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Obesity and Dyslipidemia

, MD.

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Last Update: November 2, 2020.

ABSTRACT

Abnormalities in lipid metabolism are very commonly observed in patients who are obese. Approximately 60-70% of patients with obesity are dyslipidemic. The lipid abnormalities in patients who are obese include elevated serum triglyceride, VLDL, apolipoprotein B, and non-HDL-C levels. The increase in serum triglycerides is due to increased hepatic production of VLDL particles and a decrease in the clearance of triglyceride rich lipoproteins. HDL-C levels are typically low and are associated with the increase in serum triglycerides. LDL-C levels are frequently in the normal range but there is an increase in small dense LDL. Patients who are obese are at an increased risk of developing cardiovascular disease and therefore treatment of their dyslipidemia is often indicated. Weight loss will decrease serum triglyceride and LDL-C levels and increase HDL-C levels. In most patients the changes in lipid levels with weight loss are not very robust and is proportional to the change in weight. Dietary constituents of a weight loss diet have a small but significant impact on the changes in lipid levels. Low carbohydrate diets decrease triglyceride levels to a greater extent than high carbohydrate diets. High fat diets blunt the decrease in LDL-C that occurs with weight loss. The increase in HDL-C with weight loss is greatest with a high fat diet but the significance of this increase on cardiovascular disease risk is uncertain. Bariatric surgery results in robust weight loss and has a marked effect on serum lipid levels. Remission of hyperlipidemia with gastric bypass surgery is frequently observed. The reduction in cardiovascular disease with statin therapy is no different in patients with a BMI >30 or BMI <25 (i.e. statins are effective in patients who are obese). Many, if not most, patients who are obese should be on statin therapy and some will require the addition of other LDL-C decreasing drugs to achieve satisfactory reductions in LDL-C. The mixed dyslipidemia that is frequently observed in patients who are obese will often require combination therapy. However, recent studies have failed to demonstrate that adding fenofibrate or niacin to statin therapy provides additional benefits beyond statins alone. However, the addition of the omega-3-fatty acid, icosapent ethyl, to statin therapy has been shown to decrease cardiovascular events. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

The prevalence of obesity has increased dramatically over the last several decades (1,2). In the United States it is estimated that approximately 35% of men and 40% of women are obese defined as a BMI >30 kg/m2 (2,3). Additionally, approximately 1/3 of the population is overweight defined as a BMI between 25 and 30 kg/m2 (2,4). Moreover, the obesity epidemic is not localized to the United States as there has been a marked increase in the prevalence of obesity worldwide (5). The number of individuals with morbid obesity (BMI > 40) has also greatly increased (6). It should be noted that very athletic individuals may have a high BMI without excess body fat (the increase in weight is due to muscle mass) and as a consequence not have metabolic abnormalities. Of great concern is that the prevalence of obesity has also markedly increased in children (7). Obesity is associated with insulin resistance, alterations in lipid metabolism, and the metabolic syndrome, particularly when the excess adipose tissue is located in an intra-abdominal location or in the upper chest (8-10). Obesity is a risk factor for the development of cardiovascular disease, but it appears that much of this effect is accounted for by obesity inducing dyslipidemia, diabetes, hypertension, inflammation, and a procoagulant state (8-12). The majority of deaths related to high BMI are due to cardiovascular disease (5).

LIPID ABNORMALITIES IN PATIENTS WITH OBESITY

The lipid abnormalities seen in patients who are obese include elevated triglyceride, VLDL, Apo B, and non-HDL-C levels, which are all commonly observed (8,9,13,14). HDL-C and Apo A-I levels are typically low (8,9,13,14). LDL-C levels are frequently in the normal range, but an increase in small dense LDL is often seen resulting in an increased number of LDL particles (8,9,13,14). These small dense LDL particles are considered to be more pro-atherogenic than large LDL particles for a number of reasons (15). Small dense LDL particles have a decreased affinity for the LDL receptor resulting in a prolonged period of time in the circulation. Additionally, these small particles enter the arterial wall more easily than large particles and then they bind more avidly to intra-arterial proteoglycans, which traps them in the arterial wall. Finally, small dense LDL particles are more susceptible to oxidation, which could result in an enhanced uptake by macrophages. Postprandial triglyceride levels are also increased in subjects with obesity and these chylomicron remnants are pro-atherogenic (16,17). The greater the increase in BMI the greater the abnormalities in lipid levels. Approximately 60-70% of patients who are obese are dyslipidemic while 50-60% of patients who are overweight are dyslipidemic (8). Notably, obesity in children and young adults also leads to an increased prevalence of elevated triglycerides and decreased HDL-C levels (18). The increased risk for cardiovascular disease in patients with obesity is partially accounted for by this dyslipidemia.

Table 1.

Lipid and Lipoprotein Levels in Patients who are Obese

Increased triglycerides
Increased VLDL
Increased apo B
Increased non-HDL-C
Increased small dense LDL
Increased LDL particle number
Decreased HDL-C
Decreased apo A1
LDL-C and Lp(a) are not altered

It should be emphasized that the effects of obesity on lipid metabolism are dependent on the location of the adipose tissue (19-23). Increased visceral adipose tissue and trunk (especially upper trunk) subcutaneous adipose tissue are associated with higher triglycerides and lower HDL-C levels. In contrast, increased subcutaneous adipose tissue in the leg is associated with lower triglycerides. The protective effect of leg fat may explain why women and African-Americans have lower triglycerides. In addition, increased visceral adipose tissue and upper trunk subcutaneous adipose tissue are associated with insulin resistance, which may contribute to the lipid changes described above.

PATHOPHYSIOLOGY OF THE DYSLIPIDEMIA OF OBESITY

Figure 1.

Figure 1.

Changes in Lipid/Lipoprotein Metabolism Leading to the Dyslipidemia of Obesity

Production of Triglyceride Rich Lipoproteins

There are a number of different abnormalities that contribute to the dyslipidemia seen in patients with obesity (figure 1) (8,14,17,24,25). These abnormalities are driven by the combination of the greater delivery of free fatty acids to the liver from increased total and visceral adiposity, insulin resistance, and a pro-inflammatory state, induced by macrophages infiltrating fat tissue (8,14,17,24,25). A key abnormality is the overproduction of VLDL particles by the liver, which is an important contributor to the elevation in serum triglyceride levels (8,14,17,24,25). The rate of secretion of VLDL particles is highly dependent on triglyceride availability, which is determined by the levels of fatty acids available for the synthesis of triglycerides in the liver. An abundance of triglycerides prevents the intrahepatic degradation of Apo B-100 allowing for increased VLDL formation and secretion.

