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Obesity and Dyslipidemia

, MD and , MD, PhD.

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Last Update: April 10, 2018.


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 cholesterol 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 cholesterol levels are typically low andare associated with the increase in serum triglycerides. LDL cholesterol 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 cholesterol levels and increase HDL cholesterol levels. In most patients the changes in lipid levels with weight loss are not very robust. 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 cholesterol that occurs with weight loss. The increase in HDL cholesterol 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. 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. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.


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 [3]. Additionally, approximately 1/3 of the population is overweight defined as a BMI between 25 and 30 kg/m2 [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 lipid abnormalities seen in patients who are obese include elevated triglyceride, VLDL, Apo B, and non-HDL cholesterol levels, which are all commonly observed [8, 9, 13, 14]. HDL cholesterol and Apo A-I levels are typically low [8, 9, 13, 14]. LDL cholesterol levels are frequently in the normal range, but an increase in small dense LDL is often seen [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 cholesterol levels [18]. The increased risk for cardiovascular disease in patients with obesity is partially accounted for by this dyslipidemia.

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 cholesterol 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.


Figure 1

Figure 1

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, the inhibition of triglyceride lipolysis is blunted and there is increased triglyceride breakdown 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 seleads 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 cholesterol levels when triglyceride levels are high and the increase in HDL cholesterol 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 HDLparticles [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 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 cholesterol 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 cholesterol levels while conversely, adiponectin knock-out mice have increased triglyceride and decreased HDL cholesterol 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 cholesterol 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 cholesterol 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 [35]. In the liver, pro-inflammatory cytokines stimulate de novo fatty acid and triglyceride synthesis [35]. 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 [35, 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 [37, 42].


There are many different guidelines put forth by various groups that provide recommendations on who and how to treat patients with lipid disorders. Unfortunately, these guidelines are discordant and recommend different approaches on how to categorize and treat patients with dyslipidemia. Below we will discuss several of these guidelines and then provide our approach.

American College of Cardiology/American Heart Association (ACC/AHA)

The recommendations proposed by the ACC/AHA are summarized in tables 1 and 2 [43]. In patients with pre-existing cardiovascular disease or an LDL greater than 190mg/dl intensive statin therapy is recommended (atorvastatin 40-80mg or rosuvastatin 20-40mg). In patients with diabetes moderate intensity statin therapy is recommended unless the 10-year risk for cardiovascular disease is > 7.5% in which case intensive statin therapy is recommended. In patients between 40 and 75 years of age without pre-existing cardiovascular disease or diabetes with LDL cholesterol levels between 70mg/dl and 190mg/dl, the key step is to calculate the 10-year risk of cardiovascular disease. This calculator is available at can be downloaded as an app for a smart phone or tablet. If the 10-year risk of developing cardiovascular disease is greater than 7.5% statin therapy is recommended. These guidelines do not indicate a specific LDL or non-HDL goal but rather just recommend statin treatment.

Table 1ACC/AHA Recommendations

Clinical ASCVD<75 years of age- High Intensity statin therapy
>75 years of age- High or moderate intensity statin therapy
LDL > 190mg/dlHigh Intensity statin therapy
DiabetesModerate intensity statin therapy
If 10 year risk > 7.5% then high Intensity statin therapy
10-year risk > 7.5%Moderate or high intensity statin therapy

Table 2Statin Therapy

High Intensity TherapyModerate Intensity TherapyLow Intensity Therapy
LDLc decrease > 50%LDLc decrease 30-50%LDLc decrease < 30%
Atorvastatin 40–80 mg
Rosuvastatin 20-40 mg
Atorvastatin 10-20 mg
Rosuvastatin 5-10 mg
Simvastatin 20–40 mg
Pravastatin 40-80 mg
Lovastatin 40 mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg bid
Pitavastatin 2–4 mg
Simvastatin 10 mg
Pravastatin 10–20 mg
Lovastatin 20 mg
Fluvastatin 20–40 mg
Pitavastatin 1 mg

National Lipid Association (NLA)

The National Lipid Association (NLA) guidelines recommend a different approach [44]. The first step is to identify patients at very high risk for cardiovascular disease or high risk for cardiovascular disease (Table 3). The second step in patients who are not at very high or high risk is to determine the number of major risk factors (Table 4). If the patient has three or more major risk factors the patient should be classified as high risk. If the patient has zero or one risk factor they are considered low risk unless there are other factors that increase risk (Table 5). If the patient has two risk factors, risk calculators should be employed. Using the Framingham risk calculator, high risk is defined as greater than 10% 10-year risk. Using the ACC/AHA calculator high risk is defined as greater than 15% 10-year risk or 45% lifetime risk. If the patient is not at high risk they are considered at moderate risk. The classification of patients and the treatment goals are shown in table 6.

