety associated with bariatric surgery but has also contributed to the development of several new operations. One anastomosis gastric bypass (OAGB) is particularly noteworthy with regard to its increasing popularity and growing evidence base to support it as both safe and effective in terms of weight loss and resolution of metabolic co-morbidity. OAGB currently accounts for approximately 4% of procedures world-wide although the number has steadily risen in recent years (37).

Overall, the availability of several safe and effective laparoscopic bariatric procedures allows for greater ability to choose an operation that meets both the expectations and need of the individual while matching this with the skill set of the surgeon and moving the field closer to an era of precision medicine.

CURRENT METHODS IN BARIATRIC SURGERY 

Sleeve Gastrectomy

The sleeve gastrectomy (SG) has become the most commonly performed bariatric procedure worldwide. Although initially conceived as part of the two-stage duodenal switch procedure SG has become a standalone operation having recognized the substantial weight loss it produces as well as improvement in obesity associated disease. SG involves excision of approximately 80% of the stomach by using multiple firings of a linear stapler/cutter to separate a narrow tube or sleeve of the lesser curve of the stomach from the greater curve. The initial firing starts approximately 4-7cm proximal to the pylorus which is preserved to maintain gastric emptying. A bougie (usually >32Fr) is placed in the lesser curve segment during the resection to maintain adequate lumen size. Although there is variability in the precise size, a 2012 consensus statement recommended the use of a bougie between 32-40Fr (38).

SG is relatively contraindicated in those with significant gastro-esophageal reflux disease (GERD) due to the high risk of worsening of pre-existing reflux and which can be difficult to manage symptomatically and may also play a role in the development of Barrett’s esophagus. Due to this potential risk, it is advised by the International Federation for the Surgery of Obesity (IFSO) that any person undergoing SG have surveillance endoscopy one year postoperatively and then every 2-3 years thereafter (39). Other recognized complications of SG include staple line leak and bleeding in the early postoperative period as well as de novo or worsening of GERD and stricture. As the gastric remnant is removed, SG is not a reversible procedure.

Although initially and incorrectly classified as a procedure that acted via mechanical restriction, mechanistic studies have demonstrated that SG acts by modifying key neurohormones including GLP-1 and PYY which regulate hunger, appetite, and satiety via the gut-brain axis (40). SG is also thought to reduce hunger through resection of the gastric fundus which is the site of ghrelin production (41).

Figure 1. Sleeve gastrectomy.

Laparoscopic Adjustable Gastric Banding (LAGB)

At one time LAGB was one of the most commonly performed bariatric procedures, however, it is now infrequently performed due to the perceived high complication and re-operation rate as well as the mounting evidence to support that that it does not produce equivalent weight loss to procedures such as SG and RYGB. Although previous studies have demonstrated nearly 50% excess weight loss that can be maintained with >15 year follow up, the major caveat was the requirement for very close follow up with regular band adjustments which was not sustainable in real world practice (42).

In spite of the apparent limitations of the LAGB, the less invasive nature of the operation and potential reversibility of the procedure make it a potential consideration for those who are considered higher risk. Recognized complications of LAGB include port site infection, GERD, pouch dilatation, band slippage and erosion. Studies have suggested that up to 50% of those who have a LAGB will require reoperation or band removal (43).

The exact mechanisms of action of the LAGB are unclear however they are thought to act beyond the pure mechanical effect by involving vagal afferents (44). Vagal stimulation may help regulate food intake by promoting satiety.

Figure 2. The band consists of a ring of silicone with an inner balloon. The balloon is connected to an access port.

Figure 3. The LAGB is placed over the cardia of the stomach within 1cm of the esophago-gastric junction.

Roux en Y Gastric Bypass (RYGB)

Roux en Y gastric bypass is now less commonly performed than SG due in part to the technical challenge of forming two anastomoses and previous lack of level one evidence demonstrating its superiority in terms of weight loss or resolution of obesity related disease. The emergence of recent data from several RCTs appears to support that RYGB may produce significantly higher weight loss than SG with greater improvements in obesity related disease including dyslipidemia and gastro-esophageal reflux disease (GERD). Overall, there is good long-term evidence to support the efficacy of RYGB as a safe procedure which provides significant and durable weight loss with a significant improvement in metabolic complications such as T2DM (7, 45). It is also the procedure of choice in those with significant pre-existing GERD and obesity rather than SG (46).

Similar to SG, studies have shown that RYGB produces weight loss through changes in gut hormones, namely GLP-1 and PYY, an effect which is believed to be in part the result of early delivery of nutrient in the terminal ileum and passage of undiluted bile in the bypass and the proximal jejunum (4, 5). These changes appear within days of surgery and as well as producing long-term reductions in weight are also responsible for the weight-loss independent improvements in glucose homeostasis which occur in the immediate postoperative period.

RYGB involves the formation of a small gastric pouch with an excluded gastric remnant. A loop of jejunum is then brought up and anastomosed to the gastric pouch to form the gastro-jejunostomy with the alimentary limb distal to this. Within the alimentary limb, ingested food is excluded from mixing with any digestive enzymes as the proximal jejunum has been bypassed. Approximately 100-120cm distal to the gastro-jejunostomy, a second anastomosis is formed between the biliary limb and the alimentary limb to form the jejuno-jejunostomy. It is only distal to this anastomosis that there is mixing of food and bile.

Although this is overall a very safe procedure, the most potentially serious complication which may arise is bowel obstruction or ischemia secondary to an internal hernia as two mesenteric defects are created during the procedure. Both mesenteric defects are typically closed intraoperatively, however, they may increase in size over time following weight loss and as the fat content of the mesentery decreases. Studies would support the routine closure of mesenteric defects but doing so is associated with an increased risk of complications associated with small bowel obstruction at the jejunojejunostomy (47). Additional complications include the possibility of anastomotic leaks or stricture and staple line bleeding. A small minority of people may also develop chronic abdominal pain which may be challenging to treat. It is also worth noting that due to the anatomical changes produced by RYGB, future procedures such as ERCP may require alternative approaches to accessing the excluded proximal duodenum via the remnant stomach. This may also be of concern in populations where there is concern about gastric cancer as the remnant stomach cannot be assessed by standard esophagogastroduodenoscopy.

Figure 4. RYGB showing a small gastric pouch, a narrow gastrojejunostomy and exclusion of foods from the duodenum and proximal jejunum.

One Anastomosis Gastric Bypass (OAGB)

The one gastric bypass is increasingly popular as an alternative to the RYGB owing in part to the fact that it produces significant weight loss but requires the formation of only one anastomosis. OAGB involves the formation of a small gastric pouch to which a loop of jejunum is anastomosed to form a gastro-jejunostomy. Unlike the RYGB, there is only one anastomosis and the length of duodenum and proximal jejunum which is bypassed is much longer, typically up to 150cm (48, 49). (figure 5).

The mechanism of action is thought to be very similar to that of RYGB in that it results in changes in gut hormone signaling via bypass of the proximal duodenum and studies to date would suggest that weight loss outcomes as a result are comparable (48). These changes are also responsible for the improvements in glucose homeostasis and resolution or improvement of T2DM.

Given the relative lack of long-term follow up on OAGB, there are concerns regarding the potential implications of chronic bile acid reflux and the possibility of inducing gastric and esophageal malignancy, however, there is no high-quality evidence at present to support these concerns.

Figure 5. OAGB showing the gastric pouch as a sleeve of lesser curve of stomach and the loop gastrojejunostomy.

Biliopancreatic Diversion / Duodenal Switch (BPD/DS)

Although BPD/DS is not amongst the most commonly performed bariatric procedures, accounting for only ~1% of operations worldwide, it is noteworthy for the amount of weight loss it induces as well as the resultant improvements in metabolic dysfunction. The operation is a two-stage procedure with the initial operation involving the formation of a sleeve gastrectomy with preservation of the pylorus. In the second stage, the duodenum is mobilized and divided at D1 and subsequently anastomosed to the distal ileum. The duoden-ileal anastomosis forms the alimentary limb through which ingested food will pass, without mixing with digestive enzymes. A second anastomosis is then formed between the biliary limb and the distal ileum, approximately 80-100cm proximal to the ileocecal valve. The second anastomosis creates a short common channel for mixing of ingested food and digestive enzymes.

The weight loss and metabolic improvements following BPD/DS are significantly greater than RYGB/OAGB and SG, however, it remains an infrequently performed procedure not only due to the technical challenges but primarily owing to significant long-term complications. As a result of the very short common channel, micronutrient and fat-soluble vitamin deficiencies are expected and long-term supplementation and monitoring is essential. The potential complications resulting from nutrient deficiency can be severe and in cases irreversible, including night blindness and Wernicke’s encephalopathy. Up to 10% will remain deficient despite adherence to dietary and nutritional guidelines and supplementation and will require re-operation (50).

Figure 6. The DS variant of BPD with a sleeve gastrectomy, retention of the gastric antrum, diversion of food into the mid small gut and diversion of pancreatic and biliary secretions to the distal small gut. Note both limbs are passing behind the transverse colon and a color difference is added to help follow the respective pathways. The common channel is the normal ileum terminating at the ileo-cecal junction.

Single Anastomosis Duodenal-Ileal Bypass with Sleeve (SADI-S)

The SADI-S procedure is seen as a potentially simplified version of the BPD-DS procedure. Similar to BPD-DS, the procedure involves the mobilization of the duodenum followed by sleeve gastrectomy with division of the duodenum. A duodenojejunal anastomosis is subsequently formed between the duodenal stump and a loop of ileum 250-300cm  proximal to the ileocecal junction which is brought up in an antecolic fashion (51). Weight loss and metabolic outcomes following SADI-S have been shown to be very good at five years with 40% total weight loss with 60-80% of individuals in T2DM remission (52-54). As there is a longer common channel, the risk of nutritional deficiencies is lower than seen with BPD-DS and were similar to RYGB (55).

Experimental Bariatric Procedures

In recent years, there has been growing interest in non-surgical treatments for obesity including endoscopic approaches. Although long-term data is more limited, the ability to offer less invasive procedures may further broaden the population to which effective obesity treatment is available. EndoBarrier is an endoscopically placed 60cm duodenal-jejunal bypass liner which aims to replicate the effects of RYGB. Once placed within the duodenal bulb, the liner allows the flow of gastric content to the jejunum via the lumen while pancreatic content flows along the outside, preventing any mixing until the end of the liner is reached. The device can be left in situ for a maximum of 12 months with studies demonstrating a significant improvement in weight and HbA1c, however results >1 year are limited and the device does not at present have approval for use (56).

MECHANISMS OF ACTION IN BARIATRIC SURGERY

Although the development of the set point theory would support that for the majority of adults, there appears to be a pre-determined inherent weight around which most will not significantly deviate from in the long term, there appear to be profound changes following bariatric surgery which contribute to weight loss which is maintained. Irrespective of the procedure performed, people tend to demonstrate a similar weight loss pattern following surgery with an initial period of rapid weight loss for the first 18 months followed by a period of weight stability and a subsequent very gradual weight regain. In spite of the recognized weight regain, what is key is that overall, following surgery, there seems to be a new, lower set point and the adoption of a similar weight gain trajectory as to what is seen in the general population.

Early views of bariatric surgery saw procedures characterized according to the mechanism by which they were thought to act with sleeve gastrectomy (SG) described as a volume reducing surgery, biliopancreatic diversion (BPD) seen as a hypoabsorptive procedure and Roux en Y gastric bypass (RYGB) as both. Subsequent mechanistic and behavioral studies have since produced greater insights in to the mechanisms of weight regulation, alterations in appetite and satiety and neurohormonal changes as well as bile acid metabolism which are now recognized as key regulators resulting in weight loss an improvement in metabolic dysfunction (41, 57, 58).

Neurohormonal Changes

The key to understanding many of the effects of bariatric surgery is an appreciation of the complex interaction between gut hormones and higher cortical centers which regulate appetite and satiety. Mechanistic studies following bariatric surgery have provided important insights on how these neurohormones mediate their effects as well as how these pathways may be modulated surgically and pharmacologically to produce sustained weight loss as well as improvements in metabolic dysfunction associated with obesity.

Central regulation of appetite and hunger occurs primarily within several nuclei located within the hypothalamus including the arcuate nucleus (ARC) which is one of the most well defined and characterized. Within the ARC, there are distinct neuronal subtypes which respond to signals from the brain stem as well as from within the circulation to potentiate their effects on appetite and hunger. Hunger stimulating neurons found within the medial ARC express neuropeptide Y (NPY) and agouti-related peptide (AgRP) which are recognized as the primary orexigenic neurons. Animal studies have contributed to characterizing the effects of these neurons with pharmacological activation of the NPY/AgRP neurons producing a rapid increase in food intake and fat stores while decreasing energy expenditure (59). The orexigenic effects of these neurons are counterbalanced by those within the lateral ARC, including pro-opiomelanocortin (POMC) and cocaine-and-amphetamine-related transcript (CART) neurons which decrease hunger and appetite a-melanocyte stimulating hormone (a-MSH) as it is one of the primary agonists of the anorectic melanocortin-4 receptor (MCR4) (60). The importance of the melanocortin pathway has been clearly illustrated by the effects of MCR4 deficiency in humans which has been identified as the most common cause of monogenic obesity. In these individuals, there is dysregulation of eating behaviors resulting in hyperphagia and obesity (61).

In addition, further peripheral feedback via gastrointestinal neurohormones plays an important role in modulating appetite and satiety. Although gut hormones have long been recognized to have essential roles within the gastrointestinal tract, regulating the release of insulin and exocrine secretions as well as altering motility, their central effects in regulating metabolism and energy balance via the gut brain axis are becoming increasingly well recognized and characterized.

The adipocyte derived hormone, leptin, has been identified as an important mediator in the regulation of body weight, serving as a marker of nutritional status and overall fat mass. Although leptin has a bidirectional effect and may affect both anorectic and orexigenic pathways, it appears to be predominantly related to the preservation of body weight. Falling leptin levels secondary to decreased fat mass appear to stimulate orexigenic NPY neurons in the ARC of the hypothalamus, mediating increased appetite and food intake (62, 63). Although initially considered as a potential therapeutic target for those with obesity given its effects on appetite and food intake, studies have demonstrated that those with obesity have high circulating levels of leptin and may be resistant to its effects (64). Studies have shown that in people with obesity, the administration of exogenous leptin does not significantly impact food intake, nor does it result in a reduction in body weight aside from very rare cases of congenital leptin deficiency (65).

Ghrelin is the only characterized peripherally derived orexigenic neuropeptide, mediating its effects on appetite centrally within the ARC of the hypothalamus by activating NPY/AgRP neurons (66). Ghrelin is primarily produced peripherally by the stomach and centrally within the pituitary gland and the two sources have been seen to have differing means of signaling. Pituitary derived ghrelin mediates its effect directly via the hypothalamus whereas ghrelin produced from within the stomach is believed to act via vagal afferents as its effects have been shown to be diminished following vagotomy (67). In addition to mediating central changes in appetite, ghrelin also produces important changes in glucose homeostasis with ghrelin being shown to inhibit glucose-stimulated insulin secretion and impairs glucose tolerance (68). The primary regulator of plasma ghrelin levels appears to be overall caloric intake with levels rising and falling in line with food intake and fasting although the exact mechanisms by which ghrelin secretion is controlled have still not been elucidated. The importance of ghrelin in long-term weight regulation in those with obesity has been supported by studies which have demonstrated increased levels of ghrelin following diet induced weight loss, a change which was not seen in those with surgically mediated weight loss following bariatric surgery (69). Furthermore in people living with obesity, the normal physiological reduction in ghrelin levels in the post-prandial period is attenuated which suggests a potential role for ghrelin in the development of obesity (70).

Glucagon-like peptide-1 (GLP-1) is one of the best characterized neurohormones involved in the physiological and metabolic changes mediated by bariatric surgery, acting both through central and peripheral receptors to mediate its effects. GLP-1 is an incretin hormone which is secreted by the enteroendocrine L cells primarily located within the terminal ileum and colon in response to luminal nutrient exposure, particularly fats and carbohydrates (71). Within the gastrointestinal tract, GLP-1 has an important role in regulating gastric emptying and has been demonstrated to decrease the rate of gastric emptying and increasing post prandial satiety and fullness, an effect which is thought to be mediated via the vagus nerve (72). Studies in rodent models following vagotomy have demonstrated a lack of GLP-1 secretion following ingestion of high fat test meals, supporting the importance of the vagus nerve as a mediator of this response (73). The delay in gastric emptying has also been demonstrated to have an effect on glucose absorption rates and glycemia. In those given the GLP-1 antagonist there was an increased glycemic response following a carbohydrate test meal (72). The predominant effects of GLP-1 on altering glucose metabolism occur via its action as an incretin hormone. Within the pancreas, GLP-1 binds to b-cells stimulating insulin secretion in a glucose dependent manner. In addition, GLP-1 improves glucose sensitivity in glucose resistant b-cells, allowing previously resistant b-cells to sense and respond to glucose and hyperglycemia (74). The use of GLP-1 receptor agonists have also been shown in rodents to increase b-cell proliferation while inhibiting apoptosis to increase overall b-cell mass (75). Further augmenting its effect on improving post prandial glycemia, GLP-1 also stimulates somatostatin by binding to GLP-1 receptors on pancreatic b-cells while inhibiting pancreatic glucagon secretion in a glucose dependent manner (76). Within the liver, GLP-1 inhibits hepatic glucose production while stimulating glucose uptake by muscle and adipose tissue. Centrally, GLP-1 is also produced within the nucleus of the solitary tract in the brainstem which projects to the hypothalamic paraventricular nucleus which expresses GLP-1 receptors (77). The small molecular size of GLP-1 allows it to cross the blood-brain-barrier thus GLP-1 receptor agonists given peripherally are thought to mediate central effects via receptors in the hypothalamus to promote satiety and reduce energy intake, contributing to weight loss.

Similar to GLP-1, peptide YY (PYY) is primarily secreted by the endocrine L cells within the terminal ileum in the postprandial period and has overlapping effects to GLP-1. Following its release, PYY results in delayed gastric emptying and decreased gastric secretion. Centrally, PYY acts within the arcuate nucleus of the hypothalamus by binding to the anorectic POMC neurons to inhibit feeding (78). Vagotomy results in an attenuated anorectic response to PYY, suggesting the potential role of the vagus in this pathway (79). In addition to its anorectic effects, PYY plays a role in weight maintenance via its effects on energy expenditure. In humans, peripheral infusion of PYY has been shown to increase energy expenditure as well as raising fat oxidation rates (80). Further establishing the role of PYY in body weight regulation was a study that demonstrated a negative correlation between fasting PYY levels and levels of adiposity and resting metabolic rate (81). In people living with obesity, there is a lower postprandial PYY level compared to normal body weight individuals in response to a test meal, which was associated with decreased satiety and relatively increased food intake (82). Peripheral administration of PYY produces a similar reduction in food intake in those with obesity as in those of a normal body weight, suggesting that PYY resistance is not likely contributing to the development of obesity (83). 

Bile Acid Metabolism

In addition to the critical role neurohormones are thought to play in long-term weight regulation, changes in bile acid (BA) metabolism have been recognized as a potential key mediator, which may contribute to long term weight loss following bariatric surgery. Studies in both human and rodent models have demonstrated increased plasma bile acids following Roux en Y gastric bypass (RYGB), sleeve gastrectomy (SG), and biliopancreatic diversion (BPD) in both human and rodent models. The farnesoid X receptor (FXR) is a nuclear BA receptor and is an important regulator of genes which are involved in BA synthesis and transport in addition to its role in lipid and glucose metabolism (84). There is growing interest that changes in BA metabolism via FXR are a key link between the alterations in BA composition following bariatric surgery and the improvements in glucose homeostasis and remission of T2DM. Studies in rodent models have supported the potential relationship between alterations in BA metabolism mediated by the FXR with weight loss and improvements in glycemic control. In mice with diet induced obesity undergoing SG and FXR receptor genetic disruption, there was a clear decrease in weight loss and improvements in glycemia compared to wild type littermates also undergoing SG, establishing the importance of a functional FXR to mediate some of the metabolic improvements following surgery (85). It is thought that the increase in plasma bile acids results in FXR activation which in turn produces an increase in FGF19 which has effects mimicking the actions of insulin, increasing glycogen synthesis while decreasing gluconeogenesis (86).

Increased plasma BA are also thought to induce metabolic changes following bariatric surgery by binding to the G protein coupled receptor, TRG5, which is expressed in the distal ileum. Found within the enteroendocrine L cells, BA are thought to activate TGR5, which is a key element in the signaling pathway responsible for increasing GLP-1 production (86). In addition to the changes in glucose metabolism mediated by TGR5 activation, it is thought that this receptor may play a role in contributing to an overall shift towards a negative energy balance in the postoperative period, resulting in increased oxygen consumption and energy expenditure.

OUTCOMES AFTER BARIATRIC SURGERY

Mortality And Adverse Events

PERIOPERATIVE MORTALITY

Although there is often a perception that bariatric surgery should be reserved as treatment of last resort when all other approaches have not been effective, this is not supported by current data. Early data on morbidity following bariatric surgery was significantly higher but has remarkably decreased in part owing to the near universal adoption of the minimally invasive approach and advances in surgical techniques.

UK registry data looking at all primary bariatric operations from 2009-2016 demonstrated a 30-day mortality rate of 0.08% after discharge with an overall downward trend in mortality over the study period. Similarly, a population based study comparing 30 day, 90 day, and 1 year mortality rates demonstrated that bariatric surgery had the lowest mortality rate over all time periods compared to other common elective procedures including cholecystectomy, hysterectomy, and hip and knee arthroplasty (87, 88).

Early Adverse Events (<30 days)

Overall, the incidence of adverse events in the early postoperative period is low, with similar rates seen in randomized controlled trials comparing different procedures. In a review of more than 100,000 cases, the most common early adverse events were not directly related to the procedure, rather they were myocardial infarction and pulmonary embolus which were seen in 1.15 and 1.17% of cases respectively (89). These two complications were also associated with the highest mortality rate amongst those experiencing early postoperative complications (89).  Bleeding in the early postoperative period although potentially serious and requiring a return to operation room is uncommon with rates cited between 0.5% for SG and 1% following RYGB (90).

Looking specifically at procedure related complications, staple line leak following SG although uncommon remains a concern as it can be challenging to treat. A systematic review of 148 studies including more than 40,000 individuals found an overall leak rate of 1.5% (91). Several techniques have been identified to help reduce the risk of leaks including reinforcement and buttressing, however, no consensus exists as to the ideal approach. Although RYGB is seen as a technically challenging procedure due to the formation of two anastomoses, the risk of anastomotic leak is approximately 1% and an overall complication rate of 4.4% (92, 93). Similar rates of anastomotic leak have been reported following OAGB (94).

Late Adverse Events

Depending on the specific procedure several long-term medical problems can occur and include micronutrient deficiencies, dumping syndrome, hypoglycemia, cholelithiasis, nephrolithiasis, and osteoporosis and fractures. These medical problems are discussed in detail in the Endotext chapter entitled Medical Management of the Postoperative Bariatric Surgery Patient (95).

RYBG is the procedure with the greatest amount of data to support its long-term safety and efficacy. However, there are several well characterized long-term complications which may arise. Internal herniation, although rare, occurs in approximately 2-3%  following RYGB,   presenting with symptoms of small bowel obstruction, most commonly severe abdominal pain (96). It is important to have a high index of suspicion with these symptoms as definitive diagnosis based on imaging alone is unreliable and diagnostic laparoscopy should be considered (97). It is also worth noting that studies have found that up to 10% of individuals report chronic abdominal pain following RYGB which can be difficult to treat and may impact negatively on quality of life (98, 99).

One of the primary concerns in the long-term for patients undergoing SG is the possibility of developing de novo reflux or the worsening of pre-existing symptoms which can be difficult to treat (100). A RCT with 5-year follow-up demonstrated that 16% of patients following SG developed de novo reflux vs 4% undergoing RYGB (46). The SM-BOSS study also found a reflux remission rate of 60.4% compared to 25.0% following SG (101). In patients with severe reflux following SG, conversion to RYGB has been found to be effective in improving or treating symptoms (102). Given the concerns regarding the long-term risk of reflux and the development of Barrett’s esophagus, IFSO has issued guidance to recommend surveillance endoscopy one year postoperatively and then every 2-3 years thereafter (39).

Although there is more limited long-term data for patients undergoing OAGB, studies have shown that up to 41% of patients at 5 years reported gastro-esophageal reflux compared to 18% of those undergoing RYGB (103). Given the anatomical configuration, bile acid reflux and esophagitis has also been found endoscopically and although the long-term implications are unknown, it does raise concerns regarding future cancer risk (104).

Considering the nature of bariatric surgery, a commitment to long-term follow up, particularly focusing on nutritional supplementation and monitoring, is an essential element in the decision to proceed with an operation. However, the specific requirements are largely procedure specific and determined by the anatomical changes involved. Although relatively rarely performed DS is noteworthy not only for the weight loss and improvement in metabolic dysfunction it can result in relatively high-risk nutritional deficiencies compared to other procedures.

Weight Loss Outcomes

The ability to produce not only profound weight loss but weight loss which is sustained in the long term is essential to the success of bariatric as a treatment for obesity, which is recognized as a chronic and progressive disease. As such, the importance of studies can in some ways be categorized according to the length of their follow-up period when considering their clinical relevance or impact although clearly the soundness of the overall methodology is the primary determinant. Short-term studies (1 - 3 years) are plentiful but simply suggest potential effectiveness. Medium term studies (3 -10 years) are far fewer but are more assuring of real effectiveness. There is also now mounting longer term data emerging which further adds to the more than 25-year follow up of the landmark Swedish Obese Subjects (SOS) study.  

SHORT AND MEDIUM-TERM OUTCOMES

In recent years, there have been a number of RCTs with 5-year follow up periods which have emerged comparing weight loss between different procedures. The SM-BOSS study was a multi-center RCT comparing SG to RYGB with a primary end point comparing weight loss (101). At 5 years, the study did not show a statistically significant difference in excess BMI loss with -61.1% seen following SG compared to -68.3% following RYGB. Similarly, the SLEEVEPASS study also sought to compare SG to RYGB with the primary end point of weight loss measured as % excess weight loss (EWL) (105). The %EWL at 5 years was 49% after SG and 57% following RYGB, however, this difference was not statistically significant.  The individual participant data of both studies were merged with the results supporting a greater percentage BMI loss and resolution of hypertension with RYGB compared to SG but no difference in T2DM remission or quality of life at 5 years (106).

While none of the published data at present clearly supports the superiority of one procedure over another, there are two ongoing RCTs, ByBandSleeve and Bypass Sleeve Equipoise Trial (BEST) which may change this (107, 108).