There are three major sources of fatty acids in the liver all of which may be altered in patients with obesity (8,14,17,24,25). First, the flux of fatty acids from adipose tissue to the liver is increased (8,24,25). An increased mass of adipose tissue, particularly visceral stores, results in increased fatty acid delivery to the liver. Additionally, insulin suppresses the lipolysis of triglycerides to free fatty acids in adipose tissue. In patients with obesity a decrease in insulin activity due to insulin resistance results in the blunting of the inhibition of triglyceride lipolysis and an increase in triglyceride breakdown in adipose tissue leading to increased fatty acid deliver to the liver (8,25). A second source of fatty acids in the liver is de novo fatty acid synthesis. Numerous studies have shown that fatty acid synthesis is increased in the liver in patients with obesity (14,24,26). This increase may be mediated by the hyperinsulinemia seen in patients with insulin resistance. Specifically, insulin stimulates the activity of SREBP-1c, a transcription factor that increases the expression of the enzymes required for the synthesis of fatty acids. While the liver is insulin resistant to the effects of insulin on carbohydrate metabolism, the liver remains sensitive to the effects of insulin stimulating lipid synthesis (27). The third source of fatty acids is the uptake of triglyceride rich lipoproteins by the liver. Studies have shown an increase in intestinal fatty acid synthesis accompanied by the enhanced secretion of chylomicrons in obesity (14,24,28). This increase in chylomicrons leads to the increased delivery of fatty acids to the liver. The increase in hepatic fatty acids by these three pathways results in an increase in the synthesis of triglycerides in the liver and the protection of Apo B-100 from degradation resulting in the increased formation and secretion of VLDL (14,25). Additionally, the ability of insulin to suppress Apo B secretion is diminished in patients with obesity and marked insulin resistance (24,25). Finally, increased caloric intake may contribute to circulating triglycerides, either by dietary fat leading to increased chylomicron triglyceride levels and/or providing fatty acids to the liver or dietary carbohydrate enhancing de novo hepatic lipogenesis.

Metabolism of Triglyceride Rich Lipoproteins

In addition to the overproduction of triglyceride rich lipoproteins by the liver and intestine there are also abnormalities in the subsequent metabolism of these triglyceride rich lipoproteins, which contributes to the increase in triglyceride levels (8,14,17,24). Patients who are obese have an increase in Apo C-III levels (24,29). Apo C-III expression is inhibited by insulin and hence the insulin resistance that occurs in patients with obesity could account for the increase in Apo C-III (24). Apo C-III is an inhibitor of lipoprotein lipase activity and could thereby reduce the clearance of triglyceride rich lipoproteins (30). In addition, Apo C-III also inhibits the cellular uptake of triglyceride rich lipoproteins (30). Recent studies have shown that loss of function mutations in Apo C-III lead to decreases in serum triglyceride levels and a reduced risk of cardiovascular disease (31-33). Interestingly, inhibition of Apo C-III expression results in a decrease in serum triglyceride levels even in patients deficient in lipoprotein lipase indicating that the ability of Apo C-III to modulate serum triglyceride levels is not dependent solely on regulating lipoprotein lipase activity (34). Finally, if insulin resistance is severe the insulin induced stimulation of lipoprotein lipase may be reduced, which would also decrease the clearance of triglyceride rich lipoproteins (17). Thus, a decrease in clearance of triglyceride rich lipoproteins also contributes to the elevation in serum triglyceride levels in patients with obesity.

Production of Small Dense LDL and HDL

The elevation in triglyceride rich lipoproteins in turn has effects on other lipoproteins (figure 1). Specifically, cholesterol ester transfer protein (CETP) mediates the equimolar exchange of triglycerides from triglyceride rich VLDL and chylomicrons for cholesterol from LDL and HDL (8,9,13,17). The increase in triglyceride rich lipoproteins per se leads to an increase in CETP mediated exchange, increasing the triglyceride content and decreasing the cholesterol content of both LDL and HDL. Additionally, obesity also increases the activity and mass of CETP (13). This CETP-mediated exchange underlies the commonly observed reciprocal relationship of low HDL-C levels when triglyceride levels are high and the increase in HDL-C when triglyceride levels decrease.

The triglyceride on LDL and HDL is then hydrolyzed by hepatic lipase and lipoprotein lipase leading to the production of small dense LDL and small HDL particles (8,9,17). Notably hepatic lipase activity is increased in patients who are obese with increased visceral adiposity, which will facilitate the removal of triglyceride from LDL and HDL resulting in small lipoprotein particles (8,9,17). The affinity of Apo A-I for small HDL particles is reduced leading to the disassociation of Apo A-I and the clearance and breakdown of Apo A-I by the kidneys (8). These changes result in reduced levels of Apo A-I and HDL-C in patients who are obese.

Role of Inflammation and Adipokines

Obesity is a pro-inflammatory state due to macrophages that infiltrate adipose tissue. The cytokines produced by macrophages and the adipokines that are produced by fat cells also alter lipid metabolism (25,35-37).

Adipokines, such as adiponectin and resistin, regulate lipid metabolism. The circulating levels of adiponectin are decreased in subjects who are obese (38). Decreased adiponectin levels are associated with elevations in serum triglyceride levels and decreases in HDL-C levels (38). This association is thought to be causal as studies in mice have shown that overexpressing adiponectin (transgenic mice) decreases triglyceride and increases HDL-C levels while conversely, adiponectin knock-out mice have increased triglyceride and decreased HDL-C levels (38). The adiponectin induced decrease in triglyceride levels is mediated by an increased catabolism of triglyceride rich lipoproteins due to an increase in lipoprotein lipase activity and a decrease Apo C-III, an inhibitor of lipoprotein lipase (38). The increase in HDL-C levels induced by adiponectin is mediated by an increase in hepatic Apo A-I and ABCA1, which results in the increased production of HDL particles (38).

Resistin is increased in subjects who are obese and the levels of resistin directly correlate with plasma triglyceride levels (39). Moreover, resistin has been shown to stimulate hepatic VLDL production and secretion due to an increase in the synthesis of Apo B, triglycerides, and cholesterol (25,39). Finally, resistin is associated with a decrease in HDL-C and Apo A-I levels (25).

