Dyslipidemias are characterized by abnormal concentrations of circulating lipids, increasing the risk of atherosclerosis and other serious conditions. Specific classes of dyslipidemias include elevated very-low-density lipoprotein (VLDL) cholesterol and low-density lipoprotein (LDL) cholesterol levels, hypercholesterolemia, hypertriglyceridemia, and low concentrations of high-density lipoprotein (HDL) cholesterol.
Dyslipidemias are typically asymptomatic but are frequently detected during routine screening. Occasionally, xanthelasmas and xanthomas are present. These are fatty deposits under the skin surface commonly found in patients with genetic disorders such as familial hypercholesterolemia.
Hyperlipidemia often results from overproduction of VLDL by the liver or delayed or defective hepatic clearance. VLDL is subsequently transformed into LDL. Familial hypercholesterolemia involves defective hepatic and nonhepatic LDL receptors. Excess intake of saturated fats increases the liver’s production of VLDL and triglycerides (TG) via a molecular mechanism involving protein activators. Saturated fats are mainly found in dairy products (e.g., milk, cheese, butter, and yogurt), meat, eggs, and tropical oils (palm, palm kernel, and coconut oils).
High total and LDL cholesterol concentrations and low HDL cholesterol concentrations predict cardiovascular risk in both men and women. High (TG) concentrations (> 150 mg/dL) are also associated with increased risk, particularly for women. Every 1% rise in total cholesterol concentration is associated with roughly a 2% increase in cardiovascular disease (CVD) risk.
Although dyslipidemias are a frequent finding in all demographic groups that follow Western diets, they occur somewhat more commonly in men. Additional risk factors may include:
Diets high in total fat, saturated fat, and cholesterol (see Nutritional Considerations below).
Smoking. Cigarette smoking lowers HDL cholesterol levels and is an independent risk factor for CVD.
Obesity. Obesity is associated with increased total, LDL, and VLDL cholesterol, and TG, as well as with decreased levels of HDL cholesterol.
Diabetes mellitus and the metabolic syndrome. Hyperinsulinemia is associated with low HDL cholesterol levels and hypertriglyceridemia.
Physical inactivity. A lack of regular exercise is associated with low HDL cholesterol concentrations.
Nephrotic syndrome. This condition is usually associated with elevated cholesterol and TG concentrations. Decreased vascular oncotic pressure due to proteinuria leads to increased lipoprotein production by the liver.
Chronic kidney disease. Hypertriglyceridemia is common.
Hypothyroidism. Total and LDL cholesterol concentrations may be elevated.
Alcoholism. While moderate intake may increase HDL cholesterol levels, more than moderate use leads to hypertriglyceridemia and may contribute to hypertension.
Family history. Genetic conditions, such as familial hypercholesterolemia, may contribute to dyslipidemias.
Drugs. Estrogen-progestin contraceptives, oral estrogens, tamoxifen, beta-blockers, thiazide diuretics, atypical antipsychotics, and corticosteroids may raise TG levels. Protease inhibitors and other drugs may also adversely affect lipid profiles.
Pregnancy. Triglyceride concentrations may increase.
There is still debate about who should be screened for lipid disorders and at what age. Many professional societies recommend screening starting at age 20. The presence of risk factors such as diabetes and obesity should be taken into consideration when deciding who and when to screen. Ideally, the patient should be in a steady state at the time of screening, free of significant recent weight change and acute illness. Medications should be noted, since some drugs interfere with lipid metabolism. Improvement of the conditions listed above that lead to hyperlipidemia may also improve the lipid profile. Hypothyroidism, chronic kidney disease, and insulin resistance should be considered in the diagnostic evaluation, as they may contribute to secondary dyslipidemia.
Patients should fast for about 12 hours before blood sampling, because chylomicron clearance can take up to 10 hours. A fasting sample, however, is not required for routine cholesterol (without hypertriglyceridemia) screening.
Common laboratory assays measure total plasma cholesterol, HDL cholesterol, and TG directly. VLDL cholesterol levels are calculated by dividing the triglyceride value by 5. LDL cholesterol is calculated by subtracting HDL cholesterol and VLDL cholesterol from total cholesterol. When triglycerides are above 400 mg/dL, LDL calculation is inaccurate, and LDL must be measured directly.