LONG-TERM (>10 YEAR) OUTCOMES   

The prospective Swedish Obese Subjects (SOS) study was a key step in establishing the effect of bariatric surgery in people with obesity compared to usual care and now has more than 25 years of follow-up data. Follow-up data which was measured at 2, 10, 15, and 20 years demonstrated -23%, -17%, -16% and -18% mean changes in body weight in the surgery group compared to between 1% and -1% in the standard care group at these same time points (6). It is worth noting that this study included several procedures such as gastric banding and vertical banded gastroplasty which are no longer commonly performed.

Looking specifically at RYGB, there is mounting data to support the long-term weight loss produced by the procedure. A prospective study looking at 1156 participants undergoing RYGB over a 12 year follow up period found a -26.9% mean percent weight loss (45). The mean percent weight loss at 6 years was similar at -28% suggesting that weight remained relatively stable after the initial period of weight loss in the first year. These results were similar to a retrospective cohort analysis of 10-year weight loss outcomes following RYGB which showed a mean weight change of -28.6% (109).

Data looking at >10-year outcomes for SG is more limited, however, the 10-year observational follow up study of the SLEEVEPASS study showed a mean excess weight loss (EWL) of 43.5% (110). Similarly, high quality studies evaluating the >10-year weight loss outcomes are limited for OAGB given the relative recent adoption of the procedure. However, a retrospective single-center analysis of 385 participants showed a mean % total weight loss (TWL) of 33.4% (111). Although infrequently performed due to the high complication and reoperation rate, BPD/DS remains the procedure which produces the most substantial weight loss with studies showing a 10 year TWL of 40.7% (50).

Overall, it would appear that the effect of bariatric surgery, irrespective of the procedure performed, is a period of rapid weight loss followed by prolonged weight stability which is essential to improving long-term morbidity and mortality.

Type 2 Diabetes and Bariatric Surgery

Type 2 diabetes and obesity are inherently linked diseases and improvements in glycemic control has become one of the earliest indicators that surgical modification of the gastrointestinal tract could result in profound metabolic changes and indeed could help modify the underlying disease process. Early studies looking at jejuno-ileal bypass demonstrated a rapid normalization of blood glucose in the early postoperative period, prior to any weight loss, which first raised the possibility that these operations could produce changes in a weight loss independent manner. The 1995 observational study which showed a normalization of glycemia in more than 600 people with obesity and T2DM undergoing RYGB was one of the first to create widespread interest in the possibility of employing surgery as a treatment for T2DM (112). Having recognized this effect, the metabolic effects of bariatric surgery and its implications for T2DM have become one of the main focuses of research. RCTs comparing bariatric surgery to medical management alone have consistently demonstrated that it is more effective in improving glycemia and cardiovascular risk factors, irrespective of the procedure performed. As such, it is now endorsed by governing bodies world-wide as a central element of the treatment algorithm for people with T2DM and obesity (113).

The STAMPEDE trial was a RCT comparing the use of bariatric surgery, either SG or RYGB in conjunction to intensive medical therapy (IMT) compared to IMT alone (8). Over a 5 year follow up period, only 5% of the participants in the IMT group reached an HbA1c of <6% vs 23% undergoing SG and 29% following RYGB.  A further study involving three arms compared RYGB to BPD and medication. Over a ten year follow up period, T2DM remission rates were 25% for RYGB, 50% for BPD, and 5.5% for those treated with medication, however, that includes one participant who crossed over from the medical therapy group to surgery (7). Although the study showed that the remission rates decreased in both surgical groups between the 5 and 10-year follow up period and was lower particularly within the RYGB group, even in those who did relapse, glycemic control remained very good (HbA1c<7% or <53mmol/mol). The ARMSS-T2DM study a pooled analysis of four RCTs is currently the largest analysis with the longest follow up comparing bariatric surgery with medical treatment/lifestyle modification for T2DM (114). At 12 years, the between group difference in HbA1c levels was -1.1% with none of the patients in the medical group in remission compared to 12.7% in remission in the bariatric surgery group. The patients in the bariatric surgery group were also using fewer anti-diabetes medications.

REMISSION RATES IN RCTs

As of April 2024, there were 12 randomized controlled trials which irrespective of the type of surgery have consistently demonstrated the greater improvements in glycemic control and disease remission with bariatric surgery compared to medical therapy (8, 10-16, 18, 115-117) All studies have compared one or more bariatric procedures with a group having non-surgical treatment (NST). The difficulty in drawing firm conclusions is in part due to the studies not being directly comparable due to extensive heterogeneity, including different criteria for patient selection, treatment durations, and the use of various definitions of remission of diabetes, particularly the cut-off values for HbA1c. Nevertheless, they serve to provide key comparisons with NST, the current offering to more than 99% of people with diabetes.

The first of the studies was performed the Centre for Obesity Research and Education (CORE) in Melbourne (115). 60 patients were randomized to LAGB or NST. They were required to have a BMI between 30-40kg/m² and to have been known to have T2DM duration < 2 years. At 2-year follow up, 73% of patients were in remission (defined as a HbA1c < 6.2%) following LAGB vs 13% in the NST group.

The STAMPEDE study randomized 150 patients to either intensive medical therapy (IMT) alone or IMT plus SG or RYGB. Remission was defined as an HbA1c <6.0%. At 5 years, remission rates were 5% in the IMT group vs 23% following SG and 29% following RYGB.

Mingrone et al report the longest follow up having completed a 10 year follow up of 60 patients to NST, BPD, or RYGB (7). They used criteria of HbA1c <6.5% and fasting glycemia <5.55mmol/L without medication for one year to define remission. Of all the patients who initially went into remission in the surgical group, 37.5% remained in remission at 10 years with 25% for RYGB and 50% for BPD. 20 of the 34 patients in the surgical group who were in remission at 2 years subsequently relapsed by 10 years, however, all maintained good glycemic control with a mean HbA1c of 6.7%. There were two patients within the medical group at 10 years who were in remission included in the intention to treat analysis. However, these were both patients who had surgery during the follow up period.

Ikamuddin et al (118), carried out a multicenter RCT with 120 patients undergoing either RYGB or having NST. The defined remission as HbA1c <6% at consecutive annual visits without the use of medications. None of the participants in the medical therapy group were in remission at any point during the study while 16% of the participants who underwent RYGB were in remission at year two and 7% at year five.

Courcoulas et al randomized 69 patients into 3 groups – NST, RYGB, and LAGB (13). They defined remission as HbA1c< 6.5% and FBG <125mg/dL. At five years, the reported remission rates were 30% for the RYGB group and 19% for LAGB while none of the patients in the medical group were considered to be in remission.

A Summary of the RCTs to date comparing the long-term efficacy of metabolic surgery compared to medication or lifestyle modification for T2DM can be seen in Table 2 (Adapted from Courcoulas et al (114)).

V= versus

DURABILITY OF REMISSION

As long-term evidence from RCTs has emerged, it would support that some of the metabolic effects appear to diminish over time, which perhaps in part reflects the underlying nature of diabetes, which is understood as both chronic and progressive.  The SAMPEDE study found a three-year remission rate following RYGB of 38% which fell to 22% at five-years (8, 119). The suggestion that the metabolic effects of RYGB are attenuated with time were supported by the RCT with the longest follow up which found the remission rate fell from 75% at 2 years to 37% at 5 years  and 25% at 10 years (7).

The effects of SG were examined in the STAMPEDE study which showed a reduction in remission rates  from 37% to 24% between years 1-3 and 15% at 5 years (8). The initial remission rates as well as long-term remission have been demonstrated to be highest following BPD with 63% in remission at 5 years and 50% at 10 years (7).

MACROVASCULAR AND MICROVASCULAR COMPLICATIONS  

The durability of remission and the reduction of complications has been demonstrated at a fifteen year follow up in the SOS study, a prospective matched cohort study (120). They reported that the remission rate for the surgical group, predominantly gastroplasty, at two years was 72% and at 15 years was 31%. This remission rate, though reduced with time, was significantly better than the 6.5% in the control group, indicating an important long-term benefit. Furthermore, and arguably more important than the remission rate, they found the number macrovascular and microvascular complications of diabetes were fewer at 15 years in the surgical group than in the controls.  

OTHER HEALTH OUTCOMES AFTER BARIATRIC SURGERY

Cancer

Obesity has been demonstrated to not only be a risk factor for the development of certain types of cancer but may also increase the risk of mortality associated with cancer. The SOS study was the first interventional trial which demonstrated a decreased incidence of cancer,  amongst patients undergoing bariatric surgery compared to matched controls (121). Since then, there has been increased recognition of the possibility that weight loss mediated by bariatric surgery may reduce both the incidence of cancers as well as improving long term outcomes. A subsequent matched cohort study, the SPLENDID study demonstrated reduced cumulative incidence of mortality related to 13 types of cancer in patients undergoing bariatric surgery compared to the non-surgical group with an adjusted HR of 0.52 (122). Further studies examining the effect of bariatric surgery specifically on the incidence of non-hormonal cancers demonstrated a nearly 50% reduction in patients undergoing bariatric surgery compared to matched controls (123).

Cardiovascular Disease

Obesity is one of the most important modifiable risk factors in the prevention of cardiovascular disease. However, until the publication of several critical studies, what was not clear was whether or not weight loss achieved through surgical means could modify individual cardiovascular risk factors and produce a resultant improvement in mortality. There are now more than 30 observational studies which have examined primary prevention of cardiovascular disease, demonstrating  reduced morbidity and mortality in patients with obesity undergoing surgery compared to usual care. The SOS study which has more than 30 years of follow up data has demonstrated the long-term benefits of bariatric surgery on reducing cardiovascular risk, demonstrating a 30% reduction in death from cardiovascular disease (6). One of the largest observational studies to date including nearly 14,000 patients found a 62% reduction in new onset heart failure, 31% reduction in myocardial infarction rates, 33% reduction in stroke, and a 22% reduction in atrial fibrillation (124).

Liver

The term metabolic dysfunction-associated steatotic liver disease (MASLD) is a broad categorization of a spectrum of liver diseases ranging from hepatic steatosis to metabolic dysfunction-associated steatohepatitis (MASH, which can progress to cirrhosis and end-stage liver disease. MASLD is now the most common cause of chronic liver disease globally; however, its implications have up until recently been largely underappreciated due to the fact that many patients are asymptomatic. In patients with obesity, the incidence of disease is far higher, and the entire spectrum of disease is seen, with up to 80% having steatosis, 37% MASH, 23% fibrosis, and 5.8% cirrhosis (125).

The majority of patients with MASLD are asymptomatic and a significant proportion will also be biochemically normal; thus, a diagnosis of MASLD can only be made on the basis of imaging studies. It is difficult to monitor the progression of MASLD, particularly in those with normal liver enzymes; however, one-third of patients with early-stage MASH will progress to fibrosis within five to ten years of diagnosis (126). Given the growing number of individuals affected by obesity and MASLD, it is anticipated that MASH will become the leading indication for liver transplantation (127). An increasing body of evidence supports the consideration of MASH and fibrosis as a significant obesity-related complication and recommend its inclusion as an indication for bariatric/metabolic surgery, given their potential reversibility with substantial weight loss mediated by surgery.

A meta-analysis of 21 studies, including over 2000 patients undergoing bariatric/metabolic procedures, found a resolution of steatosis or steatohepatitis and biochemical normalization in most patients (128). The critical finding was that in those with severe disease and established fibrosis there was a reversal of these changes in 30% of patients.

Dyslipidemia of Obesity

Increased fasting triglyceride and decreased high-density lipoprotein (HDL)-cholesterol concentrations characterize the dyslipidemia of obesity and insulin resistance (129). This dyslipidemia pattern is highly atherogenic and a common pattern associated with coronary artery disease (130). Bariatric surgery produces substantial decreases in fasting triglyceride levels, a normalization of HDL, and an improved total cholesterol–to–HDL-cholesterol ratio (131-133).  Although elevation of total cholesterol is not purely obesity-driven, evidence would support that procedures such as OAGB and RYGB (134) can produce significant improvements in total cholesterol levels(135).

Hypertension

There is evidence of a reduction in both systolic and diastolic blood pressure (BP) following weight loss in association with bariatric surgery (136). The GATEWAY study examined the long-term effects of bariatric surgery on hypertension (HTN) control and remission. The RCT involved 100 participants comparing 5-year outcomes in people with HTN on medical therapy alone vs RYBG and medical therapy. RYBG was associated with HTN remission in 46.9% of participants compared to 2.4% of those in the medical therapy group. The number of medications required to maintain BP<140/90mmHg was reduced by 80.7% following RYGB (137).

Asthma

There is a positive relationship between asthma and obesity with a possible dose-response effect (138, 139). The Nurses' Health study identified a five-fold increase in the relative risk of asthma with a weight gain of 25kg from age 18 when compared to a weight stable group (140).  In patients with obesity, outcomes from asthma are worse with more patients with poor control despite maximal therapy, more frequent exacerbations, and poorer quality of life (141). Given the link between sustained weight loss and improvements in asthma, there has been significant interest in the possible role of surgery in the management of patients with obesity and asthma. A systematic review of studies involving SG, LAGB, RYGB and BPD described a consistent improvement in pulmonary function tests following bariatric surgery as well as quality of life (142).  

Obstructive Sleep Apnea

Obstructive sleep apnea is characterized by recurrent episodes of upper airway obstruction and hypoxia during sleep due to abnormal airway collapsibility. Excess weight is the strongest independent risk factor in the development of obstructive sleep apnea, with a 10% change in body weight associated with a 30% worsening in the apnea-hypopnea index (AHI), one of the primary indexes for measuring severity (143). A systematic review of 69 studies found that irrespective of the procedure performed, bariatric surgery resulted in a significant improvement in most patients. These findings were supported by a further meta-analysis which found 83.6% of patients reporting resolution or improvement of symptoms (144). Although there is evidence demonstrating significant improvements with regard to the AHI, it is essential to note that despite this, most patients following treatment remain within the moderate to severe range. Bariatric surgery should not be undertaken with the goal of cure in mind, but rather to control or reduce disease severity.

IMPROVEMENT IN QUALITY OF LIFE (QOL)

Several studies clearly demonstrate major QOL improvements following bariatric procedures (145-149).  A large prospective study of QOL after bariatric surgery employed the Medical Outcomes Trust Short Form-36 (SF-36). The SF-36 is a reliable, broadly used instrument that has been validated in people living with obesity. In this study, 459 participants with complex obesity were found to have lower scores compared with a control population for all 8 aspects of QOL measured, particularly the physical health scores. Weight loss provided a dramatic and sustained improvement in all measures of the SF-36. Improvement was greater in those with more preoperative disability, however, the extent of weight loss was not a good predictor of improved QOL. Even for patients who required revisional surgery during the follow-up period, they found a similar improvement in measures of QOL. Similar improvements in QOL have been demonstrated in patients having LAGB for previously failed gastric stapling (150).

IMPROVEMENT IN SURVIVAL

The ultimate test of effectiveness of a treatment is the reduction of mortality. There is a growing body of evidence on long-term mortality of people who have undergone bariatric surgery compared to people with obesity who have not had surgery which shows improved survival. The SOS study demonstrated that over a median follow up period of 24 years that there was a lower risk of mortality in the people who had undergone surgery compared to the matched controls which resulted in a median increase in life expectancy by 2.4 years (6). The risk of death from both cardiovascular risk but also cancer was lower in the patients who had undergone surgery. In spite of these improvements, the group of patients who had undergone surgery still had an 8-year shorter life expectancy relative to the general population with the leading cause of death being cardiovascular disease.

A systematic review and meta-analysis of 16 matched cohort studies and one prospective controlled trial found that there is a median improvement in life expectancy of 6.1 years in patients who had undergone bariatric surgery compared to usual care. Although both participants with and without T2DM demonstrated an increased overall survival, the treatment effect was considerably larger for those with T2DM with an increased life expectancy of 9.3 years compared to the non-surgical group. The number needed to treat to prevent one additional death in 10 years was 8.4 for people with T2DM compared to 29.8 for those without (151).

FUTURE DIRECTIONS COMBINING MEDICATIONS WITH SURGERY  

There has long been a focus on comparing outcomes for the treatments of obesity and related diseases, particularly T2DM looking at the use of either surgery or medical therapy. Although studies have consistently demonstrated the efficacy of surgery in achieving long-term reductions in weight and improvements in diabetes, it is clear from our understanding of the disease process itself that obesity is a chronic and progressive disease which will over time require treatment intensification. Looking to the management of other diseases, including cancer, surgery is often viewed as a means of establishing disease control with adjunctive medical therapies to sustain this effect in the long-term (152, 153).

The concept of utilizing medication with bariatric surgery has been demonstrated to be both safe and effective as demonstrated by the STAMPEDE trial in which both RYGB and SG were combined with IMT.  Impressive advances in pharmacotherapy initially developed as anti-diabetes medications but equally recognized for its efficacy in producing weight loss in people without diabetes has made the potential for employing multi-modal care even more promising, improving long term disease control and remission.

WHO SHOULD BE CONSIDERED FOR BARIATRIC SURGERY?

For many years, the criteria for bariatric surgery were largely based on the National Institutes of Health (NIH) guidelines issued more than 30 years ago in 1991 (154). These guidelines were highly constrained by BMI cut offs and based on surgical outcomes from the era of open surgery. Having recognized the significant advances in surgery, safety outcomes as well as our greater understanding of the disease process, related disease, and mechanisms of action of surgery, IFSO and ASMBS jointly released updated guidelines in 2022 (1).

Major changes to the previous guidelines include:

• Metabolic and bariatric surgery (MBS) is recommended for individuals with BMI>35kg/m² regardless of the presence of obesity related disease.
• MBS should be considered for individuals with a BMI 30-34.9kg/m² with metabolic disease.
• BMI thresholds should be adjusted in the Asian population such that a BMI>25kg/m² suggests clinical obesity and individuals with a BMI>27.5kg/m² are offered MBS.
• Appropriately selected children and adolescents should be considered for MBS.

NEEDS AND CHALLENGES

Bariatric surgery should be viewed as a process of care that begins with a careful initial clinical evaluation and detailed patient education, continuing beyond the operative procedure through a permanent follow-up. The increasing number of safe and effective bariatric procedures should be seen as part of a growing number of treatments for obesity which may need to be combined in a stepwise and progressive approach to achieve long-term disease control. Improving care for people with obesity undergoing bariatric surgery is an evolving process as our understanding of the disease itself and its implications for people living with obesity deepens. Future areas which remain to be improved include

• A better understanding of the mechanisms of action of each procedure is required to enable optimum surgery and follow up.
• Accurate and comprehensive data management. Bariatric surgical procedures should be incorporated into national clinical registries to enable objective assessment of the risks and benefits across the community.
• More randomized controlled trials to improve our understanding of the long-term outcomes of different procedures and their implications for control of obesity related co-morbidity
• Improved evidence-based decision-making pathways to help determine who would benefit most from bariatric surgery.
• High quality clinical trials looking at the use of multimodal care, combining bariatric surgery with pharmacotherapy to improve long-term disease remission and control.
• Definition of safe and efficient pathways for assessment, surgery. and post-surgery care.
• Greater focus on understanding the implications of obesity stigma, how it affects patient care and what clinicians can do to address these inequalities.

Bariatric surgery has the potential to be one of the most important and powerful treatment approaches in medicine. High quality clinical care, good science, and comprehensive data management will allow optimal application of this approach to be realized.

