Obesity and Dyslipidemia

Kenneth R. Feingold

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Obesity and Dyslipidemia

Kenneth R. Feingold, MD.

Author Information and Affiliations

Last Update: March 24, 2026.

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 TG, VLDL, apolipoprotein B, and non-HDL-C levels. The increase in serum TG is due to increased hepatic production of VLDL particles and a decrease in the clearance of TG rich lipoproteins. HDL-C levels are typically low and are associated with the increase in serum TG. LDL-C levels are frequently in the normal range or only slightly elevated 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. Lifestyle induced weight loss will decrease serum TG and LDL-C levels and increase HDL-C levels. In most patients the changes in lipid levels with lifestyle induced weight loss are not very robust and are 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 TG 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. Weight loss medications and bariatric surgery will also improve dyslipidemia. 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 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 fibrates 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 40% of individuals are obese defined as a BMI >30 kg/m² (2,3). Additionally, approximately 40% 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. Conversely, in certain ethnic groups obesity occurs even though the BMI is in the normal range (7). Of great concern is that the prevalence of obesity has also markedly increased in children (8,9). 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 (10-12). 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 (10-14). The majority of deaths related to a 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 TG, VLDL, Apo B, and non-HDL-C levels, which are all commonly observed (10,11,15-17). HDL-C and Apo A-I levels are typically low (10,11,15-17). LDL-C levels are frequently in the normal to slightly elevated range, but an increase in small dense LDL is often seen resulting in an increased number of LDL particles (10,11,15-17). These small dense LDL particles are considered to be more pro-atherogenic than large LDL particles for a number of reasons (18). 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 TG levels are also increased in subjects with obesity and these chylomicron remnants are pro-atherogenic (17,19,20). 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 (10). Notably, obesity in children and young adults also leads to an increased prevalence of elevated TG and decreased HDL-C levels (21). 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 TG

Increased VLDL

Increased apo B

Increased non-HDL-C

Increased remnant cholesterol

Increased small dense LDL

Increased LDL particle number

Decreased HDL-C

Decreased apo A1

LDL-C normal or slightly increased

Lp(a) not altered

It should be emphasized that the effects of obesity on lipid metabolism are dependent on the location of the adipose tissue (22-26). Increased visceral adipose tissue and trunk (especially upper trunk) subcutaneous adipose tissue are associated with higher TG and lower HDL-C levels. In contrast, increased subcutaneous adipose tissue in the legs is associated with lower TG levels. The protective effect of leg fat may explain why women and African Americans have lower TG levels. 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.

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

Production of TG Rich Lipoproteins

There are a number of different abnormalities that contribute to the dyslipidemia seen in patients with obesity (figure 1) (10,16,20,27,28). 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 (10,16,20,27,28). A key abnormality is the overproduction of VLDL particles by the liver, which is an important contributor to the elevation in serum TG levels (10,16,20,27,28). The rate of secretion of VLDL particles is highly dependent on TG availability, which is determined by the levels of fatty acids available for the synthesis of TG in the liver. An abundance of TG 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 (10,16,20,27,28). First, the flux of fatty acids from adipose tissue to the liver is increased (10,27,28). An increased mass of adipose tissue, particularly visceral stores, results in increased fatty acid delivery to the liver. Additionally, insulin suppresses the lipolysis of TG 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 TG lipolysis and an increase in TG breakdown in adipose tissue leading to increased fatty acid deliver to the liver (10,28). 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 (16,27,29). 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 (30). The third source of fatty acids is the uptake of TG rich lipoproteins by the liver. Studies have shown an increase in intestinal fatty acid synthesis accompanied by the enhanced secretion of chylomicrons in obesity (16,27,31). 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 TG in the liver and the protection of Apo B-100 from degradation resulting in the increased formation and secretion of VLDL (16,28). Additionally, the ability of insulin to suppress Apo B secretion is diminished in patients with obesity and marked insulin resistance (27,28). Finally, increased caloric intake may contribute to circulating TG, either by dietary fat leading to increased chylomicron TG levels and providing fatty acids to the liver or dietary carbohydrate enhancing de novo hepatic lipogenesis.

