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. Life style 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 life style 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 will also improve dyslipidemia. Bariatric surgery results in robust weight loss and has a marked effect on serum lipid levels. Remission of hyperlipidemia with gastric bypass surgery is frequently observed. The reduction in cardiovascular disease with statin therapy is no different in patients with a BMI >30 or BMI <25 (i.e., statins are effective in patients who are obese). Many, if not most, patients who are obese should be on statin therapy and some will require the addition of other LDL-C decreasing drugs to achieve satisfactory reductions in LDL-C. The mixed dyslipidemia that is frequently observed in patients who are obese will often require combination therapy. However, recent studies have failed to demonstrate that adding 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 35% of men and 40% of women are obese defined as a BMI >30 kg/m² (2,3). Additionally, approximately 1/3 of the population is overweight defined as a BMI between 25 and 30 kg/m² (2,4). Moreover, the obesity epidemic is not localized to the United States as there has been a marked increase in the prevalence of obesity worldwide (5). The number of individuals with morbid obesity (BMI > 40) has also greatly increased (6). It should be noted that very athletic individuals may have a high BMI without excess body fat (the increase in weight is due to muscle mass) and as a consequence not have metabolic abnormalities. 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). 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 (9-11). 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 (9-13). The majority of deaths related to high BMI are due to cardiovascular disease (5).

LIPID ABNORMALITIES IN PATIENTS WITH OBESITY

The lipid abnormalities seen in patients who are obese include elevated TG, VLDL, Apo B, and non-HDL-C levels, which are all commonly observed (9,10,14,15). HDL-C and Apo A-I levels are typically low (9,10,14,15). 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 (9,10,14,15). These small dense LDL particles are considered to be more pro-atherogenic than large LDL particles for a number of reasons (16). 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 (17,18). 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 (9). Notably, obesity in children and young adults also leads to an increased prevalence of elevated TG and decreased HDL-C levels (19). 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 (20-24). 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 leg 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.

CURRENT TREATMENT GUIDELINES FOR SERUM LIPIDS

The purpose of treating lipid disorders is to prevent the development of other diseases, particularly cardiovascular disease. Thus, the decision to treat should be based on the risk of the hyperlipidemia leading to those medical problems. A number of guidelines have been published that discuss in detail cardiovascular risk assessment and provide recommendations on treatment strategies (44-48). It should be noted that while these guidelines are similar there are significant differences between their recommendations. The current American College of Cardiology/American Heart Association (ACC/AHA) guidelines do not emphasize specific lipid/lipoprotein goals of therapy but rather to just treat with statins to lower LDL-C by a certain percentage (44). An exception is that they do recommend in patients with very high-risk ASCVD, to use an LDL-C threshold of 70 mg/dL to consider addition of non-statins to statin therapy. In contrast, other groups, such as the National Lipid Association, International Atherosclerosis Society, European Society of Cardiology/European Atherosclerosis Society, and American Association of Clinical Endocrinologists (AACE), do recommend lowering the LDL-C and non-HDL-C levels to below certain levels depending upon the cardiovascular risk in a particular patient but the recommendations from these organizations are not identical (43,45-47) (49).These issues are discussed in detail in the chapters on Guidelines for the Management of High Blood Cholesterol (50). In addition to cardiovascular complications, marked elevations in TG can lead to pancreatitis (51). The National Lipid Association recommends treating TG levels greater than 500mg/dL while the Endocrine Society recommends treating TG if they are greater than 1000mg/dL to lower the risk of pancreatitis (48,52).

It should be noted that most lipid experts would recommend trying to achieve an LDL-C levels less than 70mg/dL and non-HDL-C levels less than 100mg/dL at a minimum in patients with cardiovascular disease or patients at very high risk for the development of cardiovascular disease. AACE and European Society of Cardiology/European Atherosclerosis Society have recommended LDL-C levels less than 55mg/dL in patients at very high risk (47,49). In other patients, an LDL-C level less than 100mg/dL and non-HDL-C level less than 130mg/dL is a reasonable goal. The recommendations for evaluating and treating dyslipidemia in patients with obesity are the same as non-obese patients. For additional details on deciding who to treat and the goals of therapy see other Endotext chapters (50,51,53)