Classification of Lipid Concentrations
Total cholesterol. According to National Cholesterol Education Program (NCEP) guidelines, total cholesterol concentrations below 200 mg/dL are desirable. A borderline high concentration is 200 to 239 mg/dL, and hypercholesterolemia is defined as greater than 240 mg/dL. Epidemiologic evidence, however, suggests that stricter standards may be appropriate. Risk of cardiac events decreases as total cholesterol levels fall until plateauing at a total cholesterol of approximately 150 mg/dL. For children, total cholesterol should be less than 180 mg/dL.
Triglyceride. Normal triglyceride concentration is less than 150 mg/dL. Recent studies suggest that even lower limits are appropriate (e.g., < 130 mg/dL). Borderline is 150 to 199 mg/dL, and high is 200 to 499 mg/dL. A meta-analysis of 26 studies including over 96,000 individuals showed that those in the top 20% for triglyceride concentrations had an 80% higher risk for fatal or nonfatal coronary heart disease (CHD) when compared with those in the lowest quintile.
HDL cholesterol. Concentrations of 60 mg/dL or higher are associated with reduced risk. In general, an HDL concentration below 40 mg/dL is considered a major risk factor for CHD, although women’s risk of CHD increases marginally with HDL cholesterol < 50.
Although individuals with higher plasma HDL cholesterol concentrations have been shown to have modest reductions in cardiovascular risk, HDL elevation is no longer a clinical goal. In Mendelian randomization studies that have examined individuals with naturally occurring genetic variants associated with elevated plasma HDL cholesterol concentrations, these genetic traits are not associated with reduced risk of myocardial infarction unless they also reduce LDL cholesterol.
In a meta-analysis of 108 studies including 299,310 participants, treatment-induced HDL cholesterol elevations led to no reductions in the risk of CHD events, coronary disease mortality, or total mortality. The LDL/HDL ratio has not been shown to be a better predictor of cardiovascular outcomes than LDL cholesterol alone.
LDL cholesterol. According to the NCEP, LDL cholesterol concentrations below 100 mg/dL are considered optimal. A range of 100 to 129 mg/dL is near optimal. Borderline is 130 to 159 mg/dL. High is 160 to 189 mg/dL. However, increasing evidence supports stricter standards, including reductions below 70 mg/dL for very-high-risk patients. Studies of hunter-gatherer populations and normal neonates have modified the concept of “normal” cholesterol levels. Normal human LDL cholesterol concentration may be as low as 50 to 70 mg/dL, approximately half the US adult population mean. CHD risk decreases as LDL cholesterol concentration decreases, reaching a nadir at approximately 40 mg/dL.
The mainstay of treatment for hyperlipidemia is dietary and lifestyle modification, followed by drug therapy, as necessary. Hyperlipidemia should not be considered refractory to dietary treatment if the therapeutic regimen includes animal products or more than minimal amounts of vegetable oils. Such diets do not lower LDL cholesterol concentrations as effectively as high-fiber, low-fat diets that exclude animal products (see Nutritional Considerations below).
Regular exercise can improve lipid concentrations. Low to moderate amounts of physical activity, such as walking, lower triglyceride concentrations by an average of 10 mg/dL, while raising HDL cholesterol by 5 mg/dL (these numbers are means drawn from large groups). More strenuous activity may have greater effects.
Patients with familial hypercholesterolemia typically require medication starting in early childhood.
HMG-CoA reductase inhibitors (statins) reduce cholesterol production in the liver and are first-line agents in the treatment of elevated LDL cholesterol. Statins also have important effects on cardiovascular risk aside from their ability to reduce lipid concentrations, and they may be indicated for high-risk patients even when lipid targets can be achieved without drug therapy. The 2018 ACC/AHA Blood Cholesterol Guideline recommends initiating statin therapy for patients with clinical atherosclerotic cardiovascular disease (ASCVD), patients with primary elevation of LDL-C ≥190 mg/dL, patients 40-75 years of age with diabetes and LDL cholesterol of 70 to 189 mg/dL without clinical ASCVD, and patients without clinical ASCVD or diabetes who are 40-75 years old with LDL cholesterol concentrations of 70 to 189 mg/dL and an estimated 10-year ASCVD risk of ≥ 7.5%.
Statins are generally well tolerated; however, they do have side effects, most notably myopathy and hepatotoxicity. A meta-analysis of 20 studies found that individuals taking statins had a 44% increased risk for developing diabetes, compared with those not taking them. The risk appears to increase with longer use and higher doses. Statins can cause mild weight gain and, in rare cases, memory loss that can be severe and mistaken for Alzheimer’s disease or other forms of dementia, though this remits with discontinuation of the statin.