The pro-inflammatory cytokines, TNF and IL-1, stimulate lipolysis in adipocytes increasing circulating free fatty acid levels, which will provide substrate for hepatic triglyceride synthesis (36). In the liver, pro-inflammatory cytokines stimulate de novo fatty acid and triglyceride synthesis (36). These alterations will lead to the increased production and secretion of VLDL. At higher levels the pro-inflammatory cytokines decrease the expression of lipoprotein lipase and increase the expression of angiopoietin like protein 4, an inhibitor of lipoprotein lipase (36,40). Together these changes decrease lipoprotein lipase activity, thereby delaying the clearance of triglyceride rich lipoproteins. Thus, increases in the levels of pro-inflammatory cytokines will stimulate the production of triglyceride rich lipoproteins and delay the clearance of triglyceride rich lipoproteins, which together will contribute to the increase in serum triglycerides that occurs in patients with obesity.

Pro-inflammatory cytokines also affect HDL metabolism (41,42). First, they decrease the production of Apo A-I, the main protein constituent of HDL. Second, in macrophages pro-inflammatory cytokines decrease the expression of ABCA1 and ABCG1, which will lead to a decrease in the efflux of phospholipids and cholesterol from the cell to HDL. Third, pro-inflammatory cytokines decrease the production and activity of LCAT, which will limit the conversion of cholesterol to cholesterol esters in HDL. This step is required for the formation of a normal spherical HDL particle and facilitates the ability of HDL to transport cholesterol. Fourth, pro-inflammatory cytokines decrease CETP levels, which will decrease the movement of cholesterol from HDL to Apo B containing lipoproteins. Finally, pro-inflammatory cytokines decrease the expression of SR-B1 in the liver. SR-B1 plays a key role in the uptake of cholesterol from HDL particles into hepatocytes. Together these changes induced by pro-inflammatory cytokines result in a decrease in reverse cholesterol transport. Reverse cholesterol transport plays a key role in preventing cholesterol accumulation in macrophages thereby reducing atherosclerosis. Inflammation also decreases other important functions of HDL, such as its ability to prevent LDL oxidation (35,42).

CURRENT TREATMENT GUIDELINES FOR SERUM LIPIDS

The purpose of treating lipid disorders is to prevent the development of other diseases, particularly cardiovascular disease. Thus, the decision to treat should be based on the risk of the hyperlipidemia leading to those medical problems. A number of guidelines have been published that discuss in detail cardiovascular risk assessment and provide recommendations on treatment strategies (43-47). It should be noted that while these guidelines are similar there are significant differences between their recommendations. The current American College of Cardiology/American Heart Association (ACC/AHA) guidelines do not emphasize specific lipid/lipoprotein goals of therapy but rather to just treat with statins to lower LDL-C by a certain percentage (44). An exception is that they do recommend in patients with very high-risk ASCVD, to use an LDL-C threshold of 70 mg/dL to consider addition of non-statins to statin therapy. In contrast, other groups, such as the National Lipid Association, International Atherosclerosis Society, European Society of Cardiology/European Atherosclerosis Society, and American Association of Clinical Endocrinologists (AACE), do recommend lowering the LDL-C and non-HDL-C levels to below certain levels depending upon the cardiovascular risk in a particular patient but the recommendations from these organizations are not identical (43,45-47) (48).These issues are discussed in detail in the chapters on Guidelines for the Management of High Blood Cholesterol (49). In addition to cardiovascular complications, marked elevations in triglycerides can lead to pancreatitis (50). The National Lipid Association recommends treating triglyceride levels greater than 500mg/dl while the Endocrine Society recommends treating triglycerides if they are greater than 1000mg/dl to lower the risk of pancreatitis (47,51).

It should be noted that most lipid experts would recommend trying to achieve an LDL-C levels less than 70mg/dl and non-HDL-C levels less than 100mg/dl at a minimum in patients with cardiovascular disease or patients at very high risk for the development of cardiovascular disease. AACE and European Society of Cardiology/European Atherosclerosis Society have recommended LDL-C levels less than 55mg/dl in patients at very high risk (46,48). In other patients, an LDL-C level less than 100mg/dl and non-HDL-C level less than 130mg/dl is a reasonable goal. The recommendations for evaluating and treating dyslipidemia in patients with obesity are the same as non-obese patients. For additional details on deciding who to treat and the goals of therapy see other Endotext chapters (49,50,52)

MODALITIES TO TREAT LIPID ABNORMALITIES IN PATIENTS WITH OBESITY

Effect of diet

There are two issues with regards to diet. First is the effect of weight loss on serum lipids. Second is the effect of dietary constituents (macronutrients) on serum lipids. For additional details on the effect of diet on lipid and lipoproteins please see the chapter “Lifestyle Changes: Effect of Diet, Exercise, Functional Food, and Obesity Treatment, on Lipids and Lipoproteins” (53) and for additional information on weight loss diets see the chapter on “Dietary Treatment of Obesity” (54).

Low-Calorie Diet-Induced Weight loss

In 1992, Dattilo and Kris-Etherton published a meta-analysis that evaluated the effect of weight loss on serum lipids (55). For every 1Kg decrease in body weight there was a 0.77mg/dl decrease in LDL-C and 1.33mg/dl decrease in triglycerides. The effect of weight loss on HDL-C was more complex. For every 1kg decrease in body weight there is a 0.27mg/dl decrease in HDL-C during active weight loss. However, when weight is stabilized there is a 0.35mg/dl increase in HDL-C for every 1kg decrease in body weight that has occurred. In a more recent systemic review and meta-analysis Zomer et al. reported that a 5-10% weight loss resulted in a 16mg/dl decrease in triglycerides, 10mg/dl decrease in LDL-C, and a nonsignificant effect on HDL (+0.5 mg/dL) (56). Finally, in a very recent meta-analysis of 30 randomized controlled trials with 2,434 participants by Hasan et al it was reported that lifestyle (diet and/or exercise) induced weight loss at 12 months resulted in a 4mg/dl decrease in triglycerides, a 1.28 mg/dL decease in LDL-C, and 0.46 mg/dL increase in HDL-C per 1kg weight loss (57). Using the results of the most recent meta-analysis if a patient lost 10Kg of body weight and maintained the weight loss, one would expect that LDL-C would have decreased by 12.8mg/dl, triglycerides would have decreased by 40mg/dl, and HDL-C would have increased by 4.6mg/dl. Of course, many, if not most patients, will not be able to loss 10kg and maintain that weight loss for an extended period of time.