REFERENCES

1. Eisenberg D, Shikora SA, Aarts E, Aminian A, Angrisani L, Cohen RV, et al. 2022 American Society of Metabolic and Bariatric Surgery (ASMBS) and International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) Indications for Metabolic and Bariatric Surgery. Obes Surg. 2023;33(1):3-14.
2. Lean MEJ, Leslie WS, Barnes AC, Brosnahan N, Thom G, McCombie L, et al. Durability of a primary care-led weight-management intervention for remission of type 2 diabetes: 2-year results of the DiRECT open-label, cluster-randomised trial. Lancet Diabetes Endocrinol. 2019;7(5):344-55.
3. Sjöström L, Narbro K, Sjöström CD, Karason K, Larsson B, Wedel H, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med. 2007;357(8):741-52.
4. Pournaras DJ, Aasheim ET, Bueter M, Ahmed AR, Welbourn R, Olbers T, et al. Effect of bypassing the proximal gut on gut hormones involved with glycemic control and weight loss. Surg Obes Relat Dis. 2012;8(4):371-4.
5. Pournaras DJ, le Roux CW. Obesity, gut hormones, and bariatric surgery. World J Surg. 2009;33(10):1983-8.
6. Carlsson LMS, Sjöholm K, Jacobson P, Andersson-Assarsson JC, Svensson PA, Taube M, et al. Life Expectancy after Bariatric Surgery in the Swedish Obese Subjects Study. N Engl J Med. 2020;383(16):1535-43.
7. Mingrone G, Panunzi S, De Gaetano A, Guidone C, Iaconelli A, Capristo E, et al. Metabolic surgery versus conventional medical therapy in patients with type 2 diabetes: 10-year follow-up of an open-label, single-centre, randomised controlled trial. Lancet. 2021;397(10271):293-304.
8. Schauer PR, Bhatt DL, Kirwan JP, Wolski K, Aminian A, Brethauer SA, et al. Bariatric Surgery versus Intensive Medical Therapy for Diabetes - 5-Year Outcomes. N Engl J Med. 2017;376(7):641-51.
9. Kashyap SR, Bhatt DL, Wolski K, Watanabe RM, Abdul-Ghani M, Abood B, et al. Metabolic effects of bariatric surgery in patients with moderate obesity and type 2 diabetes: analysis of a randomized control trial comparing surgery with intensive medical treatment. Diabetes Care. 2013;36(8):2175-82.
10. Ding SA, Simonson DC, Wewalka M, Halperin F, Foster K, Goebel-Fabbri A, et al. Adjustable Gastric Band Surgery or Medical Management in Patients With Type 2 Diabetes: A Randomized Clinical Trial. J Clin Endocrinol Metab. 2015;100(7):2546-56.
11. Halperin F, Ding SA, Simonson DC, Panosian J, Goebel-Fabbri A, Wewalka M, et al. Roux-en-Y gastric bypass surgery or lifestyle with intensive medical management in patients with type 2 diabetes: feasibility and 1-year results of a randomized clinical trial. JAMA Surg. 2014;149(7):716-26.
12. Ikramuddin S, Billington CJ, Lee WJ, Bantle JP, Thomas AJ, Connett JE, et al. Roux-en-Y gastric bypass for diabetes (the Diabetes Surgery Study): 2-year outcomes of a 5-year, randomised, controlled trial. The lancet Diabetes & endocrinology. 2015;3(6):413-22.
13. Courcoulas AP, Goodpaster BH, Eagleton JK, Belle SH, Kalarchian MA, Lang W, et al. Surgical vs medical treatments for type 2 diabetes mellitus: a randomized clinical trial. JAMA surgery. 2014;149(7):707-15.
14. Simonson DC, Halperin F, Foster K, Vernon A, Goldfine AB. Clinical and Patient-Centered Outcomes in Obese Patients With Type 2 Diabetes 3 Years After Randomization to Roux-en-Y Gastric Bypass Surgery Versus Intensive Lifestyle Management: The SLIMM-T2D Study. Diabetes Care. 2018;41(4):670-9.
15. Cummings DE, Arterburn DE, Westbrook EO, Kuzma JN, Stewart SD, Chan CP, et al. Gastric bypass surgery vs intensive lifestyle and medical intervention for type 2 diabetes: the CROSSROADS randomised controlled trial. Diabetologia. 2016;59(5):945-53.
16. Wentworth JM, Playfair J, Laurie C, Ritchie ME, Brown WA, Burton P, et al. Multidisciplinary diabetes care with and without bariatric surgery in overweight people: a randomised controlled trial. Lancet Diabetes Endocrinol. 2014;2(7):545-52.
17. Dixon JB, O'Brien PE, Playfair J, Chapman L, Schachter LM, Skinner S, et al. Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial. JAMA. 2008;299(3):316-23.
18. Liang Z, Wu Q, Chen B, Yu P, Zhao H, Ouyang X. Effect of laparoscopic Roux-en-Y gastric bypass surgery on type 2 diabetes mellitus with hypertension: a randomized controlled trial. Diabetes Res Clin Pract. 2013;101(1):50-6.
19. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577-89.
20. Kremen A, Linner JH, Nelson CH. An experimental evaluation of the nutritional importance of proximal and distal small intestine. Annals of Surgery. 1954;140:439-44.
21. Jorizzo JL, Apisarnthanarax P, Subrt P, Hebert AA, Henry JC, Raimer SS, et al. Bowel-bypass syndrome without bowel bypass. Bowel-associated dermatosis-arthritis syndrome. Archives of Internal Medicine. 1983;143(3):457-61.
22. O'Leary JP. Hepatic complications of jejunoileal bypass. Seminars in Liver Disease. 1983;3(3):203-15.
23. Corrodi P. Jejunoileal bypass: change in the flora of the small intestine and its clinical impact. Reviews of Infectious Diseases. 1984;6 (Suppl 1):S80-4.
24. Parfitt AM, Podenphant J, Villanueva AR, Frame B. Metabolic bone disease with and without osteomalacia after intestinal bypass surgery: a bone histomorphometric study. Bone. 1985;6(4):211-20.
25. DeWind LT, Payne JH. Intestinal bypass surgery for morbid obesity. Long-term results. Journal of the American Medical Association. 1976;236(20):2298-301.
26. Mason EE, Ito C. Gastric bypass in obesity. Surgical Clinics of North America. 1967;47(6):1345-51.
27. Printen KJ, Mason EE. Gastric surgery for relief of morbid obesity. Archices of Surgery. 1973;106(4):428-31.
28. Mason EE. Vertical banded gastroplasty for obesity. Archices of Surgery. 1982;117(5):701-6.
29. Hall JC, Watts JM, O'Brien PE, Dunstan RE, Walsh JF, Slavotinek AH, et al. Gastric surgery for morbid obesity. The Adelaide Study. Annals of Surgery. 1990;211(4):419-27.
30. Pories WJ, Flickinger EG, Meelheim D, Van Rij AM, Thomas FT. The effectiveness of gastric bypass over gastric partition in morbid obesity: consequence of distal gastric and duodenal exclusion. Annals of Surgery. 1982;196(4):389-99.
31. Sugerman HJ, Starkey JV, Birkenhauer R. A randomized prospective trial of gastric bypass versus vertical banded gastroplasty for morbid obesity and their effects on sweets versus non- sweets eaters. Annals of Surgery. 1987;205(6):613-24.
32. Sugerman HJ, Londrey GL, Kellum JM, Wolf L, Liszka T, Engle KM, et al. Weight loss with vertical banded gastroplasty and Roux-Y gastric bypass for morbid obesity with selective versus random assignment. American Journal of Surgery. 1989;157(1):93-102.
33. Scopinaro N, Gianetta E, Civalleri D, Bonalumi U, Bachi V. Bilio-pancreatic bypass for obesity: II. Initial experience in man. British Journal of Surgery. 1979;66(9):618-20.
34. Scopinaro N, Gianetta E, Adami GF, Friedman D, Traverso E, Marinari GM, et al. Biliopancreatic diversion for obesity at eighteen years. Surgery. 1996;119(3):261-8.
35. Marceau P, Biron S, Bourque RA, Potvin M, Hould FS, Simard S. Biliopancreatic diversion with a new type of gastrectomy. Obesity Surgery. 1993;3(1):29-35.
36. Marceau P, Hould FS, Simard S, Lebel S, Bourque RA, Potvin M, et al. Biliopancreatic diversion with duodenal switch. World Journal of Surgery. 1998;22(9):947-54.
37. Brown WA, Liem R, Al-Sabah S, Anvari M, Boza C, Cohen RV, et al. Metabolic Bariatric Surgery Across the IFSO Chapters: Key Insights on the Baseline Patient Demographics, Procedure Types, and Mortality from the Eighth IFSO Global Registry Report. Obes Surg. 2024;34(5):1764-77.
38. Bhandari M, Fobi MAL, Buchwald JN, Group: BMSSBW. Standardization of Bariatric Metabolic Procedures: World Consensus Meeting Statement. Obes Surg. 2019;29(Suppl 4):309-45.
39. Brown WA, Johari Halim Shah Y, Balalis G, Bashir A, Ramos A, Kow L, et al. IFSO Position Statement on the Role of Esophago-Gastro-Duodenal Endoscopy Prior to and after Bariatric and Metabolic Surgery Procedures. Obes Surg. 2020;30(8):3135-53.
40. Zakeri R, Batterham RL. Potential mechanisms underlying the effect of bariatric surgery on eating behaviour. Curr Opin Endocrinol Diabetes Obes. 2018;25(1):3-11.
41. Kalinowski P, Paluszkiewicz R, Wróblewski T, Remiszewski P, Grodzicki M, Bartoszewicz Z, et al. Ghrelin, leptin, and glycemic control after sleeve gastrectomy versus Roux-en-Y gastric bypass-results of a randomized clinical trial. Surg Obes Relat Dis. 2017;13(2):181-8.
42. O'Brien PE, MacDonald L, Anderson M, Brennan L, Brown WA. Long-term outcomes after bariatric surgery: fifteen-year follow-up of adjustable gastric banding and a systematic review of the bariatric surgical literature. Ann Surg. 2013;257(1):87-94.
43. Himpens J, Cadière GB, Bazi M, Vouche M, Cadière B, Dapri G. Long-term outcomes of laparoscopic adjustable gastric banding. Arch Surg. 2011;146(7):802-7.
44. Stefanidis A, Forrest N, Brown WA, Dixon JB, O'Brien PB, Juliane Kampe, et al. An investigation of the neural mechanisms underlying the efficacy of the adjustable gastric band. Surg Obes Relat Dis. 2016;12(4):828-38.
45. Adams TD, Davidson LE, Litwin SE, Kim J, Kolotkin RL, Nanjee MN, et al. Weight and Metabolic Outcomes 12 Years after Gastric Bypass. N Engl J Med. 2017;377(12):1143-55.
46. Biter LU, 't Hart JW, Noordman BJ, Smulders JF, Nienhuijs S, Dunkelgrün M, et al. Long-term effect of sleeve gastrectomy vs Roux-en-Y gastric bypass in people living with severe obesity: a phase III multicentre randomised controlled trial (SleeveBypass). Lancet Reg Health Eur. 2024;38:100836.
47. Stenberg E, Szabo E, Ågren G, Ottosson J, Marsk R, Lönroth H, et al. Closure of mesenteric defects in laparoscopic gastric bypass: a multicentre, randomised, parallel, open-label trial. Lancet. 2016;387(10026):1397-404.
48. Robert M, Espalieu P, Pelascini E, Caiazzo R, Sterkers A, Khamphommala L, et al. Efficacy and safety of one anastomosis gastric bypass versus Roux-en-Y gastric bypass for obesity (YOMEGA): a multicentre, randomised, open-label, non-inferiority trial. Lancet. 2019;393(10178):1299-309.
49. Mahawar KK, Parmar C, Graham Y. One anastomosis gastric bypass: key technical features, and prevention and management of procedure-specific complications. Minerva Chir. 2019;74(2):126-36.
50. Bolckmans R, Himpens J. Long-term (>10 Yrs) Outcome of the Laparoscopic Biliopancreatic Diversion With Duodenal Switch. Ann Surg. 2016;264(6):1029-37.
51. Sánchez-Pernaute A, Rubio Herrera MA, Pérez-Aguirre E, García Pérez JC, Cabrerizo L, Díez Valladares L, et al. Proximal duodenal-ileal end-to-side bypass with sleeve gastrectomy: proposed technique. Obes Surg. 2007;17(12):1614-8.
52. Torres A, Rubio MA, Ramos-Leví AM, Sánchez-Pernaute A. Cardiovascular Risk Factors After Single Anastomosis Duodeno-Ileal Bypass with Sleeve Gastrectomy (SADI-S): a New Effective Therapeutic Approach? Curr Atheroscler Rep. 2017;19(12):58.
53. Surve A, Cottam D, Medlin W, Richards C, Belnap L, Horsley B, et al. Long-term outcomes of primary single-anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S). Surg Obes Relat Dis. 2020;16(11):1638-46.
54. Sánchez-Pernaute A, Herrera MA, Pérez-Aguirre ME, Talavera P, Cabrerizo L, Matía P, et al. Single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S). One to three-year follow-up. Obes Surg. 2010;20(12):1720-6.
55. Dijkhorst PJ, Boerboom AB, Janssen IMC, Swank DJ, Wiezer RMJ, Hazebroek EJ, et al. Failed Sleeve Gastrectomy: Single Anastomosis Duodenoileal Bypass or Roux-en-Y Gastric Bypass? A Multicenter Cohort Study. Obes Surg. 2018;28(12):3834-42.
56. Ryder REJ, Yadagiri M, Burbridge W, Irwin SP, Gandhi H, Bashir T, et al. Duodenal-jejunal bypass liner for the treatment of type 2 diabetes and obesity: 3-year outcomes in the First National Health Service (NHS) EndoBarrier Service. Diabet Med. 2022;39(7):e14827.
57. Pournaras DJ, le Roux CW. Are bile acids the new gut hormones? Lessons from weight loss surgery models. Endocrinology. 2013;154(7):2255-6.
58. Karamanakos SN, Vagenas K, Kalfarentzos F, Alexandrides TK. Weight loss, appetite suppression, and changes in fasting and postprandial ghrelin and peptide-YY levels after Roux-en-Y gastric bypass and sleeve gastrectomy: a prospective, double blind study. Ann Surg. 2008;247(3):401-7.
59. Krashes MJ, Koda S, Ye C, Rogan SC, Adams AC, Cusher DS, et al. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J Clin Invest. 2011;121(4):1424-8.
60. Sohn JW. Network of hypothalamic neurons that control appetite. BMB Rep. 2015;48(4):229-33.
61. Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O'Rahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med. 2003;348(12):1085-95.
62. Sahu A. Leptin signaling in the hypothalamus: emphasis on energy homeostasis and leptin resistance. Front Neuroendocrinol. 2003;24(4):225-53.
63. Flier JS. Clinical review 94: What's in a name? In search of leptin's physiologic role. J Clin Endocrinol Metab. 1998;83(5):1407-13.
64. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996;334(5):292-5.
65. Blüher S, Mantzoros CS. Leptin in humans: lessons from translational research. Am J Clin Nutr. 2009;89(3):991S-7S.
66. Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, et al. A role for ghrelin in the central regulation of feeding. Nature. 2001;409(6817):194-8.
67. le Roux CW, Neary NM, Halsey TJ, Small CJ, Martinez-Isla AM, Ghatei MA, et al. Ghrelin does not stimulate food intake in patients with surgical procedures involving vagotomy. J Clin Endocrinol Metab. 2005;90(8):4521-4.
68. Tong J, Prigeon RL, Davis HW, Bidlingmaier M, Kahn SE, Cummings DE, et al. Ghrelin suppresses glucose-stimulated insulin secretion and deteriorates glucose tolerance in healthy humans. Diabetes. 2010;59(9):2145-51.
69. Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med. 2002;346(21):1623-30.
70. le Roux CW, Patterson M, Vincent RP, Hunt C, Ghatei MA, Bloom SR. Postprandial plasma ghrelin is suppressed proportional to meal calorie content in normal-weight but not obese subjects. J Clin Endocrinol Metab. 2005;90(2):1068-71.
71. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132(6):2131-57.
72. Deane AM, Nguyen NQ, Stevens JE, Fraser RJ, Holloway RH, Besanko LK, et al. Endogenous glucagon-like peptide-1 slows gastric emptying in healthy subjects, attenuating postprandial glycemia. J Clin Endocrinol Metab. 2010;95(1):215-21.
73. Rocca AS, Brubaker PL. Role of the vagus nerve in mediating proximal nutrient-induced glucagon-like peptide-1 secretion. Endocrinology. 1999;140(4):1687-94.
74. Holz GG, Kühtreiber WM, Habener JF. Pancreatic beta-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1(7-37). Nature. 1993;361(6410):362-5.
75. Vilsbøll T. The effects of glucagon-like peptide-1 on the beta cell. Diabetes Obes Metab. 2009;11 Suppl 3:11-8.
76. Ørgaard A, Holst JJ. The role of somatostatin in GLP-1-induced inhibition of glucagon secretion in mice. Diabetologia. 2017;60(9):1731-9.
77. Tang-Christensen M, Vrang N, Larsen PJ. Glucagon-like peptide containing pathways in the regulation of feeding behaviour. Int J Obes Relat Metab Disord. 2001;25 Suppl 5:S42-7.
78. Batterham RL, Cowley MA, Small CJ, Herzog H, Cohen MA, Dakin CL, et al. Gut hormone PYY(3-36) physiologically inhibits food intake. Nature. 2002;418(6898):650-4.
79. Abbott CR, Monteiro M, Small CJ, Sajedi A, Smith KL, Parkinson JR, et al. The inhibitory effects of peripheral administration of peptide YY(3-36) and glucagon-like peptide-1 on food intake are attenuated by ablation of the vagal-brainstem-hypothalamic pathway. Brain Res. 2005;1044(1):127-31.
80. Sloth B, Holst JJ, Flint A, Gregersen NT, Astrup A. Effects of PYY1-36 and PYY3-36 on appetite, energy intake, energy expenditure, glucose and fat metabolism in obese and lean subjects. Am J Physiol Endocrinol Metab. 2007;292(4):E1062-8.
81. Guo Y, Ma L, Enriori PJ, Koska J, Franks PW, Brookshire T, et al. Physiological evidence for the involvement of peptide YY in the regulation of energy homeostasis in humans. Obesity (Silver Spring). 2006;14(9):1562-70.
82. le Roux CW, Batterham RL, Aylwin SJ, Patterson M, Borg CM, Wynne KJ, et al. Attenuated peptide YY release in obese subjects is associated with reduced satiety. Endocrinology. 2006;147(1):3-8.
83. Batterham RL, Cohen MA, Ellis SM, Le Roux CW, Withers DJ, Frost GS, et al. Inhibition of food intake in obese subjects by peptide YY3-36. N Engl J Med. 2003;349(10):941-8.
84. Claudel T, Staels B, Kuipers F. The Farnesoid X receptor: a molecular link between bile acid and lipid and glucose metabolism. Arterioscler Thromb Vasc Biol. 2005;25(10):2020-30.
85. Ryan KK, Tremaroli V, Clemmensen C, Kovatcheva-Datchary P, Myronovych A, Karns R, et al. FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature. 2014;509(7499):183-8.
86. Bozadjieva N, Heppner KM, Seeley RJ. Targeting FXR and FGF19 to Treat Metabolic Diseases-Lessons Learned From Bariatric Surgery. Diabetes. 2018;67(9):1720-8.
87. Alam M, Bhanderi S, Matthews JH, McNulty D, Pagano D, Small P, et al. Mortality related to primary bariatric surgery in England. BJS Open. 2017;1(4):122-7.
88. Böckelman C, Hahl T, Victorzon M. Mortality Following Bariatric Surgery Compared to Other Common Operations in Finland During a 5-Year Period (2009-2013). A Nationwide Registry Study. Obes Surg. 2017;27(9):2444-51.
89. Chang SH, Freeman NLB, Lee JA, Stoll CRT, Calhoun AJ, Eagon JC, et al. Early major complications after bariatric surgery in the USA, 2003-2014: a systematic review and meta-analysis. Obes Rev. 2018;19(4):529-37.
90. Heneghan HM, Meron-Eldar S, Yenumula P, Rogula T, Brethauer SA, Schauer PR. Incidence and management of bleeding complications after gastric bypass surgery in the morbidly obese. Surg Obes Relat Dis. 2012;8(6):729-35.
91. Gagner M, Kemmeter P. Comparison of laparoscopic sleeve gastrectomy leak rates in five staple-line reinforcement options: a systematic review. Surg Endosc. 2020;34(1):396-407.
92. Jacobsen HJ, Nergard BJ, Leifsson BG, Frederiksen SG, Agajahni E, Ekelund M, et al. Management of suspected anastomotic leak after bariatric laparoscopic Roux-en-y gastric bypass. Br J Surg. 2014;101(4):417-23.
93. Robertson AGN, Wiggins T, Robertson FP, Huppler L, Doleman B, Harrison EM, et al. Perioperative mortality in bariatric surgery: meta-analysis. Br J Surg. 2021;108(8):892-7.
94. Kermansaravi M, Kassir R, Valizadeh R, Parmar C, Davarpanah Jazi AH, Shahmiri SS, et al. Management of leaks following one-anastomosis gastric bypass: an updated systematic review and meta-analysis of 44 318 patients. Int J Surg. 2023;109(5):1497-508.
95. Kim TY, Kim S, Schafer AL, Medical Management of the Postoperative Bariatric Surgery Patient.In Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, et al. Endotext. 2020.
96. Ekelund M. Systematic review and meta-analysis of internal herniation after gastric bypass surgery (Br J Surg 2015; 102: 451-460). Br J Surg. 2015;102(5):460-1.
97. Farukhi MA, Mattingly MS, Clapp B, Tyroch AH. CT Scan Reliability in Detecting Internal Hernia after Gastric Bypass. JSLS. 2017;21(4).
98. Gormsen J, Burcharth J, Gögenur I, Helgstrand F. Prevalence and Risk Factors for Chronic Abdominal Pain After Roux-en-Y Gastric Bypass Surgery: A Cohort Study. Ann Surg. 2021;273(2):306-14.
99. Høgestøl IK, Chahal-Kummen M, Eribe I, Brunborg C, Stubhaug A, Hewitt S, et al. Chronic Abdominal Pain and Symptoms 5 Years After Gastric Bypass for Morbid Obesity. Obes Surg. 2017;27(6):1438-45.
100. DuPree CE, Blair K, Steele SR, Martin MJ. Laparoscopic sleeve gastrectomy in patients with preexisting gastroesophageal reflux disease : a national analysis. JAMA Surg. 2014;149(4):328-34.
101. Peterli R, Wölnerhanssen BK, Peters T, Vetter D, Kröll D, Borbély Y, et al. Effect of Laparoscopic Sleeve Gastrectomy vs Laparoscopic Roux-en-Y Gastric Bypass on Weight Loss in Patients With Morbid Obesity: The SM-BOSS Randomized Clinical Trial. JAMA. 2018;319(3):255-65.
102. Parmar CD, Mahawar KK, Boyle M, Schroeder N, Balupuri S, Small PK. Conversion of Sleeve Gastrectomy to Roux-en-Y Gastric Bypass is Effective for Gastro-Oesophageal Reflux Disease but not for Further Weight Loss. Obes Surg. 2017;27(7):1651-8.
103. Robert M, Poghosyan T, Maucort-Boulch D, Filippello A, Caiazzo R, Sterkers A, et al. Efficacy and safety of one anastomosis gastric bypass versus Roux-en-Y gastric bypass at 5 years (YOMEGA): a prospective, open-label, non-inferiority, randomised extension study. Lancet Diabetes Endocrinol. 2024;12(4):267-76.
104. Saarinen T, Pietiläinen KH, Loimaala A, Ihalainen T, Sammalkorpi H, Penttilä A, et al. Bile Reflux is a Common Finding in the Gastric Pouch After One Anastomosis Gastric Bypass. Obes Surg. 2020;30(3):875-81.
105. Salminen P, Helmiö M, Ovaska J, Juuti A, Leivonen M, Peromaa-Haavisto P, et al. Effect of Laparoscopic Sleeve Gastrectomy vs Laparoscopic Roux-en-Y Gastric Bypass on Weight Loss at 5 Years Among Patients With Morbid Obesity: The SLEEVEPASS Randomized Clinical Trial. JAMA. 2018;319(3):241-54.
106. Wölnerhanssen BK, Peterli R, Hurme S, Bueter M, Helmiö M, Juuti A, et al. Laparoscopic Roux-en-Y gastric bypass versus laparoscopic sleeve gastrectomy: 5-year outcomes of merged data from two randomized clinical trials (SLEEVEPASS and SM-BOSS). Br J Surg. 2021;108(1):49-57.
107. Group B-B-SC. Roux-en-Y gastric bypass, gastric banding, or sleeve gastrectomy for severe obesity: Baseline data from the By-Band-Sleeve randomized controlled trial. Obesity (Silver Spring). 2023;31(5):1290-9.
108. Hedberg S, Olbers T, Peltonen M, Österberg J, Wirén M, Ottosson J, et al. BEST: Bypass equipoise sleeve trial; rationale and design of a randomized, registry-based, multicenter trial comparing Roux-en-Y gastric bypass with sleeve gastrectomy. Contemp Clin Trials. 2019;84:105809.
109. Maciejewski ML, Arterburn DE, Van Scoyoc L, Smith VA, Yancy WS, Weidenbacher HJ, et al. Bariatric Surgery and Long-term Durability of Weight Loss. JAMA Surg. 2016;151(11):1046-55.
110. Salminen P, Grönroos S, Helmiö M, Hurme S, Juuti A, Juusela R, et al. Effect of Laparoscopic Sleeve Gastrectomy vs Roux-en-Y Gastric Bypass on Weight Loss, Comorbidities, and Reflux at 10 Years in Adult Patients With Obesity: The SLEEVEPASS Randomized Clinical Trial. JAMA Surg. 2022;157(8):656-66.
111. Carandina S, Soprani A, Zulian V, Cady J. Long-Term Results of One Anastomosis Gastric Bypass: a Single Center Experience with a Minimum Follow-Up of 10 Years. Obes Surg. 2021;31(8):3468-75.
112. Pories WJ, Swanson MS, MacDonald KG, Long SB, Morris PG, Brown BM, et al. Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus. Ann Surg. 1995;222(3):339-50; discussion 50-2.
113. Rubino F, Nathan DM, Eckel RH, Schauer PR, Alberti KG, Zimmet PZ, et al. Metabolic Surgery in the Treatment Algorithm for Type 2 Diabetes: A Joint Statement by International Diabetes Organizations. Diabetes Care. 2016;39(6):861-77.
114. Courcoulas AP, Patti ME, Hu B, Arterburn DE, Simonson DC, Gourash WF, et al. Long-Term Outcomes of Medical Management vs Bariatric Surgery in Type 2 Diabetes. JAMA. 2024;331(8):654-64.
115. Dixon JB, O'Brien PE, Playfair J, Chapman L, Schachter LM, Skinner S, et al. Adjustable gastric banding and conventional therapy for Type 2 Diabetes: A randomized controlled trial. Journal of the American Medical Association. 2008;299(3):316-23.
116. Mingrone G, Panunzi S, De Gaetano A, Guidone C, Iaconelli A, Nanni G, et al. Bariatric-metabolic surgery versus conventional medical treatment in obese patients with type 2 diabetes: 5 year follow-up of an open-label, single-centre, randomised controlled trial. Lancet. 2015;386(9997):964-73.
117. Kirwan JP, Courcoulas AP, Cummings DE, Goldfine AB, Kashyap SR, Simonson DC, et al. Diabetes Remission in the Alliance of Randomized Trials of Medicine Versus Metabolic Surgery in Type 2 Diabetes (ARMMS-T2D). Diabetes Care. 2022;45(7):1574-83.
118. Ikramuddin S, Korner J, Lee WJ, Connett JE, Inabnet WB, Billington CJ, et al. Roux-en-Y gastric bypass vs intensive medical management for the control of type 2 diabetes, hypertension, and hyperlipidemia: the Diabetes Surgery Study randomized clinical trial. JAMA. 2013;309(21):2240-9.
119. Schauer PR, Bhatt DL, Kirwan JP, Wolski K, Brethauer SA, Navaneethan SD, et al. Bariatric surgery versus intensive medical therapy for diabetes--3-year outcomes. N Engl J Med. 2014;370(21):2002-13.
120. Sjostrom L, Peltonen M, Jacobson P, Ahlin S, Andersson-Assarsson J, Anveden A, et al. Association of Bariatric Surgery With Long-term Remission of Type 2 Diabetes and With Microvascular and Macrovascular Complications. JAMA. 2014;311(22):2297-304.
121. Sjöström L, Gummesson A, Sjöström CD, Narbro K, Peltonen M, Wedel H, et al. Effects of bariatric surgery on cancer incidence in obese patients in Sweden (Swedish Obese Subjects Study): a prospective, controlled intervention trial. Lancet Oncol. 2009;10(7):653-62.
122. Aminian A, Wilson R, Al-Kurd A, Tu C, Milinovich A, Kroh M, et al. Association of Bariatric Surgery With Cancer Risk and Mortality in Adults With Obesity. JAMA. 2022;327(24):2423-33.
123. Clapp B, Portela R, Sharma I, Nakanishi H, Marrero K, Schauer P, et al. Risk of non-hormonal cancer after bariatric surgery: meta-analysis of retrospective observational studies. Br J Surg. 2022;110(1):24-33.
124. Aminian A, Zajichek A, Arterburn DE, Wolski KE, Brethauer SA, Schauer PR, et al. Association of Metabolic Surgery With Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes and Obesity. JAMA. 2019.
125. Lazo M, Clark JM. The epidemiology of nonalcoholic fatty liver disease: a global perspective. Semin Liver Dis. 2008;28(4):339-50.
126. Caldwell S, Argo C. The natural history of non-alcoholic fatty liver disease. Dig Dis. 2010;28(1):162-8.
127. Bzowej NH. Nonalcoholic steatohepatitis: the new frontier for liver transplantation. Curr Opin Organ Transplant. 2018;23(2):169-74.
128. Fakhry TK, Mhaskar R, Schwitalla T, Muradova E, Gonzalvo JP, Murr MM. Bariatric surgery improves nonalcoholic fatty liver disease: a contemporary systematic review and meta-analysis. Surg Obes Relat Dis. 2019;15(3):502-11.
129. Despres J. The insulin resistance-dyslipidemia syndrome: The most prevalent cause of coronary artery disease. Canadian Medical Association Journal. 1993;148(8):1339-40.
130. Koba S, Hirano T, Sakaue T, Sakai K, Kondo T, Yorozuya M, et al. Role of small dense low-density lipoprotein in coronary artery disease patients with normal plasma cholesterol levels. Journal of Cardiology. 2000;36(6):371-8.
131. Busetto L, Pisent C, Rinaldi D, Longhin PL, Segato G, De Marchi F, et al. Variation in lipid levels in morbidly obese patients operated with the LAP-BAND adjustable gastric banding system: effects of different levels of weight loss. Obesity Surgery. 2000;10(6):569-77.
132. Bacci V, Basso MS, Greco F, Lamberti R, Elmore U, Restuccia A, et al. Modifications of metabolic and cardiovascular risk factors after weight loss induced by laparoscopic gastric banding. Obesity Surgery. 2002;12(1):77-82.
133. Dixon J, O'Brien P. Ovarian dysfunction, androgen excess and neck circumference in obese women: Changes with weight loss (abstract). Obesity Surgery. 2002;12(2):193.
134. Brolin RE, Bradley LJ, Wilson AC, Cody RP. Lipid risk profile and weight stability after gastric restrictive operations for morbid obesity. Journal of Gastrointestinal Surgery. 2000;4(5):464-9.
135. Carbajo MA, Fong-Hirales A, Luque-de-León E, Molina-Lopez JF, Ortiz-de-Solórzano J. Weight loss and improvement of lipid profiles in morbidly obese patients after laparoscopic one-anastomosis gastric bypass: 2-year follow-up. Surg Endosc. 2017;31(1):416-21.
136. Sjostrom CD, Lissner L, Wedel H, Sjostrom L. Reduction in incidence of diabetes, hypertension and lipid disturbances after intentional weight loss induced by bariatric surgery: the SOS Intervention Study. Obesity Research. 1999;7(5):477-84.
137. Schiavon CA, Cavalcanti AB, Oliveira JD, Machado RHV, Santucci EV, Santos RN, et al. Randomized Trial of Effect of Bariatric Surgery on Blood Pressure After 5 Years. J Am Coll Cardiol. 2024;83(6):637-48.
138. Beuther DA, Sutherland ER. Overweight, obesity, and incident asthma: a meta-analysis of prospective epidemiologic studies. American Journal of Respiratory and Critical Care Medicine. 2007;175(7):661-6.
139. Young SY, Gunzenhauser JD, Malone KE, McTiernan A. Body mass index and asthma in the military population of the northwestern United States. Archives of Internal Medicine. 2001;161(13):1605-11.
140. Camargo C, Weiss S, Zhang S, Willett W, Speizer F. Prospective study of body mass index, weight change, and risk of adult-onset asthma in women. Arch Intern Med. 1999;159(Nov):2582-88.
141. Diaz J, Farzan S. Clinical implications of the obese-asthma phenotypes. Immunol Allergy Clin North Am. 2014;34(4):739-51.
142. Khalooeifard R, Adebayo R, Rahmani J, Clark C, Shadnoush M, Mohammadi Farsani G. Health Effect of Bariatric Surgery on Patients with Asthma: A Systematic Review and Meta-Analysis. Bariatric Surgical Practice and Patient Care. 2021;16(1):2-9.
143. Peppard PE, Young T, Palta M, Dempsey J, Skatrud J. Longitudinal study of moderate weight change and sleep-disordered breathing. JAMA. 2000;284(23):3015-21.
144. Camargo CA, Weiss ST, Zhang S, Willett WC, Speizer FE. Prospective study of body mass index, weight change, and risk of adult-onset asthma in women. Arch Intern Med. 1999;159(21):2582-8.
145. Dixon JB. Elevated homocysteine with weight loss. Obesity Surgery. 2001;11(5):537-8.
146. Weiner R, Datz M, Wagner D, Bockhorn H. Quality-of-life outcome after laparoscopic adjustable gastric banding for morbid obesity. Obesity Surgery. 1999;9(6):539-45.
147. Schok M, Geenen R, van Antwerpen T, de Wit P, Brand N, van Ramshorst B. Quality of life after laparoscopic adjustable gastric banding for severe obesity: postoperative and retrospective preoperative evaluations. Obesity Surgery. 2000;10(6):502-8.
148. Balsiger BM, Kennedy FP, Abu-Lebdeh HS, Collazo-Clavell M, Jensen MD, O'Brien T, et al. Prospective evaluation of Roux-en-Y gastric bypass as primary operation for medically complicated obesity [see comments]. Mayo Clinic Proceedings. 2000;75(7):673-80.
149. Horchner R, Tuinebreijer MW, Kelder PH. Quality-of-life assessment of morbidly obese patients who have undergone a Lap-Band operation: 2-year follow-up study. Is the MOS SF- 36 a useful instrument to measure quality of life in morbidly obese patients? Obesity Surgery. 2001;11(2):212-8; discussion 9.
150. O'Brien P, Brown W, Dixon J. Revisional Surgery for Morbid Obesity- Conversion to the Lap-Band System. Obesity Surgery. 2000;10(6):557-63.
151. Syn NL, Cummings DE, Wang LZ, Lin DJ, Zhao JJ, Loh M, et al. Association of metabolic-bariatric surgery with long-term survival in adults with and without diabetes: a one-stage meta-analysis of matched cohort and prospective controlled studies with 174 772 participants. Lancet. 2021;397(10287):1830-41.
152. Pournaras DJ, Hardwick RH, le Roux CW. Gastrointestinal surgery for obesity and cancer: 2 sides of the same coin. Surg Obes Relat Dis. 2017;13(4):720-1.
153. Sudlow A, le Roux CW, Pournaras DJ. Review of multimodal treatment for type 2 diabetes: combining metabolic surgery and pharmacotherapy. Ther Adv Endocrinol Metab. 2019;10:2042018819875407.
154. NIH conference. Gastrointestinal surgery for severe obesity. Consensus Development Conference Panel. Ann Intern Med. 1991;115(12):956-61.