When statin therapy is not sufficient for reaching clinical goals, the addition of other medications may further reduce LDL cholesterol concentrations. It is not clear that this leads to improvements in clinical outcomes.
Statins that are hepatically metabolized are contraindicated in patients with active liver disease, but a renally metabolized statin (pravastatin) may still be used if necessary. Statins are also contraindicated in pregnant or nursing women, and in those with hypersensitivity to any of the components in the medication.
Bile acid sequestrants (e.g., cholestyramine, colestipol, colesevelam) are second-line agents for LDL cholesterol reduction. They inhibit bile acid resorption from the intestine and further reduce plasma LDL cholesterol through other mechanisms. Side effects can include gastrointestinal distress, constipation, and impaired absorption of other drugs.
Fibrates (e.g., gemfibrozil, fenofibrate) are first-line treatments for elevated triglyceride concentrations and may be prescribed in combination with the above drug classes. They also raise HDL cholesterol concentrations. Gallstones, dyspepsia, and myopathy may occur, the latter of which may be particularly high when fibrates are combined with statins.
Nicotinic acid (niacin) is a second-line therapy for all lipid disorders. Niacin is often combined with statins, as it raises HDL cholesterol levels at low doses. LDL cholesterol lowering occurs at higher doses, which unfortunately often cause side effects, including skin itching or burning. GI distress, flushing, hepatotoxicity, hyperglycemia, hyperuricemia, and gout may also occur.
Ezetimibe reduces GI cholesterol absorption and is a favored second-line therapy (followed by colesevelam) because of its effectiveness, safety, and relative rarity of side effects. It lowers LDL cholesterol and is particularly effective when combined with statins. In combination, lipid targets may be met with lower statin doses, and Framingham Risk Scores may be reduced more than typically occurs with statin therapy alone. Clinical outcomes, however, comparing statin monotherapy with combined ezetimibe therapy are not well characterized.
Proprotein convertase subtilisin 9 inhibitors (PSK-9 Inhibitors) (e.g., evolocumab, alirocumab) are the newest agents, available in injectable form, approved in 2015 to treat hyperlipidemia. These agents help to attenuate the breakdown of LDL receptors, making more LDL receptors available to bind to circulating LDL particles. In a large clinical trial, use of evolocumab not only decreased LDL cholesterol as compared to standard therapy, but also decreased overall cardiovascular events. Currently, PSK-9 inhibitor use is indicated for patients with familial hypercholesterolemia or those with clinical atherosclerotic cardiac disease who require additional lowering of LDL cholesterol (in addition to optimal statin therapy).
Bempedoic acid. Effective in lowering LDL cholesterol, this is a newer class of drug that works at a different entry point along the statin pathway.
Icosapent ethyl is a highly purified EPA extract which lowers triglycerides and works to lower CVD risk in those at highest risk (i.e., those with diabetes and a recent coronary event).
Although dyslipidemia is commonly addressed with statins, it is important for patients to understand that lipid abnormalities are not caused by a “statin deficiency.” Rather, they are usually the result of dietary factors, particularly the inclusion of dairy products, meat, eggs, and hydrogenated oils, and the absence of soluble fiber in the diet.
Dietary Factors that Elevate LDL Cholesterol
Animal-derived food products. Dietary cholesterol is found in foods of animal origin. Dairy products, meat, and eggs contain both saturated fat and cholesterol, especially eggs. Saturated fat intake increases LDL cholesterol concentrations. Dairy products are the leading source in Western diets, followed by meats. Red meat, chicken, and fish all contain significant amounts of saturated fat.
Although there has been some controversy in the lay press regarding the effects of dietary cholesterol, it is clear that dietary cholesterol influences blood cholesterol concentrations, albeit to a lesser degree than saturated fat. Roughly half of dietary cholesterol is absorbed into the bloodstream, with some variation from person to person.
Avoidance of even fat-reduced sources of dairy products is helpful for control of lipid concentrations, given that these products cause small but significant increases in LDL cholesterol.
Palm oil and coconut oil. Palm and coconut are high in saturated fat and, despite intense commercial promotion of these products, their effect on blood lipids is similar to that of animal-derived saturated fat., A systematic review of 16 studies found that consumption of coconut oil significantly raised total, LDL, and HDL cholesterol levels when compared to consumption of nontropical vegetable oils, such as olive and canola oil.