Table 3Patients at Very High Risk of High Risk for Cardiovascular Disease

Very High Risk PatientsHigh Risk patients
Pre-existing cardiovascular diseaseDiabetes < 2 major risk factors
Diabetes with 2 or more risk factors or end organ damageChronic kidney disease stage 3B or 4
LDL> 190mg/dl

Table 4Major Risk Factors

age > 45 years for males and age > 55 years for females
family history of early heart disease; < 55 years for males and < 65 years for females
current cigarette smoking
blood pressure >140/>90 mm HG or on blood pressure medications
HDL < 40mg/dl in males or HDL < 50mg/dl in females

Table 5Other Risk Indicators

A severe disturbance in a major risk indicator
Indicators of subclinical disease; coronary artery calcium score > 300 Agatston units
LDLc > 160mg/dl or non HDLc > 190mg/dl
hsCRP > 2mg/L
Lipoprotein (a) > 50mg/dl using an isoform insensitive assay
Urine albumin/creatinine ratio > 30mg/g

Table 6NLA Treatment Goals

Risk CategoryCriteriaTreatment GoalConsider Drug Therapy
Low0-1 major risk factorsnon-HDLc <130
LDLc <100
non-HDLc <190
LDLc <160
Moderate2 major risk factorsnon-HDLc <130
LDLc <100
non-HDLc <160
LDLc <130
High>3 major risk factors
Diabetes < 2 risk factors
Chronic kidney disease
LDL > 190mg/dl
non-HDLc <130
LDLc <100
non-HDLc <130
LDLc <100
Very highASCVD
Diabetes (2+ risk factors)
non-HDLc <100
LDLc <70
non-HDLc <100
LDLc <70

American Association of Clinical Endocrinologists and American College of Endocrinology

These guidelines use risk factors and 10-year risk to categorize patients which then allows one to determine treatment goals [45]. The risk factors are shown in Table 7 and the 10-year risk is calculated using the Framingham risk score. Risk categories and treatment goals are shown in table 8.

Table 7Risk Factors

High LDL cholesterol consistent with Familial Hypercholesterolemia
Polycystic ovary syndrome
Cigarette smoking
Hypertension (BP > 140/90 or on hypertensive medication
Low HDL cholesterol (<40mg/dl)
Family history of coronary artery disease (male first degree relative < 55 years of age or female first degree relative < 65 years of age)
Chronic renal disease (stage 3 or 4)
Evidence of coronary artery calcification
Men > 45 years of age and women > 55 years of age
Subtract one risk factor if HDL cholesterol is high (>60mg/dl)

Table 8Risk Categories and Treatment Goals

Risk CategoryRisk Factors/10-year riskLDLc
Apo B
Extreme Risk- Progressive ASCVD including unstable angina in patients after achieving an LDLc <70 mg/dL
- Established clinical cardiovascular disease in patients with DM, CKD 3/4, or Familial Hypercholesterolemia
- History of premature ASCVD (<55 male, <65 female)



Very High Risk- Established or recent hospitalization for ACS, coronary, carotid or peripheral vascular disease, 10-year risk >20%
- Diabetes or CKD 3/4 with 1 or more risk factor(s)
- Familial Hypercholesterolemia



High Risk- ≥2 risk factors and 10-year risk 10-20%
- Diabetes or CKD 3/4 with no other risk factors
Moderate Risk≤2 risk factors and 10-year risk <10%<100<130<90
Low Risk0 risk factors<130<160Not Recommended

ASCVD- atherosclerotic cardiovascular disease; ACS- acute coronary syndrome; DM- diabetes mellitus; CKD- chronic kidney disease