Metabolism of TG Rich Lipoproteins

In addition to the overproduction of TG rich lipoproteins by the liver and intestine there are also abnormalities in the subsequent metabolism of these TG rich lipoproteins, which contributes to the increase in TG levels (10,16,20,27). Patients who are obese have an increase in Apo C-III levels (27,32). 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 (27). Apo C-III is an inhibitor of lipoprotein lipase activity and could thereby reduce the clearance of TG rich lipoproteins (33). In addition, Apo C-III also inhibits the hepatic uptake of TG rich lipoproteins (33). Recent studies have shown that loss of function mutations in Apo C-III lead to decreases in serum TG levels and a reduced risk of cardiovascular disease (34-36). Interestingly, inhibition of Apo C-III expression results in a decrease in serum TG levels even in patients deficient in lipoprotein lipase indicating that the ability of Apo C-III to modulate serum TG levels is not dependent solely on regulating lipoprotein lipase activity (37). Apo A-V facilitates the activation of lipoprotein lipase and is decreased in obese patients (38). Finally, if insulin resistance is severe the insulin induced stimulation of lipoprotein lipase may be reduced, which would also decrease the clearance of TG rich lipoproteins (20). Thus, a decrease in clearance of TG rich lipoproteins also contributes to the elevation in serum TG levels in patients with obesity.

Production of Small Dense LDL and HDL

The elevation in TG rich lipoproteins in turn has effects on other lipoproteins (figure 1). Specifically, cholesterol ester transfer protein (CETP) mediates the equimolar exchange of TG from TG rich VLDL and chylomicrons for cholesterol from LDL and HDL (10,11,15,20). The increase in TG rich lipoproteins per se leads to an increase in CETP mediated exchange, increasing the TG content and decreasing the cholesterol content of both LDL and HDL. Additionally, obesity also increases the activity and mass of CETP (15). This CETP-mediated exchange underlies the commonly observed reciprocal relationship of low HDL-C levels when TG levels are high and the increase in HDL-C when TG levels decrease.

The TG 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 (10,11,20). Notably hepatic lipase activity is increased in patients who are obese with increased visceral adiposity, which will facilitate the removal of TG from LDL and HDL resulting in small lipoprotein particles (10,11,20). 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 (10). 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 (28,39-41).

Adipokines, for example adiponectin and resistin, regulate lipid metabolism. The circulating levels of adiponectin are decreased in subjects who are obese (42). Decreased adiponectin levels are associated with elevations in serum TG levels and decreases in HDL-C levels (42). This association is thought to be causal as studies in mice have shown that overexpressing adiponectin (transgenic mice) decreases TG and increases HDL-C levels while conversely, adiponectin knock-out mice have increased TG and decreased HDL-C levels (42). The adiponectin induced decrease in TG levels is mediated by an increased catabolism of TG rich lipoproteins due to an increase in lipoprotein lipase activity and a decrease Apo C-III, an inhibitor of lipoprotein lipase (42). 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 (42).

Resistin is increased in subjects who are obese and the levels of resistin directly correlate with plasma TG levels (43). Moreover, resistin has been shown to stimulate hepatic VLDL production and secretion due to an increase in the synthesis of Apo B, TG, and cholesterol (28,43). Finally, resistin is associated with a decrease in HDL-C and Apo A-I levels (28).

The pro-inflammatory cytokines, TNF and IL-1, stimulate lipolysis in adipocytes increasing circulating free fatty acid levels, which will provide substrate for hepatic TG synthesis (40). In the liver, pro-inflammatory cytokines stimulate de novo fatty acid and TG synthesis (40). 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 (40,44). Together these changes decrease lipoprotein lipase activity, thereby delaying the clearance of TG rich lipoproteins. Thus, increases in the levels of pro-inflammatory cytokines will stimulate the production of TG rich lipoproteins and delay the clearance of TG rich lipoproteins, which together will contribute to the increase in serum TG that occurs in patients with obesity.