Additionally, one should recognize that the response of lipid levels to weight loss will vary greatly in individual patients but in general one can expect a decrease in serum triglyceride and LDL-C levels and an increase in HDL-C levels. The degree of decrease in serum triglyceride levels is related to baseline triglyceride levels with higher levels typically demonstrating a greater reduction with weight loss. In the Look-Ahead Trial decreases in LDL-C (15-18mg/dl) and triglyceride (21-25mg/dl) levels were similar across BMI categories in lifestyle participants who lost weight but in the severely obese the increase in HDL-C levels was blunted (58). Interestingly, in metabolically healthy patients who are obese and do not have lipid abnormalities or other metabolic abnormalities a calorie deficient diet still results in a decrease in triglycerides with no change in HDL-C levels (59). Finally, a systematic review of studies has shown that weight loss in children also decreases triglycerides and increases HDL-C levels (60).

Whether particular diets are better at inducing weight loss is hotly debated with many “experts” recommending certain diets as being advantageous. Sacks and colleagues in a large trial of 811 obese subjects compared four different diets (fat 20%/protein 15%/carbohydrate 65%; fat 20%/protein 25%/carbohydrate 55%; fat 40%/protein 121-25mg/dl)5%/carbohydrate 45%; and fat 40% protein 25% carbohydrate 35%) in which total calories were also reduced. They found that after two years weight loss was similar (61). Other studies that compared different diets over an extended of time period (at least one year) have reached similar conclusions (62-64). During the first 6 months of many diet studies, patients lose a significant amount of weight but unfortunately over an extended period of time most patients regain weight such that after two years the amount of weight loss is relatively modest. For example, in the study of Sacks et al patients lost approximately 6kg of weight during the first six months but by 24 months the total weight loss was only between 3-4kg (61). It is therefore essential that one focuses on “long-term” studies when comparing different diet approaches. At this time, it is not clear that any particular diet is “best” for inducing weight loss and individual weight loss is highly variable. The key is the ability of the patient to follow the diet for an extended period of time.

Dietary Macronutrient Constituents

The effect of different weight loss diets that differ by macronutrient content on the lipid profile has been evaluated in a large number of studies. A meta-analysis by Hu and colleagues examined the effect of a low-carbohydrate vs. a low-fat diet in 23 studies with 2,788 participants (63). They found, as expected, that both types of weight loss diets decreased LDL-C and triglyceride levels and increased HDL-C levels. However, the low carbohydrate diet decreased triglycerides and increased HDL-C to a greater extent than the low-fat diet. Conversely, the low-fat diet was more effective in lowering LDL-C levels. The results of this meta-analysis are shown in table 2. It should be noted that the magnitude of these changes, except for the decrease in triglycerides are small. Similarly, Mansoor et al in a meta-analysis of 11 RCT with 1369 participants reported that a low carbohydrate diet resulted in a decreased triglyceride level (23mg/dl) and increased HDL-C level (5.5mg/dl) compared to a high fat diet but LDL-C levels were also increased (6.2mg/dl) with the low carbohydrate diet (65). Additionally, Naude and colleagues in a meta-analysis of 12 studies with 1603 subjects, found that a low carbohydrate diet compared to a “balanced” diet resulted in lower triglyceride levels and higher HDL-C and LDL-C levels but once again the differences were relatively small (66). Additionally, a meta-analysis by Schwingshackl and Hoffmann compared high fat vs. low fat diets and observed that the decrease in LDL-C was more pronounced with a low-fat diet whereas the increase in HDL-C and the decrease in triglycerides were greater with the high-fat diet (67). Finally, a meta-analysis comparing ketogenic diets that are very-low in carbohydrates with low-fat diets resulted, as expected, in greater decreases in triglycerides and increases in HDL-C levels with the ketogenic than the low-fat diet but the ketogenic diet leads to an increase in LDL-C levels (68).

Table 2.

Comparison of High and Low Fat and Carbohydrate Diets

Low carbohydrate/high fatLow fat/high carbohydrate
Weight Loss (kg)-6.1-5.0
LDL-C (mg/dl)-2.1-6.0
HDL-C (mg/dl)4.51.6
Triglycerides (mg/dl)-30.4-17.1

A meta-analysis by Wycherley et al evaluated the effect of high protein vs. low protein diet on lipid levels in 24 studies with over a 1000 subjects (69). Weight loss was similar between the two diet strategies with less than a 1kg difference in weight loss between the high protein vs. low protein diets. Similarly, there were no differences in LDL-C or HDL-C levels but the high protein diet resulted in a greater decrease in triglyceride levels (20mg/dl).

A meta-analysis by Schwingshackl and Hoffmann compared the effect of low fat diets that were either low or high in protein (70). They observed no significant differences in LDL-C, HDL-C, or triglyceride levels indicating that high protein diets have neither beneficial nor detrimental effects on lipid levels.

In summary, low carbohydrate/high fat diets result in greater decreases in triglycerides and increases in HDL-C but LDL-C decreases are blunted. In contrast, low fat/high carbohydrate diets are more effective in lowering LDL-C levels but the decrease in triglycerides and the increase in HDL-C are blunted. Stated simply, diets that contain carbohydrates tend to increase triglyceride levels while diets high in fat increase HDL-C levels and if they contain saturated fats and/or trans fats increase LDL-C levels.

Glycemic Index

The glycemic index of foods is a marker for the rapid absorption and appearance of glucose in the blood during meal consumption. Higher glycemic index foods result in greater glucose and insulin excursions than low-glycemic index foods. A meta-analysis by Goff et al has examined the effect of foods with a high glycemic index vs. foods with a low glycemic index in 28 studies with over a 1000 subjects (71). There was no significant effect of glycemic index on either HDL-C or triglyceride levels. However, the low glycemic index foods resulted in a small decrease in LDL-C (approximately 6mg/dl). The decrease in LDL-C was only seen in the studies where the low glycemic diet also had an increase in dietary fiber, indicating that the observed differences were due to dietary fiber, a factor well known to decrease LDL-C levels. The effect of glycemic index has to be distinguished from that of carbohydrate levels. Indeed, in a recent study in which fiber was kept constant, a low glycemic index diet increased LDL-C when carbohydrate intake was high, but decreased LDL-C when carbohydrate was low (72).