Our Strategy

Our strategy is to combine the approaches described above. In patients with obesity without pre-existing cardiovascular disease, diabetes, or an LDL>190mg/dl we use the ACC/AHA calculator to determine the 10-year and lifetime risk for developing cardiovascular disease. Based on the level of risk and after discussion with the patient of the advantages and disadvantages of therapy the patient and provider can decide on whether treatment is indicated. Six to twelve weeks after initiating statin therapy we obtain a lipid panel to determine if the values are at goal (goals are based on LDL cholesterol and non-HDL cholesterol levels suggested by the NLA and AACE). If the levels are not at goal we either increase the statin dose or consider adding additional medications. In patients with obesity the non-HDL cholesterol levels are often elevated to a greater degree than LDL cholesterol because of the increased triglyceride levels. In patients with obesity with pre-existing cardiovascular or LDL levels > 190mg/dl we follow the ACC/AHA guidelines, which recommend treatment with high intensity statin therapy (atorvastatin 40-80mg or rosuvastatin 20-40mg). Once again we obtain a lipid panel six to twelve weeks after initiating therapy to determine if the values are at the goals proposed by the NLA and AACE guidelines. If the levels are not at goal we either increase the statin dose or consider adding additional medications. Recommendations for patients with obesity and diabetes are discussed in detail in the chapter on lipid disorders in patients with diabetes [46, 47].


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” [48]and for additional information on weight loss diets see the chapter on “Dietary Treatment of Obesity” [49].

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 [50]. For every 1Kg decrease in body weight there was a 0.77mg/dl decrease in LDL cholesterol and 1.33mg/dl decrease in triglycerides. The effect of weight loss on HDL cholesterol is more complex. For every 1kg decrease in body weight there is a 0.27mg/dl decrease in HDL cholesterol during active weight loss. However, when weight is stabilized there is a 0.35mg/dl increase in HDL cholesterol for every 1kg decrease in body weight that has occurred. Thus, if a patient lost 10Kg of body weight and maintained the weight loss, one would expect that LDL cholesterol would have decreased by 7.7mg/dl, triglycerides would have decreased by 13.3mg/dl, and HDL cholesterol would have increased by 3.5mg/dl. In practice these changes are frequently blunted by the inability to maintain weight loss. 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 cholesterol levels and an increase in HDL cholesterol 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. 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 cholesterol levels[51]. Finally, a systematic review of studies has shown that weight loss in children also decreases triglycerides and increases HDL cholesterol levels [52].

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 15%/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 [53]. Other studies that compared different diets over an extended of time period (at least one year) have reached similar conclusions [54-56]. 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 [53]. 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 timeand the associations of that diet with improvements in health (e.g., improvements in lipid levels, reduction in risk for type 2 diabetes, lower mortality rates) even when weight loss is modest.

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 [55]. They found, as expected, that both types of weight loss diets decreased LDL cholesterol and triglyceride levels and increased HDL cholesterol levels. However, the low carbohydrate diet decreased triglycerides and increased HDL cholesterol to a greater extent than the low-fat diet. Conversely, the low-fat diet was more effective in lowering LDL cholesterol levels. The results of this meta-analysis are shown in table 9. It should be noted that the magnitude of these changes, except for the decrease in triglycerides are small. Similarly, 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 cholesterol and LDL cholesterol levels but once again the differences were relatively small [57]. Additionally, a meta-analysis by Schwingshackl and Hoffmann compared high fat vs. low fat diets and observed that the decrease in LDL cholesterol was more pronounced with a low-fat diet whereas the increase in HDL cholesterol and the decrease in triglycerides were greater with the high-fat diet [58]. 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 cholesterol levels with the ketogenic than the low-fat diet but the ketogenic diet leads to an increase in LDL cholesterol levels [59].

Table 9Comparison of High and Low Fat and Carbohydrate Diets

Low carbohydrate/high fatLow fat/high carbohydrate
Weight Loss (kg)-6.1-5.0
LDLc (mg/dl)-2.1-6.0
HDLc (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 [60]. 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 cholesterol or HDL cholesterol 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 [61]. They observed no significant differences in LDL cholesterol, HDL cholesterol, or triglyceride levels indicating that high protein diets have neither beneficial nor detrimental effects on lipid 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 [62]. There was no significant effect of glycemic index on either HDL cholesterol or triglyceride levels. However, the low glycemic index foods resulted in a small decrease in LDL cholesterol levels (approximately 6mg/dl). The decrease in LDL cholesterol 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 cholesterol 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 cholesterol when carbohydrate intake was high, but decreased LDL cholesterol when carbohydrate was low [63].