Pro-inflammatory cytokines also affect HDL metabolism (45,46). 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. Together these changes induced by pro-inflammatory cytokines could result in a decrease in HDL-C and Apo AI levels.

CURRENT TREATMENT GUIDELINES FOR SERUM LIPIDS

The purpose of treating lipid disorders is to prevent the development of other diseases, particularly cardiovascular disease and if the TG levels are very high pancreatitis. 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 (47-52). Similarly, there are guidelines addressing the risk of high TG levels and pancreatitis. The National Lipid Association considers TG levels greater than 500mg/dL, the European Atherosclerosis Society TG levels greater than 880mg/dL, and the Endocrine Society TG levels greater than 1000mg.dL a high risk for pancreatitis (53-55).

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 (51,56,57)

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 “The Effect of Diet on Cardiovascular Disease and Lipid and Lipoprotein Levels” (58) and for additional information on weight loss diets see the chapter on “Dietary Treatment of Obesity” (59).

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 (60). For every 1Kg decrease in body weight there was a 0.77mg/dL decrease in LDL-C and 1.33mg/dL decrease in TG. 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 TG, 10mg/dL decrease in LDL-C, and a nonsignificant effect on HDL (+0.5 mg/dL) (61). Finally, in a 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 TG, a 1.28 mg/dL decease in LDL-C, and 0.46 mg/dL increase in HDL-C per 1kg weight loss (62). 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, TG 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 lose 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 TG and LDL-C levels and an increase in HDL-C levels. The degree of decrease in serum TG levels is related to baseline TG 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 TG (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 (63). 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 TG with no change in HDL-C levels (64). Finally, a systematic review of studies has shown that weight loss in children also decreases TG and increases HDL-C levels (65).

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 (66). Other studies that compared different diets over an extended of time period (at least one year) have reached similar conclusions (67-69). 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 (66). 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 (68). They found, as expected, that both types of weight loss diets decreased LDL-C and TG levels and increased HDL-C levels. However, the low carbohydrate diet decreased TG 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 TG levels 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 TG 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 (70). 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 TG levels and higher HDL-C and LDL-C levels but once again the differences were relatively small (71). 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 TG were greater with the high-fat diet (72). Finally, a meta-analysis comparing ketogenic diets that are very-low in carbohydrates with low-fat diets resulted, as expected, in greater decreases in TG 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 (73). Thus, diets low in carbohydrates reduce TG levels more effectively than a high carbohydrate diet while a high fat diet increases LDL-C and HDL-C more than a low-fat diet.

Table 2.

Comparison of High and Low Fat and Carbohydrate Diets (68)

	Low carbohydrate/high fat	Low fat/high carbohydrate
Weight Loss (kg)	-6.1	-5.0
LDL-C (mg/dL)	-2.1	-6.0
HDL-C (mg/dL)	4.5	1.6
TG (mg/dL)	-30.4	-17.1

While the typical increases in LDL-C levels observed with a ketogenic diet are modest, recently a series of reports have described marked elevations in LDL-C levels in some patients on a ketogenic diet (74-76). For example, Goldberg et al reported 5 patients with marked increases in LDL-C levels on a ketogenic diet (77). Three patients had LDL-C levels greater than 500mg/dl. Similarly, Schaffer et al described 3 patients in which a very low carbohydrate diet induced LDL-C levels greater then 400mg/dL (78). Finally, Schmidt et al reported 17 patients with LDL-C levels greater than 200mg/dL on a ketogenic diet (79). In these patients there was an average increase in their LDL-C level of 187 mg/dL (79). The elevations in LDL-C levels decrease towards normal with cessation of the ketogenic diet (77-79). It should be noted that most of the patients with marked elevations in LDL-C in response to a ketogenic diet had normal LDL-C levels prior to the dietary change (75). This hyper response seems to occur more commonly in patients who are lean (75) but has also been seen in obese patients (77).