To summarize dietary constituents of weight loss diets have a small but significant impact on the changes in lipid levels. Low carbohydrate diets decrease triglyceride levels to a greater extent than high carbohydrate diets. High saturated fat diets blunt the decrease in LDL-C that occurs with weight loss. HDL-C levels increase with weight loss and this increase is greatest with a high fat diet. A weight loss diet that contains a markedly reduced fat content my result in a decrease in HDL-C levels. Finally, a diet high in soluble fiber will lower LDL-C levels. As should be apparent from these data the effect of diet induced weight loss on the lipid profile is modest and thus in most patient’s pharmacologic therapy will be required to induce significant changes in the lipid profile.

It should be emphasized that the inability to decrease weight with diet therapy is not a reason to abandon dietary therapy. Patients should be encouraged to decrease their intake of saturated fats (<7% of calories) and trans fats and increase their intake of soluble fiber, which will favorably effect LDL-C levels. Additionally, reducing intake of simple sugars and alcohol will lower triglyceride levels. Thus, even in the absence of significant weight loss dietary therapy can be beneficial and should be encouraged.

Effect of Exercise

Exercise alone is usually not sufficient to induce significant weight loss (73,74). However, exercise when combined with diet therapy can facilitate weight loss and is considered very important for weight loss maintenance (73). It may also diminish the loss of muscle mass during weight loss (73). The effect of exercise on serum LDL-C varies with some studies showing a 4-7% decrease and some even showing increases (75,76). The decrease in LDL-C levels typically occurs in association with weight loss. However, the levels of small dense LDL decrease with exercise, while the levels of large LDL increase, an effect that occurs even in the absence of significant weight loss (76). To significantly increase HDL-C levels requires a considerable amount of exercise (700-2000kcal of exercise per week) (75,77). Serum triglyceride levels are most responsive to exercise with various studies showing a 4-37% decrease in serum triglyceride levels with exercise (mean decrease 24%) (75). Of note the changes in HDL-C and triglycerides induced by exercise occur independent of weight loss (75). Resistance training alone has minimal effects on triglyceride and HDL-C levels (78). It is recommended that patients exercise 150 minutes or more per week (for example 30 minutes 5x per week). The more intensive the exercise program the greater the effect on weight and lipid levels.

Effect of Weight Loss Drugs

There are several weight loss drugs currently approved for the long-term treatment of obesity. For a detailed discussion of weight loss drugs see the chapter on “Pharmacologic Treatment of Overweight and Obese Adults” (79). Weight loss drugs tend to decrease triglyceride and LDL-C levels and increase HDL-C levels due to their ability to decrease weight but the results vary in individual patients.

Orlistat (Xenical)

Orlistat is a lipase inhibitor that decreases fat absorption. Total cholesterol and LDL-C levels decrease with orlistat treatment to a greater degree than expected with diet alone (80-82). For example, in the XENDOS study LDL-C decreased by 12.8% in the orlistat group vs. 5.1% in the placebo group (80). Additionally, studies have shown that the levels of small dense LDL are reduced and the average LDL particle size increased with orlistat treatment (83). It has been shown that orlistat, in addition to reducing dietary triglyceride absorption, also decreases cholesterol absorption (84). A likely mechanism for the decrease in cholesterol absorption is orlistat inhibition of NPC1L1, a transporter in the intestine that mediates cholesterol absorption (85). Despite the effect on triglyceride absorption, orlistat does not markedly affect either triglyceride or HDL-C levels beyond what one would expect with weight loss (81,86).

Phenteramine + Topiramate (Qsymia)

Phenteramine is a sympathomimetic amine that induces satiety and topiramate is a neurostabilizer that also decreases appetite. In randomized controlled trials, phenteramine + topiramate combination therapy decreased triglyceride levels and increased HDL-C without a consistent effect on LDL-C levels (87-89). It is likely that these changes primarily represent the effect of the weight loss induced by this drug.

Lorcaserin (Belviq)

Lorcaserin is a serotonin 2C receptor agonist that suppresses appetite and induces weight loss. In randomized controlled trials, lorcaserin modestly decreased triglyceride levels and increased HDL-C levels with no effect on LDL-C levels (90-93). Similar to phenteramine + topiramate combination therapy, it is likely that the changes induced by lorcaserin treatment primarily represent the effect of the weight loss induced by this drug. Note that lorcaserin has been withdrawn from the market due to an increased risk of cancer.

Naltrexone + Bupropion (Contrave)

Naltrexone is an opioid antagonist and bupropion is an antidepressant. In large randomized control trials naltrexone + bupropion decreased triglyceride levels by approx. 8-12%, decreased LDL-C levels by 0-6%, and increased HDL-C by 3-8% (94-97). The magnitude of these changes in lipid levels mimics what one would expect from weight loss.

Liraglutide (Saxenda)

Liraglutide is a GLP-1 agonist that has been approved for the treatment of obesity. A large randomized trial demonstrated modest reductions in triglycerides (9%) and LDL-C levels (2.4%) and increases in HDL-C (1.9%) with liraglutide treatment (98). Another randomized trial failed to demonstrate changes in lipid parameters (99). However, a trial in patients with diabetes also resulted in modest improvements in triglyceride and HDL-C levels (100). Thus, liraglutide induces modest changes in the lipid profile that mimics what one observes with weight loss.

Summary of Weight Loss Drugs

Except for orlistat, which appears to lower LDL-C beyond what would be expected with weight loss alone, the effect of these weight loss drugs on lipid levels seems to reflect their ability to induce weight loss. It should be noted that the change in lipid levels induced by weight loss drugs is modest and variable.

Effect of Bariatric Surgery on Lipids

Bariatric surgery is more effective at inducing weight loss than either diet or medications (101,102). Associated with this greater decrease in weight is a more robust decrease in serum triglyceride levels and increase in HDL-C levels (103-105). In some studies, a marked decrease in LDL-C is also observed. For example, Nguyen et al reported that in patients with severe obesity, Roux-en-Y gastric bypass (RYGB) resulted in a 63% decrease in serum triglycerides, a 31% decrease in LDL-C, and a 39% increase in HDL-C (106). Studies have also shown a decrease in postprandial lipemia and Lp(a) levels (107-109). Moreover, the ability of HDL to mediate cholesterol efflux from cells is improved following bariatric surgery (110-112). Many patients are able to discontinue their lipid lowering drugs post bariatric surgery.