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 cholesterol that occurs with weight loss. HDL cholesterol 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 cholesterol levels. Finally, a diet high in soluble fiber will lower LDL cholesterol 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 cholesterol 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 [64, 65]. However, exercise when combined with diet therapy can facilitate weight loss and is considered very important for weight loss maintenance [65]. It may also diminish the loss of muscle mass during weight loss [65]. The effect of exercise on serum LDL cholesterol varies with some studies showing a 4-7% decrease [66]. The decrease in LDL cholesterol 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. To significantly increase HDL cholesterol levels requires a considerable amount of exercise (700-2000kcal of exercise per week) [66, 67]. 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%) [66]. Of note the changes in HDL cholesterol and triglycerides induced by exercise occur independent of weight loss [66]. 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 Obesity” [68].

Orlistat (Xenical):

Orlistat is a lipase inhibitor that decreases fat absorption. Total cholesterol and LDL cholesterol levels decrease with orlistat treatment to a greater degree than expected with diet alone [69, 70]. For example, in the XENDOS study LDL cholesterol decreased by 12.8% in the orlistat group vs. 5.1% in the placebo group [69]. Additionally, studies have shown that the levels of small dense LDL are reduced and the average LDL particle size increased with orlistat treatment [71]. It has been shown that orlistat, in addition to reducing dietary triglyceride absorption, also decreases cholesterol absorption [72]. A likely mechanism for the decrease in cholesterol absorption is orlistat inhibition of NPC1L1, a transporter in the intestine that mediates cholesterol absorption [73]. Despite the effect on triglyceride absorption, orlistat does not markedly affect either triglyceride or HDL cholesterol levels [70, 74].

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 cholesterol without a consistent effect on LDL cholesterol levels [75-77]. 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, lorcaserindecreased triglyceride levels and increased HDL cholesterol levels without a consistent effect on LDL cholesterol levels [78-80]. 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.

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. 10-12%, decreased LDL cholesterol levels by 2-6%, and increased HDL cholesterol by 3-8%[81-83]. 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 cholesterol levels (2.4%) and increases in HDL cholesterol levels (1.9%) with liraglutide treatment [84]. Similar results were observed in another randomized trial [85]. Moreover, a trial in patients with diabetes also resulted in modest improvements in triglyceride and HDL cholesterol levels [86]. 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 may lower LDL cholesterol 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.

Effect Of Bariatric Surgery On Lipids

Bariatric surgery is more effective at inducing weight loss than either diet or medications [87, 88]. Associated with this greater decrease in weight is a more robust decrease in serum triglyceride levels and increase in serum HDL cholesterol levels [89-91]. In some studies, a marked decrease in LDL cholesterol 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 cholesterol, and a 39% increase in HDL cholesterol [92]. Studies have also shown a decrease in postprandial lipemia and Lp(a) levels [93-95]. Moreover, the ability of HDL to mediate cholesterol efflux from cells is improved following bariatric surgery[96-98]. 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 [99, 100]. 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) [101]. A similar greater decrease in LDL cholesterol 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 [102]. They reported that the remission of hyperlipidemia (defined as total cholesterol < 200mg/dl, HDL > 40mg/dl, LDL < 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 [91]. 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, 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 [103, 104].


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 [105, 106]. 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 [107]. 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 [108]. However, a recent review concluded that statins do not consistently reduce muscle strength, endurance, or overall exercise performance [109].

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 [110, 111]. Thus, one can anticipate that statin treatment will achieve the same beneficial outcomes in patients who are obese as seen in the general population.


Ezetimibe is easy to use and generally well tolerated by patients who are obese.


Fibrates are easy to use and generally well tolerated by patients who are obese. When combining fibrates with statin therapy it is best to use fenofibrate as the risk of inducing myositis is much less than when statins are used in combination with gemfibrozil [103]. The dose of fenofibrate needs to be adjusted in patients with renal disease and fenofibrate can induce a reversible increase in serum creatinine levels [103].

