Dyslipidemia

Primary causes are single or multiple gene mutations that result either in overproduction or defective clearance of triglycerides and LDL or in underproduction or excessive clearance of HDL (see table ).

Secondary causes contribute to many cases of dyslipidemia in adults.

The most important secondary cause of dyslipidemia in high-resource countries is

Trans fats are polyunsaturated or monounsaturated fatty acids to which hydrogen atoms have been added; they are used in some processed foods and are as atherogenic as saturated fat.

Other common secondary causes of dyslipidemia include

Secondary causes of low levels of HDL-C include cigarette smoking, anabolic steroids, HIV infection Human Immunodeficiency Virus (HIV) Infection Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more , and nephrotic syndrome Overview of Nephrotic Syndrome Nephrotic syndrome is urinary excretion of > 3 g of protein/day due to a glomerular disorder plus edema and hypoalbuminemia. It is more common among children and has both primary and secondary... read more .

Diabetes is an especially significant secondary cause because patients tend to have an atherogenic combination of high TGs; high small, dense LDL fractions; and low HDL (diabetic dyslipidemia, hypertriglyceridemic hyperapo B). Patients with type 2 diabetes are especially at risk. The combination may be a consequence of obesity, poor control of diabetes, or both, which may increase circulating free fatty acids (FFAs), leading to increased hepatic very-low-density lipoprotein (VLDL) production. TG-rich VLDL then transfers TG and cholesterol to LDL and HDL, promoting formation of TG-rich, small, dense LDL and clearance of TG-rich HDL. Diabetic dyslipidemia is often exacerbated by the increased caloric intake and physical inactivity that characterize the lifestyle of some patients with type 2 diabetes. Women with diabetes may be at special risk of cardiac disease as a result of this form of dyslipidemia.

Total cholesterol (TC), triglycerides (TGs), and HDL-C are measured directly. TC and TG values reflect cholesterol and TGs in all circulating lipoproteins, including chylomicrons, VLDL, intermediate-density lipoprotein (IDL), LDL, and HDL. TC values can vary by 10% and TGs by up to 25% day-to-day even in the absence of a disorder.

TC and HDL-C may be measured in the nonfasting state, but most patients should have all lipids measured while fasting (usually for 12 hours) for maximum accuracy and consistency.

Testing should be postponed if a patient has an acute illness, because TG and lipoprotein(a) levels increase and cholesterol levels decrease in inflammatory states. Also, lipid profiles can vary for about 30 days after an acute myocardial infarction (MI); however, results obtained within 24 hours after MI are usually reliable enough to guide initial lipid-lowering therapy.

LDL-C values are most often calculated as the amount of cholesterol not contained in HDL and VLDL. VLDL is estimated by TG ÷ 5 because the cholesterol concentration in VLDL particles is usually one fifth of the total lipid in the particle. Thus, the Friedewald formula estimates LDL-C as follows:

The calculated LDL cholesterol value incorporates measures of all non-HDL and nonchylomicron cholesterol, including that in IDL and lipoprotein (a) (Lp(a)).

For patients who have elevated TG levels, errors in estimating VLDL-C are magnified while using the constant factor of 5. The Martin-Hopkins equation may be used to obtain a more reliable estimate of LDL-C. The constant factor of 5 is replaced with a novel factor based on a patient's non-HDL-C and TG values (1 Diagnosis reference Dyslipidemia is elevation of plasma cholesterol, triglycerides (TGs), or both, or a low high-density lipoprotein cholesterol (HDL-C) level that contributes to the development of atherosclerosis... read more ). The novel factor is an adjustable factor that is based on the patient's non-HDL-C and TG levels and is derived from a table. Both the Friedewald and Martin-Hopkins equations were developed and validated for fasting patients with serum TG levels < 400 mg/dL (< 4.5 mmol/L).

The Martin-Hopkins equation is as follows:

LDL-C can also be measured directly using plasma ultracentrifugation, which separates chylomicrons and VLDL fractions from HDL-C and LDL-C, and by an immunoassay method. Direct measurement may be useful in some patients with elevated TGs, but these direct measurements are not usually necessary.