Many of the individuals who develop marked increases in LDL-C on a very low carbohydrate ketogenic diet have low triglyceride levels, elevated HDL-C levels, and are thin (74,75). This phenotype has been called the lean mass hyper-responder (LMHR) phenotype (74,75). LMHR individuals have been defined as having triglycerides <70mg/dL, HDL-C > 80mg/dL, and LDL-C > 200mg/dL (74,75). The mechanism for the marked increase in LDL-C levels is unknown.

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 (80). 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 TG 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 (81). They observed no significant differences in LDL-C, HDL-C, or TG levels indicating that high protein diets have neither beneficial nor detrimental effects on lipid levels when coupled with a low-fat diet.

There are many diet programs that a widely advertised. In a network meta-analysis of 121 eligible trials with 21, 942 overweight or obese patients Ge and colleagues compared the effect of 14 different diets on LDL-C and HDL-C levels (82). The diets could be grouped into low CHO diets (Atkins, South Beach, Zone), moderate macronutrients diets (Biggest Loser, DASH, Jenny Craig, Mediterranean, Portfolio, Slimming World, Volumetrics, Weight Watchers), and low-fat diets (Ornish, Rosemary Conley). The effect of these different diets on LDL-C and HDL-C levels are shown in table 3. It should be noted that despite considerable weight loss the effect of these diets on LDL-C and HDL-C levels was very modest except for the LDL-C lowering seen with the Portfolio diet. The Portfolio dietary pattern is a plant-based dietary pattern that includes four cholesterol-lowering foods; a) tree nuts or peanuts, b) plant protein from soy products, beans, peas, chickpeas, or lentils, c) viscous soluble fiber from oats, barley, psyllium, eggplant, okra, apples, oranges, or berries, and d) plant sterols initially provided in a plant sterol-enriched margarine. Unfortunately, a comparison of the effect of these 14 different diets on TG levels was not reported.

Table 3.

Effect of Different Diets in Comparison with Usual Diet

Diet vs. Usual Diet	Decrease in Weight (Kg)	Change in LDL-C (mg/dL)	Change in HDL-C (mg/dL)
Atkins	5.46	+2.75	-3.41
Zone	4.07	+2.89	+0.33
Dash	3.63	-3.93	+1.90
Mediterranean	2.87	-4.59	+0.61
Paleolithic	5.31	-7.27	+2.52
Low Fat	4.87	-1.92	+2.13
Jenny Craig	7.77	-0.21	+2.85
Volumetrics	5.95	-7.13	+0.13
Weight Watchers	3.90	-7.13	+0.88
Rosemary Conley	3.76	-7.15	+2.04
Ornish	3.64	-4.71	+4.87
Portfolio	3.64	-21.29	+3.26
Biggest Loser	2.88	-3.90	+0.01
Slimming World	2.15	N/A	N/A
South Beach	9.86	+0.64	-3.60
Dietary Advice	0.31	+2.01	+1.71

In a study carried out in a single center the Atkins, Zone, Weight Watchers, and Ornish diets were compared and the effect on TG levels was also reported (83). Table 4 shows the results of this study at 2 months, a period at which dietary compliance was still high. The magnitude of weight loss was similar but the decrease in LDL-C that occurs with weight loss was blunted with a diet that was high in fat (Atkins diet). In contrast HDL-C levels increased with a high fat diet, particularly saturated fatty acids (Atkins diet) and decreased with a very low-fat diet (Ornish diet). The weight loss induced decrease in TG levels was blunted by a high carbohydrate intake (Ornish diet). These observations confirm and extend the results described above.

Table 4.