ABSTRACT

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

LIST OF ABBREVIATIONS

INTRODUCTION

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

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

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

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

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

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

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

THE THROMBOTIC RESPONSE AND ITS PHARMACOLOGY

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

Platelet Activation

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

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

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

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

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

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

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

Activation of the Coagulation Cascade

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

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

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

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

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

Crosstalk Between Platelets and the Coagulation Cascade

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

SPECIAL PATHOPHYSIOLOGICAL CONSIDERATIONS IN DIABETES

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

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

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

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

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

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

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

CURRENT EVIDENCE AND TREATMENT RECOMMENDATIONS FOR ANTITHROMBOTIC THERAPY IN DIABETES

The Need for Therapeutic Oral Anticoagulation

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

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

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

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

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

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

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

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

Treating Acute Atherothrombotic Events

ACUTE CORONARY SYNDROMES (ACS)

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

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

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

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

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

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

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

ACUTE ISCHEMIC STROKE

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

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

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

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

Preventing Atherothrombotic Events in Individuals with Diabetes and Established Cardiovascular Disease

CORONARY ARTERY DISEASE

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

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

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

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

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

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

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

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

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

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

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

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

CEREBROVASCULAR DISEASE  

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

PERIPHERAL ARTERY DISEASE

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

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

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

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

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

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

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

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

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

CONCLUSIONS

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

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

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

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

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

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

REFERENCES

1. Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, Di Angelantonio E, Ingelsson E, Lawlor DA, Selvin E, Stampfer M, Stehouwer CD, Lewington S, Pennells L, Thompson A, Sattar N, White IR, Ray KK, Danesh J. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375(9733):2215-2222.
2. Parker WAE, Gorog DA, Geisler T, Vilahur G, Sibbing D, Rocca B, Storey RF. Prevention of stroke in patients with chronic coronary syndromes or peripheral arterial disease. Eur Heart J Suppl. 2020;22(Supplement_M):M26-M34.
3. Jackson SP. Arterial thrombosis--insidious, unpredictable and deadly. Nat Med. 2011;17(11):1423-1436.
4. Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing G-J, Harjola V-P, Huisman MV, Humbert M, Jennings CS, Jiménez D, Kucher N, Lang IM, Lankeit M, Lorusso R, Mazzolai L, Meneveau N, Ní Áinle F, Prandoni P, Pruszczyk P, Righini M, Torbicki A, Van Belle E, Zamorano JL, ESC Scientific Document Group. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). Eur Heart J. 2020;41(4):543-603.
5. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285(22):2864-2870.
6. Libby P, Buring JE, Badimon L, Hansson GK, Deanfield J, Bittencourt MS, Tokgozoglu L, Lewis EF. Atherosclerosis. Nat Rev Dis Primers. 2019;5(1):56.
7. Biondi-Zoccai GGL, Abbate A, Liuzzo G, Biasucci LM. Atherothrombosis, inflammation, and diabetes. J Am Coll Cardiol. 2003;41(7):1071-1077.
8. Patrono C, Morais J, Baigent C, Collet JP, Fitzgerald D, Halvorsen S, Rocca B, Siegbahn A, Storey RF, Vilahur G. Antiplatelet agents for the treatment and prevention of coronary atherothrombosis. J Am Coll Cardiol. 2017;70(14):1760-1776.
9. Storey RF. The long journey of individualizing antiplatelet therapy after acute coronary syndromes. Eur Heart J. 2020;41:3546-3548.
10. Bagot CN, Arya R. Virchow and his triad: a question of attribution. Br J Haematol. 2008;143(2):180-190.
11. Moroi M, Jung SM, Okuma M, Shinmyozu K. A patient with platelets deficient in glycoprotein VI that lack both collagen-induced aggregation and adhesion. J Clin Invest. 1989;84(5):1440-1445.
12. Santoro SA, Rajpara SM, Staatz WD, Woods VL, Jr. Isolation and characterization of a platelet surface collagen binding complex related to VLA-2. Biochem Biophys Res Commun. 1988;153(1):217-223.
13. Handa M, Titani K, Holland LZ, Roberts JR, Ruggeri ZM. The von Willebrand factor-binding domain of platelet membrane glycoprotein Ib. Characterization by monoclonal antibodies and partial amino acid sequence analysis of proteolytic fragments. J Biol Chem. 1986;261(27):12579-12585.
14. Aslan JE, Itakura A, Gertz JM, McCarty OJ. Platelet shape change and spreading. Methods Mol Biol. 2012;788:91-100.
15. Patrono C. Aspirin as an antiplatelet drug. N Engl J Med. 1994;330(18):1287-1294.
16. Parker WAE, Orme RC, Hanson J, Stokes HM, Bridge CM, Shaw PA, Sumaya W, Thorneycroft K, Petrucci G, Porro B, Judge HM, Ajjan RA, Rocca B, Storey RF. Very-low-dose twice-daily aspirin maintains platelet inhibition and improves haemostasis during dual-antiplatelet therapy for acute coronary syndrome. Platelets. 2019;30(2):148-157.
17. Harrison P, Cramer EM. Platelet alpha-granules. Blood Rev. 1993;7:52-62.
18. Fagura MS, Dainty IA, McKay GD, Kirk IP, Humphries RG, Robertson MJ, Dougall IG, Leff P. P2Y1-receptors in human platelets which are pharmacologically distinct from P2Y(ADP)-receptors. Br J Pharmacol. 1998;124(1):157-164.
19. Mahaut-Smith MP, Jones S, Evans RJ. The P2X1 receptor and platelet function. Purinergic Signal. 2011;7(3):341-356.
20. Storey RF, Sanderson HM, White AE, May JA, Cameron KE, Heptinstall S. The central role of the P(2T) receptor in amplification of human platelet activation, aggregation, secretion and procoagulant activity. Br J Haematol. 2000;110(4):925-934.
21. Pytela R, Pierschbacher MD, Ginsberg MH, Plow EF, Ruoslahti E. Platelet membrane glycoprotein IIb/IIIa: member of a family of Arg-Gly-Asp--specific adhesion receptors. Science. 1986;231(4745):1559-1562.
22. Parker WAE, Storey RF. Antithrombotic therapy for patients with chronic coronary syndromes. Heart 2021;107:925-933.
23. Parker WAE, Storey RF. Novel approaches to P2Y12 inhibition and aspirin dosing. Platelets. 2020;32(1):7-14.
24. Joshi RR, Hossain R, Morton AC, Ecob R, Judge HM, Wales C, Walker JV, Karunakaran A, Storey RF. Evolving pattern of platelet P2Y12 inhibition in patients with acute coronary syndromes. Platelets. 2014;25(6):416-422.
25. Parker WA, Bhatt DL, Prats J, Day JRS, Steg PG, Stone GW, Hamm CW, Mahaffey KW, Price MJ, Gibson CM, White HD, Storey RF. Characteristics of dyspnoea and associated clinical outcomes in the CHAMPION PHOENIX study. Thromb Haemost. 2017;117(6):1093-1100.
26. Parker W, Storey R. Pharmacology and Potential Role of Selatogrel, a Subcutaneous Platelet P2Y 12 Receptor Antagonist. Expert Opin Emerg Drugs. 2020;25(1):1-6.
27. Ajjan R, Grant PJ. Coagulation and atherothrombotic disease. Atherosclerosis. 2006;186(2):240-259.
28. Renné T, Schmaier AH, Nickel KF, Blombäck M, Maas C. In vivo roles of factor XII. Blood. 2012;120(22):4296-4303.
29. Mackman N, Tilley RE, Key NS. Role of the extrinsic pathway of blood coagulation in hemostasis and thrombosis. Arterioscler Thromb Vasc Biol. 2007;27(8):1687-1693.
30. Krishnaswamy S, Jones KC, Mann KG. Prothrombinase complex assembly. Kinetic mechanism of enzyme assembly on phospholipid vesicles. J Biol Chem. 1988;263(8):3823-3834.
31. Crawley JT, Lane DA. The haemostatic role of tissue factor pathway inhibitor. Arterioscler Thromb Vasc Biol. 2008;28(2):233-242.
32. Ariens RA, Lai TS, Weisel JW, Greenberg CS, Grant PJ. Role of factor XIII in fibrin clot formation and effects of genetic polymorphisms. Blood. 2002;100(3):743-754.
33. Verstraete M. The fibrinolytic system: from petri dishes to genetic engineering. Thromb Haemost. 1995;74:25-35.
34. Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002;347(13):969-974.
35. Yeh CH, Hogg K, Weitz JI. Overview of the new oral anticoagulants: opportunities and challenges. Arterioscler Thromb Vasc Biol. 2015;35(5):1056-1065.
36. Kahn ML, Nakanishi-Matsui M, Shapiro MJ, Ishihara H, Coughlin SR. Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin. J Clin Invest. 1999;103(6):879-887.
37. Monroe DM, Hoffman M, Roberts HR. Platelets and thrombin generation. Arterioscler Thromb Vasc Biol. 2002;22(9):1381-1389.
38. Mi Y, Yan S, Lu Y, Liang Y, Li C. Venous thromboembolism has the same risk factors as atherosclerosis: A PRISMA-compliant systemic review and meta-analysis. Medicine (Baltimore). 2016;95(32):e4495.
39. Ibebuogu UN, Nasir K, Gopal A, Ahmadi N, Mao SS, Young E, Honoris L, Nuguri VK, Lee RS, Usman N, Rostami B, Pal R, Flores F, Budoff MJ. Comparison of atherosclerotic plaque burden and composition between diabetic and non diabetic patients by non invasive CT angiography. Int J Cardiovasc Imaging. 2009;25(7):717-723.
40. Larsen JR, Tsunoda T, Tuzcu EM, Schoenhagen P, Brekke M, Arnesen H, Hanssen KF, Nissen SE, Dahl-Jorgensen K. Intracoronary ultrasound examinations reveal significantly more advanced coronary atherosclerosis in people with type 1 diabetes than in age- and sex-matched non-diabetic controls. Diab Vasc Dis Res. 2007;4(1):62-65.
41. Lowry D, Saeed M, Narendran P, Tiwari A. A review of distribution of atherosclerosis in the lower limb arteries of patients with diabetes mellitus and peripheral vascular disease. Vasc Endovascular Surg. 2018;52(7):535-542.
42. Carrizzo A, Izzo C, Oliveti M, Alfano A, Virtuoso N, Capunzo M, Di Pietro P, Calabrese M, De Simone E, Sciarretta S, Frati G, Migliarino S, Damato A, Ambrosio M, De Caro F, Vecchione C. The main determinants of diabetes mellitus vascular complications: endothelial dysfunction and platelet hyperaggregation. Int J Mol Sci. 2018;19(10).
43. Stentz FB, Umpierrez GE, Cuervo R, Kitabchi AE. Proinflammatory cytokines, markers of cardiovascular risks, oxidative stress, and lipid peroxidation in patients with hyperglycemic crises. Diabetes. 2004;53(8):2079-2086.
44. Chaudhuri A, Umpierrez GE. Oxidative stress and inflammation in hyperglycemic crises and resolution with insulin: implications for the acute and chronic complications of hyperglycemia. J Diabetes Complications. 2012;26(4):257-258.
45. Patrono C, Rocca B. Measurement of thromboxane biosynthesis in health and disease. Front Pharmacol. 2019;10:1244.
46. Soma P, Swanepoel AC, du Plooy JN, Mqoco T, Pretorius E. Flow cytometric analysis of platelets type 2 diabetes mellitus reveals 'angry' platelets. Cardiovasc Diabetol. 2016;15:52.
47. Watala C, Boncler M, Golański J, Koziołkiewcz W, Trojanowski Z, Walkowiak B. Platelet membrane lipid fluidity and intraplatelet calcium mobilization in type 2 diabetes mellitus. Eur J Haematol. 1998;61(5):319-326.
48. Gawaz M, Ott I, Reininger AJ, Neumann FJ. Effects of magnesium on platelet aggregation and adhesion. Magnesium modulates surface expression of glycoproteins on platelets in vitro and ex vivo. Thromb Haemost. 1994;72(6):912-918.
49. Santilli F, Simeone P, Liani R, Davì G. Platelets and diabetes mellitus. Prostaglandins Other Lipid Mediat. 2015;120:28-39.
50. Hunter RW, Hers I. Insulin/IGF-1 hybrid receptor expression on human platelets: consequences for the effect of insulin on platelet function. J Thromb Haemost. 2009;7(12):2123-2130.
51. Westein E, Hoefer T, Calkin AC. Thrombosis in diabetes: a shear flow effect? Clin Sci (Lond). 2017;131(12):1245-1260.
52. Vernstrom L, Funck KL, Grove EL, Laugesen E, Baier JM, Hvas AM, Poulsen PL. Antiplatelet effect of aspirin during 24h in patients with type 2 diabetes without cardiovascular disease. Thromb Res. 2018;161:1-6.
53. Neergaard-Petersen S, Hvas AM, Ajjan R, Larsen SB, Würtz M, Kristensen SD, Grove EL. Platelet count, platelet turnover and fibrin clot structure in patients with coronary artery disease. Thromb Res. 2014;133(6):1161-1163.
54. Parker WAE, Storey RF. Aspirin dosing in atherosclerotic cardiovascular disease: should we be more ADAPTABLE? Cardiovasc Res. 2021;117(10):e123-e125.
55. Fejes Z, Poliska S, Czimmerer Z, Kaplar M, Penyige A, Gal Szabo G, Beke Debreceni I, Kunapuli SP, Kappelmayer J, Nagy B, Jr. Hyperglycaemia suppresses microRNA expression in platelets to increase P2RY12 and SELP levels in type 2 diabetes mellitus. Thromb Haemost. 2017;117(3):529-542.
56. Pordzik J, Jakubik D, Jarosz-Popek J, Wicik Z, Eyileten C, De Rosa S, Indolfi C, Siller-Matula JM, Czajka P, Postula M. Significance of circulating microRNAs in diabetes mellitus type 2 and platelet reactivity: bioinformatic analysis and review. Cardiovasc Diabetol. 2019;18(1):113.
57. Alzahrani SH, Ajjan RA. Coagulation and fibrinolysis in diabetes. Diab Vasc Dis Res. 2010;7:260-273.
58. Kim HK, Kim JE, Park SH, Kim YI, Nam-Goong IS, Kim ES. High coagulation factor levels and low protein C levels contribute to enhanced thrombin generation in patients with diabetes who do not have macrovascular complications. J Diabetes Complications. 2014;28(3):365-369.
59. Kearney K, Tomlinson D, Smith K, Ajjan R. Hypofibrinolysis in diabetes: a therapeutic target for the reduction of cardiovascular risk. Cardiovasc Diabetol. 2017;16(1):34.
60. Ajjan RA, Gamlen T, Standeven KF, Mughal S, Hess K, Smith KA, Dunn EJ, Anwar MM, Rabbani N, Thornalley PJ, Philippou H, Grant PJ. Diabetes is associated with posttranslational modifications in plasminogen resulting in reduced plasmin generation and enzyme-specific activity. Blood. 2013;122(1):134-142.
61. Du XL, Edelstein D, Rossetti L, Fantus IG, Goldberg H, Ziyadeh F, Wu J, Brownlee M. Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci U S A. 2000;97(22):12222-12226.
62. Wang Y, Beck W, Deppisch R, Marshall SM, Hoenich NA, Thompson MG. Advanced glycation end products elicit externalization of phosphatidylserine in a subpopulation of platelets via 5-HT2A/2C receptors. Am J Physiol Cell Physiol. 2007;293(1):C328-336.
63. Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, Boriani G, Castella M, Dan G-A, Dilaveris PE, Fauchier L, Filippatos G, Kalman JM, La Meir M, Lane DA, Lebeau J-P, Lettino M, Lip GYH, Pinto FJ, Thomas GN, Valgimigli M, Van Gelder IC, Van Putte BP, Watkins CL, ESC Scientific Document Group. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J. 2021;42(5):373-498.
64. Pallisgaard JL, Schjerning AM, Lindhardt TB, Procida K, Hansen ML, Torp-Pedersen C, Gislason GH. Risk of atrial fibrillation in diabetes mellitus: A nationwide cohort study. Eur J Prev Cardiol. 2016;23(6):621-627.
65. Overvad TF, Skjøth F, Lip GY, Lane DA, Albertsen IE, Rasmussen LH, Larsen TB. Duration of diabetes mellitus and risk of thromboembolism and bleeding in atrial fibrillation: nationwide cohort study. Stroke. 2015;46(8):2168-2174.
66. Dublin S, Glazer NL, Smith NL, Psaty BM, Lumley T, Wiggins KL, Page RL, Heckbert SR. Diabetes mellitus, glycemic control, and risk of atrial fibrillation. J Gen Intern Med. 2010;25(8):853-858.
67. Anselmino M, Matta M, D'Ascenzo F, Pappone C, Santinelli V, Bunch TJ, Neumann T, Schilling RJ, Hunter RJ, Noelker G, Fiala M, Frontera A, Thomas G, Katritsis D, Jais P, Weerasooriya R, Kalman JM, Gaita F. Catheter ablation of atrial fibrillation in patients with diabetes mellitus: a systematic review and meta-analysis. Europace. 2015;17(10):1518-1525.
68. Fatemi O, Yuriditsky E, Tsioufis C, Tsachris D, Morgan T, Basile J, Bigger T, Cushman W, Goff D, Soliman EZ, Thomas A, Papademetriou V. Impact of intensive glycemic control on the incidence of atrial fibrillation and associated cardiovascular outcomes in patients with type 2 diabetes mellitus (from the Action to Control Cardiovascular Risk in Diabetes Study). Am J Cardiol. 2014;114(8):1217-1222.
69. Chang SH, Wu LS, Chiou MJ, Liu JR, Yu KH, Kuo CF, Wen MS, Chen WJ, Yeh YH, See LC. Association of metformin with lower atrial fibrillation risk among patients with type 2 diabetes mellitus: a population-based dynamic cohort and in vitro studies. Cardiovasc Diabetol. 2014;13:123.
70. Zhang Z, Zhang X, Korantzopoulos P, Letsas KP, Tse G, Gong M, Meng L, Li G, Liu T. Thiazolidinedione use and atrial fibrillation in diabetic patients: a meta-analysis. BMC Cardiovasc Disord. 2017;17(1):96.
71. Zelniker TA, Bonaca MP, Furtado RHM, Mosenzon O, Kuder JF, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Budaj A, Kiss RG, Padilla F, Gause-Nilsson I, Langkilde AM, Raz I, Sabatine MS, Wiviott SD. Effect of dapagliflozin on atrial fibrillation in patients with type 2 diabetes mellitus. Circulation. 2020;141(15):1227-1234.
72. Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, Federici M, Filippatos G, Grobbee DE, Hansen TB, Huikuri HV, Johansson I, Juni P, Lettino M, Marx N, Mellbin LG, Ostgren CJ, Rocca B, Roffi M, Sattar N, Seferovic PM, Sousa-Uva M, Valensi P, Wheeler DC. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020;41(2):255-323.
73. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest. 2010;137(2):263-272.
74. Lip GYH, Clementy N, Pierre B, Boyer M, Fauchier L. The impact of associated diabetic retinopathy on stroke and severe bleeding risk in diabetic patients with atrial fibrillation: the loire valley atrial fibrillation project. Chest. 2015;147(4):1103-1110.
75. Patti G, Di Gioia G, Cavallari I, Nenna A. Safety and efficacy of nonvitamin K antagonist oral anticoagulants versus warfarin in diabetic patients with atrial fibrillation: A study-level meta-analysis of phase III randomized trials. Diabetes Metab Res Rev. 2017;33(3).
76. Olesen JB, Lip GYH, Hansen ML, Hansen PR, Tolstrup JS, Lindhardsen J, Selmer C, Ahlehoff O, Olsen A-MS, Gislason GH, Torp-Pedersen C. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. BMJ. 2011;342:d124.
77. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC, Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014;64(21):e1-e76.
78. Olesen JB, Torp-Pedersen C, Hansen ML, Lip GY. The value of the CHA2DS2-VASc score for refining stroke risk stratification in patients with atrial fibrillation with a CHADS2 score 0-1: a nationwide cohort study. Thromb Haemost. 2012;107(6):1172-1179.
79. Lip GYH, Keshishian A, Li X, Hamilton M, Masseria C, Gupta K, Luo X, Mardekian J, Friend K, Nadkarni A, Pan X, Baser O, Deitelzweig S. Effectiveness and Safety of Oral Anticoagulants Among Nonvalvular Atrial Fibrillation Patients. Stroke. 2018;49(12):2933-2944.
80. Sim SY, Morrison A, Gregory R, Kong M. Anticoagulation in hyperosmolar hyperglycaemic state: a case report and review of the literature. Brit J Diabetes. 2021;21(2):250-254.
81. Dhatariya K, Weston P. The argument against everyone with hyperosmolar hyperglycaemic syndrome being given prophylactic treatment dose anticoagulation. Brit J Diabetes. 2021;21(2):282-283.
82. Cosentino F, Ceriello A, Baeres FMM, Fioretto P, Garber A, Stough WG, George JT, Grant PJ, Khunti K, Langkilde AM, Plutzky J, Rydén L, Scheen A, Standl E, Tuomilehto J, Zannad F. Addressing cardiovascular risk in type 2 diabetes mellitus: a report from the European Society of Cardiology Cardiovascular Roundtable. Eur Heart J. 2019;40(34):2907-2919.
83. Collet J-P, Thiele H, Barbato E, Barthélémy O, Bauersachs J, Bhatt DL, Dendale P, Dorobantu M, Edvardsen T, Folliguet T, Gale CP, Gilard M, Jobs A, Jüni P, Lambrinou E, Lewis BS, Mehilli J, Meliga E, Merkely B, Mueller C, Roffi M, Rutten FH, Sibbing D, Siontis GCM, Group ESD. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2021;42(14):1289-1367.
84. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, Caforio ALP, Crea F, Goudevenos JA, Halvorsen S, Hindricks G, Kastrati A, Lenzen MJ, Prescott E, Roffi M, Valgimigli M, Varenhorst C, Vranckx P, Widimský P, Group ESD. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2017;39(2):119-177.
85. ISIS-2 Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet. 1988;2(8607):349-360.
86. Rocca B, Santilli F, Pitocco D, Mucci L, Petrucci G, Vitacolonna E, Lattanzio S, Mattoscio D, Zaccardi F, Liani R, Vazzana N, Del Ponte A, Ferrante E, Martini F, Cardillo C, Morosetti R, Mirabella M, Ghirlanda G, Davi G, Patrono C. The recovery of platelet cyclooxygenase activity explains interindividual variability in responsiveness to low-dose aspirin in patients with and without diabetes. J Thromb Haemost. 2012;10(7):1220-1230.
87. Capodanno D, Patel A, Dharmashankar K, Ferreiro JL, Ueno M, Kodali M, Tomasello SD, Capranzano P, Seecheran N, Darlington A, Tello-Montoliu A, Desai B, Bass TA, Angiolillo DJ. Pharmacodynamic effects of different aspirin dosing regimens in type 2 diabetes mellitus patients with coronary artery disease. Circ Cardiovasc Interv. 2011;4:180-187.
88. Spectre G, Arnetz L, Ostenson CG, Brismar K, Li N, Hjemdahl P. Twice daily dosing of aspirin improves platelet inhibition in whole blood in patients with type 2 diabetes mellitus and micro- or macrovascular complications. Thromb Haemost. 2011;106(3):491-499.
89. Wiviott SD, Braunwald E, Angiolillo DJ, Meisel S, Dalby AJ, Verheugt FW, Goodman SG, Corbalan R, Purdy DA, Murphy SA, McCabe CH, Antman EM, for the TRITON-TIMI Investigators. Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-thrombolysis in myocardial infarction 38. Circulation. 2008;118:1626-1636.
90. Franchi F, James SK, Ghukasyan Lakic T, Budaj AJ, Cornel JH, Katus HA, Keltai M, Kontny F, Lewis BS, Storey RF, Himmelmann A, Wallentin L, Angiolillo DJ. impact of diabetes mellitus and chronic kidney disease on cardiovascular outcomes and platelet P2Y(12) receptor antagonist effects in patients with acute coronary syndromes: insights from the PLATO trial. J Am Heart Assoc. 2019;8(6):e011139.
91. Yusuf S, Zhao F, Mehta S, Chrolavicius S, Tognoni G, Fox K. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. New Eng J Med. 2001;345:494-502.
92. Sabatine MS, Cannon CP, Gibson CM, Lopez-Sendon JL, Montalescot G, Theroux P, Claeys MJ, Cools F, Hill KA, Skene AM, McCabe CH, Braunwald E. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005;352(12):1179-1189.
93. Chen ZM, Jiang LX, Chen YP, Xie JX, Pan HC, Peto R, Collins R, Liu LS, COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group. Addition of clopidogrel to aspirin in 45 852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005;366(9497):1607-1621.
94. Wiviott S, Braunwald E, McCabe C, Montalescot G, Ruzyllo W, Gottlieb S, Neumann F-J, Ardissino D, De Servi S, Murphy S, Riesmeyer J, Weerakkody G, Gibson C, Antman E. Prasugrel versus clopidogrel in patients with acute coronary syndromes. New Eng J Med. 2007;357:2001-2015.
95. Roe MT, Armstrong PW, Fox KA, White HD, Prabhakaran D, Goodman SG, Cornel JH, Bhatt DL, Clemmensen P, Martinez F, Ardissino D, Nicolau JC, Boden WE, Gurbel PA, Ruzyllo W, Dalby AJ, McGuire DK, Leiva-Pons JL, Parkhomenko A, Gottlieb S, Topacio GO, Hamm C, Pavlides G, Goudev AR, Oto A, Tseng CD, Merkely B, Gasparovic V, Corbalan R, Cinteza M, McLendon RC, Winters KJ, Brown EB, Lokhnygina Y, Aylward PE, Huber K, Hochman JS, Ohman EM. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med. 2012;367(14):1297-1309.
96. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057.
97. Schupke S, Neumann FJ, Menichelli M, Mayer K, Bernlochner I, Wohrle J, Richardt G, Liebetrau C, Witzenbichler B, Antoniucci D, Akin I, Bott-Flugel L, Fischer M, Landmesser U, Katus HA, Sibbing D, Seyfarth M, Janisch M, Boncompagni D, Hilz R, Rottbauer W, Okrojek R, Mollmann H, Hochholzer W, Migliorini A, Cassese S, Mollo P, Xhepa E, Kufner S, Strehle A, Leggewie S, Allali A, Ndrepepa G, Schuhlen H, Angiolillo DJ, Hamm CW, Hapfelmeier A, Tolg R, Trenk D, Schunkert H, Laugwitz KL, Kastrati A. Ticagrelor or prasugrel in patients with acute coronary syndromes. N Engl J Med. 2019;381(16):1524-1534.
98. Storey RF. Ticagrelor versus prasugrel for PCI-managed myocardial infarction: the battle of the giants continues. Heart. 2021;107(14):1111.
99. Ndrepepa G, Kastrati A, Menichelli M, Neumann F-J, Wöhrle J, Bernlochner I, Richardt G, Witzenbichler B, Sibbing D, Gewalt S, Angiolillo Dominick J, Hamm Christian W, Hapfelmeier A, Trenk D, Laugwitz K-L, Schunkert H, Schüpke S, Mayer K. Ticagrelor or prasugrel in patients with acute coronary syndromes and diabetes mellitus. JACC: Cardiovasc Intervent. 2020;13(19):2238-2247.
100. Mehran R, Baber U, Sharma SK, Cohen DJ, Angiolillo DJ, Briguori C, Cha JY, Collier T, Dangas G, Dudek D, Dzavik V, Escaned J, Gil R, Gurbel P, Hamm CW, Henry T, Huber K, Kastrati A, Kaul U, Kornowski R, Krucoff M, Kunadian V, Marx SO, Mehta SR, Moliterno D, Ohman EM, Oldroyd K, Sardella G, Sartori S, Shlofmitz R, Steg PG, Weisz G, Witzenbichler B, Han YL, Pocock S, Gibson CM. Ticagrelor with or without aspirin in high-risk patients after PCI. N Engl J Med. 2019;381(21):2032-2042.
101. Vranckx P, Valgimigli M, Juni P, Hamm C, Steg PG, Heg D, van Es GA, McFadden EP, Onuma Y, van Meijeren C, Chichareon P, Benit E, Mollmann H, Janssens L, Ferrario M, Moschovitis A, Zurakowski A, Dominici M, Van Geuns RJ, Huber K, Slagboom T, Serruys PW, Windecker S. Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: a multicentre, open-label, randomised superiority trial. Lancet. 2018;392(10151):940-949.
102. Chichareon P, Modolo R, Kogame N, Takahashi K, Chang CC, Tomaniak M, Botelho R, Eeckhout E, Hofma S, Trendafilova-Lazarova D, Kőszegi Z, Iñiguez A, Wykrzykowska JJ, Piek JJ, Garg S, Hamm C, Steg PG, Jüni P, Vranckx P, Valgimigli M, Windecker S, Onuma Y, Serruys PW. Association of diabetes with outcomes in patients undergoing contemporary percutaneous coronary intervention: Pre-specified subgroup analysis from the randomized GLOBAL LEADERS study. Atherosclerosis. 2020;295:45-53.
103. Bhalla A, Patel M, Birns J. An update on hyper-acute management of ischaemic stroke. Clin Med (Lond). 2021;21(3):215-221.
104. Capodanno D, Alberts M, Angiolillo DJ. Antithrombotic therapy for secondary prevention of atherothrombotic events in cerebrovascular disease. Nat Rev Cardiol. 2016;13(10):609-622.
105. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B, Jauch EC, Kidwell CS, Leslie-Mazwi TM, Ovbiagele B, Scott PA, Sheth KN, Southerland AM, Summers DV, Tirschwell DL, null n. Guidelines for the early management of patients with acute ischemic Stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2019;50(12):e344-e418.
106. Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, Wang C, Li H, Meng X, Cui L, Jia J, Dong Q, Xu A, Zeng J, Li Y, Wang Z, Xia H, Johnston SC. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. New Eng J Med. 2013;369(1):11-19.
107. Johnston SC, Easton JD, Farrant M, Barsan W, Conwit RA, Elm JJ, Kim AS, Lindblad AS, Palesch YY. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med. 2018;379(3):215-225.
108. Johnston SC, Amarenco P, Albers GW, Denison H, Easton JD, Evans SR, Held P, Jonasson J, Minematsu K, Molina CA, Wang Y, Wong KS. Ticagrelor versus aspirin in acute stroke or transient ischemic attack. N Engl J Med. 2016;375(1):35-43.
109. Johnston SC, Amarenco P, Denison H, Evans SR, Himmelmann A, James S, Knutsson M, Ladenvall P, Molina CA, Wang Y. Ticagrelor and aspirin or aspirin alone in acute ischemic stroke or tia. New Eng J Med. 2020;383(3):207-217.
110. Antiplatelet Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324(7329):71-86.
111. Parker WAE, Sagar R, Kurdee Z, Hawkins F, Naseem KM, Grant PJ, Storey RF, Ajjan RA. A randomised controlled trial to assess the antithrombotic effects of aspirin in type 1 diabetes: role of dosing and glycaemic control. Cardiovasc Diabetol. 2021;20(1):238.
112. CURRENT-OASIS 7 Investigators, Mehta S, Bassand J, Chrolavicius S, Diaz R, Eikelboom J, Fox K, Granger C, Jolly S, Joyner C, Rupprecht H, Widimsky P, Afzal R, Pogue J, Yusuf S. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. New Eng J Med. 2010;363(10):930-942.
113. Jones WS, Mulder H, Wruck LM, Pencina MJ, Kripalani S, Muñoz D, Crenshaw DL, Effron MB, Re RN, Gupta K, Anderson RD, Pepine CJ, Handberg EM, Manning BR, Jain SK, Girotra S, Riley D, DeWalt DA, Whittle J, Goldberg YH, Roger VL, Hess R, Benziger CP, Farrehi P, Zhou L, Ford DE, Haynes K, VanWormer JJ, Knowlton KU, Kraschnewski JL, Polonsky TS, Fintel DJ, Ahmad FS, McClay JC, Campbell JR, Bell DS, Fonarow GC, Bradley SM, Paranjape A, Roe MT, Robertson HR, Curtis LH, Sharlow AG, Berdan LG, Hammill BG, Harris DF, Qualls LG, Marquis-Gravel G, Modrow MF, Marcus GM, Carton TW, Nauman E, Waitman LR, Kho AM, Shenkman EA, McTigue KM, Kaushal R, Masoudi FA, Antman EM, Davidson DR, Edgley K, Merritt JG, Brown LS, Zemon DN, McCormick TE, 3rd, Alikhaani JD, Gregoire KC, Rothman RL, Harrington RA, Hernandez AF. Comparative effectiveness of aspirin dosing in cardiovascular disease. N Engl J Med. 2021;384(21):1981-1990.
114. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348(9038):1329-1339.
115. Bhatt DL, Fox KAA, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, Flather MD, Haffner SM, Hamm CW, Hankey GJ, Johnston SC, Mak K-H, Mas J-L, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Brennan DM, Fabry-Ribaudo L, Booth J, Topol EJ, the CI. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. New Eng J Med. 2006;354(16):1706-1717.
116. Bhatt DL, Flather MD, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, Hamm CW, Hankey GJ, Johnston SC, Mak KH, Mas JL, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Fabry-Ribaudo L, Hu T, Topol EJ, Fox KA. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol. 2007;49(19):1982-1988.
117. Mauri L, Elmariah S, Yeh RW, Cutlip DE, Steg PG, Windecker S, Wiviott SD, Cohen DJ, Massaro JM, D'Agostino RB, Sr., Braunwald E, Kereiakes DJ. Causes of late mortality with dual antiplatelet therapy after coronary stents. Eur Heart J. 2016;37(4):378-385.
118. Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, Magnani G, Bansilal S, Fish MP, Im K, Bengtsson O, Ophuis TO, Budaj A, Theroux P, Ruda M, Hamm C, Goto S, Spinar J, Nicolau JC, Kiss RG, Murphy SA, Wiviott SD, Held P, Braunwald E, Sabatine MS. Long-term use of ticagrelor in patients with prior myocardial infarction. New Engl J Med. 2015;372:1791-1800.
119. Bhatt DL, Bonaca MP, Bansilal S, Angiolillo DJ, Cohen M, Storey RF, Im K, Murphy SA, Held P, Braunwald E, Sabatine MS, Steg PG. Reduction in ischemic events with ticagrelor in diabetic patients: from the PEGASUS-TIMI 54 trial. J Am Coll Cardiol. 2016;67:2732-2740.
120. Magnani G, Ardissino D, Im K, Budaj A, Storey RF, Steg PG, Bhatt DL, Cohen M, Oude Ophius T, Goudev A, Parkhomenko A, Kamensky G, Angiolillo DJ, López-Sendón J, Johanson P, Braunwald E, Sabatine MS, Bonaca MP. Predictors, type, and impact of bleeding on the net clinical benefit of long-term ticagrelor in stable patients with prior myocardial infarction. J Am Heart Assoc. 2021;10(4):e017008.
121. Steg PG, Bhatt DL, Simon T, Fox K, Mehta SR, Harrington RA, Held C, Andersson M, Himmelmann A, Ridderstrale W, Leonsson-Zachrisson M, Liu Y, Opolski G, Zateyshchikov D, Ge J, Nicolau JC, Corbalan R, Cornel JH, Widimsky P, Leiter LA. Ticagrelor in Patients with Stable Coronary Disease and Diabetes. N Engl J Med. 2019;381(14):1309-1320.
122. Bhatt DL, Steg PG, Mehta SR, Leiter LA, Simon T, Fox K, Held C, Andersson M, Himmelmann A, Ridderstrale W, Chen J, Song Y, Diaz R, Goto S, James SK, Ray KK, Parkhomenko AN, Kosiborod MN, McGuire DK, Harrington RA. Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI): a phase 3, placebo-controlled, randomised trial. Lancet. 2019;394(10204):1169-1180.
123. Lackey LG, Garnett CE, Senatore F. Applying decision analysis to inform the US Food and Drug Administration’s benefit–risk assessment of ticagrelor for primary prevention of myocardial infarction or stroke based on THEMIS. Circulation. 2021;144(8):655-658.
124. Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O, Diaz R, Alings M, Lonn EM, Anand SS, Widimsky P, Hori M, Avezum A, Piegas LS, Branch KRH, Probstfield J, Bhatt DL, Zhu J, Liang Y, Maggioni AP, Lopez-Jaramillo P, O'Donnell M, Kakkar AK, Fox KAA, Parkhomenko AN, Ertl G, Stork S, Keltai M, Ryden L, Pogosova N, Dans AL, Lanas F, Commerford PJ, Torp-Pedersen C, Guzik TJ, Verhamme PB, Vinereanu D, Kim JH, Tonkin AM, Lewis BS, Felix C, Yusoff K, Steg PG, Metsarinne KP, Cook Bruns N, Misselwitz F, Chen E, Leong D, Yusuf S. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med. 2017;377(14):1319-1330.
125. Knuuti J, Wijns W, Saraste A, Capodanno D, Barbato E, Funck-Brentano C, Prescott E, Storey RF, Deaton C, Cuisset T, Agewall S, Dickstein K, Edvardsen T, Escaned J, Gersh BJ, Svitil P, Gilard M, Hasdai D, Hatala R, Mahfoud F, Masip J, Muneretto C, Valgimigli M, Achenbach S, Bax JJ. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J. 2020;41(3):407-477.
126. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324(7329):71-86.
127. Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet. 2006;367(9523):1665-1673.
128. Pan Y, Elm JJ, Li H, Easton JD, Wang Y, Farrant M, Meng X, Kim AS, Zhao X, Meurer WJ, Liu L, Dietrich D, Johnston SC. Outcomes associated with clopidogrel-aspirin use in minor stroke or transient ischemic attack: a pooled analysis of Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events (CHANCE) and Platelet-Oriented Inhibition in New TIA and minor ischemic stroke (POINT) trials. JAMA Neurol. 2019;76(12):1466-1473.
129. Johnston SC, Amarenco P, Denison H, Evans SR, Himmelmann A, James S, Knutsson M, Ladenvall P, Molina CA, Wang Y. The acute stroke or transient ischemic attack treated with ticagrelor and aspirin for prevention of stroke and death (THALES) trial: rationale and design. Int J Stroke. 2019:1747493019830307.
130. Benavente OR, Hart RG, McClure LA, Szychowski JM, Coffey CS, Pearce LA. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med. 2012;367(9):817-825.
131. Greving JP, Diener HC, Reitsma JB, Bath PM, Csiba L, Hacke W, Kappelle LJ, Koudstaal PJ, Leys D, Mas JL, Sacco RL, Algra A. Antiplatelet Therapy After Noncardioembolic Stroke. Stroke. 2019;50(7):1812-1818.
132. Aboyans V, Ricco JB, Bartelink MEL, Bjorck M, Brodmann M, Cohnert T, Collet JP, Czerny M, De Carlo M, Debus S, Espinola-Klein C, Kahan T, Kownator S, Mazzolai L, Naylor AR, Roffi M, Rother J, Sprynger M, Tendera M, Tepe G, Venermo M, Vlachopoulos C, Desormais I. 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS): Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteriesEndorsed by: the European Stroke Organization (ESO)The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS). Eur Heart J. 2018;39(9):763-816.
133. Hiatt WR, Fowkes FG, Heizer G, Berger JS, Baumgartner I, Held P, Katona BG, Mahaffey KW, Norgren L, Jones WS, Blomster J, Millegård M, Reist C, Patel MR. Ticagrelor versus clopidogrel in symptomatic peripheral artery disease. N Engl J Med. 2017;376:32-40.
134. Parker WAE, Schulte C, Barwari T, Phoenix F, Pearson SM, Mayr M, Grant PJ, Storey RF, Ajjan RA. Aspirin, clopidogrel and prasugrel monotherapy in patients with type 2 diabetes mellitus: a double-blind randomised controlled trial of the effects on thrombotic markers and microRNA levels. Cardiovasc Diabetol. 2020;19(1):3.
135. Cacoub PP, Bhatt DL, Steg PG, Topol EJ, Creager MA. Patients with peripheral arterial disease in the CHARISMA trial. Eur Heart J. 2009;30(2):192-201.
136. Anand SS, Bosch J, Eikelboom JW, Connolly SJ, Diaz R, Widimsky P, Aboyans V, Alings M, Kakkar AK, Keltai K, Maggioni AP, Lewis BS, Stork S, Zhu J, Lopez-Jaramillo P, O'Donnell M, Commerford PJ, Vinereanu D, Pogosova N, Ryden L, Fox KAA, Bhatt DL, Misselwitz F, Varigos JD, Vanassche T, Avezum AA, Chen E, Branch K, Leong DP, Bangdiwala SI, Hart RG, Yusuf S. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet. 2018;391(10117):219-229.
137. Bonaca MP, Bauersachs RM, Anand SS, Debus ES, Nehler MR, Patel MR, Fanelli F, Capell WH, Diao L, Jaeger N, Hess CN, Pap AF, Kittelson JM, Gudz I, Mátyás L, Krievins DK, Diaz R, Brodmann M, Muehlhofer E, Haskell LP, Berkowitz SD, Hiatt WR. Rivaroxaban in peripheral artery disease after revascularization. New Eng J Med. 2020;382(21):1994-2004.
138. Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, Buring J, Hennekens C, Kearney P, Meade T, Patrono C, Roncaglioni MC, Zanchetti A. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009;373(9678):1849-1860.
139. Belch J, MacCuish A, Campbell I, Cobbe S, Taylor R, Prescott R, Lee R, Bancroft J, MacEwan S, Shepherd J, Macfarlane P, Morris A, Jung R, Kelly C, Connacher A, Peden N, Jamieson A, Matthews D, Leese G, McKnight J, O’Brien I, Semple C, Petrie J, Gordon D, Pringle S, MacWalter R. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ. 2008;337.
140. Ogawa H, Nakayama M, Morimoto T, Uemura S, Kanauchi M, Doi N, Jinnouchi H, Sugiyama S, Saito Y. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA. 2008;300(18):2134-2141.
141. Bowman L, Mafham M, Wallendszus K, Stevens W, Buck G, Barton J, Murphy K, Aung T, Haynes R, Cox J, Murawska A, Young A, Lay M, Chen F, Sammons E, Waters E, Adler A, Bodansky J, Farmer A, McPherson R, Neil A, Simpson D, Peto R, Baigent C, Collins R, Parish S, Armitage J. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med. 2018;379(16):1529-1539.