In some patients, additional lipid tests should be done.

Lp(a) levels and C-reactive protein levels should be measured in patients with premature atherosclerotic cardiovascular disease, cardiovascular disease (even if they have lower risk lipid levels; see table ), or high LDL-C levels refractory to drug therapy. Lp(a) levels may also be directly measured in patients with borderline-high LDL-C levels to determine whether drug therapy is warranted.

Measurements of LDL particle number or apoprotein B-100 (apo B) is useful in patients with elevated TGs and the metabolic syndrome Metabolic Syndrome Metabolic syndrome is characterized by a large waist circumference (due to excess abdominal adipose tissue), hypertension, abnormal fasting plasma glucose or insulin resistance, and dyslipidemia... read more . Apo B provides similar information to LDL particle number because there is one apo B molecule for each LDL particle. Apo B measurement includes all atherogenic particles, including remnants and Lp(a).

Apo B value reflects all non-HDL-C (in VLDL, IDL, and LDL) and is more predictive of CAD risk than LDL-C. Non-HDL-C (TC − HDL-C) is also more predictive of CAD risk than LDL-C, especially in patients with hypertriglyceridemia.

Tests for secondary causes of dyslipidemia should be done in most patients with newly diagnosed dyslipidemia and repeated when a component of the lipid profile has inexplicably changed for the worse. Such tests include measurements of

Most physicians recommend screening per the 2012 National Heart Lung and Blood Institute Guidelines (1 Screening references Dyslipidemia is elevation of plasma cholesterol, triglycerides (TGs), or both, or a low high-density lipoprotein cholesterol (HDL-C) level that contributes to the development of atherosclerosis... read more ) as follows

Adults should be screened at age 20 (2, 3 Screening references Dyslipidemia is elevation of plasma cholesterol, triglycerides (TGs), or both, or a low high-density lipoprotein cholesterol (HDL-C) level that contributes to the development of atherosclerosis... read more ) and every 5 years thereafter.

An age to discontinue screening has not been established, but evidence supports screening of patients into their 80s, especially if they have atherosclerotic cardiovascular disease (4 Screening references Dyslipidemia is elevation of plasma cholesterol, triglycerides (TGs), or both, or a low high-density lipoprotein cholesterol (HDL-C) level that contributes to the development of atherosclerosis... read more ).

Patients with an extensive family history of heart disease—heart attack, stroke, or coronary artery disease before age 55 (in men) or age 65 (in women) without known risk factors, such as high LDL, smoking, diabetes, or obesity, or known family history of high Lp(a)—should also be screened by measuring Lp(a) levels.

The main goal for dyslipidemia treatment is prevention of atherosclerotic cardiovascular disease (ASCVD), including acute coronary syndromes Overview of Acute Coronary Syndromes (ACS) Acute coronary syndromes result from acute obstruction of a coronary artery. Consequences depend on degree and location of obstruction and range from unstable angina to non–ST-segment elevation... read more , stroke Overview of Stroke Strokes are a heterogeneous group of disorders involving sudden, focal interruption of cerebral blood flow that causes neurologic deficit. Strokes can be Ischemic (80%), typically resulting... read more , transient ischemic attack Transient Ischemic Attack (TIA) A transient ischemic attack (TIA) is focal brain ischemia that causes sudden, transient neurologic deficits and is not accompanied by permanent brain infarction (eg, negative results on diffusion-weighted... read more , or peripheral arterial disease Peripheral Arterial Disease Peripheral arterial disease (PAD) is atherosclerosis of the extremities (virtually always lower) causing ischemia. Mild PAD may be asymptomatic or cause intermittent claudication; severe PAD... read more presumed caused by atherosclerosis Atherosclerosis Atherosclerosis is characterized by patchy intimal plaques (atheromas) that encroach on the lumen of medium-sized and large arteries. The plaques contain lipids, inflammatory cells, smooth muscle... read more . Treatment is indicated for all patients with ASCVD (secondary prevention) and for some without (primary prevention).