Bile Acid Sequestrants:

Bile acid sequestrants are relatively difficult to take due to GI toxicity (mainly constipation) [104]. Bile acid sequestrants may also increase serum triglyceride levels, which can be a problem in some patients with obesity who are already hypertriglyceridemic [104]. An additional difficulty in using bile acid sequestrants is their potential for binding other drugs [104]. Other drugs should be taken either two hours before or four hours after taking a bile resin binder to avoid the potential of decreased drug absorption. 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. The usual dose is three pills twice a day with meals or one packet of powder in water, fruit juice, or other liquids once a day with a meal. 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 [112].


Niacin is well known to cause skin flushing, itching, and GI upset[113]. Additionally, niacin reduces insulin sensitivity (i.e., causes insulin resistance), which can worsen glycemic control [113]. In the HPS2-Thrive trial, niacin therapy induced new onset diabetes in subjects that were non-diabetic [114]. 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 [113]. Additionally, recent trials have reported an increased incidence of infection and bleeding with niacin therapy [114-116]. However, niacin is the most effective drug in increasing HDL cholesterol levels, which are frequently low in patients with obesity. Whether a niacin-induced increase in HDL contributes to lower cardiovascular disease is unresolved.

Fish oil:

Fish oil decreases triglyceride levels [103]. In some patient's high dose fish oil increases LDL cholesterol levels, particularly when serum triglyceride levels are very high [103]. It should be noted that fish oil products that contain just EPA (Vascepa) do not adversely affect LDL cholesterol levels [117]. When using fish oil to lower serum triglyceride levels it is important to recognize that one is aiming to provide 3-4 grams of DHA/EPA per day [103]. The quantity of these active omega 3 fatty acids can vary greatly from product to product. Prescription fish oil products contain large amounts of these active ingredients whereas the amount of DHA/EPA in over the counter preparations can vary greatly and in some instances is very low (for example 100mg per 1gram fish oil capsule).

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) [104]. Alirocumab is administered as either 75mg or 150mg subcutaneously every 2 weeks or 300mg subcutaneously every 4 weeks while evolocumab is administered as either 70mg subcutaneously every 2 weeks or 420mg subcutaneously once a month. 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 [104, 118, 119].

The FOURIER trial was a randomized, double-blind, placebo-controlled trial of evolocumab vs. placebo in 27,564 patients with atherosclerotic cardiovascular disease and an LDL cholesterol level of 70 mg/dl or higher who were on statin therapy [120]. The primary end-point was cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization and the key secondary end-point was cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years. Baseline LDL cholesterol levels were 92mg/dl and evolocumab resulted in a 59% decrease in LDL levels (LDL cholesterol level on treatment approximately 30mg/dl). Evolocumab treatment significantly reduced the risk of the primary end-point (hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P<0.001) and the key secondary end point (hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P<0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for baseline LDL cholesterol levels (median, 74 mg/dl). This study demonstrates that treatment with a PCSK9 inhibitor can reduce cardiovascular events.


The first priority in treating lipid disorders in patients with obesity is to lower the LDL cholesterol levels to goal, unless triglycerides are markedly elevated (> 500mg/dl), which increases the risk of pancreatitis. LDL cholesterol is the usual first priority because the database linking lowering LDL cholesterol with reducing cardiovascular disease is extremely strong and we now have the ability to markedly decrease LDL cholesterol levels. Dietary therapy is the initial step but in most patients diet alone will not be sufficient to achieve the LDL cholesterol goals. If patients are willing and able to make major changes in their diet it is possible to achieve remarkable reductions in LDL cholesterol levels but this seldom occurs in clinical practice [121].

Statins are the first-choice drugs to lower LDL cholesterol levels and many patients who are obese will require statin therapy. There are several statins currently available in the US and one should be sure to choose a statin that is capable of lowering the LDL cholesterol to goal. The effect of different doses of the various statins on LDL cholesterol levels is shown in Table 11. Currently four statins are available as generic drugs, lovastatin, pravastatin, atorvastatin, and simvastatin, and these statins are relatively inexpensive.