ABSTRACT  

Depression is characterized by a disturbance of mood, affecting between 3–5% of the general population at any one time. The prevalence of depression is approximately doubled in people with diabetes compared to the general population, with similar rates between type 1 diabetes and type 2 diabetes. Although many cases of depression are coincidental to the presence of diabetes, certain diabetes factors including diabetes-related complications, diabetes treatments and obesity are associated with an increased risk of depression. There is a bi-directional relationship between diabetes and depression with specific disease and treatment factors explaining why diabetes pre-disposes to depression and vice versa. Genetics, early intra-uterine development, and social determinants of health may create a “common soil” for both conditions. The presence of depression in people with diabetes worsens both diabetes and depression outcomes. Mortality is increased, quality of life diminished, and healthcare costs are increased. Diabetes self-management is also impaired. It may be possible to reduce the incidence of depression in people with diabetes by considering the way in which the diagnosis of diabetes is conveyed and the psychosocial support that is given through an individual’s journey with diabetes. Several short screening questionnaires have been validated in people with diabetes. A diagnosis should be confirmed by a diagnostic interview. The main aims of treatment are to improve both diabetes and mental health outcomes with complete remission of depressive symptoms.  Various psychological treatments, including cognitive behavioral therapy, problem-solving, and psychodynamic techniques have been used to treat depression in people with diabetes. Antidepressants reduce depressive symptoms in people with diabetes as well as the general population. All antidepressants appear to have similar effects on depressive symptoms as long as adequate doses are used. Treatment should be maintained for at least 4–6 months after remission of symptoms to reduce the risk of relapse and recurrence. The choice of antidepressant depends largely on the side-effect profile, individual preference, and response. Selective serotonin reuptake inhibitors are widely used as first-choice agents. A common model of care for depression is the Stepped Care Model which is designed to provide a rational approach to the treatment of depression, while reducing costs and side effects of antidepressants through more appropriate prescribing. A case management model known as collaborative care is a clinical- and cost-effective treatment of depression that also improves diabetes outcomes by involving a multidisciplinary team that works together to identify and treat depression within primary care settings. Although diabetes and depression remain a considerable clinical challenge, there are grounds for considerable optimism as the scientific knowledge that underpins clinical practices has expanded markedly in the last two decades. However, further research is needed to understand what can be done to prevent depression in people with diabetes and to identify the optimal treatment for an individual that improves both depressive symptoms and diabetes outcomes.

INTRODUCTION

The importance of considering the interaction between mind and body in the management and outcome of chronic diseases has been recognized for over 2,500 years but is particularly poignant for people with diabetes. Diabetes places high behavioral demands on those living with the condition whilst mental disorders, such as depression, may compromise an individual’s ability to perform the self-care needed to optimize health and prevent the long-term consequences of diabetes. Much of diabetes care is focused around the identification and treatment of long-term diabetes-related complications and diabetes healthcare professionals are adept in managing microvascular and macrovascular conditions. An appreciation, however, of the psychological consequences of diabetes has lagged behind, despite these being common and the morbidity, mortality, and health costs associated with the co-morbidity being disproportionately increased compared with the effects of either condition alone (1, 2).

Several factors contribute to the poorer health outcomes seen in people with diabetes and mental disorders. Despite the increased burden of disease, people with co-morbid mental disorders have often been disadvantaged by health services and have received sub-optimal medical care (3). They have been less likely to receive the necessary diabetes processes of care, self-management education, and cardiovascular preventative medication despite increased visits to their primary healthcare teams and despite similar interest in caring for their physical illness as the general population (4). Clinicians may fail to recognize that those with mental illness are more likely to develop physical illnesses and so physical complaints are either ignored or not taken seriously. Mental health symptoms often “over-shadow” other complaints leading healthcare professionals to focus on the mental illness to the detriment of any physical illness (5). Health services are often poorly configured with clinics focusing on either the treatment of physical illnesses or mental disorders rather than treating both conditions at the same time (3). The stigma associated with mental illness may prevent people and their families from seeking help for mental illness, thereby depriving them of effective treatments, which not only harms mental well-being but is detrimental to diabetes management (6).

Diabetes and mental disorders are both common, and so a degree of co-occurrence would be expected purely by chance. The evidence suggests, however, that diabetes is more frequently associated with a range of mental and psychosocial disorders than expected (7, 8). Furthermore, several mental disorders, including depression, are associated with an increased risk of developing diabetes. An understanding of this complex interaction is crucial to the management and outcome of people with diabetes.

This chapter focuses on the co-morbidity of diabetes and depression; both are common, are relatively easy to diagnose, and have established effective treatments (8). They may also serve as an exemplar for other mental disorders and provide a model for the successful management of other co-morbid mental and physical health conditions. The chapter will describe the epidemiology of diabetes and depression and will discuss the mechanisms underlying the association between diabetes and depression. It will also highlight the clinical implications and consequences of co-occurring diabetes and depression. Diabetes healthcare professionals need to be aware of how to screen for depression and to provide “first response” management, while recognizing when to refer for specialist psychiatric care (9).

DEPRESSION

Depression belongs to a group of mental disorders where the primary abnormality is a disturbance of mood. The cardinal features of depression are low mood, and loss of interest or pleasure, lasting longer than two weeks. During a depressive episode, other symptoms may include poor concentration, feelings of excessive guilt or low self-worth, hopelessness about the future, thoughts about dying or suicide, disrupted sleep, changes in appetite or weight, and feeling especially tired or low in energy. People with depression are at an increased risk of suicide. Depressive symptoms exist on a continuum of severity, and it is important to recognize that depression is different from usual fluctuations in mood that occur with everyday life. 

Major depressive disorder (also known as clinical depression, unipolar depression, or major depression) is defined by the diagnostic criteria of the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders(DSM-5), based on the number and duration of symptoms (Table 1) (10). The DSM-5 definition approximates a level of severity of symptoms that is associated with both disability and dysfunction. DSM-5 also recognizes several sub-types of depressive disorder where the symptoms are less severe but nevertheless may still compromise diabetes self-care and outcomes.

Epidemiology of Depression

Depression is one of the commonest mental disorders, affecting between 3–5% of the general population at any one time; the lifetime prevalence is 8-12% but there is considerable geographical variation ranging from 3% in Japan to 17% in India. The highest rates of depression are found in the United States of America (USA), the Middle East and South Asia (11). In 2019, 280 million people were living with depression, including 23 million children and adolescents (12). The incidence of depression worldwide increased by 50% between 1990 and 2017 to an age standardized rate of 3.25 per 1000 (13). Depressive disorders are now ranked as the single largest contributor to non-fatal health loss (7.5% of all years lost to disability) (14).

Depression can affect any age group, with depression being seen in infants as young as 6 months old after separation from their mothers (15). The commonest age of onset is between the ages of 30 and 40 years, but there is a second, smaller peak in incidence between ages 50 and 60 years (16). The risk of depression is doubled in women compared with men (17). Although the cause of depression remains uncertain, other risk factors for a depressive episode are recognized and include a family history of depression, certain personality types, childhood adversity, the postpartum period, social isolation, and a lack of close interpersonal relationships (18). An episode of depression is often triggered by a stressful life event, particularly for the first few depressive episodes (Table 2). Depression may accompany other mental illnesses and long-term physical conditions (19). All these risk factors apply to people living with diabetes and so consequently much of the depression seen in people living with diabetes is coincidental to the diabetes.

DIABETES AND DEPRESSION

The association between diabetes and depression has been recognized for many years. In the 17^th century, Thomas Willis, an English physician, described how “diabetes is a consequence of prolonged sorrow” (20). Until the last two decades, the focus of any discussion of mood and diabetes was on the increased likelihood of depression in people with diabetes, where the comorbidity was viewed as an understandable reaction to the difficulties and challenges of living with a demanding and life-limiting long-term physical illness. In this regard, it was treated no differently from other long-term physical conditions that are also associated with increased rates of depression. We now understand that the relationship between the two conditions is more complex and, at least for type 2 diabetes, is bidirectional (8).

Understanding the scale of the co-morbidity is challenging because the epidemiological studies examining the relationship have been hampered by considerable variation in measurement, study design, and use of terminology that have contributed to significant heterogeneity and inconsistency between studies (8). An example of this variability is illustrated by one meta-analysis that reported a range of prevalence rates of depression in people with diabetes from 1.8% to 88% (21).

The gold standard for the diagnosis of depression is a diagnostic interview, but many studies have relied on self-rating scales (22). These scales identify depressive symptoms rather than depression and do not differentiate between symptoms that could be caused by either diabetes or depression, for example, fatigue or weight change. This can lead to significant overestimates of the prevalence of depression in those with diabetes, as shown in an early meta-analysis where the prevalence of depression in people with diabetes identified by diagnostic interview was 11.4% compared to 31.0% in studies using self-rating questionnaire (23). However, a more recent meta-analysis argued that the symptom overlap does not affect prevalence (21). Nevertheless, the authors argue that depression measures that focus on the cardinal symptoms of depression rather than overlapping symptoms may most accurately diagnose depression.

Studies have often used mixed populations of people with type 1 diabetes and type 2 diabetes. This distinction is important because people with type 2 diabetes are generally older, and depression prevalence varies with age (16).There are differences in the prevalence of diabetes-related complications and other comorbid conditions such as obesity and heart disease, which independently affect the likelihood of developing depression (24). The pathogenesis and etiology of the two main types of diabetes differ, which may affect the risk of depression in different ways (25). Finally, the burden of management differs between type 1 diabetes and type 2 diabetes.