Treatment of children is controversial because there is no evidence that lowering lipid levels in childhood effectively prevents heart disease in adulthood. Moreover, the safety and effectiveness of long-term lipid-lowering treatment in children are unknown. Nevertheless, the American Academy of Pediatrics (AAP) recommends treatment for some children who have elevated LDL-C Elevated LDL-C in children Dyslipidemia is elevation of plasma cholesterol, triglycerides (TGs), or both, or a low high-density lipoprotein cholesterol (HDL-C) level that contributes to the development of atherosclerosis... read more levels. Children with heterozygous familial hypercholesterolemia should be treated beginning at age 8 to 10 years. Children with homozygous familial hypercholesterolemia require diet, medications, and often LDL apheresis to prevent premature death; treatment is begun when the diagnosis is made.

Treatment options depend on the specific lipid abnormality, although different lipid abnormalities often coexist. In some patients, a single abnormality may require several therapies; in others, a single treatment may be adequate for several abnormalities. Treatment should always include treatment of hypertension Treatment Hypertension is sustained elevation of resting systolic blood pressure (≥ 130 mm Hg), diastolic blood pressure (≥ 80 mm Hg), or both. Hypertension with no known cause (primary; formerly, essential... read more and diabetes Treatment Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia. Early symptoms are related to hyperglycemia and include polydipsia... read more and smoking cessation Smoking Cessation Most people who smoke want to quit and have tried doing so with limited success. Effective interventions include cessation counseling and pharmacologic treatment, such as varenicline, bupropion... read more . Treatment should also include daily low-dose aspirin in patients age 40 to 79 years with a low risk of bleeding and with a 10-year risk of myocardial infarction or death due to CAD of ≥ 20%. In general, treatment options for men and women are the same.

For all individuals, the prevention of ASCVD requires an emphasis on a heart-healthy lifestyle, particularly diet and exercise. Other options to lower LDL-C in all age groups include medications, dietary supplements, and procedural interventions. Many of these options are also effective for treating other lipid abnormalities.

Dietary changes help to maintain ideal body weight and provide other benefits. These changes include

Referral to a dietitian is often useful.

Exercise lowers LDL-C in some people and also helps maintain ideal body weight.

Dietary changes and exercise should be used whenever feasible, but American Heart Association (AHA)/American College of Cardiology (ACC) guidelines recommend also using drug therapy for certain groups of patients after discussion of the risks and benefits of statin therapy (1 Treatment references Dyslipidemia is elevation of plasma cholesterol, triglycerides (TGs), or both, or a low high-density lipoprotein cholesterol (HDL-C) level that contributes to the development of atherosclerosis... read more ).

For drug therapy in adults, the AHA/ACC Guidelines recommend treatment with a statin for 4 groups of patients, comprised of those with any of the following:

Risk of ASCVD is estimated using the pooled cohort risk assessment equations. This risk is based on sex, age, race, total and HDL-C, systolic and diastolic blood pressure, diabetes and smoking status, and use of antihypertensives or statins.

Increased lifetime risk (identified using the AHA/ACC risk calculator) is relevant because 10-year risk may be low in younger patients, in whom longer-term risk should be taken into account.

When considering whether to give a statin, clinicians may also take into account other factors, including

Statins are the treatment of choice for LDL-C reduction because evidence has demonstrated that they reduce cardiovascular morbidity and mortality (2 Treatment references Dyslipidemia is elevation of plasma cholesterol, triglycerides (TGs), or both, or a low high-density lipoprotein cholesterol (HDL-C) level that contributes to the development of atherosclerosis... read more ). Other classes of lipid-lowering drugs are not the first choice for treating elevated LDL-C because they have not demonstrated equivalent efficacy for decreasing ASCVD.

Statins inhibit hydroxymethylglutaryl CoA reductase, a key enzyme in cholesterol synthesis, leading to up-regulation of LDL receptors and increased LDL clearance. They reduce LDL-C by up to 60% and produce small increases in HDL-C and modest decreases in TGs. Statins also appear to decrease intra-arterial inflammation, systemic inflammation, or both by stimulating production of endothelial nitric oxide and may have other beneficial effects.