Effect of Different Diets on Lipid Levels

	Weight (kg)	LDL-C (mg/dL)	HDL-C (mg/dL)	TG (mg/dL)
Atkins	-3.6	1.3	3.2	-32
Zone	-3.8	-9.7	1.8	-54
Weight Watchers	-3.5	-12.1	-0.2	-9.2
Ornish	-3.6	-16.5	-3.6	-0.4

In summary, low carbohydrate/high fat diets result in greater decreases in TG 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 TG and the increase in HDL-C are blunted. Stated simply, diets that contain carbohydrates tend to increase TG 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 (84). There was no significant effect of glycemic index on either HDL-C or TG 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 likely due to dietary fiber, a factor well known to decrease LDL-C levels.

SUMMARY

To summarize dietary constituents of weight loss diets have a small but significant impact on the changes in lipid levels. Low carbohydrate diets decrease TG 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 may 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. For additional information on the effect of diet on lipid levels see the Endotext chapter entitled “ The Effect of Diet on Cardiovascular Disease and Lipid and Lipoprotein Levels” (58).

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 TG 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 (85,86). However, exercise when combined with diet therapy can facilitate weight loss and is considered very important for weight loss maintenance (85). It may also diminish the loss of muscle mass during weight loss (85). The effect of exercise on serum LDL-C varies with some studies showing a 4-7% decrease and some even showing increases (87,88). 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 (88). To significantly increase HDL-C levels requires a considerable amount of exercise (700-2000kcal of exercise per week) (87,89). Serum TG levels are most responsive to exercise with various studies showing a 4-37% decrease in serum TG levels with exercise (mean decrease 24%) (87). Of note the changes in HDL-C and TG induced by exercise occur independent of weight loss (87). Resistance training alone has minimal effects on TG and HDL-C levels (90). It is recommended that patients exercise 150 minutes or more per week (for example 30 minutes 5x per week) and muscle-strengthening exercises on two or more days 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” (91). Weight loss drugs tend to decrease TG 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 (92-94). For example, in the XENDOS study LDL-C decreased by 12.8% in the orlistat group vs. 5.1% in the placebo group (92). A meta-analysis of 33 studies with over 10,000 participants reported a weight loss of 2.12kg associated with a decrease in TGs of 8mg/dL, HDL-C of 1.3mg/dL and LDL-C of 10.4mg/dL (95). Additionally, studies have shown that the levels of small dense LDL are reduced and the average LDL particle size increased with orlistat treatment (96). It has been shown that orlistat, in addition to reducing dietary TG absorption, also decreases cholesterol absorption (97). A likely mechanism for the decrease in cholesterol absorption is orlistat inhibition of NPC1L1, a transporter in the intestine that mediates cholesterol absorption (98). Despite the effect on TG absorption, orlistat does not markedly affect either fasting TG or HDL-C levels beyond what one would expect with weight loss (93,95). However, orlistat does reduce postprandial TG levels and has been used to treat patients with the familial chylomicronemia syndrome (99).

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 TG levels and increased HDL-C without a consistent effect on LDL-C levels (100-102). A meta-analysis of 4 studies with over 4,000 participants reported a weight loss of 7.7kg with a decrease in TGs of 13.4% and LDL-C of 1% with an increase of HDL-C of 4.6% (103). It is likely that these changes primarily represent the effect of the weight loss induced by this drug.

NALTREXONE + BUPROPION (CONTRAVE)

Naltrexone is an opioid antagonist and bupropion is an antidepressant. In large randomized control trials naltrexone + bupropion decreased TG levels by approx. 8-12%, decreased LDL-C levels by 0-6%, and increased HDL-C by 3-8% (104-107). 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 TG (9%) and LDL-C levels (2.4%) and increases in HDL-C (1.9%) with liraglutide treatment (108). Another randomized trial failed to demonstrate changes in lipid parameters (109). However, a trial in patients with diabetes also resulted in modest improvements in TG and HDL-C levels (110). Note in patients with diabetes some of the benefits of GLP-1 receptor agonists may be attributed to improvement in glycemic control. Thus, liraglutide induces modest changes in the lipid profile that mimics what one observes with weight loss.