Partially hydrogenated oils (trans fats). Partially hydrogenated oils increase LDL cholesterol. Found in fried fast foods, stick margarines, processed foods, and in trace amounts, in animal-derived products. Intake of these fats has a linear relationship with LDL cholesterol levels when consumption is above approximately 3% of calorie intake.
Unfiltered coffee. Daily coffee intake is associated with an increase of roughly 8 mg/dL in total cholesterol, a 5 mg/dL increase in LDL cholesterol, and a 13 mg/dL increase in triglyceride levels, and unfiltered coffee is responsible for these effects to a greater extent than filtered coffee. Tea does not appear to have this effect. Higher (compared with lower) intake of green tea is associated with a reduction of more than 5 mg/dL total and LDL cholesterol levels, while regular consumers of black tea have been observed to have reductions in LDL of close to 5 mg/dL, with no effect on total or HDL cholesterol levels.,
Dietary Factors that Reduce LDL Cholesterol
Vegetables, fruits, grains, and legumes. Most foods from plant sources are extremely low in saturated fat and contain no cholesterol. In addition, beans and other legumes, oats, barley, and many fruits and vegetables are rich in soluble fiber. This reduces cholesterol concentrations through fecal bile excretion, reducing insulin-mediated hepatic cholesterol synthesis, and inhibition of cholesterol synthesis by fermentation products of soluble fiber. A meta-analysis of diet studies that included > 3 g/d of oat fiber found reductions in total and LDL cholesterol of roughly 12 mg/dL and 10 mg/dL, respectively.
Soy products. Soy products are often used to displace meat, dairy, or eggs from the diet and, in so doing, reduce the intake of saturated fat and cholesterol. Soy isoflavones also have inhibitory effects on cholesterol synthesis, and the fiber content of soy foods promotes cholesterol excretion. Clinical trials have demonstrated that individuals consuming soy products (soy milk, soy nuts) have LDL cholesterol reductions of up to 11 mg/dL and total cholesterol reductions of approximately 7%.
Plant sterols and stanols. Food sources of plant sterols include vegetable oils, nuts, seeds, and grains, as well as certain margarines (e.g., Benecol and Take Control). Although current plant sterol consumption ranges from 160 mg/d to 400 mg/d, it may have been as high as 1,000 mg/d earlier in human history. Individuals adopting plant-based diets can easily double their intake. In clinical trials, these diets have been found to reduce LDL cholesterol by between 10% and 16%, and to lower triglycerides by 0.8% to 28%.
Nuts (almonds, peanuts, pecans, and walnuts) are high in fat, although their fat is typically much lower in saturated fat compared with dairy products or meats. Moreover, nuts may have hypolipidemic effects through their fiber or plant sterol content. A dose-response meta-analysis concluded that for every daily 1-ounce serving of nuts, total and LDL cholesterol are lowered by roughly 5%. Because of their fat content, however, nuts can impede weight loss efforts if not compensated for by reducing calories from other sources.
Vegetable oils. Some authorities recommend replacing fats that contain saturated or trans fatty acids with those richer in monounsaturated and polyunsaturated fats. In omnivorous populations, replacing saturated fat with unsaturated fat has been shown to reduce LDL significantly. It is imperative to bear in mind that all oils are mixtures containing varying amounts of saturated fat. For example, olive oil is approximately 13% saturated fat. In addition, all fats are energy dense (9 kcals per gram) and can promote weight gain. Studies of heart disease reversal have therefore avoided the use of added oils.
From Foods to Dietary Patterns
The effects of individual foods combine into dietary patterns, which have been studied for their effects on blood lipid concentrations.
Plant-based dietary patterns. Vegetarian, especially vegan, diets have been found to be superior to other types of diets for lowering total and LDL cholesterol. This is understandable given that plant-based diets contain no animal fat or cholesterol and are often rich in soluble fiber. A systematic review and meta-analysis found a difference of 14 mg/dL (0.36 mmol/L) difference for total cholesterol and a 13 mg/dL (0.34 mmol/L) difference for LDL cholesterol, compared with control diets.
A “portfolio” combining the effects of a vegan diet emphasizing soluble fiber, soy protein, nuts, and plant sterols has been shown to lower LDL cholesterol by nearly 30% in 4 weeks.
Similarly, a diet based on the Dietary Approaches to Stop Hypertension (DASH) study has been found to reduce total and LDL cholesterol by 14 mg/dL and 11 mg/dL, respectively. Mediterranean diets were found to lower total cholesterol by about 9 mg/dL.