Statin therapy is classified as high-, moderate-, or low-intensity and is given based on treatment group and age (see table ). The choice of statin depends on the patient's co-morbidities, other drugs, risk factors for adverse events, statin intolerance, cost, and patient preference.

Adverse effects with statins are uncommon but include liver enzyme elevations and myositis or rhabdomyolysis Rhabdomyolysis Rhabdomyolysis is a clinical syndrome involving the breakdown of skeletal muscle tissue. Symptoms and signs include muscle weakness, myalgias, and reddish-brown urine, although this triad is... read more . Liver enzyme elevations are uncommon, and serious liver toxicity is extremely rare. Symptoms or severe adverse effects involving muscle occur in up to 10% of patients taking statins and may be dose-dependent. Muscle symptoms can occur without muscle enzyme (eg, creatine kinase) elevation. Adverse effects are more common among older patients, patients with several disorders, and patients taking several drugs. In some patients, changing from one statin to another or lowering the dose (after temporarily discontinuing the drug) relieves the problem. Muscle toxicity seems to be most common when some of the statins are used with drugs that inhibit cytochrome P3A4 (eg, macrolide antibiotics, azole antifungals, cyclosporine) and with fibrates, especially gemfibrozil. Statins are contraindicated during pregnancy and lactation.

In patients with ASCVD, risk reduction increases with decreasing LDL-C levels. Thus, initial treatment is a statin at maximally tolerated dose with the goal of lowering LDL-C by > 50% (high-intensity therapy). For very high-risk patients with ASCVD (eg, those with a recent myocardial infarction Acute Myocardial Infarction (MI) Acute myocardial infarction is myocardial necrosis resulting from acute obstruction of a coronary artery. Symptoms include chest discomfort with or without dyspnea, nausea, and/or diaphoresis... read more or unstable angina Unstable Angina Unstable angina results from acute obstruction of a coronary artery without myocardial infarction. Symptoms include chest discomfort with or without dyspnea, nausea, and diaphoresis. Diagnosis... read more or with high-risk comorbidities such as diabetes Diabetes Mellitus (DM) Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia. Early symptoms are related to hyperglycemia and include polydipsia... read more ), a LDL-C level > 70 mg/dL (> 1.2 mmol/L) despite maximal statin therapy should prompt the addition of ezetimibe or a PCSK9 inhibitor (eg, evolocumab, alirocumab). These therapies have been proven to reduce major adverse cardiovascular events in conjunction with statin therapy in large clinical outcome trials (3 Treatment references Dyslipidemia is elevation of plasma cholesterol, triglycerides (TGs), or both, or a low high-density lipoprotein cholesterol (HDL-C) level that contributes to the development of atherosclerosis... read more , 4 Treatment references Dyslipidemia is elevation of plasma cholesterol, triglycerides (TGs), or both, or a low high-density lipoprotein cholesterol (HDL-C) level that contributes to the development of atherosclerosis... read more ).

Non-statin medications also have a place in lowering LDL-C (see table ). The 2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies provides guidance to clinicians on the role of non-statin therapy in both primary and secondary prevention of ASCVD (5 Treatment references Dyslipidemia is elevation of plasma cholesterol, triglycerides (TGs), or both, or a low high-density lipoprotein cholesterol (HDL-C) level that contributes to the development of atherosclerosis... read more ). Statins are generally first-line medications, but in patients with statin intolerance, or those who are not able to achieve target LDL-C levels despite statin use, non-statin medications are used.

The adenosine triphosphate citrate lyase inhibitor, bempedoic acid impairs cholesterol synthesis in the liver and increases LDL receptors. It lowers LDL-C by 15 to 17% (6, 7 Treatment references Dyslipidemia is elevation of plasma cholesterol, triglycerides (TGs), or both, or a low high-density lipoprotein cholesterol (HDL-C) level that contributes to the development of atherosclerosis... read more ). Bempedoic acid is especially useful in patients with statin-associated muscle adverse effects because it does not cause muscle pain or weakness. It can be used as monotherapy or as an add-on to other lipid-lowering therapy. Risks include hyperuricemia and tendon rupture.