There are differences in the ability of different bariatric surgeries to impact lipids. Two randomized trials demonstrated a greater effect of RYGB compared to sleeve gastrectomy on dyslipidemia (113,114). Furthermore, in a meta-analysis comparing randomized trials of RNYGB vs. sleeve gastrectomy, Li et al reported that serum triglycerides decreased to a greater degree in the RYGB patients (approximately 20mg/dl) (115). A similar greater decrease in LDL-C levels was also seen in the RYGB groups (approximately 28mg/dl). Puzziferri et al published a systemic review of the long-term follow-up of patients after bariatric surgery (116). They reported that the remission of hyperlipidemia (defined as total cholesterol < 200mg/dl, HDL-C > 40mg/dl, LDL-C < 160mg/dl, and triglycerides < 200mg/dl) was 60.4% after RYGB but only 22.7% after gastric band. Thus, RYGB is the most effective procedure for reducing dyslipidemia in patients with obesity, followed by sleeve gastrectomy, followed by gastric banding (105). Whether the greater beneficial effects of RYGB on lipids is due to greater weight loss, endocrine changes, or enhanced bile-acid absorption and increases in circulating bile-acid levels induced by this procedure remains to be fully elucidated.

Effect of Lipid Lowering Drugs

In general, the effect of lipid lowering drugs in patients with obesity is similar to the effects observed in normal weight patients. Statins are the first line drug except in patients with very high triglyceride levels (>500mg/dl) where fibrates, fish oil (omega-3-fatty acids), or niacin may be used initially to specifically target the high triglycerides. For additional information on lipid lowering drugs please see the chapters on cholesterol lowering drugs and triglyceride lowering drugs (117,118). Below we address issues of using lipid lowering drugs that have importance for patients who are obese.

STATINS

Statins are easy to use and generally well tolerated by patients who are obese. Statins can adversely affect glucose homeostasis. In non-diabetics the risk of developing diabetes is increased by approximately 10% with higher doses of statins causing a greater risk than more moderate doses (119,120). The mechanism for this adverse effect is unknown but a recent study suggests that decreases in HMG-coenzyme A activity leads to weight gain, which could increase the risk of developing diabetes (121). Older patients who are obese with higher baseline glucose levels are at greatest risk for developing diabetes on statin therapy.

Muscle symptoms occur in patients with obesity similar to what is observed in normal weight patients. One study has shown that the cardiorespiratory benefits of exercise were blunted in patients who are overweight or obese on statin therapy (122). However, a recent review concluded that statins do not consistently reduce muscle strength, endurance, or overall exercise performance (123).

Statin outcome trials have not specifically focused on the benefits of statins in patients with obesity. However, subgroup analysis of the statin trials has demonstrated that the beneficial effects also occur in patients who are obese. In the Cholesterol Clinical Trialists meta-analysis, the reduction in cardiovascular events was no different in patients with a BMI greater than 30 or less than 25 (124,125). Thus, one can anticipate that statin treatment will achieve the same beneficial outcomes in patients who are obese as seen in the general population.

BILE ACID SEQUESTRANTS

Bile acid sequestrants may increase serum triglyceride levels, which can be a problem in some patients with obesity who are already hypertriglyceridemic (117). Colesevelam (Welchol) is a bile acid sequestrants that comes in pill or powder form that causes fewer side effects and has fewer interactions with other drugs than other preparations. Of particular note is that a number of studies have shown that colesevelam decreases A1c levels (approximately 0.5% decrease) and therefore this drug may have an added advantage in patients with obesity who are at high risk of developing diabetes (126).

NIACIN

Niacin reduces insulin sensitivity (i.e., causes insulin resistance), which can worsen glycemic control (127). In the HPS2-Thrive trial, niacin therapy induced new onset diabetes in subjects that were non-diabetic (128). In patients with obesity, who are at risk of developing diabetes, niacin therapy increases the risk of these patients progressing to diabetes. Niacin can also increase serum uric acid levels and induce gout, an abnormality that is already common in patients with obesity (127).

PCSK9 INHIBITORS

In 2015 two monoclonal antibodies that inhibit PCSK9 (proprotein convertase subtilisin kexin type 9) were approved for the lowering of LDL cholesterol levels; Alirocumab (Praluent) and evolocumab (Repatha) (117). The reduction in LDL cholesterol levels with PCSK9 inhibitor treatment is similar in obese and non-obese subjects and results in a 50-60% decrease in LDL cholesterol levels when added to statin therapy (117,129,130).

BEMPEDOIC ACID

Bempedoic acid was approved in the US in February 2020 and is an adenosine triphosphate-citrate lyase (ACL) inhibitor that decreases hepatic cholesterol synthesis (117). Patients with obesity often have elevated uric acid levels and an increased risk of gouty attacks and a major side effect of bempedoic acid is elevating uric acid levels (117). In clinical trials, 26% of bempedoic acid-treated patients with normal baseline uric acid values experienced hyperuricemia one or more times versus 9.5% in the placebo group (package insert). The increase in uric acid is due to bempedoic acid inhibiting renal tubular OAT2 (117). Elevations in blood uric acid levels may lead to the development of gout and gout was reported in 1.5% of patients treated with bempedoic acid vs. 0.4% of patients treated with placebo. The risk for gout attacks were higher in patients with a prior history of gout (11.2% for bempedoic acid treatment vs. 1.7% in the placebo group) (package insert). In patients with no prior history of gout only 1% of patients treated with bempedoic acid and 0.3% of the placebo group had a gouty attack (package insert).

EZETIMIBE, FIBRATES, AND OMEGA-3-FATTY ACIDS

These drugs are well tolerated in patients with obesity and their use in patients with obesity does not have any unique concerns.

TREATMENT APPROACH

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

Primary Prevention Patients

The first step is determining the risk for developing atherosclerotic cardiovascular disease. There are a number of different calculators for determining risk. In the US the most popular is the ACC/AHA risk calculator (http://www.cvriskcalculator.com/) whereas in Europe the SCORE (Systematic Coronary Risk Estimation) is popular (http://www.heartscore.org/en_GB/access). The ACC/AHA recommendations are shown in Figure 2 and the European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) recommendations are shown in Figure 3 (44,46). Note that the risk shown in the ADD/AHA calculator is for major cardiovascular events while the risk in the SCORE calculator is for mortality.