Many studies have not taken broad population approaches but have concentrated on convenience samples, usually drawn from specialist diabetes clinics, where the participants may not reflect the wider population of people living with diabetes. This bias is illustrated in the meta-analysis by Farooqi et al which reported that the prevalence of depression in people with diabetes was 36% in studies carried out in specialist care compared to 12% in community or primary care settings (26). Biases may also occur where there are low or unknown response rates, because the presence of depressive symptoms may affect the willingness of an individual to participate.

A further confounding factor is the concept of diabetes distress which describes the emotional response to living with diabetes, including the demands of self-management, the threat of complications, the social impact of stigma and discrimination, and the financial costs of treatment (27). Diabetes distress can fluctuate over time and may peak during challenging periods such as soon after diagnosis, during major treatment changes, or during the development or worsening of long-term complications (Table 3). Diabetes distress is distinct from depression in its association with self-management and glycemic levels, but the two conditions may co-exist in about 5-15% of people with diabetes. By contrast depression occurs without distress in 5-10% of people while distress alone affects 20-30% (28). The importance of diabetes distress was first proposed in 1995, and it is likely that early studies of diabetes and depression were capturing distress as well as depression, thereby contributing to an overestimate of the prevalence of depression.

Despite these caveats, several meta-analyses have indicated that the prevalence of depression is approximately doubled in people with diabetes compared to the background population (23, 26), with the prevalence of depression similar between type 1 diabetes (22%) and type 2 diabetes (19%) (26). Although most studies come from Western Europe or North America, the increased rates of depression or depressive symptoms have been found across the world (29, 30), with the prevalence being higher in low- and middle-income countries (26). A meta-analysis of 248 observational studies including over 8 million people with type 2 diabetes found a global prevalence of depression of 28%, with the highest rates observed in Asia and Australia whilst the lowest rates were found in studies from Europe (31). Cohort studies have shown an increase in incident depression in people with diabetes; one meta-analysis of 11 studies involving approximately 50,000 people with type 2 diabetes but without depression at baseline reported that the incidence of depression was 24% higher in people with diabetes (32), while another meta-analysis of 13 studies found incident depression was increased by 15% in people with diabetes (33).

An increased prevalence of depression has also been found in children with diabetes. A meta-analysis of 109 studies involving over 50,000 children with diabetes estimated that the prevalence of depression was 22.2% among children with type 1 diabetes and 22.7% in children with type 2 diabetes (34). Consistent with studies in adults, the prevalence of depression was higher among girls than boys (29.7% vs. 19.7%) and in low- to- middle-income countries.

Type 2 diabetes is a common comorbidity in people with mental disorders, with a reported prevalence ranging from 5% to 22% depending on the specific psychiatric disorder. Overall, the prevalence of diabetes in people with depression is 9% but there is considerable heterogeneity between studies (35). Consistent with this finding, the incidence of diabetes in people with depression is increased by 18-60% (33, 36, 37). People with depression, however, may receive more screening for diabetes than those without because of their increased contact with healthcare professionals and an awareness of the risk of diabetes by mental health practitioners, which may lead to an overestimate of the difference in diabetes risk between those with and without depression, particularly in studies that rely on routinely collected healthcare data.

Diabetes Factors That Increase the Risk of Depression

Although many cases of depression are coincidental to the presence of diabetes, certain diabetes factors including diabetes-related complications and obesity are associated with an increased risk of depression (38).

DIABETES COMPLICATIONS

The development of macrovascular and microvascular complications increases the risk of depression in people with type 1 diabetes and type 2 diabetes  (24, 39). Overall, the presence of diabetes complications increases the risk of incident depressive disorder by 14% but the increased risk of developing depression is 24% higher for microvascular complications compared with 9% higher for those with macrovascular complications (39). The risk of depression increases as more complications develop such that the presence of two or more complications more than doubled the risk of depression in people with type 2 diabetes in one specialized outpatient clinic, with neuropathy and nephropathy showing the strongest association (40).

DIABETES TREATMENTS

The use of insulin in type 2 diabetes is associated with higher rates of depression compared to non-insulin medications or dietary and lifestyle interventions alone. One meta-analysis of 28 studies reported an overall 59% higher risk of developing depression in people taking insulin and 42% higher risk when compared with oral anti-diabetes agents (41). It seems unlikely that insulin per se increases depressive symptoms, but insulin is associated with higher treatment demands that not only include self-injection but more intensive self-monitoring, which may adversely affect depressive symptoms (42). Insulin is also used in those with longer duration of type 2 diabetes, which may be associated with a higher prevalence of diabetes-related complications and elevated HbA_1c, a further risk factor of depression (43). Insulin has been used erroneously as a threat by healthcare professionals to encourage people to follow certain health behaviors or take medications. As type 2 diabetes is associated with progressive β-cell decline, many people ultimately need insulin. Where insulin has been used as a threat, commencing insulin can evoke feelings of guilt, blame or failure, which may increase the likelihood of depression. Furthermore, people may have strongly held beliefs about insulin usage, seeing it as an “end of the road” treatment. They may also associate insulin with the development of diabetes complications or death if they have seen a family member with diabetes developing complications while using insulin. Insulin therapy is associated with significant weight gain, again a risk factor for depression, and an increased risk of hypoglycemia. In a 10-year study of 3,742 people with type 1 diabetes requiring emergency room visit or hospitalization, those admitted with a hypoglycemic event were 74% more likely to develop depression (43).

Other anti-diabetes treatments, by contrast, may be associated with a reduced risk of depression and there has been discussion about whether these could be re-purposed as treatments for depression (44). A meta-analysis of current therapies indicated that pioglitazone was associated with improved depressive symptoms, more so in women, but metformin had no consistent benefit (44). A more recent systematic review, however, suggested that metformin might help treat comorbid depression, although the evidence was too weak to recommend its use for this indication (45). A review of observational studies also indicated that metformin was associated with reduced depressive symptoms (46). GLP-1 receptors are widely expressed in the brain and have putative neuroprotective properties. A meta-analysis of six studies including 2,071 participants showed a small but significant reduction in depressive symptoms in those treated with GLP-1 receptor agonists (47). Whether the improvement is a direct effect or mediated through weight loss is unknown. This observation was also seen in a large population-based cohort and nested case-control study that found that low doses of metformin, dipeptidyl peptidase-4 (DPP4) inhibitors, GLP-1 receptor agonists, and sodium-glucose transporter 2 (SGLT2) inhibitors were associated with lower risk of depression in people with diabetes compared to those using other treatments, with the lowest risk seen with SGLT2 inhibitors (48). Further studies of the impact of SGLT2 inhibitors are warranted as abnormal brain bioenergetic metabolism occurs in depression and endogenous ketones may exert a neuroprotective effect that might improve mood. As SGLT2 inhibitors induce ketogenesis, there is a rationale to test whether SGLT2 inhibitors improve depressive symptoms (49).

MECHANISMS TO EXPLAIN THE LINK BETWEEN DIABETES AND DEPRESSION

No one mechanism explains the association between diabetes and depression, but specific disease and treatment factors may account for why diabetes pre-disposes to depression and vice versa (Figure 1). These are, however, superimposed on other factors, such as genetics, early intra-uterine development, and social determinants of health, that create a “common soil” for both conditions.

Figure 1. The possible mechanisms that lead to the co-morbidity of diabetes and depression.

Underlying Factors That Predispose to Both Diabetes and Depression

GENETICS

Modern genetic technologies, such as genome-wide association (GWAS) studies and Mendelian randomization analyses have revolutionized our understanding of how genetics may underlie many polygenic mental and physical disorders and their association as well as health behavior traits, such as smoking and alcohol consumption that influence health. These studies have shown overlap of genetic polymorphisms that increase the risk of several mental disorders, including depression, and physical disorders, including diabetes, metabolic syndrome, and obesity (50). There are nearly 500 single nuclear polymorphisms that are associated with an increased risk of both diabetes and depression across a broad range of pathways that include immune function, lipid metabolism, cancer-related pathways, and cell signaling (51).

FETAL DEVELOPMENT

The ‘developmental origins of health and disease’ hypothesis emerged from epidemiological studies that found that infants with low birth weight had an increased risk of cardiovascular disease, diabetes, and other chronic conditions in adulthood (52, 53). Although the early studies focused on physical illness, the fetal environment is linked to psychiatric conditions, including depression, although the effect size is weak and inconsistent across studies (54).

SOCIAL DETERMINANTS OF HEALTH

The broad conditions in which people are born, live, learn, work, play, worship, and age affect a wide range of health, functioning, and quality-of-life outcomes and risks throughout the life course, which together are known as the ‘social determinants of health’ (55). These can be divided into macro-level factors, such as government policy, meso-level factors, such as neighborhood and workplace, and individual factors, such as health behaviors and are broadly grouped into five domains: economic stability, educational access and quality, health care access and quality, neighborhood and built environment, and social and community context, which include gender and race. These social factors are more robust predictors of population health than either the provision of healthcare services or individual health behaviors and explain up to 80% of a person’s health (56).

Many of the risk factors for depression described earlier in the chapter include or are affected by social factors, such as childhood adversity, low socio-economic status, or lived environment. Many of these same factors also affect the risk of diabetes. For example, access to recreational spaces, safe housing and surroundings, clean air, and shops that sell nutritious and wholesome foods provide an environment where an individual can more easily choose behaviors that would reduce the risk of diabetes.

Diabetes-Specific Factors

Both psychological and biological mechanisms contribute to the increased risk of depression in people with diabetes.

PSYCHOLOGIOCAL FACTORS

The psychological model proposes that depression is an understandable response to the difficulties of living with a demanding and life-shortening long-term physical illness that is associated with potentially debilitating complications. This model is supported by a systematic review of 11 studies that found no difference in the prevalence of depression between those with undiagnosed diabetes, those with impaired glucose metabolism, and people with normal glucose metabolism (57). By contrast, an increased prevalence of depression was only found in those with diagnosed diabetes suggesting that the knowledge of the diagnosis and the burden of managing the condition and its complications are associated with the development of depression. A more recent meta-analysis showed an 11% and 27% increased risk of depression in those with pre-diabetes and undiagnosed diabetes, respectively, compared with people with normal glucose metabolism but this was lower than the 80% increase in those with known diabetes (58). The increase was only seen in people aged less than 60 years old and was partially explained by the presence of comorbid cardiovascular disease. Since this publication, studies from Mexico (59), Germany (60) and rural China (61) did not find increased rates of depression in people with undiagnosed diabetes. However, a large study from the Netherlands found a similarly increased rate of depression in those with diagnosed and undiagnosed diabetes (62).

Although these findings generally support the psychological model, it is important to recognize that the people with undiagnosed diabetes differ from those with diagnosed diabetes by more than just the knowledge of their condition. For example, those with diagnosed diabetes are likely to have had diabetes for longer and have developed complications and other co-morbidities that may affect their risk of depression.

EFFECT OF DIABETES ON BRAIN STRUCTURE AND FUNCTION

It is well recognized that acute hyperglycemia and hypoglycemia can affect mood (63, 64). This is unsurprising because the brain is dependent on a continuous supply of glucose as its principal source of energy, and changes in blood glucose levels rapidly affect cerebral function. However, longer term effects of diabetes on brain structure and function have also been seen in animal models of diabetes and in humans. In animals, diabetes negatively affects hippocampal integrity and neurogenesis, both of which are areas that are important in cognition and mood (65). In adults with type 1 diabetes, magnetic resonance imaging (MRI) studies have shown hippocampal atrophy together with increased prefrontal glutamate-glutamine-gamma-aminobutyric acid (GABA) levels in a way that correlates with mild depressive symptoms (65, 66). In the brain, insulin stimulates glucose uptake, in part by increasing the synthesis of the glucose transporters in neurons and neuroglia (67). Consequently, abnormal insulin signaling in the brain could affect glucose transport across the blood-brain barrier leading to reduced neuronal glucose uptake and neuronal loss. As the amygdala and hippocampus are the regions that contain a high density of insulin receptors, they may be disproportionately affected by insulin resistance, which is independently associated with depression (68).

At a cellular level within the hippocampus, diabetes is associated with an increase in astrocytes and microglia reactivity and apoptosis of pyramidal neurons, and reduced neurogenesis and synaptic plasticity with dendritic retraction (69). In addition to the changes in GABA, there are other molecular changes, including increased glucocorticoid signaling, reduced brain-derived neurotrophic factor (BDNF) production, increased mGluR2/3 activity and caspase 3 activation, and an increase in the TLR4/NFκB signaling pathway, together with increased production of reactive oxygen species and pro-inflammatory cytokines, such as TNF-β. These changes lead to increased apoptosis and decreased progenitor proliferation, which in turn lead to a decrease in the hippocampal size.

Depression-Specific Factors

Depression may increase the risk of diabetes through health behaviors as well as the biological effects of depression and its treatment with antidepressants.

ADULT HEALTH BEHAVIORS

Health behaviors play an important role in determining an individual’s risk of developing diabetes.

Diet

A healthy diet protects against many long-term conditions including diabetes, obesity, and depression. Both epidemiological studies and intervention studies have shown how maintaining normal weight, reducing fat, particularly saturated fat, and increasing the fiber content of the diet reduces the risk of type 2 diabetes (70, 71). Certain dietary patterns, such as the Mediterranean diet, are associated with a lower risk of diabetes (72).

High levels of refined sugars and saturated fats may also increase the risk of depression, while a Mediterranean diet and diets that include more vegetables, fruits, fish, and whole grains seem to be protective (73). Once present, depression may entrench less prudent eating habits, creating a vicious cycle where poor diet and depression reinforce each other while simultaneously increasing the risk of diabetes. Depression increases the risk of obesity, with those with depression being 58% more likely to develop obesity than those without (74).

Excessive alcohol intake is associated with an increased risk of diabetes (75). Alcohol misuse is one of the most prevalent mental disorders, especially in more affluent countries (76). About a quarter of those with alcohol dependency have co-morbid mental disorders including depression, where alcohol is often used as a coping mechanism to manage stress, anxiety, or depressive symptoms.

Physical Activity

The health benefits of physical activity are overwhelming and include a lowered risk of type 2 diabetes and depression. There is a graded response with some physical activity being better than none, but further benefits accrue with more physical activity. Avoidance of sedentary behavior is also important for health. People with depression are less physically active than the general population; a meta-analysis of 24 studies including 2901 people with major depression disorder found that compared to the general population, those with depression spent less time engaged in overall and moderate to vigorous physical activity and were more likely to be sedentary. People with depression were 50% less likely to meet the recommended physical activity guidelines of taking at least 150 minutes of moderate-to-high intensity physical activity in a week through a variety of activities (77). Over two-thirds of people with depression do not reach this target (78).

Smoking

Tobacco use is the single most preventable cause of death and disease throughout the life-course and increases the risk of diabetes by 30-40% (79, 80). Smoking is one of the most important modifiable risk factors of physical morbidity and mortality in people with mental illness (81). Adults with depression are twice as likely to smoke as adults without depression. There also appears to be a bi-directional relationship where smoking increases the risk of depression while people with depression are more likely to start smoking (82).

Sleep

The health benefits of sleep include a lower risk of diabetes and maintenance of a healthy weight (83). Sleep problems are a cardinal feature of depression with difficulty falling asleep and waking during the night, being common symptoms of depression (10).

BIOLOGICAL EFFECTS OF DEPRESSION

Several biological changes occur during an episode of depression that might increase the risk of diabetes. First, acute episodes of depression are associated with hyperinsulinemia and insulin resistance and are unaffected by antidepressant treatment (68). Depression is also associated with a state of chronic inflammation that is characterized by increased C-reactive protein, TNF-α, and proinflammatory cytokines that might partially explain the change in insulin sensitivity. These proteins are linked to sickness behavior in animal models of depression and in humans are associated with an increase in type 2 diabetes and the metabolic syndrome (84, 85). Depression is further associated with abnormalities of hypothalamic-pituitary adrenal (HPA) axis function, which manifests as subclinical hypercortisolism, blunted diurnal cortisol rhythm, or hypocortisolism with impaired glucocorticoid sensitivity (86). Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor expressed in several tissues, including the brain, gut, and pancreas. As described earlier, BDNF plays an important role in maintaining neuronal plasticity, including neurogenesis, synaptogenesis, and neuronal maturation. Depression decreases BDNF expression in the hippocampus and prefrontal cortex (87). Outside the brain, BDNF activation leads to reduced hepatic gluconeogenesis, increased hepatic insulin signal transduction, and protects against pancreatic β-cell loss. Serum BDNF concentrations are lower in people with diabetes (88).

ANTIDEPRESSANTS

Although essential components of the management of depression, it is possible that the use of antidepressants contribute to the risk of diabetes. Case reports, and observational studies have generally shown that people receiving antidepressant medications have a higher risk of diabetes but whether this relationship is causative remains unproven (89, 90). Randomized controlled trials have emphasized that antidepressants vary considerably in their association with weight gain and both hyperglycemia and hypoglycemic effects have been observed (89). Some antidepressants, including paroxetine, mirtazapine, and various tricyclic antidepressants are associated with significant weight gain which could increase the risk of diabetes in the long term. By contrast, buproprion is associated with weight loss (91).

CONSEQUENCES OF DIABETES AND DEPRESSION CO-MORBIDITY

The presence of depression in people with diabetes worsens both diabetes and depression outcomes (Figure 2).

Figure 2. The consequences of living with diabetes and depression.

Mortality

Mortality rates from physical illnesses, including cardiovascular disease, cancer, and diabetes, are higher in people with depression. Among people with diabetes, depression increases the risk of mortality by approximately 50% (92, 93). Where depression co-exists with anxiety, which is also more common in people with diabetes, mortality rates are further increased (94).

Depression Outcomes

Once depressive symptoms occur or a diagnosis of depression is made, the symptoms appear to be persistent and likely to recur in people with diabetes. A longitudinal study of 2,460 people with type 2 diabetes in a primary care setting found that 26% met the criterion for depression on at least one occasion, with incident depression occurring in 14% over a 3-year period (95). Recurrent or persistent depression occurred in two-thirds of those with baseline depression. In two other studies from the USA, self-reported depressive symptoms persisted in 73% of people 12 months after a diabetes education program (96) while major depressive disorder relapsed in 79% of people with diabetes over a 5-year period (97).

Depression is a major cause of excess hospitalization in people with diabetes and is the leading cause of psychiatric admissions in people with diabetes accounting for 6.1 admissions per 1,000 person years in people with type 1 diabetes and 7.05 admissions in people with type 2 diabetes in Australia, with higher admission rates for women (98). These rates are 2-3-fold higher than the general Australian population (99).

People with diabetes have an increased risk of completed suicide compared with the general population and are more likely to report suicidal ideation, one of the strongest predictors of completed suicide, and intentional self-harm (100). The risk of suicidal behavior is highest in young people with type 1 diabetes, in whom suicide may account for up to 7% of deaths. Suicidal ideation is also increased among adolescents and young adults with type 1 diabetes compared with the general population (15.0% vs. 9.4%) and is seen in all ethnic groups (101). It is likely, however, that the true incidence of suicidal attempts and completed suicides is considerably higher amongst people with diabetes because of ineffective identification and coding (100). Many hospital admissions for diabetes ketoacidosis or hypoglycemia of ‘unknown’ etiology result from insulin omission or overdose, but whether these are deliberate acts is frequently unrecognized or unrecorded. There is also anecdotal evidence that healthcare professionals are unwilling to record suicide as a cause of death because of the associated stigma. Suicide rates are higher in people with long-term health conditions than in people in the general population, but what makes diabetes stand out is access to insulin, providing a means for suicide either by omission or overdose, the latter of which is the commonest method of suicide in people with insulin-treated diabetes. 

Diabetes Outcomes

ACUTE METABOLIC COMPLICATIONS

People with type 1 diabetes and depression have an increased risk of admission to hospital with diabetic ketoacidosis and severe hypoglycemia. In one study involving 3,742 people with type 1 diabetes who attended the emergency room or who were admitted to hospital between 1996 and 2015, those with depression had a 2.5-fold increased risk of severe hyperglycemia events and an 89% increased risk of severe hypoglycemia (43). The risk was greatest within the first 6 months following a diagnosis of depression, when the risk was 7.14-fold higher for hyperglycemia events and 5.58-fold higher for hypoglycemia.

MICROVASCULAR COMPLICATIONS

An early meta-analysis showed that the risk of microvascular complications was increased with small to moderate weighted effect sizes of 0.17 to 0.32 (24). The increased risk was similar in people with type 1 diabetes and people with type 2 diabetes while sexual dysfunction and painful peripheral neuropathy seemed to be associated with the highest risk. Most of these studies were cross-sectional but a more recent meta-analysis of 16 studies that examined the relationship between baseline depression and incident diabetes complications found that depression was associated with a 33% increased risk of incident microvascular disease (39). Most studies reported a composite of neuropathy, retinopathy, and nephropathy but one study reported nephropathy alone and found a 18% increase in incident chronic kidney disease (102). Depression is associated with a 68% increased risk of a first diabetes-related foot ulcer but not ulcer recurrence (103). This contrasted an earlier study that found a third of all individuals with diabetes-related foot ulcer had depression and that depression was associated with a threefold increased risk of dying (104).

MACROVASCULAR COMPLICATIONS

A recent meta-analysis has reported that incident macrovascular complications were increased by 38% in people with baseline depression (39). Most studies used a composite macrovascular outcome which included atherosclerotic vascular disease, myocardial infarction, and stroke as well as congestive heart failure and stroke. Some studies also included cardiovascular procedures, such as coronary artery bypass grafting or other revascularization techniques. Only one study reported separate outcomes for stroke (HR 1.22) and coronary heart disease (HR 1.32) (102).

QUALITY OF LIFE

Quality of life has been assessed by several different measures in people with diabetes and depression, including the Diabetes Specific Quality of Life scale and SF-36. These studies consistently show that quality of life is impaired in people with the co-morbidity (105). The effect of diabetes and depression appears to be additive across several domains with the exception of mental health where most of the effect stems from depression (106).

COST OF TREATMENT

The presence of depression among people with diabetes can substantially increase health care costs. An analysis of 147,095 adults living in the US found that depression and diabetes alone increased healthcare expenditure by $2,654 and $2,692, respectively, compared with neither condition but when both conditions occurred together, the cost was increased by $6,037 (107). Based on these figures, the estimated total cost of treating co-morbid diabetes and depression in the US was $77.6 billion per year. A more recent study found that total health costs increased from $11,550 for people with diabetes alone to $16,511 for people with diabetes and depression (108). This was in part driven by higher rates of hospitalization (26.1% vs 17.4%) and emergency room visits (55.3% vs 43.0%). Ironically, the increased cost occurred despite decreased healthcare utilization. In a US study of 22,642 people with diabetes enrolled in the 2019 Behavioral Risk Factor Surveillance System, those with a diagnosis of a depressive disorder were 82% more likely to report not seeing a doctor because of healthcare costs in the previous year (109).

DIABETES MANAGEMENT

Glycemic Levels

It has been hypothesized that changes in glycemic levels may mediate the association between depression and diabetes micro- and macrovascular complications and mortality. However, studies that have investigated this have produced inconsistent findings. An early meta-analysis reported a small to moderate association between depression and elevated HbA_1c for type 1 diabetes and type 2 diabetes, but included mainly cross-sectional studies that precluded an inference on temporality (110). A recent meta-analysis investigated the longitudinal association between self-reported depressive symptoms and HbA_1c. The six longitudinal studies had a combined sample size of 3,683 participants who were followed for a mean period of 37 months (range six months to five years). There was a small significant association between baseline depressive symptoms and subsequent HbA_1c levels (111). A further meta-analysis of 14 studies in children and adolescents with type 1 diabetes reported a correlation between depressive symptoms and HbA_1c (112). The timing of the diagnosis of diabetes and depression may also be important. In a study of 11,837 people with type 2 diabetes registered with the UK Biobank followed for a median of 6.9 years, those diagnosed with major depression decades prior to type 2 diabetes had lower HbA_1c over time compared to individuals without depression and those diagnosed closer to their diabetes diagnosis date (113). For individuals whose depression was diagnosed after diabetes, the time since the onset of depression also shaped the trajectory of HbA_1c, with the adverse effect of a diagnosis of depression on HbA_1cbeing greatest in those whose diagnosis occurred shortly after the onset of diabetes. Furthermore, the variability of HbA_1c within any individual was 16% higher in those with post-diabetes depression (113).

Diabetes Self-Management

Optimizing glucose levels is highly dependent on self-care activities that include regular glucose monitoring, taking medication as prescribed, and engaging in health behavior change to improve diet and physical activity. Depression compromises an individual’s ability to self-manage their diabetes. A meta-analysis of 47 studies reported that depression significantly reduced the likelihood of engaging in self-management behaviors, including missed medical appointments, less medication taking and glucose monitoring, and less foot care (114, 115). Similar to anti-diabetes medications, people with co-morbid depression are also less likely to take anti-hypertensive medications and lipid-lowering therapy (115). Depression is associated with a less nutritious diet that is characterized by lower consumption of fruit and vegetables and increased refined carbohydrates (116). Physical activity is reduced while smoking and alcohol consumption is increased (115). The effect of depression appears to be mediated through its adverse effects on self-efficacy and illness perception (115).

MANAGEMENT OF DIABETES AND DEPRESSION

Preventing Depression in People with Diabetes

The implication of the psychological model of depression in diabetes is that healthcare professionals could play an important role in moderating the psychological burden associated with diabetes by considering the way in which the diagnosis of diabetes is conveyed and the psychosocial support that is given through an individual’s journey with diabetes. Many people with diabetes experience stigma, some of which stem from their healthcare team. They report feelings of shame and blame because they are held responsible for developing overweight, obesity, or diabetes (117). However well-intentioned the healthcare professional is, it is clear that evoking these feelings is associated with worse clinical outcomes. By contrast, the use of person-centered, non-stigmatizing language can create a trusted and safe space for meaningful clinical discussion (118).

Several individual and group-based interventions with the aim of preventing the development of depressive symptoms have been trialed in people with diabetes. Of the twelve studies reported in a recent narrative review, half had a positive effect (119). Features associated with a reduction in the likelihood of developing depressive symptoms included diabetes self-management education and support, problem-solving and resilience-focused approaches, and emotion-targeted techniques.

Screening and Diagnosis of Depression

Given the importance of depression in people with diabetes and the availability of effective treatment, there is a strong rationale to screen for depression in people with diabetes (120), not least because depression is under-recognized in clinical practice. Primary care doctors do not diagnose and treat depression in 50–77% of cases (121, 122), while diabetologists only initiate antidepressant treatment in approximately one-third of their patients with clinical depression (123). Similarly diabetes nurses do not recognize depression and anxiety, missing 75-80% of those with the conditions (124).