Bile acid sequestrants (cholestyramine, colestipol, colesevelam) block intestinal bile acid reabsorption, forcing up-regulation of hepatic LDL receptors to recruit circulating cholesterol for bile synthesis. They have been shown to reduce cardiovascular mortality. Bile acid sequestrants are usually used with statins or with nicotinic acid Low HDL-C to augment LDL-C reduction. They are the drugs of choice for women who are or are planning to become pregnant. Statins are contraindicated in pregnancy because they maybe teratogenic due to the interruption of cholesterol synthesis, which is essential in fetal development. Bile acid sequestrants are safe, but their use is limited by adverse effects of bloating, nausea, cramping, and constipation. They may also increase TGs, so their use is contraindicated in patients with hypertriglyceridemia. Cholestyramine, colestipol, and colesevelam (but to a lesser degree), interfere with absorption of other drugs—notably thiazides, beta-blockers, warfarin, digoxin, and thyroxine—an effect that can be decreased by administration at least 4 hours before or 1 hour after other drugs. Bile acid sequestrants should be given with meals to increase their efficacy.

The cholesterol absorption inhibitor ezetimibe inhibits intestinal absorption of cholesterol and phytosterol. Ezetimibe usually lowers LDL-C by 15 to 20% and causes small increases in HDL-C and a mild decrease in triglycerides. Ezetimibe can be used as monotherapy in patients intolerant to statins or added to statins for patients taking maximum statin doses with persistent LDL-C elevation. Adverse effects are infrequent.

PCSK9 monoclonal antibodies (alirocumab, evolocumab) are available as subcutaneous injections given once or twice per month. These drugs keep PCSK9 from attaching to LDL receptors, leading to improved function of these receptors. LDL-C is lowered by 40 to 70%. Cardiovascular outcomes trials with evolocumab and alirocumab showed a decrease in cardiovascular events in patients with prior atherosclerotic cardiovascular disease (3 Treatment references Dyslipidemia is elevation of plasma cholesterol, triglycerides (TGs), or both, or a low high-density lipoprotein cholesterol (HDL-C) level that contributes to the development of atherosclerosis... read more ).

SiRNA targeting PCSK9 is given as a subcutaneous injection every 6 months. Inclisiran inhibits PCSK9 production in the liver, thereby prolonging activity of LDL receptors and lowering LDL-C levels. Although LDL-C is lowered, cardiovascular outcome trials with inclisiran are ongoing. Inclisiran can be used as an adjunct to diet and maximally tolerated statin therapy for patients with ASCVD or heterozygous familial hypercholesterolemia.

Dietary supplements that lower LDL-C levels include fiber supplements and commercially available margarines and other products containing plant sterols (sitosterol, campesterol) or stanols. Fiber supplements decrease cholesterol levels in multiple ways, including decreased absorption and increased excretion. Oat-based fiber supplements can decrease total cholesterol by up to 18%. Plant sterols and stanols decrease cholesterol absorption by displacing cholesterol from intestinal micelles and can reduce LDL-C by up to 10% without affecting HDL-C or TGs.

Cholesterylester transfer protein inhibitors are a class of drugs that are under investigation and that may simultaneously raise HDL-C and lower LDL-C. Cholesterylester transfer protein (CETP) is a plasma glycoprotein produced in the liver and adipose tissue that circulates in the blood bound primarily to HDL, which mediates the transfer of cholesteryl esters from HDL to ApoB containing particles.

Childhood risk factors besides family history and diabetes Diabetes Mellitus in Children and Adolescents Diabetes mellitus involves absence of insulin secretion (type 1) or peripheral insulin resistance (type 2), causing hyperglycemia. Early symptoms are related to hyperglycemia and include polydipsia... read more include cigarette smoking, hypertension Hypertension in Children Hypertension is sustained elevation of resting systolic blood pressure, diastolic blood pressure, or both; the pressures considered abnormal in children vary based on age up to age 13. Hypertension... read more , low HDL-C (< 35 mg/dL [< 0.9 mmol/L]), obesity, and physical inactivity.