SEMAGLUTIDE (WEGOVY)

Several studies have determined the effect of semaglutide on lipid levels during weight loss trials. In the STEP 1 trial 1961 adults who were obese or overweight were randomized to semaglutide 2.4mg weekly or placebo (111). The individuals in the semaglutide group lost 12.4% of their body weight compared to the placebo group. TG and LDL-C levels decreased by 16% and 4% respectively in the semaglutide group vs. the placebo group while HDL-C increased by 4%. In the STEP 3 trial 611 obese or overweight individuals were randomized to semaglutide 2.4mg weekly or placebo (112). In this trial LDL-C was decreased by 7mg/dL and TG by 17mg/dL while HDL-C was increased by 1.5mg/dL. In the SELECT trial, which was a cardiovascular outcome study with 17,604 patients, semaglutide decreased TGs by 16%, LDL-C by 2.2% and increased HDL-C by 4.2% with a weight loss of 8.5% (113). In a meta-analysis of 5 randomized studies with 3890 individuals TGs were decreased by 16.5% and LDL-C by 5.2% while HDL-C was increased by 2.1% (weight was decreased by 11.8%) (114). In other studies it has been shown that GLP-1 receptor agonists reduce postprandial TGs by reducing circulating chylomicrons due to decreasing intestinal lipoprotein production (115).

Note that the studies described above are in obese or overweight patients without diabetes. Semaglutide markedly improves glycemic control, which can favorably affect lipid levels (116,117).

TIRZEPATIDE

In the SURMOUNT 1 trial 2539 participants were randomized to placebo or tirzepatide 5, 10, or 15mg weekly (118). The change in weight at week 72 was −15.0% with 5-mg, −19.5% with 10-mg and −20.9% with 15-mg tirzepatide compared to −3.1% with placebo. In the pooled tirzepatide groups TGs were decreased by 20mg/dL and LDL-C by 4.2mg/dL while HDL-C was increased by 8.8mg/dL compared to the placebo group. Not unexpectedly the greater the weight loss the greater the change in lipid levels (119). For example, weight loss of < 10% of body weight results in a decrease in TG levels of approximately 11% and LDL-C of 1% while weight loss of > 30% results in a decrease in TG levels of approximately 40% and LDL-C of 14%. Similarly, HDL-C levels increased by less than 1% in individuals who lost less than 10% of their body weight while HDL-C levels increased by approximately 16% in individuals who lost greater than 30% of their body weight.

In the SURMONT 3 trial 806 participants who had lost greater than 5% of their body weight with lifestyle changes were randomized to placebo or a maximally tolerated dose of tirzepatide (10 or 15mg) (120). Weight at 72 weeks was decreased by 21% in the tirzepatide group compared to placebo. TG and LDL-C levels were reduced by 28% and 11.5% respectively in the tirzepatide group compared to placebo while HDL-C increased by 11.4%.

Note that the studies described above are in obese or overweight patients without diabetes. Tirzepatide markedly improves glycemic control, which can favorably affect lipid levels (116,117).

TIRZEPATIDE COMPARED TO SEMAGLUTIDE

In the SURMOUNT 5 trial 751 participants with obesity but without type 2 diabetes were randomly assigned to receive the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or the maximum tolerated dose of semaglutide (1.7 mg or 2.4 mg) weekly for 72 weeks. The change in weight at week 72 was -20.2% in the tirzepatide group and -13.7% in the semaglutide group (P<0.001). The changes in lipid levels are shown in Table 5.

Table 5.