A formal diagnosis of depression requires a validated interview method, such as the Mini International Neuropsychiatric Interview (MINI) or Composite International Diagnostic Interview (CIDI). No laboratory investigations are needed to diagnose depression, but it is prudent to rule out general medical conditions that may mimic the symptoms of a depressive episode. The diagnostic interviews are too labor-intensive to make them suitable for population screening or for screening in primary care or other clinical settings. However, numerous brief screening instruments or questionnaires that are simple to administer and have reasonable clinical specificity and sensitivity have been developed (Table 4). Not all screening questionnaires are appropriate because of the overlap of symptoms of depression and diabetes, including tiredness, lethargy, lack of energy, appetite changes, and sleeping difficulties. However, the Beck Depression Inventory (BDI), the Centre for Epidemiologic Studies Depression Scale (CED), the Patient Health Questionnaire (PHQ-9), and the Hospital Anxiety and Depression Scale (HADS) are all suitable for use in people with diabetes (22). Of these, the PHQ-9 is the best validated and most widely used in people with diabetes (125). It is also short, containing nine questions making it easy to administer in primary and secondary care settings. It has been suggested that the cut-off for major depression, which is ≥10 in primary care populations, should be increased by two points to ≥12 points in people with diabetes to help differentiate between diabetes-related symptoms and depressive symptoms (126).

Sensitivity= Number of true positives (cases of depression)/Number of true positives + number of false negatives; Specificity = Number of true negatives/ Number of true negatives + false positives; Positive Predictive Value (PPV) = the proportion of cases with positive test results who are correctly diagnosed. Negative Predictive Value (NPV) = the proportion of cases with negative test results who are correctly diagnosed.

Another simple approach with good sensitivity and reasonable specificity is to ask two questions (127):

• During the past month, have you been bothered by having little interest or pleasure in doing things?
• During the past month, have you been bothered by feeling down, depressed, or hopeless?

If the answer to either is yes, and the person with diabetes wants helps with this problem, the healthcare professional should undertake a diagnostic interview and offer appropriate referral and treatment.

Although screening for depression is acceptable to people living with diabetes (128), its value has not been proven and remains controversial despite being recommended by several professional bodies, including the International Diabetes Federation (129), American Diabetes Association (130), and the UK National Institute for Health and Clinical Excellence (131). A 2008 Cochrane review reported that depression screening alone in the general population had little or no impact on the detection and management of depression (132). However, a more recent meta-analysis of depression screening interventions, many of which included additional components beyond screening, showed these were associated with less depression or depressive symptoms in the general population 6-12 months after screening (133). This issue is important because of the potential harms of screening, which include the stigma associated with depression, the risk of transient distress being labelled as having depression, and discrimination from insurance companies, and so studies demonstrating the effectiveness of screening in people with diabetes are needed.

Primary care depression screening in people with diabetes was introduced in the UK in 2006 as part of the Quality and Outcomes Framework (a performance management and payment scheme for NHS general practitioners) with mixed results. In one semi-rural general practice, 365 of 435 eligible people with diabetes or ischemia heart disease were screened, but only three people without a current diagnosis of depression screened positive and none were subsequently diagnosed with depression (134). By contrast, in a study of 112 general practices in Leeds, UK, the rates of diagnosis of depression increased from 21 to 94 per 100,000 population per month after introduction of the screening compared with 27 to 77 per 100,000 population per month in people without screening (135). Despite the increased diagnosis, after an initial increase in antidepressant treatment, screening had little impact on prescribing habits.

Two clinical trials of depression screening in people with diabetes have not demonstrated a benefit. In the first study from the Netherlands, written feedback was provided to both the person with diabetes and the doctor following depression screening, but this did not change use of mental health services or improve depression scores compared with routine care (136). The second study from the USA examined the benefits of training healthcare technicians about the importance of discussing mental health with their patients (137). Although there was an improvement in depressive symptoms, this was no different from the control group and all the participants continued to have moderate to severe depressive symptoms.

Several reasons may explain the lack of effectiveness of depression screening in people with diabetes including a low acceptance of screening and subsequent referral to further care by people with diabetes, failure to screen those at highest risk of depression, reluctance by healthcare professionals, and generally poor quality of depression care in primary care systems (138). While identification of those with depression is an essential first step in treatment, screening alone will not improve clinical outcomes unless linked to appropriate care pathways and treatment (120, 139).  By contrast, studies of care pathways that have clearly linked screening to diagnosis and treatment improved depression outcomes (140, 141).

Treatment of Depression

The main aims of treatment are to improve both mental health and diabetes outcomes (Table 5). Ideally, any depression treatment for people with diabetes would simultaneously improve both sets of outcomes, but from a clinical perspective, the rapid improvement or remission of depression should be the first priority (138). This recommendation partly reflects the time course of treatment responses, which can be seen within 2–4 weeks for depression but also because treating the depression may aid optimal diabetes self-management.

Until relatively recently, people with diabetes have been under-represented in trials of depression treatment and so, there were few studies examining antidepressant and psychological treatment of depression. However, over the last two decades, the evidence base for treatment has grown substantially and has clearly indicated that treatment with either psychological therapies or antidepressant medication is effective (142) .

PSYCHOLOGICAL TREATMENT

Various psychological treatments, including cognitive behavioral therapy, problem-solving, and psychodynamic techniques have been used to treat depression in people with diabetes. Different members of the healthcare team have been utilized to deliver these interventions in primary and secondary care either in person or virtually through the internet or telephone (142, 143). The majority of trials have included people with type 2 diabetes with no trials conducted solely in people with type 1 diabetes.

A meta-analysis of psychological treatments, including group-based and online therapies, reported they were effective for the treatment of depression with large effect sizes (142). The follow-up ranged between 4 weeks and 1 year and thus, the longer term effects are unknown. Cognitive behavioral therapy is the most studied intervention, with its core components being cognitive restructuring, behavioral activation, and problem solving. This intervention was judged to be moderately effective in two recent meta-analyses (144, 145). Mindfulness also has an moderate benefit in treating depression (146), but there is mixed evidence on the benefit of motivational interviewing in reducing depressive symptoms (147, 148). Although psychological treatments are better than no treatment, the rates of recovery are low post-psychological intervention (17% vs 9% in controls) (149), indicating that many people will need additional support if they are to recover fully from their depression.

There is more debate about the effect of psychological interventions on diabetes outcomes (138) with one systematic review reporting a reduction in HbA_1c of ~0.6 % (6 mmol/mol) (150) while another only reporting a non-significant improvement in glycemic levels (151). A meta-analysis of cognitive behavioral therapy showed a statistically significant but clinically insignificant reduction in HbA_1c of 0.14% (1 mmol/mol). There was a greater effect on HbA_1c if the intervention was delivered in a group-based and face-to-face fashion and included psycho-education, behavioral, cognitive, goal-setting, and homework assignment strategies as central components (145).

One of the challenges in delivering psychological interventions is the lack of trained personnel, a situation which appears to be worsening, at least in the United Kingdom (152). To address this deficiency, interventions have been designed to be delivered online or using mobile technologies, a trend which has increased dramatically since the Covid-19 pandemic. This has the potential to increase accessibility to treatment while limiting costs (142). One meta-analysis reported large effect sizes on depressive symptoms for online therapy and a moderate effect for telephone interventions, although no change in diabetes outcomes was seen (142). The beneficial effect on depressive symptoms up to 12 months after the interventions was supported by another systematic review, albeit again without improvement in diabetes outcomes (153). However, this finding was contradicted by a recent meta-analysis of 24 randomized controlled trials, 14 non-randomized controlled trials and three observational studies which reported no significant effect on depression outcomes (154). The discrepancy may partly explained by drop-out rates which vary from 13% to 42%; for those who remain in treatment, the interventions appear effective (155) and so the challenge will be to deliver services that engage people with diabetes and depression.

In the United Kingdom in 2008, the National Health Service introduced the Improving Access to Psychological Therapies (now NHS Talking Therapies for anxiety and depression) program to improve the delivery of, and access to, psychological therapies for depression. By 2021/22, nearly 1.2 million people had accessed these services. Although the clinical workforce is appropriately trained and supervised, many practitioners do not have experience of the challenges of living with diabetes. To address this issue, the Southampton diabetes team has formed a partnership with the local NHS Talking Therapies service. A practitioner joins the multidisciplinary team in the young adult clinic once a fortnight, helping to engage the person with diabetes and facilitate referral and access to the service. There is also a wider benefit to the city as the NHS Talking Therapies team have become much more aware of the challenges of living with diabetes. Introducing this service led to reductions in depressive symptoms and diabetes distress and was well received by people with diabetes and staff alike (156).

ANTIDEPRESSANTS

Antidepressants have been used to treat depressive symptoms since the late 1950s. There are many different antidepressants, but these fall into five main categories:

• Selective Serotonin Reuptake Inhibitors (SSRI)
• Serotonin and Noradrenaline Reuptake Inhibitors (SNRI)
• Noradrenaline and Specific Serotoninergic Antidepressants (NASSA)
• Tricyclics (TCA)
• Monoamine Oxidase Inhibitors (MAOI)

The discovery of the first clinically useful antidepressants paved the way for an understanding of the underlying biological or neuroanatomical basis for depression. The first antidepressant was the tricyclic antidepressant (TCA), imipramine. It was first synthesized in 1951 as a potential antipsychotic and derived from work on chlorpromazine, which had pronounced sedative and antihistamine effects (157). Although imipramine has no antipsychotic effect, it was found to possess antidepressant effects. Other TCAs, such as amitriptyline, were subsequently synthesized by modifying the structure of imipramine. Iproniazid, a monoamine oxidase inhibitor (MAOI), was the next antidepressant to be discovered; again, this drug was initially developed for a different purpose, the treatment of tuberculosis, before its antidepressant effect was recognized. MAOIs prevent the breakdown of monoamine neurotransmitters (e.g. noradrenaline, dopamine and serotonin) while TCAs block the uptake of serotonin and noradrenaline resulting in an elevation of the synaptic concentrations of these transmitters. An understanding of the pharmacology led to the hypothesis that depression was caused by low catecholamine levels in the central nervous system (158). Both TCA and MAOI affect the serotonin system and in 1967, Coppen proposed that this was a more important neurotransmitter in depression than noradrenaline (159). Fluoxetine was the first in the class of selective serotonin re-uptake inhibitors (SSRI) and was developed by design following a search for molecules that could selectively block the re-uptake of serotonin. A major advantage of this approach was that it minimized adverse effects such as cardiovascular toxicity and anticholinergic effects. First synthesized in 1972 and launched in 1987, fluoxetine became the most widely prescribed drug in North America by 1990 (157). Although better tolerated than earlier antidepressants, SSRI still caused side effects, including sexual dysfunction, appetite change, nausea and vomiting, irritability, anxiety, insomnia, and headaches. In an attempt to reduce these adverse effects, other antidepressant classes were developed, including serotonin and noradrenaline reuptake inhibitors (SNRI, e.g. venlafaxine) and noradrenaline and specific serotoninergic antidepressants (NASSA, e.g. mirtazapine).

Antidepressants reduce depressive symptoms in people with diabetes as well as the general population; however, there have been relatively few formal efficacy trials in people with diabetes and even these have been are limited to a small group of antidepressants, including fluoxetine, sertraline, paroxetine, citalopram, escitalopram, agomelatine, nortriptyline, and vortioxetine (138, 160). Furthermore, most studies are short-term and so the medium- and long-term sustainability of pharmacological interventions after treatment cessation is uncertain. A systematic review and meta-analysis suggested that all antidepressants have similarly large effect size on depression outcomes as long as adequate doses are used (151). However, a more recent network meta-analysis of 12 randomized controlled trials involving 792 participants reported that there may be a greater reduction in depressive symptoms with escitalopram and agomelatine (160). Vortioxetine was associated with the greatest reduction in HbA_1c with escitalopram, agomelatine, sertraline and fluoxetine also associated with a fall in HbA_1c. No antidepressant was found to disrupt glucose levels (160). These differences should be viewed with caution as the number of trials and participants for each drug is small. Further head-to-head randomized controlled trials would help us understand more about the relative benefits and safety of different antidepressants on depression and glucose metabolism.

Given the similar efficacy between antidepressants, the treatment of choice depends largely on the side-effect profile, individual preference, and response. SSRI are widely used as first-choice agents because they are less cardiotoxic than TCA and are safer in overdose. Some antidepressants, notably mirtazapine, paroxetine and some TCA, may cause undesirable weight gain (91) and should be used with caution in people with type 2 diabetes. By contrast, buproprion, which is available in the USA, is associated with weight loss and, unlike SSRIs, does not appear to worsen sexual function (161).

The aim of treatment is complete remission of depressive symptoms. Treatment should be maintained at an adequate dose for at least 4–6 months after remission of symptoms to reduce the risk of relapse and recurrence. Recovery from depression may lead to a change in the individual’s behavior and routine which may have an effect on diabetes self-management. For example, if appetite improves, insulin requirements may increase, while on the other hand, if the person becomes more active, they may decrease. An individual approach is therefore needed to support the person’s glycemic management. There are important drug–drug interactions between antidepressants and oral anti-diabetes agents through inhibition of the cytochrome P450 3A4 and 2C9 isoenzyme. For example, the use of fluoxetine may potentiate the effect of sulfonylureas precipitating hypoglycemia (84).

EXERCISE

Many depression guidelines recommend exercise and other aspects of a healthy lifestyle as an integral component of management. Coupled with the importance of exercise in glycemic management, interventions to increase physical activity have been trialed and shown to be effective in reducing depressive symptoms and improving glycemic measures (162).

PREVENTING SUICIDE

A detailed description of the many effective interventions to prevent suicide is beyond the scope of this article (163),however, it is important for diabetes healthcare professionals to understand how to identify those at risk, particularly given the high prevalence of suicidal ideation and acts and immediate availability of a means of suicide. It is crucial that suicide can be discussed with people with diabetes in a safe and non-judgmental way. Talking about suicide remains highly stigmatized and choosing to reveal suicidal ideation can be difficult. The isolation that suicidal people feel can be reinforced by a critical response from the healthcare team. A recent survey of diabetes healthcare professionals found that the vast majority of respondents believed it is their professional responsibility to ask about suicide and self-harm, with nearly half reporting that this should be addressed every visit (164). Around three-quarters reported feeling comfortable discussing these issues, but those who were more reluctant to do so were concerned about their lack of training and uncertainty about what to do if someone reported self-harming behavior. Once an individual has discussed suicidal intention, it is important that the person is supported and has access to mental healthcare and suicide prevention interventions.

ORGANIZATION OF CARE

A common model of care of depression is the Stepped Care Model which provides a framework in which service delivery is organized to help those with depression, their caregivers, and healthcare professionals identify and access the most effective interventions (Figure 3) (131). The model utilizes a sequenced treatment process depending on the severity of depressive symptoms and response to previous treatments. The model allows a rational approach to the treatment of depression, while reducing costs and side effects of antidepressant through more appropriate prescribing.

Figure 3. Stepped Care Model for management of depression (131).

The first step involves the recognition of depression through screening and diagnostic interview and is reserved for those with suspected depression. For those with mild depression, step 2 involves the use of guided self-help, computerized CBT, and brief psychological interventions which can be delivered by the primary healthcare team or psychologist. The third step, which is also delivered in primary care settings, is indicated for those who do not respond to step 2 interventions, or for those with moderate and severe depression. Treatments include medication, high-intensity psychological interventions, or combined treatment. Step 4 corresponds to severe or treatment-resistant depression; the interventions are similar to those used in step 3 but now involve the mental health team. The final step is for those with life-threatening depression and/or severe self-neglect. In addition to medication and high-intensity psychological interventions, electroconvulsive therapy may be required under the supervision of a mental health crisis services and involve hospitalization.

A meta-analysis of 18 randomized controlled trial of stepped care showed improvements in depressive symptoms and better remission rates (165). A significant benefit on quality of life was also observed. More people in the stepped care model were prescribed antidepressants.

The increasing fragmentation of medical services and super-specialization in modern medicine has resulted in clinicians focusing on the conditions with which they are most familiar and being unable or unwilling to recognize and treat comorbid illnesses when they occur (166). The need for integrated holistic healthcare has never been greater but many diabetes healthcare professionals feel ill-equipped to manage depression. To address this, a case management model known as collaborative care was developed in the U.S., that involves a multidisciplinary team working together to identify and treat depression within primary care settings. The prototype intervention led to improvements in depression symptoms but without change in glycemia (167). Subsequently, greater attention was paid to intervention strategies for diabetes, resulting in simultaneous improvements in glycemic and blood pressure management and improved depressive symptoms (140). In a meta-analysis of five studies from the U.S., collaborative care was shown to be a clinical- and cost-effective treatment of depression, with a moderate effect size for depression outcomes and a small effect size for glycemic levels (142, 168).

CONCLUSION

Diabetes and depression remain a considerable clinical challenge. While an awareness of this co-morbidity has increased in recent years, this has not necessarily translated into better care or outcomes. Effective treatments are available and these need to be made available to those with diabetes and depression in clear treatment pathways. There are grounds for considerable optimism as the scientific knowledge that underpins clinical practices has expanded markedly in the last two decades. However, further research is needed to understand what can be done to prevent depression in people with diabetes and to identify the optimal treatment for an individual that improves both depressive symptoms and diabetes outcomes.