Figure 1. . ACC/AHA Recommendations for Patients without ASCVD, Diabetes, or LDL-C greater than 190mg/dl.

Figure 1.

ACC/AHA Recommendations for Patients without ASCVD, Diabetes, or LDL-C greater than 190mg/dl. Risk enhancers are listed in table 3. (note the risk is for MI and stroke, both fatal and nonfatal)

Figure 2. . European Society of Cardiology/European Atherosclerosis Society Recommendations for Primary Prevention Patients.

Figure 2.

European Society of Cardiology/European Atherosclerosis Society Recommendations for Primary Prevention Patients. Risk categories are shown in table 4. (note that the SCORE risk is for a fatal event). Goals of therapy are shown in table 5.

Table 3.

ASCVD Risk Enhancers (ACC/AHA)


Family history of premature ASCVD
Persistently elevated LDL > 160mg/dl
Chronic kidney disease
Metabolic syndrome
History of preeclampsia
History of premature menopause
Inflammatory disease (especially rheumatoid arthritis, psoriasis, HIV)
Ethnicity (e.g., South Asian ancestry)
Persistently elevated triglycerides > 175mg/dl
Hs-CRP > 2mg/L
Lp(a) > 50mg/dl or >125nmol/L
Apo B > 130mg/dl
Ankle-brachial index (ABI) < 0.9

Table 4.

Cardiovascular Risk Categories (ESC/EAS)

Very High RiskASCVD
DM with target organ damage or at least three major risk factors or early onset of T1DM of long duration (>20 years)
Severe CKD (eGFR <30 mL/min/1.73 m2)
A calculated SCORE >10% for 10-year risk of fatal CVD
FH with ASCVD or with another major risk factor
High RiskMarkedly elevated single risk factors, in particular TC >310 mg/dL, LDL-C >190 mg/dL, or BP >180/110 mmHg
Patients with FH without other major risk factors
Patients with DM without target organ damage with DM duration >10 years or another additional risk factor
Moderate CKD (eGFR 30-59 mL/min/1.73 m2).
A calculated SCORE >5% and <10% for 10-year risk of fatal CVD
Moderate RiskYoung patients (T1DM <35 years; T2DM <50 years) with DM duration <10 years, without other risk factors
Calculated SCORE >1% and <5% for 10-year risk of fatal CVD.
Low RiskCalculated SCORE <1% for 10-year risk of fatal CVD

Table 5.

Treatment Targets and Goals (ECS/EAS)

LDL-CNon-HDL-C**Apo B**
Very High Risk< 55mg/L; 1.4mmol/L*< 85mg/dL; 2.2mmol/L< 65mg/dL
High Risk< 70mg/dL; 1.8mmol/L*< 100mg/dL; 2.6mmol/L< 80mg/dL
Moderate Risk< 100mg/L; 2.6mmol/L< 130mg/dL; 3.4mmol/L< 100mg/dL
Low Risk< 116mg/dL; 3.0mmol/L
*

>50% LDL-C reduction from baseline; ** Secondary goals

A few caveats are worth noting. First, in patients less than 60 years of age it is very helpful to calculate the life-time risk of ASCVD events. Often one will find that the 10-year risk is modest but the life-time risk is high and this information should be included in the risk discussion to help in the decision process. Second, patients should be made aware of the natural history of ASCVD and that it begins early in life and slowly progresses overtime with high LDL-C levels accelerating the rate of development of atherosclerosis and low LDL-C leading to a slower progression of atherosclerosis (131). Third, patients should be made aware of genetic studies demonstrating that variants in genes that lead to lifetime decreases in LDL-C levels (for example the HMG-CoA reductase gene, NPC1L1 gene, PCSK9 gene, ATP citrate lyase gene, and LDL receptor gene) result in a decreased risk of cardiovascular events. In a recent study it was reported that a 10mg/dL lifetime decrease in LDL-C with any of these genetic variants was associated with a 16-18% decrease in cardiovascular events whereas a 10mg/dl reduction in LDL-C with lipid lowering therapy later in life results in only approximately a 5% decrease in cardiovascular events ((132,133). The combination of the natural history and the results observed with genetic variants strongly suggests that early therapy to lower LDL-C levels will have greater effects on reducing the risk of ASCVD events than starting therapy later in life. This information needs to be discussed with the patient. Fourth, in patients/health care providers who are uncertain of the best course of action obtaining a cardiac calcium scan can be very helpful in the decision-making process, particularly in older individuals (44). A score of 0, particularly in an older patient would indicate that statin therapy is not needed whereas a score > 100 would indicate a need for statin therapy. A score of 1-99 favors the use of a statin.

In most primary prevention patients, statin therapy is sufficient to lower LDL-C levels to goal (< 100mg/dl). One can usually start with moderate statin therapy (for example atorvastatin 10-20mg or rosuvastatin 5-10mg) and increase the statin dose if necessary, to achieve LDL-C goals. In some instances, primary prevention patients are at high risk (see figures 2 and 3) and should be started on intensive statin therapy with lower LDL-C goals. Statins are available as generic drugs and therefore are relatively inexpensive. If a patient does not achieve their LDL-C goal on intensive statin therapy, cannot tolerate statin therapy, or is able to take only a low dose of a statin one can use ezetimibe (generic drug), bempedoic acid, bile acid sequestrant, or PCSK9 inhibitors to further lower LDL-C levels (for detailed discussion of cholesterol lowering drugs see (117)). It should be noted that the addition of ezetimibe or a PCSK9 inhibitor to statin therapy has been shown to reduce cardiovascular events (134-137). In most situations, ezetimibe is the drug of choice given its low cost, ability to reduce ASCVD events, and long-term safety record.

Patients with Diabetes

Patients with diabetes without risk factors should be started on moderate statin therapy (for example atorvastatin 10-20mg or rosuvastatin 5-10mg) and the dose increased as needed to reach therapy goals. Patients with diabetes with ASCVD or risk factors should be started on intensive statin therapy. In my opinion reasonable goals are shown in table 6 (similar to AACE and ECS/EAS guidelines) (46,48,138). If moderate statin therapy does not achieve the LDL-C goal the dose can be increased. If intensive therapy does not achieve LDL-C goals additional drugs can be added. If reasonably close to the LDL-C goal the initial drug added should be ezetimibe. If far from goal one could add a PCSK9 inhibitor. Once LDL-C is at goal if the non-HDL-C remains high one can consider the approaches described in the section describing the approach to patients with LDL-C at goal and triglycerides elevated.