Dietary changes can foster weight loss, which is helpful for improving blood lipid concentrations. This has been particularly true for plant-based diets. On average, every kg of weight loss decreases LDL cholesterol and triglyceride levels by roughly 1 mg/dL each.
Low-Carbohydrate Diets Raise LDL Cholesterol
Weight loss by any means typically causes a reduction in total cholesterol of roughly 2 mg/dL per kilogram lost. Low-carbohydrate fad diets, on the other hand, are typically high in saturated fat and cholesterol, leading to LDL cholesterol elevations in many individuals attempting such diets.,,,,The degree of LDL cholesterol change varies widely, but on average, is about a 10% increase, which persists if the diet continues.,
It has been suggested that the rise in LDL cholesterol is not of concern if the increase is mainly in larger LDL particles. However, LDL is potentially atherogenic regardless of particle size. In the Women’s Health Study, the hazard ratio for incident cardiovascular disease associated with large LDL particles was 1.44 (indicating a 44% increased risk). For small LDL, it was 1.63 (a 63% increased risk). Both were highly statistically significant. In other words, large LDL particles are atherogenic, albeit less so than small LDL particles.
Nutritional Effects on HDL and Triglycerides
Dietary factors tend to simultaneously influence HDL cholesterol and triglyceride concentrations, although increased HDL no longer appears to reduce cardiovascular risk, as noted above. Factors under study include the following:
Avoiding high-glycemic-index foods. The glycemic index is a measure of the effect of foods on blood glucose values. For example, wheat bread has a higher glycemic index than rye or pumpernickel, reflecting its greater effect on blood glucose. Diets favoring low-glycemic-index foods not only help reduce blood sugar concentrations; they have also been shown to significantly reduce triglyceride levels. Avoiding sugar-sweetened beverages is also associated with lower triglyceride and HDL cholesterol levels. In a study in adults, each additional sweetened beverage per day was associated with a roughly 13 mg/dL increase in triglycerides and a roughly 2 mg/dL decrease in HDL cholesterol.
Increasing legume intake. A higher intake of legumes is associated with lower triglyceride levels, as well as lower total and LDL cholesterol.
Avoiding or limiting alcohol. Alcohol has diverse effects in lipoprotein metabolism, depending in part on the dose. Individuals consuming 1-2 drinks per day have lower serum triglycerides, whereas higher intakes have an adverse effect on LDL cholesterol levels in older men, and raise triglyceride levels.,
Fish oil and DHA supplements. Fish oil and docosahexaenoic acid from algal oil have both been found to significantly lower triglycerides by roughly up to 30 mg/dL; however, LDL levels also increased significantly by roughly 9 mg/dL.
Other Nutrient Issues under Study
Garlic. Some reviewers have suggested that daily consumption of garlic in the form of powder, raw garlic, or garlic oil reduces total and LDL cholesterol by roughly 17 mg/dL and 9 mg/dL, respectively, in hypercholesterolemic individuals when taken for more than 2 months. Caution is advised, however, given that this is an area where commercial products are eager for research support and there is risk of publication bias. A large, well-controlled randomized trial found no effects of garlic.
Probiotics. Probiotic supplementation in the form of either capsules or fermented milk products produced significant reductions in both total and LDL cholesterol of 6.5 and 8.5 mg/dL, respectively.
Caution with use of red yeast rice. An active metabolite of red yeast rice, called monacolin K, is identical to lovastatin. Red yeast rice, however, may contain citritin, a mycotoxin known to cause nephrotoxicity. Anaphylaxis, toxic hepatitis, and rhabdomyolysis have also been associated with the use of this product. Careful medical and laboratory monitoring would thereby be indicated for individuals who choose to use red yeast rice.
Diet: Vegetarian, low-fat, nondairy, high in soluble fiber. Avoid trans fats.
Nutrition consultation to advise patient in above diet and arrange follow-up.
Exercise prescription (patient-specific).
Alcohol restriction for hypertriglyceridemia.
Avoid oral contraceptives, if relevant.
What to Tell the Family
Dyslipidemias are common contributors to atherosclerosis. Cholesterol and triglyceride concentrations can be reduced through restriction of saturated fat, cholesterol, trans fatty acids, and total fat. Increasing dietary fiber, soy foods, and exercise can make these measures more effective. The patient’s family may also be at risk for lipid disorders and other cardiovascular problems. Their adoption of the same diet and lifestyle changes made by the patient, including smoking cessation, will encourage patient adherence and improve family members’ health.
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