Effect of Treatment with Tirzepatide or Semaglutide on Lipid Levels

	Tirzepatide	Semaglutide
Change in TG (mg/dL)	-35	-28
Change in LDL-C (mg/dL)	-7.8	-5.9
Change in HDL-C (mg/dL)	5.7	2.9
Change in non-HDL-C (mg/dL)	16	13

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 fasting lipid levels induced by weight loss drugs is modest, variable, and roughly correlates with the degree of weight loss. GLP-1 receptor agonist have been shown to reduce cardiovascular events and it is likely that the lipid changes induced by these drugs contributes to the decrease in events (116).

Effect of Bariatric Surgery on Lipids

Bariatric surgery is more effective at inducing weight loss than either diet or medications (121,122). Adjustable gastric banding, sleeve gastrectomy, roux-en-Y gastric bypass (RYGB), and biliopancreatic diversion/duodenal switch decrease TG and LDL-C levels and increase HDL-C and the greater the weight loss, the greater the improvement in dyslipidemia (123). Associated with this greater decrease in weight is a more robust decrease in serum TG levels and increase in HDL-C levels (124-126). In some studies, a marked decrease in LDL-C is also observed. For example, Nguyen et al reported that in patients with severe obesity, RYGB resulted in a 63% decrease in serum TG, a 31% decrease in LDL-C, and a 39% increase in HDL-C (127). Studies have also shown a decrease in postprandial lipemia (123,128). Several studies have also shown a decrease in Lp(a) levels and RYGB was more effective at decreasing Lp(a) than sleeve gastrectomy (129-133). 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 (134,135). In contrast, another randomized trial did not observe a difference in the effect of RYGB compared to sleeve gastrectomy on triglycerides, HDL-C, or LDL-C (136). However, in a meta-analysis comparing randomized trials of RNYGB vs. sleeve gastrectomy, Li et al reported that serum TG decreased to a greater degree in the RYGB patients (approximately 20mg/dL) (137). 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 (138). They reported that the remission of hyperlipidemia (defined as total cholesterol < 200mg/dL, HDL-C > 40mg/dL, LDL-C < 160mg/dL, and TG < 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 (126). Whether the greater beneficial effects of RYGB on lipids is due to greater weight loss, endocrine changes, nutrient malabsorption, or enhanced bile-acid absorption and increases in circulating bile-acid levels induced by this procedure remains to be fully elucidated.

It should be noted that observational studies have found large reductions in cardiovascular events with bariatric surgery in both patients with and without pre-existing cardiovascular disease (139). It is likely that improvements in dyslipidemia contribute to this decrease in cardiovascular events.

Summary of Weight Loss Effect on Lipid Levels

A meta-analysis of 73 studies enrolling 32,496 patients examined the effect of weight loss due to diet, drugs, and bariatric surgery on lipid levels at 12 months (table 6) (62). One should recognize that there is quite a bit of variability and the results shown in table 6 only provide a rough estimate of the effect of weight loss in an individual patient with the different treatments. Note that the changes in lipid levels are reported as mg/dL per kg weight loss.

Table 6.

Change in Lipid Levels with Weight Loss Interventions (mg/dL per kg weight loss)

	Triglycerides	LDL Cholesterol	HDL Cholesterol
Diet and/or Exercise	-4.00; 95% CI -5.24, -2.77	-1.28; 95% CI -2.19, -0.37	0.46; 95% CI 0.19, 0.71
Weight Loss Drugs	-1.25; 95% CI -2.94, 0.43	-1.67; 95% CI -2.28, -1.06	0.37; 95% CI 0.23, 0.52
Bariatric Surgery	-2.47, 95% CI -3.14, -1.80	-0.33; 95% CI -0.77, 0.10	0.42; 95% CI 0.37, 0.47

: Note- The decrease in LDL-C with weight loss drugs included a relatively large number of patients treated with orlistat, which may have enhanced the LDL-C reduction.