MODALITIES TO TREAT LIPID ABNORMALITIES IN PATIENTS WITH OBESITY

TREATMENT APPROACH

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

Primary Prevention Patients

The first step is determining the risk for developing atherosclerotic cardiovascular disease. There are a number of different calculators for determining risk. In the US the most popular is the ACC/AHA risk calculator (http://www.cvriskcalculator.com/) whereas in Europe the SCORE (Systematic Coronary Risk Estimation) is popular (http://www.heartscore.org/en_GB/access). The ACC/AHA recommendations are shown in Figure 2 and the European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) recommendations are shown in Figure 3 (45,47). Note that the risk shown in the ACC/AHA calculator is for major cardiovascular events while the risk in the SCORE calculator is for mortality.

Figure 2.

ACC/AHA Recommendations for Patients without ASCVD, Diabetes, or LDL-C greater than 190mg/dL. Risk enhancers are listed in table 6. (Note the risk is for MI and stroke, both fatal and nonfatal).

Figure 3.

European Society of Cardiology/European Atherosclerosis Society Recommendations for Primary Prevention Patients. Risk categories are shown in table 7. (Note that the SCORE risk is for a fatal event). Goals of therapy are shown in table 8.

Table 6. ASCVD Risk Enhancers (ACC/AHA)

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

Table 7.

Cardiovascular Risk Categories (ESC/EAS)

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

Table 8.

Treatment Targets and Goals (ECS/EAS)

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

*

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

A few caveats are worth noting. First, in patients less than 60 years of age it is very helpful to calculate the life-time risk of ASCVD events. Often one will find that the 10-year risk is modest but the life-time risk is high and this information should be included in the risk discussion to help in the decision process. Second, patients should be made aware of the natural history of ASCVD and that it begins early in life and slowly progresses overtime with high LDL-C levels accelerating the rate of development of atherosclerosis and low LDL-C leading to a slower progression of atherosclerosis (144). Third, patients should be made aware of genetic studies demonstrating that variants in genes that lead to lifetime decreases in LDL-C levels (for example the HMG-CoA reductase gene, NPC1L1 gene, PCSK9 gene, ATP citrate lyase gene, and LDL receptor gene) result in a decreased risk of cardiovascular events. In a recent study it was reported that a 10mg/dL lifetime decrease in LDL-C with any of these genetic variants was associated with a 16-18% decrease in cardiovascular events whereas a 10mg/dL reduction in LDL-C with lipid lowering therapy later in life results in only approximately a 5% decrease in cardiovascular events ((145,146). The combination of the natural history and the results observed with genetic variants strongly suggests that early therapy to lower LDL-C levels will have greater effects on reducing the risk of ASCVD events than starting therapy later in life. This information needs to be discussed with the patient. Fourth, when patients and/or health care providers are uncertain of the best course of action obtaining a cardiac calcium scan can be very helpful in the decision-making process, particularly in older individuals (45). A score of 0, particularly in an older patient would indicate that statin therapy is not needed whereas a score > 100 would indicate a need for statin therapy. A score of 1-99 favors the use of a statin.

In most primary prevention patients, statin therapy is sufficient to lower LDL-C levels to goal (< 100mg/dL). One can usually start with moderate statin therapy (for example atorvastatin 10-20mg or rosuvastatin 5-10mg) and increase the statin dose, if necessary, to achieve LDL-C goals. In some instances, primary prevention patients are at high risk (see figures 2 and 3) and should be started on intensive statin therapy with lower LDL-C goals. Statins are available as generic drugs and therefore are relatively inexpensive. If a patient does not achieve their LDL-C goal on intensive statin therapy, cannot tolerate statin therapy, or is able to take only a low dose of a statin one can use ezetimibe (generic drug), bempedoic acid, bile acid sequestrant, or PCSK9 inhibitors to further lower LDL-C levels (for detailed discussion of cholesterol lowering drugs see (129)). It should be noted that the addition of ezetimibe or a PCSK9 inhibitor to statin therapy has been shown to reduce cardiovascular events (147-150). Bempedoic acid has been shown to reduce cardiovascular event in statin intolerant patients (151). In most situations, ezetimibe is the drug of choice given its low cost, ability to reduce ASCVD events, and long-term safety record.

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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