If a patient is unable to tolerate statins or statins as monotherapy are not sufficient to lower LDL cholesterol to goal the second-choice drug is either ezetimibe or a PCSK9 inhibitor. Ezetimibe can be added to any statin. PCSK9 inhibitors can also be added to any statin and are the drug of choice if a large decrease in LDL cholesterol is required to reach goal (PCSK9 inhibitors will lower LDL cholesterol levels by 50-60% when added to a statin, whereas ezetimibe will only lower LDL cholesterol by approximately 20%). However, PCSK9 inhibitors are expensive and reimbursement may be restricted. Bile acid sequestrants are an alternative particularly if a reduction in A1c level is also needed and the patient does not have significant hypertriglyceridemia. Ezetimibe, PCSK9 inhibitors, and bile acid sequestrants additively lower LDL cholesterol levels when used in combination with a statin, because these drugs increase hepatic LDL receptor levels by different mechanisms, thereby resulting in a reduction in serum LDL cholesterol levels [104]. Niacin and the fibrates also lower LDL cholesterol levels but are primarily reserved for those with elevated triglyceride and non-HDL cholesterol (see table 12).

Table 11Comparative Efficacy of Available Statins

% LDL ReductionSimvastatin (Zocor)Atorvastatin (Lipitor)Lovastatin (Mevacor)Pravastatin (Pravachol)Fluvastatin (Lescol)Rosuvastatin (Crestor)Pitavastatin

Table 12Effect of Lipid Lowering Drugs

Statins↓ 20-60%↑ 5-15%↓ 0-35%*
Bile acid binders↓ 10-30%↑ 0-10%↑ 0-10%**
Fibrates↓ 0-15%***↑ 5-15%↓ 20-50%
Niacin↓ 10-25%↑ 10-30%↓ 20-50%
Ezetimibe↓ 15-25%↑ 1-3%↓ 10-20%
High Dose Fish Oil↑ 0- 50%**↑ 4- 9%↓ 20- 50%*
PCSK9 Inhibitors↓ 50-60%↑ 5-15%↓ 5-20%

*Patients with elevated TG have largest decrease

** In patients with high TG may cause marked increase

*** In some patients may increase LDL

The second priority should be non-HDL cholesterol (non-HDL cholesterol = total cholesterol – HDL cholesterol), which is particularly important in patients with elevated triglyceride levels (>200mg/dl). Non-HDL cholesterol is a measure of all the pro-atherogenic apolipoprotein B containing particles. Numerous studies have shown that non-HDL cholesterol is a strong risk factor for the development of cardiovascular disease [122]. Many experts feel that reaching non-HDL cholesterol goals is as important as reaching LDL cholesterol goals and non-HDL cholesterol is given equal emphasis in the National Lipid Association and AACE guidelines (see above discussion of guidelines). The non-HDL cholesterol goals are 30mg/dl greater than the LDL cholesterol goals. For example, if the LDL goal is <100mg/dl then the non-HDL cholesterol goal would be <130mg/dl. Drugs that reduce either LDL cholesterol or triglyceride levels will reduce non-HDL cholesterol levels.

The third priority in treating lipid disorders is to decrease triglyceride levels. Initial therapy should focus on lifestyle changes including a decrease in simple sugars and ethanol intake. Improving glycemic control can have profound effects on serum triglyceride levels. Additionally, the treatment of disorders that can increase triglyceride levels (for example diabetes) and discontinuing drugs (such as ethanol and estrogens) that can increase triglycerides can be very helpful. If triglycerides remain elevated fibrates, niacin, statins, and fish oil can be used to reduce serum triglyceride levels (see Table 12). Typically, one will target triglyceride levels when one is trying to lower non-HDL cholesterol levels to goal. Patients with very high triglyceride levels (> 500mg/dl) are at risk of pancreatitis and therefore lifestyle and triglyceride lowering drug therapy should be initiated early. Note that there is limited evidence demonstrating that lowering triglyceride levels reduces cardiovascular events.

The fourth priority in treating lipid disorders is to increase HDL cholesterol levels. There is strong epidemiologic data linking low HDL cholesterol levels with cardiovascular disease but whether increasing HDL levels with lifestyle changes or drugs reduces cardiovascular disease is unknown. Life style changes are the initial step and include increased exercise, weight loss, and stopping cigarette smoking. The role of recommending ethanol, which increases HDL levels, is controversial but in patients who already drink moderately there is no reason to recommend that they stop unless they have significant hypertriglyceridemia. The most effective drug for increasing HDL cholesterol levels is niacin (see Table 12), but studies have not demonstrated a reduction in cardiovascular events when niacin is added to statin therapy [114, 115]. Fibrates and statins also raise HDL cholesterol levels but the increases are modest (usually less than 15%). Additionally, the ACCORD-LIPID trial failed to demonstrate that adding fenofibrate to statin therapy reduces cardiovascular disease [123]. Unfortunately, given the currently available drugs, it is very difficult to significantly increase HDL levels and in many of our patients we are unable to achieve HDL levels in the recommended range. Furthermore, whether this will result in a reduction in cardiovascular events is unknown.