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 TG levels (>500mg/dL) where fibrates or fish oil (omega-3-fatty acids) may be used initially to specifically target very high TG (>500-1000mg/dL). For additional information on lipid lowering drugs please see the chapters on cholesterol lowering drugs and TG lowering drugs (140,141). Below we address issues of using lipid lowering drugs that have importance specifically 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 (142,143). The mechanism for this adverse effect is unknown but a study has suggested that decreases in HMG-coenzyme A activity leads to weight gain, which could increase the risk of developing diabetes (144). 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 (145). However, a recent review concluded that statins do not consistently reduce muscle strength, endurance, or overall exercise performance (146).

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 (147,148). 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 TG levels, which can be a problem in some patients with obesity who are already hypertriglyceridemic (140). 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 (149).

NIACIN

Niacin reduces insulin sensitivity (i.e., causes insulin resistance), which can worsen glycemic control (150). In the HPS2-Thrive trial, niacin therapy induced new onset diabetes in subjects that were non-diabetic (151). In patients with obesity, who are at an increased 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 (150).

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) (140). Inclisiran, a small interfering RNA that stimulates the catalytic breakdown of PCSK9 mRNA, was approved in the US in 2021. 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 (140,152-154).

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 (140). 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 (140). 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 (140). 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 was 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 treatment approach to dyslipidemia in patients with obesity is identical to the treatment of patients who are not obese. For a detailed discussion of the treatment of patients with dyslipidemia see other Endotext chapters ((51,56,57,140,141). Because weight loss has favorable effects on lipid levels it is important to recognize that this should be strongly encouraged and in some cases is sufficient to ameliorate the dyslipidemia.

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 TG to reduce the risk of pancreatitis.

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Feingold KR. Obesity and Dyslipidemia. [Updated 2026 Mar 24]. In: Feingold KR, Adler RA, Ahmed SF, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-.

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ABSTRACT
INTRODUCTION
LIPID ABNORMALITIES IN PATIENTS WITH OBESITY
PATHOPHYSIOLOGY OF THE DYSLIPIDEMIA OF OBESITY
CURRENT TREATMENT GUIDELINES FOR SERUM LIPIDS
MODALITIES TO TREAT LIPID ABNORMALITIES IN PATIENTS WITH OBESITY
TREATMENT APPROACH
SUMMARY
REFERENCES

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Endotext [Internet].

Obesity and Dyslipidemia

ABSTRACT

INTRODUCTION

LIPID ABNORMALITIES IN PATIENTS WITH OBESITY

Table 1.

PATHOPHYSIOLOGY OF THE DYSLIPIDEMIA OF OBESITY

Figure 1.

Production of TG Rich Lipoproteins

Metabolism of TG Rich Lipoproteins

Production of Small Dense LDL and HDL

Role of Inflammation and Adipokines

CURRENT TREATMENT GUIDELINES FOR SERUM LIPIDS

MODALITIES TO TREAT LIPID ABNORMALITIES IN PATIENTS WITH OBESITY

Effect of Diet

Low-Calorie Diet-Induced Weight loss

Dietary Macronutrient Constituents

Table 2.

Table 3.

Table 4.

Glycemic Index

SUMMARY

Effect of Exercise

Effect of Weight Loss Drugs

ORLISTAT (XENICAL)

PHENTERAMINE + TOPIRAMATE (QSYMIA)

NALTREXONE + BUPROPION (CONTRAVE)

LIRAGLUTIDE (SAXENDA)

SEMAGLUTIDE (WEGOVY)

TIRZEPATIDE

TIRZEPATIDE COMPARED TO SEMAGLUTIDE

Table 5.

SUMMARY OF WEIGHT LOSS DRUGS

Effect of Bariatric Surgery on Lipids

Summary of Weight Loss Effect on Lipid Levels

Table 6.

Effect of Lipid Lowering Drugs

STATINS

BILE ACID SEQUESTRANTS

NIACIN

PCSK9 INHIBITORS

BEMPEDOIC ACID

EZETIMIBE, FIBRATES, AND OMEGA-3-FATTY ACIDS

TREATMENT APPROACH

SUMMARY

REFERENCES

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