Table 6.

ASCVD Risk Categories and Treatment Goals

Risk CategoryRisk Factors/10-year riskLDL-C mg/dlNon-HDL-C mg/dl
Extreme RiskDiabetes and clinical cardiovascular disease<55<80
Very High RiskDiabetes with one or more risk factors<70<100
High RiskDiabetes and no other risk factors<100<130

Secondary Prevention Patients

Patients with ASCVD (secondary prevention patients) should be started on intensive statin therapy (atorvastatin 40-80mg per day or rosuvastatin 20-40mg per day). Given the extensive data showing that the lower the LDL-C the greater the reduction in ASCVD events most secondary prevention patients would benefit from the addition of ezetimibe to maximize LDL-C lowering without markedly increasing costs (133). The goal LDL-C in this patient population is an LDL<70mg/dl but many experts and some guidelines (ACCE, ECS/EAS) would prefer an LDL-C<55mg/dl if possible. If on intensive statin therapy and ezetimibe treatment the LDL-C is far above goal one could consider adding a PCSK9 inhibitor (this is particularly necessary if the LDL-C is greater than 100mg/dl or the patient is at very high risk due to other factors (diabetes, cerebral vascular disease, peripheral vascular disease, recent MI, history of multiple Mis, etc.) (133).

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

Patients with an LDL-C at goal but high triglyceride levels (>150mg/dl to <500mg/dl) will often have increased non-HDL-C levels. Numerous studies have shown that the risk of ASCVD events is increased in this patient population (139). The initial step should be to improve lifestyle, treat secondary disorders that may be contributing to the increase in triglycerides, and if possible, discontinue medications that increase triglyceride levels (52). Studies have not demonstrated a reduction in cardiovascular events when niacin is added to statin therapy and given the side effects of niacin enthusiasm for using niacin in combination with statins to reduce ASCVD is limited (128,140). Additionally, the ACCORD-LIPID trial also failed to demonstrate that adding fenofibrate to statin therapy reduces cardiovascular disease (141). However, there was a suggestion of benefit with fenofibrate therapy in the patients in whom the baseline triglyceride levels were elevated (>204mg/dl) and HDL cholesterol levels decreased (<34mg/dl). This observation agrees with a meta-analysis of five fibrate trials that analyzed patients who had both low HDL-C levels (<35mg/dl) and elevated triglycerides (>200mg/dl) and found that fibrates reduced cardiovascular risk by 30% (P < 0.0001) (142). Thus, while not definitive these observations suggest that adding fenofibrate to statin therapy in patients with high triglyceride levels may be beneficial. It should also be noted that in patients with diabetes fenofibrate reduces the development of diabetic microvascular disease (118).

Recently, the REDUCE-IT trial demonstrated that adding the omega-3-fatty acid icosapent ethyl (EPA; Vascepa) to statin therapy in patients with elevated triglyceride levels reduced the risk of ASCVD events by 25% while decreasing triglyceride levels by 18% (143). Similar decreases in cardiovascular disease were seen in the JELIS trial (144). In these trials the reduction in triglyceride levels was relatively modest and would not have been expected to result in the magnitude of the decrease in cardiovascular disease observed in the JELIS and REDUCE-IT trials. Other actions of EPA, such as decreasing platelet function, anti-inflammation, decreasing lipid oxidation, stabilizing membranes, etc. could account for or contribute to the reduction in cardiovascular events (145). Recently the National Lipid Association has recommended “that for patients aged ≥45 years with clinical ASCVD, or aged ≥50 years with diabetes mellitus requiring medication plus ≥1 additional risk factor, with fasting TGs 135 to 499 mg/dL on high-intensity or maximally tolerated statin therapy (±ezetimibe), treatment with icosapent ethyl is recommended for ASCVD risk reduction” (146).

Thus, in certain patients with elevated triglyceride levels and LDL-C at goal combination therapy should be considered. Given the positive outcome studies with icosapent ethyl this agent would be a good choice. In patients with diabetes and microvascular disease one could consider fenofibrate to both reduce ASCVD and microvascular complications. For a detailed discussion of triglyceride lowering drugs see the Endotext chapter on this topic (118).

Patients with Very High Triglyceride Levels (>500-1000mg/dl)

The main aim is to keep triglyceride levels below 500 mg/dL to prevent triglyceride-induced pancreatitis (147,148). Very high triglyceride levels are frequently due to the coexistence of a genetic predisposition to hypertriglyceridemia with 1 or more secondary causes of hypertriglyceridemia (147,148). Initial treatment is a very low-fat diet to reduce triglyceride levels into a safe range (<1000mg/dl). Treating secondary disorders that raise triglyceride levels and when possible, stopping drugs that increase triglyceride levels is essential (147,148). Avoidance of simple sugars and ethanol is also indicated. If the triglyceride levels remain above 500mg/dl the addition of fenofibrate or omega-3-fatty acids is indicated. Many patients with very high triglyceride levels are at high risk for ASCVD and therefore after triglyceride levels are controlled the patient should be evaluated for cardiovascular disease risk and if indicated LDL-C lowering therapy initiated.

Decreased HDL Cholesterol Levels

There are no studies demonstrating that increasing HDL-C levels reduces cardiovascular disease (149). It should be recognized that the crucial issue with HDL may not be the HDL-C levels per se but rather the function of the HDL particles (149). Assays have been developed to determine the ability of HDL to facilitate cholesterol efflux from macrophages and these studies have shown that the levels of HDL-C do not necessarily indicate the ability to mediate cholesterol efflux (150). Similarly, the ability of HDL to protect LDL from oxidation may also play an important role in the ability of HDL to reduce ASCVD (151). Thus, the functional capability of HDL may be more important than HDL-C levels (150,151).

SUMMARY

In summary, modern therapy of patients with obesity demands that we aggressively treat lipids to reduce the high risk of cardiovascular disease in this susceptible population and in those with very high triglycerides to reduce the risk of pancreatitis.

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