Note that there is very limited evidence that adding drugs that lower triglyceride levels or increase HDL levels to statin therapy will reduce cardiovascular events [103].

Many patients with obesity have multiple lipid abnormalities. As discussed in detail above life style changes are the initial therapy. If life style changes are not sufficient in patients with both elevations in LDL and triglycerides (and elevations in non-HDL cholesterol) one approach is to base drug therapy on the triglyceride levels (Figure 2). If the serum triglycerides are very high (greater than 500mg/dl), where there is an increased risk for pancreatitis and hyperviscosity syndromes, initial pharmacological therapy is directed at the elevated triglycerides and the initial drug choice is either a fibrate, niacin, or high dose fish oil (3 grams EPA/DHA per day). After lowering triglyceride levels to < 500mg/dl statin therapy should be initiated if the LDL and/or non-HDL cholesterol is not at goal. If the serum triglycerides are less than 500mg/dl, statin therapy to lower the LDL level to goal is the initial therapy (see Figure 2). Studies have clearly demonstrated that statins are effective drugs in lowering triglyceride levels in patients with elevated triglycerides [104]. In patients with low triglyceride levels, statins do not greatly affect serum triglyceride levels. If the non-HDLc levels remain above goal after one reaches the LDL goal, one should then consider combination therapy to lower triglyceride levels which will lower non-HDLc levels.

Figure 2. Combined Hyperlipidemia. Increased LDL and TG

Figure 2

Combined Hyperlipidemia. Increased LDL and TG

Often monotherapy is not sufficient to completely normalize the lipid profilein patients with obesity. For example, with statin therapy one may often lower the LDL cholesterol to goal but the non-HDL cholesterol, HDL cholesterol, and triglycerides remain in the abnormal range. Currently, there are no randomized controlled trials demonstrating that combination therapy with fibrates or niacin reduces cardiovascular disease to a greater extent than statin monotherapy. In fact three recent outcome studies adding either niacin or fenofibrate to statin therapy failed to demonstrate additional benefit [114, 115, 123]. However, many experts believe that further improvements in the lipid profile will be beneficial and that the studies completed so far should not be considered definitive as they had flaws such as not treating patients with the appropriate lipid profile. When using combination therapy, one must be aware that the addition of either fibrates or niacin to statin therapy may increase the risk of myositis. The increased risk of myositis is greatest when gemfibrozil is used in combination with statins. Fenofibrate has a much more modest risk and the FDA approved the use of fenofibrate in combination with moderate doses of statins. Additionally, in the ACCORD LIPID trial the combination of simvastatin and fenofibrate was well tolerated [123]. The increased risk with niacin appears to be very modest. In the AIM-HIGH trial the risk of myositis was not increased in patients on the combination of niaspan and statin, whereas in the HPS2-Thrive trial myopathy was increased in the group treated with the combination of statin and niacin with laropripant [114, 115]. The absolute risks of combination therapy are relatively modest if patients are carefully selected; in many patients at high risk for cardiovascular disease combination therapy may be appropriate (Table 13). As with many decisions in medicine one needs to balance the benefits of therapy with the risks of therapy and determine for the individual patient the best approach. In deciding to use combination therapy a key focus is the non-HDL cholesterol level. When the LDL cholesterol is at goal but the non-HDL cholesterol is still markedly above goal it may be appropriate to resort to combination therapy in patients at high risk, but randomized outcome studies have not yet shown that this approach reduces cardiovascular events.

Table 13When to Use Combination Therapy

· Clinical Evidence of Arteriosclerosis

· High Risk Patient

o Hypertension

o Family History of CAD

o Cigarettes

o Proteinurea

o Central Obesity

o Inactivity

o Elevated CRP

· No Contraindications

o Renal or Liver Disease

o Non-compliant patient

o Use of other drugs that effect statin metabolism

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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