REFERENCES

1. Katon WJ. Epidemiology and treatment of depression in patients with chronic medical illness. Dialogues Clin Neurosci. 2011;13(1):7-23.
2. Ciechanowski PS, Katon WJ, Russo JE. Depression and diabetes: impact of depressive symptoms on adherence, function, and costs. Arch Intern Med. 2000;160(21):3278-85.
3. Mitchell AJ, Malone D, Doebbeling CC. Quality of medical care for people with and without comorbid mental illness and substance misuse: systematic review of comparative studies. Br J Psychiatry. 2009;194(6):491-9.
4. Buhagiar K, Parsonage L, Osborn DP. Physical health behaviours and health locus of control in people with schizophrenia-spectrum disorder and bipolar disorder: a cross-sectional comparative study with people with non-psychotic mental illness. BMC Psychiatry. 2011;11:104.
5. Disability Rights Commission. Equal Treatment: Closing the gap. A formal investigation into physical Health inequalities experienced by people with learning difficulties and mental health problems. London: Disability Rights Commission; 2006.
6. Schomerus G, Angermeyer MC. Stigma and its impact on help-seeking for mental disorders: what do we know? Epidemiol Psichiatr Soc. 2008;17(1):31-7.
7. Holt RI, Mitchell AJ. Diabetes mellitus and severe mental illness: mechanisms and clinical implications. Nat Rev Endocrinol. 2015;11(2):79-89.
8. Holt RI, de Groot M, Golden SH. Diabetes and depression. Curr Diab Rep. 2014;14(6):491.
9. Royal College of Psychiatrists. Positive Cardiometabolic Health Resource: Don't just screen, intervene! 2014 [Available from: https://www.rcpsych.ac.uk/docs/default-source/improving-care/ccqi/national-clinical-audits/ncap-library/rcp17056-lester-uk-adaptation-4pp-a4-leaflet_4_updated.pdf?sfvrsn=7bc177e9_2.
10. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. Arlington: American Psychiatric Association; 2013. 1-947 p.
11. Ferrari AJ, Charlson FJ, Norman RE, Patten SB, Freedman G, Murray CJ, et al. Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010. PLoS Med. 2013;10(11):e1001547.
12. GBD Mental Disorders Collaborators. Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Psychiatry. 2022;9(2):137-50.
13. Liu Q, He H, Yang J, Feng X, Zhao F, Lyu J. Changes in the global burden of depression from 1990 to 2017: Findings from the Global Burden of Disease study. J Psychiatr Res. 2020;126:134-40.
14. World Health Organisation. Depression and Other Common Mental Disorders: Global Health Estimates. Geneva: World Health Organisation; 2017. 1-24 p.
15. Ayuso-Mateos JL, Vazquez-Barquero JL, Dowrick C, Lehtinen V, Dalgard OS, Casey P, et al. Depressive disorders in Europe: prevalence figures from the ODIN study. Br J Psychiatry. 2001;179:308-16.
16. Eaton WW, Anthony JC, Gallo J, Cai G, Tien A, Romanoski A, et al. Natural history of Diagnostic Interview Schedule/DSM-IV major depression. The Baltimore Epidemiologic Catchment Area follow-up. Arch Gen Psychiatry. 1997;54(11):993-9.
17. Ford DE, Erlinger TP. Depression and C-reactive protein in US adults: data from the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2004;164(9):1010-4.
18. Ferenchick EK, Ramanuj P, Pincus HA. Depression in primary care: part 1-screening and diagnosis. BMJ. 2019;365:l794.
19. Holt RI, Phillips DI, Jameson KA, Cooper C, Dennison EM, Peveler RC. The relationship between depression and diabetes mellitus: findings from the Hertfordshire Cohort Study. Diabet Med. 2009;26(6):641-8.
20. Willis T. Pharmaceutice rationalis sive diabtriba de medicamentorum operantionibus in humano corpore. Oxford; 1675.
21. Harding KA, Pushpanathan ME, Whitworth SR, Nanthakumar S, Bucks RS, Skinner TC. Depression prevalence in Type 2 diabetes is not related to diabetes-depression symptom overlap but is related to symptom dimensions within patient self-report measures: a meta-analysis. Diabet Med. 2019;36(12):1600-11.
22. Roy T, Lloyd CE, Pouwer F, Holt RI, Sartorius N. Screening tools used for measuring depression among people with Type 1 and Type 2 diabetes: a systematic review. Diabet Med. 2012;29(2):164-75.
23. Anderson BJ, Edelstein S, Abramson NW, Katz LE, Yasuda PM, Lavietes SJ, et al. Depressive symptoms and quality of life in adolescents with type 2 diabetes: baseline data from the TODAY study. Diabetes Care. 2011;34(10):2205-7.
24. de Groot M, Anderson R, Freedland KE, Clouse RE, Lustman PJ. Association of depression and diabetes complications: a meta-analysis. Psychosom Med. 2001;63(4):619-30.
25. Mehdi S, Wani SUD, Krishna KL, Kinattingal N, Roohi TF. A review on linking stress, depression, and insulin resistance via low-grade chronic inflammation. Biochem Biophys Rep. 2023;36:101571.
26. Farooqi A, Gillies C, Sathanapally H, Abner S, Seidu S, Davies MJ, et al. A systematic review and meta-analysis to compare the prevalence of depression between people with and without Type 1 and Type 2 diabetes. Prim Care Diabetes. 2022;16(1):1-10.
27. Fisher L, Polonsky WH, Hessler D. Addressing diabetes distress in clinical care: a practical guide. Diabet Med. 2019;36(7):803-12.
28. Skinner TC, Joensen L, Parkin T. Twenty-five years of diabetes distress research. Diabet Med. 2020;37(3):393-400.
29. Mommersteeg PM, Herr R, Pouwer F, Holt RI, Loerbroks A. The association between diabetes and an episode of depressive symptoms in the 2002 World Health Survey: an analysis of 231,797 individuals from 47 countries. Diabet Med. 2013;30(6):e208-e14.
30. Hussain S, Habib A, Singh A, Akhtar M, Najmi AK. Prevalence of depression among type 2 diabetes mellitus patients in India: A meta-analysis. Psychiatry Res. 2018;270:264-73.
31. Khaledi M, Haghighatdoost F, Feizi A, Aminorroaya A. The prevalence of comorbid depression in patients with type 2 diabetes: an updated systematic review and meta-analysis on huge number of observational studies. Acta Diabetol. 2019;56(6):631-50.
32. Nouwen A, Winkley K, Twisk J, Lloyd CE, Peyrot M, Ismail K, et al. Type 2 diabetes mellitus as a risk factor for the onset of depression: a systematic review and meta-analysis. Diabetologia. 2010;53(12):2480-6.
33. Mezuk B, Eaton WW, Albrecht S, Golden SH. Depression and type 2 diabetes over the lifespan: a meta-analysis. Diabetes Care. 2008;31(12):2383-90.
34. Akbarizadeh M, Naderi Far M, Ghaljaei F. Prevalence of depression and anxiety among children with type 1 and type 2 diabetes: a systematic review and meta-analysis. World J Pediatr. 2022;18(1):16-26.
35. Lindekilde N, Scheuer SH, Rutters F, Knudsen L, Lasgaard M, Rubin KH, et al. Prevalence of type 2 diabetes in psychiatric disorders: an umbrella review with meta-analysis of 245 observational studies from 32 systematic reviews. Diabetologia. 2022;65(3):440-56.
36. Yu M, Zhang X, Lu F, Fang L. Depression and Risk for Diabetes: A Meta-Analysis. Can J Diabetes. 2015;39(4):266-72.
37. Graham EA, Deschenes SS, Khalil MN, Danna S, Filion KB, Schmitz N. Measures of depression and risk of type 2 diabetes: A systematic review and meta-analysis. J Affect Disord. 2020;265:224-32.
38. Busili A, Kumar K, Kudrna L, Busaily I. The risk factors for mental health disorders in patients with type 2 diabetes: An umbrella review of systematic reviews with and without meta-analysis. Heliyon. 2024;10(7):e28782.
39. Nouwen A, Adriaanse MC, van Dam K, Iversen MM, Viechtbauer W, Peyrot M, et al. Longitudinal associations between depression and diabetes complications: a systematic review and meta-analysis. Diabet Med. 2019;36(12):1562-72.
40. van Steenbergen-Weijenburg KM, van Puffelen AL, Horn EK, Nuyen J, van Dam PS, van Benthem TB, et al. More co-morbid depression in patients with Type 2 diabetes with multiple complications. An observational study at a specialized outpatient clinic. Diabet Med. 2011;28(1):86-9.
41. Bai X, Liu Z, Li Z, Yan D. The association between insulin therapy and depression in patients with type 2 diabetes mellitus: a meta-analysis. BMJ Open. 2018;8(11):e020062.
42. Li C, Ford ES, Strine TW, Mokdad AH. Prevalence of depression among U.S. adults with diabetes: findings from the 2006 behavioral risk factor surveillance system. Diabetes Care. 2008;31(1):105-7.
43. Gilsanz P, Karter AJ, Beeri MS, Quesenberry CP, Jr., Whitmer RA. The Bidirectional Association Between Depression and Severe Hypoglycemic and Hyperglycemic Events in Type 1 Diabetes. Diabetes Care. 2018;41(3):446-52.
44. Moulton CD, Hopkins CWP, Ismail K, Stahl D. Repositioning of diabetes treatments for depressive symptoms: A systematic review and meta-analysis of clinical trials. Psychoneuroendocrinology. 2018;94:91-103.
45. Hamal C, Velugoti L, Tabowei G, Gaddipati GN, Mukhtar M, Alzubaidee MJ, et al. Metformin for the Improvement of Comorbid Depression Symptoms in Diabetic Patients: A Systematic Review. Cureus. 2022;14(8):e28609.
46. Zhang Y, Chan VK, Chan SSM, Chan EWY, Lee CH, Wong IC, et al. Effect of metformin on the risk of depression: A systematic review and meta-regression of observational studies. Asian J Psychiatr. 2024;92:103894.
47. Chen X, Zhao P, Wang W, Guo L, Pan Q. The Antidepressant Effects of GLP-1 Receptor Agonists: A Systematic Review and Meta-Analysis. Am J Geriatr Psychiatry. 2024;32(1):117-27.
48. Wium-Andersen IK, Osler M, Jorgensen MB, Rungby J, Wium-Andersen MK. Diabetes, antidiabetic medications and risk of depression - A population-based cohort and nested case-control study. Psychoneuroendocrinology. 2022;140:105715.
49. Liebers DT, Ebina W, Iosifescu DV. Sodium-Glucose Cotransporter-2 Inhibitors in Depression. Harv Rev Psychiatry. 2023;31(4):214-21.
50. Postolache TT, Del Bosque-Plata L, Jabbour S, Vergare M, Wu R, Gragnoli C. Co-shared genetics and possible risk gene pathway partially explain the comorbidity of schizophrenia, major depressive disorder, type 2 diabetes, and metabolic syndrome. Am J Med Genet B Neuropsychiatr Genet. 2019;180(3):186-203.
51. Ji HF, Zhuang QS, Shen L. Genetic overlap between type 2 diabetes and major depressive disorder identified by bioinformatics analysis. Oncotarget. 2016;7(14):17410-4.
52. Barker DJ. The Wellcome Foundation Lecture, 1994. The fetal origins of adult disease. Proc Biol Sci. 1995;262(1363):37-43.
53. Barker DJ. Fetal origins of coronary heart disease. BMJ. 1995;311(6998):171-4.
54. Schlotz W, Phillips DI. Fetal origins of mental health: evidence and mechanisms. Brain Behav Immun. 2009;23(7):905-16.
55. Marmot M, Friel S, Bell R, Houweling TA, Taylor S, Commission on Social Determinants of H. Closing the gap in a generation: health equity through action on the social determinants of health. Lancet. 2008;372(9650):1661-9.
56. Hood CM, Gennuso KP, Swain GR, Catlin BB. County Health Rankings: Relationships Between Determinant Factors and Health Outcomes. Am J Prev Med. 2016;50(2):129-35.
57. Nouwen A, Nefs G, Caramlau I, Connock M, Winkley K, Lloyd CE, et al. Prevalence of depression in individuals with impaired glucose metabolism or undiagnosed diabetes: a systematic review and meta-analysis of the European Depression in Diabetes (EDID) Research Consortium. Diabetes Care. 2011;34(3):752-62.
58. Chen S, Zhang Q, Dai G, Hu J, Zhu C, Su L, et al. Association of depression with pre-diabetes, undiagnosed diabetes, and previously diagnosed diabetes: a meta-analysis. Endocrine. 2016;53(1):35-46.
59. Olvera RL, Fisher-Hoch SP, Williamson DE, Vatcheva KP, McCormick JB. Depression in Mexican Americans with diagnosed and undiagnosed diabetes. Psychol Med. 2016;46(3):637-46.
60. Weikert B, Buttery AK, Heidemann C, Rieckmann N, Paprott R, Maske UE, et al. Glycaemic status and depressive symptoms among adults in Germany: results from the German Health Interview and Examination Survey for Adults (DEGS1). Diabet Med. 2018;35(11):1552-61.
61. Li Z, Guo X, Jiang H, Sun G, Sun Y, Abraham MR. Diagnosed but Not Undiagnosed Diabetes Is Associated with Depression in Rural Areas. Int J Environ Res Public Health. 2016;13(11).
62. Meurs M, Roest AM, Wolffenbuttel BH, Stolk RP, de Jonge P, Rosmalen JG. Association of Depressive and Anxiety Disorders With Diagnosed Versus Undiagnosed Diabetes: An Epidemiological Study of 90,686 Participants. Psychosom Med. 2016;78(2):233-41.
63. Sommerfield AJ, Deary IJ, Frier BM. Acute hyperglycemia alters mood state and impairs cognitive performance in people with type 2 diabetes. Diabetes Care. 2004;27(10):2335-40.
64. Hermanns N, Scheff C, Kulzer B, Weyers P, Pauli P, Kubiak T, et al. Association of glucose levels and glucose variability with mood in type 1 diabetic patients. Diabetologia. 2007;50(5):930-3.
65. Ho N, Sommers MS, Lucki I. Effects of diabetes on hippocampal neurogenesis: links to cognition and depression. Neurosci Biobehav Rev. 2013;37(8):1346-62.
66. Lyoo IK, Yoon S, Jacobson AM, Hwang J, Musen G, Kim JE, et al. Prefrontal cortical deficits in type 1 diabetes mellitus: brain correlates of comorbid depression. ArchGenPsychiatry. 2012;69(12):1267-76.
67. Leonard BE, Wegener G. Inflammation, insulin resistance and neuroprogression in depression. Acta Neuropsychiatr. 2020;32(1):1-9.
68. Fernandes BS, Salagre E, Enduru N, Grande I, Vieta E, Zhao Z. Insulin resistance in depression: A large meta-analysis of metabolic parameters and variation. Neurosci Biobehav Rev. 2022;139:104758.
69. Mazala-de-Oliveira T, Silva BT, Campello-Costa P, Carvalho VF. The Role of the Adrenal-Gut-Brain Axis on Comorbid Depressive Disorder Development in Diabetes. Biomolecules. 2023;13(10).
70. Crandall JP, Knowler WC, Kahn SE, Marrero D, Florez JC, Bray GA, et al. The prevention of type 2 diabetes. Nat Clin Pract Endocrinol Metab. 2008;4(7):382-93.
71. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393-403.
72. Dyson PA, Twenefour D, Breen C, Duncan A, Elvin E, Goff L, et al. Diabetes UK evidence-based nutrition guidelines for the prevention and management of diabetes. Diabet Med. 2018;35(5):541-7.
73. Shafiei F, Salari-Moghaddam A, Larijani B, Esmaillzadeh A. Adherence to the Mediterranean diet and risk of depression: a systematic review and updated meta-analysis of observational studies. Nutr Rev. 2019;77(4):230-9.
74. Luppino FS, de Wit LM, Bouvy PF, Stijnen T, Cuijpers P, Penninx BW, et al. Overweight, obesity, and depression: a systematic review and meta-analysis of longitudinal studies. Arch Gen Psychiatry. 2010;67(3):220-9.
75. Knott C, Bell S, Britton A. Alcohol Consumption and the Risk of Type 2 Diabetes: A Systematic Review and Dose-Response Meta-analysis of More Than 1.9 Million Individuals From 38 Observational Studies. Diabetes Care. 2015;38(9):1804-12.
76. Carvalho AF, Heilig M, Perez A, Probst C, Rehm J. Alcohol use disorders. Lancet. 2019;394(10200):781-92.
77. King AC, Whitt-Glover MC, Marquez DX, Buman MP, Napolitano MA, Jakicic J, et al. Physical Activity Promotion: Highlights from the 2018 Physical Activity Guidelines Advisory Committee Systematic Review. Med Sci Sports Exerc. 2019;51(6):1340-53.
78. Schuch F, Vancampfort D, Firth J, Rosenbaum S, Ward P, Reichert T, et al. Physical activity and sedentary behavior in people with major depressive disorder: A systematic review and meta-analysis. J Affect Disord. 2017;210:139-50.
79. World Health Organisation. Effects of tobacco on health 2016 [Available from: https://www.who.int/europe/news-room/fact-sheets/item/effects-of-tobacco-on-health.
80. Pan A, Wang Y, Talaei M, Hu FB, Wu T. Relation of active, passive, and quitting smoking with incident type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2015;3(12):958-67.
81. Tam J, Warner KE, Meza R. Smoking and the Reduced Life Expectancy of Individuals With Serious Mental Illness. Am J Prev Med. 2016;51(6):958-66.
82. Fluharty M, Taylor AE, Grabski M, Munafo MR. The Association of Cigarette Smoking With Depression and Anxiety: A Systematic Review. Nicotine Tob Res. 2017;19(1):3-13.
83. Cappuccio FP, D'Elia L, Strazzullo P, Miller MA. Sleep duration and all-cause mortality: a systematic review and meta-analysis of prospective studies. Sleep. 2010;33(5):585-92.
84. Musselman DL, Betan E, Larsen H, Phillips LS. Relationship of depression to diabetes types 1 and 2: epidemiology, biology, and treatment. Biol Psychiatry. 2003;54(3):317-29.
85. Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9(1):46-56.
86. Champaneri S, Wand GS, Malhotra SS, Casagrande SS, Golden SH. Biological basis of depression in adults with diabetes. Curr Diab Rep. 2010;10(6):396-405.
87. Duman RS, Deyama S, Fogaca MV. Role of BDNF in the pathophysiology and treatment of depression: Activity-dependent effects distinguish rapid-acting antidepressants. Eur J Neurosci. 2021;53(1):126-39.
88. Moosaie F, Mohammadi S, Saghazadeh A, Dehghani Firouzabadi F, Rezaei N. Brain-derived neurotrophic factor in diabetes mellitus: A systematic review and meta-analysis. PLoS One. 2023;18(2):e0268816.
89. Barnard K, Peveler RC, Holt RI. Antidepressant medication as a risk factor for type 2 diabetes and impaired glucose regulation: systematic review. Diabetes Care. 2013;36(10):3337-45.
90. Greene CRL, Ward-Penny H, Ioannou MF, Wild SH, Wu H, Smith DJ, et al. Antidepressant and antipsychotic drug prescribing and diabetes outcomes: A systematic review of observational studies. Diabetes Res Clin Pract. 2023;199:110649.
91. Serretti A, Mandelli L. Antidepressants and body weight: a comprehensive review and meta-analysis. J Clin Psychiatry. 2010;71(10):1259-72.
92. Park M, Katon WJ, Wolf FM. Depression and risk of mortality in individuals with diabetes: a meta-analysis and systematic review. Gen Hosp Psychiatry. 2013;35(3):217-25.
93. van Dooren FE, Nefs G, Schram MT, Verhey FR, Denollet J, Pouwer F. Depression and risk of mortality in people with diabetes mellitus: a systematic review and meta-analysis. PLoS One. 2013;8(3):e57058.
94. Meier SM, Mattheisen M, Mors O, Mortensen PB, Laursen TM, Penninx BW. Increased mortality among people with anxiety disorders: total population study. Br J Psychiatry. 2016;209(3):216-21.
95. Nefs G, Pouwer F, Denollet J, Pop V. The course of depressive symptoms in primary care patients with type 2 diabetes: results from the Diabetes, Depression, Type D Personality Zuidoost-Brabant (DiaDDZoB) Study. Diabetologia. 2012;55(3):608-16.
96. Peyrot M, Rubin RR. Persistence of depressive symptoms in diabetic adults. Diabetes Care. 1999;22(3):448-52.
97. Lustman PJ, Griffith LS, Clouse RE. Depression in adults with diabetes. Results of 5-yr follow-up study. Diabetes Care. 1988;11(8):605-12.
98. Tomic D, Morton JI, Salim A, Lambert T, Magliano DJ, Shaw JE. Hospitalisation for mental health disorders in Australians with type 1 or type 2 diabetes. Diabetes Res Clin Pract. 2023;196:110244.
99. Draper B, Low LF. Patterns of hospitalisation for depressive and anxiety disorders across the lifespan in Australia. J Affect Disord. 2009;113(1-2):195-200.
100. Barnard-Kelly KD, Naranjo D, Majidi S, Akturk HK, Breton M, Courtet P, et al. Suicide and Self-inflicted Injury in Diabetes: A Balancing Act. J Diabetes Sci Technol. 2020;14(6):1010-6.
101. Majidi S, O'Donnell HK, Stanek K, Youngkin E, Gomer T, Driscoll KA. Suicide Risk Assessment in Youth and Young Adults With Type 1 Diabetes. Diabetes Care. 2020;43(2):343-8.
102. Novak M, Mucsi I, Rhee CM, Streja E, Lu JL, Kalantar-Zadeh K, et al. Increased Risk of Incident Chronic Kidney Disease, Cardiovascular Disease, and Mortality in Patients With Diabetes With Comorbid Depression. Diabetes Care. 2016;39(11):1940-7.
103. Westby M, Norman G, Vedhara K, Game F, Cullum N. Psychosocial and behavioural prognostic factors for diabetic foot ulcer development and healing: a systematic review. Diabet Med. 2020;37(8):1244-55.
104. Ismail K, Winkley K, Stahl D, Chalder T, Edmonds M. A cohort study of people with diabetes and their first foot ulcer: the role of depression on mortality. Diabetes Care. 2007;30(6):1473-9.
105. Jing X, Chen J, Dong Y, Han D, Zhao H, Wang X, et al. Related factors of quality of life of type 2 diabetes patients: a systematic review and meta-analysis. Health Qual Life Outcomes. 2018;16(1):189.
106. Goldney RD, Phillips PJ, Fisher LJ, Wilson DH. Diabetes, depression, and quality of life: a population study. Diabetes Care. 2004;27(5):1066-70.
107. Egede LE, Bishu KG, Walker RJ, Dismuke CE. Impact of diagnosed depression on healthcare costs in adults with and without diabetes: United States, 2004-2011. J Affect Disord. 2016;195:119-26.
108. Kangethe A, Lawrence DF, Touya M, Chrones L, Polson M, Evangelatos T. Incremental burden of comorbid major depressive disorder in patients with type 2 diabetes or cardiovascular disease: a retrospective claims analysis. BMC Health Serv Res. 2021;21(1):778.
109. McClintock HF, Edmonds SE, Bogner HR. Depression and Cost-Related Health Care Utilization Among Persons with Diabetes. Popul Health Manag. 2023;26(4):232-8.
110. Lustman PJ, Anderson RJ, Freedland KE, de GM, Carney RM, Clouse RE. Depression and poor glycemic control: a meta-analytic review of the literature. Diabetes Care. 2000;23(7):934-42.
111. Beran M, Muzambi R, Geraets A, Albertorio-Diaz JR, Adriaanse MC, Iversen MM, et al. The bidirectional longitudinal association between depressive symptoms and HbA(1c) : A systematic review and meta-analysis. Diabet Med. 2022;39(2):e14671.
112. Buchberger B, Huppertz H, Krabbe L, Lux B, Mattivi JT, Siafarikas A. Symptoms of depression and anxiety in youth with type 1 diabetes: A systematic review and meta-analysis. Psychoneuroendocrinology. 2016;70:70-84.
113. Gillett AC, Hagenaars SP, Handley D, Casanova F, Young KG, Green H, et al. The impact of major depressive disorder on glycaemic control in type 2 diabetes: a longitudinal cohort study using UK Biobank primary care records. BMC Med. 2024;22(1):211.
114. Gonzalez JS, Peyrot M, McCarl LA, Collins EM, Serpa L, Mimiaga MJ, et al. Depression and diabetes treatment nonadherence: a meta-analysis. Diabetes Care. 2008;31(12):2398-403.
115. Derese A, Gebreegzhiabhere Y, Medhin G, Sirgu S, Hanlon C. Impact of depression on self-efficacy, illness perceptions and self-management among people with type 2 diabetes: A systematic review of longitudinal studies. PLoS One. 2024;19(5):e0302635.
116. Sumlin LL, Garcia TJ, Brown SA, Winter MA, Garcia AA, Brown A, et al. Depression and adherence to lifestyle changes in type 2 diabetes: a systematic review. Diabetes Educ. 2014;40(6):731-44.
117. Speight J, Holmes-Truscott E, Garza M, Scibilia R, Wagner S, Kato A, et al. Bringing an end to diabetes stigma and discrimination: an international consensus statement on evidence and recommendations. Lancet Diabetes Endocrinol. 2024;12(1):61-82.
118. Holt RIG, Speight J. The language of diabetes: the good, the bad and the ugly. Diabet Med. 2017;34(11):1495-7.
119. Guerin E, Jaafar H, Amrani L, Prud'homme D, Aguer C. Intervention Strategies for Prevention of Comorbid Depression Among Individuals With Type 2 Diabetes: A Scoping Review. Front Public Health. 2019;7:35.
120. Holt RI, van der Feltz-Cornelis CM. Key concepts in screening for depression in people with diabetes. J Affect Disord. 2012;142 Suppl:S72-S9.
121. Mitchell AJ, Vaze A, Rao S. Clinical diagnosis of depression in primary care: a meta-analysis. Lancet. 2009;374(9690):609-19.
122. Mitchell AJ, Rao S, Vaze A. Can general practitioners identify people with distress and mild depression? A meta-analysis of clinical accuracy. J Affect Disord. 2011;130(1-2):26-36.
123. Lustman PJ, Harper GW. Nonpsychiatric physicians' identification and treatment of depression in patients with diabetes. Compr Psychiatry. 1987;28(1):22-7.
124. Pouwer F, Beekman AT, Lubach C, Snoek FJ. Nurses' recognition and registration of depression, anxiety and diabetes-specific emotional problems in outpatients with diabetes mellitus. Patient Educ Couns. 2006;60(2):235-40.
125. Kroenke K, Spitzer RL, Williams JB, Lowe B. The Patient Health Questionnaire Somatic, Anxiety, and Depressive Symptom Scales: a systematic review. Gen Hosp Psychiatry. 2010;32(4):345-59.
126. van Steenbergen-Weijenburg KM, de Vroege L, Ploeger RR, Brals JW, Vloedbeld MG, Veneman TF, et al. Validation of the PHQ-9 as a screening instrument for depression in diabetes patients in specialized outpatient clinics. BMC Health Serv Res. 2010;10:235.
127. Whooley MA, Avins AL, Miranda J, Browner WS. Case-finding instruments for depression. Two questions are as good as many. J Gen Intern Med. 1997;12(7):439-45.
128. Lloyd CE, Dyer PH, Barnett AH. Prevalence of symptoms of depression and anxiety in a diabetes clinic population. Diabet Med. 2000;17(3):198-202.
129. International Diabetes Federation Guideline Development Group. Global guideline for type 2 diabetes. Diabetes Res Clin Pract. 2014;104(1):1-52.
130. American Diabetes Association Professional Practice C. 4. Comprehensive Medical Evaluation and Assessment of Comorbidities: Standards of Care in Diabetes-2024. Diabetes Care. 2024;47(Suppl 1):S52-S76.
131. National Collaborating Centre for Mental Health. Depression in adults with a chronic physical health problem CG91. London: The British Psychological Society and The Royal College of Psychiatrists; 2010.
132. Gilbody S, Sheldon T, House A. Screening and case-finding instruments for depression: a meta-analysis. CMAJ. 2008;178(8):997-1003.
133. O'Connor EA, Perdue LA, Coppola EL, Henninger ML, Thomas RG, Gaynes BN. Depression and Suicide Risk Screening: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 2023;329(23):2068-85.
134. Subramanian DN, Hopayian K. An audit of the first year of screening for depression in patients with diabetes and ischaemic heart disease under the Quality and Outcomes Framework. Qual Prim Care. 2008;16(5):341-4.
135. McLintock K, Russell AM, Alderson SL, West R, House A, Westerman K, et al. The effects of financial incentives for case finding for depression in patients with diabetes and coronary heart disease: interrupted time series analysis. BMJ Open. 2014;4(8):e005178.
136. Pouwer F, Tack CJ, Geelhoed-Duijvestijn PH, Bazelmans E, Beekman AT, Heine RJ, et al. Limited effect of screening for depression with written feedback in outpatients with diabetes mellitus: a randomised controlled trial. Diabetologia. 2011;54(4):741-8.
137. Scollan-Koliopoulos M, Herrera I, Romano K, Gregory C, Rapp K, Bleich D. Healthcare technician delivered screening of adults with diabetes to improve primary care provider recognition of depression. J Family Med Prim Care. 2012;1(2):97-102.
138. Petrak F, Baumeister H, Skinner TC, Brown A, Holt RI. Depression and diabetes: treatment and health-care delivery. Lancet Diabetes Endocrinol. 2015;3(6):472-85.
139. Hermanns N, Caputo S, Dzida G, Khunti K, Meneghini LF, Snoek F. Screening, evaluation and management of depression in people with diabetes in primary care. Prim Care Diabetes. 2013;7(1):1-10.
140. Katon WJ, Lin EH, Von KM, Ciechanowski P, Ludman EJ, Young B, et al. Collaborative care for patients with depression and chronic illnesses. N Engl J Med. 2010;363(27):2611-20.
141. Ell K, Katon W, Xie B, Lee PJ, Kapetanovic S, Guterman J, et al. Collaborative care management of major depression among low-income, predominantly Hispanic subjects with diabetes: a randomized controlled trial. Diabetes Care. 2010;33(4):706-13.
142. van der Feltz-Cornelis C, Allen SF, Holt RIG, Roberts R, Nouwen A, Sartorius N. Treatment for comorbid depressive disorder or subthreshold depression in diabetes mellitus: Systematic review and meta-analysis. Brain Behav. 2021;11(2):e01981.
143. van Bastelaar KM, Pouwer F, Cuijpers P, Riper H, Snoek FJ. Web-based depression treatment for type 1 and type 2 diabetic patients: a randomized, controlled trial. Diabetes Care. 2011;34(2):320-5.
144. An Q, Yu Z, Sun F, Chen J, Zhang A. The Effectiveness of Cognitive Behavioral Therapy for Depression Among Individuals with Diabetes: a Systematic Review and Meta-Analysis. Curr Diab Rep. 2023;23(9):245-52.
145. Li Y, Storch EA, Ferguson S, Li L, Buys N, Sun J. The efficacy of cognitive behavioral therapy-based intervention on patients with diabetes: A meta-analysis. Diabetes Res Clin Pract. 2022;189:109965.
146. Ni YX, Ma L, Li JP. Effects of mindfulness-based intervention on glycemic control and psychological outcomes in people with diabetes: A systematic review and meta-analysis. J Diabetes Investig. 2021;12(6):1092-103.
147. Berhe KK, Gebru HB, Kahsay HB. Effect of motivational interviewing intervention on HgbA1C and depression in people with type 2 diabetes mellitus (systematic review and meta-analysis). PLoS One. 2020;15(10):e0240839.
148. Bilgin A, Muz G, Yuce GE. The effect of motivational interviewing on metabolic control and psychosocial variables in individuals diagnosed with diabetes: Systematic review and meta-analysis. Patient Educ Couns. 2022;105(9):2806-23.
149. Mather S, Fisher P, Nevitt S, Cherry MG, Maturana C, Warren JG, et al. The limited efficacy of psychological interventions for depression in people with Type 1 or Type 2 diabetes: An Individual Participant Data Meta-Analysis (IPD-MA). J Affect Disord. 2022;310:25-31.
150. Ismail K, Winkley K, Rabe-Hesketh S. Systematic review and meta-analysis of randomised controlled trials of psychological interventions to improve glycaemic control in patients with type 2 diabetes. Lancet. 2004;363(9421):1589-97.
151. Baumeister H, Hutter N, Bengel J. Psychological and pharmacological interventions for depression in patients with diabetes mellitus and depression. Cochrane Database Syst Rev. 2012;12:CD008381.
152. Winocour PH, Gosden C, Walton C, Nagi D, Turner B, Williams R, et al. Association of British Clinical Diabetologists (ABCD) and Diabetes-UK survey of specialist diabetes services in the UK, 2006. 1. The consultant physician perspective. Diabet Med. 2008;25(6):643-50.
153. Varela-Moreno E, Carreira Soler M, Guzman-Parra J, Jodar-Sanchez F, Mayoral-Cleries F, Anarte-Ortiz MT. Effectiveness of eHealth-Based Psychological Interventions for Depression Treatment in Patients With Type 1 or Type 2 Diabetes Mellitus: A Systematic Review. Front Psychol. 2021;12:746217.
154. Fernandez-Rodriguez R, Zhao L, Bizzozero-Peroni B, Martinez-Vizcaino V, Mesas AE, Wittert G, et al. Are e-Health Interventions Effective in Reducing Diabetes-Related Distress and Depression in Patients with Type 2 Diabetes? A Systematic Review with Meta-Analysis. Telemed J E Health. 2024;30(4):919-39.
155. Franco P, Gallardo AM, Urtubey X. Web-Based Interventions for Depression in Individuals with Diabetes: Review and Discussion. JMIR Diabetes. 2018;3(3):e13.
156. Holt RIG. Transforming the diabetes outcomes for people with mental illness. Practical Diabetes. 2024;41(4):3-8.
157. Pereira VS, Hiroaki-Sato VA. A brief history of antidepressant drug development: from tricyclics to beyond ketamine. Acta Neuropsychiatr. 2018;30(6):307-22.
158. Schildkraut JJ, Gordon EK, Durell J. Catecholamine metabolism in affective disorders. I. Normetanephrine and VMA excretion in depressed patients treated with imipramine. J Psychiatr Res. 1965;3(4):213-28.
159. Coppen A. The biochemistry of affective disorders. Br J Psychiatry. 1967;113(504):1237-64.
160. Srisurapanont M, Suttajit S, Kosachunhanun N, Likhitsathian S, Suradom C, Maneeton B. Antidepressants for depressed patients with type 2 diabetes mellitus: A systematic review and network meta-analysis of short-term randomized controlled trials. Neurosci Biobehav Rev. 2022;139:104731.
161. Sayuk GS, Gott BM, Nix BD, Lustman PJ. Improvement in sexual functioning in patients with type 2 diabetes and depression treated with bupropion. Diabetes Care. 2011;34(2):332-4.
162. Mohammad Rahimi GR, Aminzadeh R, Azimkhani A, Saatchian V. The Effect of Exercise Interventions to Improve Psychosocial Aspects and Glycemic Control in Type 2 Diabetic Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Biol Res Nurs. 2022;24(1):10-23.
163. Hofstra E, van Nieuwenhuizen C, Bakker M, Ozgul D, Elfeddali I, de Jong SJ, et al. Effectiveness of suicide prevention interventions: A systematic review and meta-analysis. Gen Hosp Psychiatry. 2020;63:127-40.
164. Majidi S, Cohen L, Holt RIG, Clements M, O'Neill S, Renard E, et al. Healthcare Professional Experiences and Opinions on Depression and Suicide in People With Diabetes. J Diabetes Sci Technol. 2024;18(3):667-75.
165. Rivero-Santana A, Perestelo-Perez L, Alvarez-Perez Y, Ramos-Garcia V, Duarte-Diaz A, Linertova R, et al. Stepped care for the treatment of depression: a systematic review and meta-analysis. J Affect Disord. 2021;294:391-409.
166. Holt RI, Katon WJ. Dialogue on Diabetes and Depression: Dealing with the double burden of co-morbidity. JAffectDisord. 2012;142 Suppl:S1-S3.
167. Katon WJ, Von Korff M, Lin EH, Simon G, Ludman E, Russo J, et al. The Pathways Study: a randomized trial of collaborative care in patients with diabetes and depression. Arch Gen Psychiatry. 2004;61(10):1042-9.
168. Simon GE, Katon WJ, Lin EH, Rutter C, Manning WG, Von Korff M, et al. Cost-effectiveness of systematic depression treatment among people with diabetes mellitus. Arch Gen Psychiatry. 2007;64(1):65-72.