The American Heart Association recommends dietary treatment for children with LDL-C > 110 mg/dL (> 2.8 mmol/L) (8 Treatment references Dyslipidemia is elevation of plasma cholesterol, triglycerides (TGs), or both, or a low high-density lipoprotein cholesterol (HDL-C) level that contributes to the development of atherosclerosis... read more ).

Drug therapy is recommended for children > 8 years and with either of the following:

Medications used in children include many of the statins. Children with familial hypercholesterolemia may require a second drug to achieve LDL-C reduction of at least 50%.

Although it is unclear whether elevated TGs independently contribute to cardiovascular disease, they are associated with multiple metabolic abnormalities that contribute to coronary artery disease (eg, diabetes Diabetes Mellitus (DM) Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia. Early symptoms are related to hyperglycemia and include polydipsia... read more , metabolic syndrome Metabolic Syndrome Metabolic syndrome is characterized by a large waist circumference (due to excess abdominal adipose tissue), hypertension, abnormal fasting plasma glucose or insulin resistance, and dyslipidemia... read more ). Consensus is emerging that lowering elevated TGs is beneficial. No target goals exist, but levels < 150 mg/dL (< 1.7 mmol/L) are generally considered desirable. No guidelines specifically address treatment of elevated TGs in children.

The overall treatment strategy is to first implement lifestyle changes, including exercise, weight loss, and avoidance of concentrated dietary sugar and alcohol. Intake of 2 to 4 servings/week of marine fish high in omega-3 fatty acids may be effective, but the amount of omega-3 fatty acids is often lower than needed; supplemental doses may be helpful. In patients with diabetes, glucose levels should be tightly controlled. If these measures are ineffective, lipid-lowering drugs should be considered. Patients with very high TG levels (> 1,000 mg/dL [> 11 mmol/L]) may need to begin drug therapy at diagnosis to more quickly reduce the risk of acute pancreatitis Acute Pancreatitis Acute pancreatitis is acute inflammation of the pancreas (and, sometimes, adjacent tissues). The most common triggers are gallstones and alcohol intake. The severity of acute pancreatitis is... read more .

Fibrates reduce TGs by about 50%. They appear to stimulate endothelial lipoprotein lipase (LPL), leading to increased fatty acid oxidation in the liver and muscle and decreased hepatic VLDL synthesis. They also increase HDL-C by up to 20%. Fibrates can cause gastrointestinal adverse effects, including dyspepsia, abdominal pain, and elevated liver enzymes. They uncommonly cause cholelithiasis Cholelithiasis Cholelithiasis is the presence of one or more calculi (gallstones) in the gallbladder. Gallstones tend to be asymptomatic. The most common symptom is biliary colic; gallstones do not cause dyspepsia... read more . Fibrates may potentiate muscle toxicity when used with statins and potentiate the effects of warfarin.

Statins can be used in patients with TGs < 500 mg/dL (< 5.65 mmol/L) if LDL-C elevations are also present; statins may reduce both LDL-C and TGs through reduction of VLDL. If only TGs are elevated, fibrates are the drug of choice.

Omega-3 fatty acids in high doses (1 to 6 g a day of eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) can be effective in reducing TGs. The omega-3 fatty acids EPA and DHA are the active ingredients in marine fish oil or omega-3 capsules. Adverse effects include eructation and diarrhea. These effects may be decreased by giving the fish oil capsules with meals in divided doses (eg, twice a day or 3 times a day). Omega-3 fatty acids can be a useful adjunct to other therapies. Prescription omega-3 fatty acid preparations are indicated for TG levels > 500 mg/dL (> 5.65 mmol/L).

The Apo CIII inhibitor (an antisense inhibitor of apo CIII), volanesorsen, is available in some countries. It lowers triglyceride levels in patients with severely elevated TG levels, including people with lipoprotein lipase deficiency. It is given as a weekly injection.

Although higher HDL-C levels predict lower cardiovascular risk, it is not clear whether treatments to increase HDL-C levels decrease risk of death. Guidelines in the Third Report of the NCEP Expert Panel define low HDL-C as < 40 mg/dL [< 1.04 mmol/L]; the guidelines do not specify an HDL-C target level and recommend interventions to raise HDL-C only after LDL-C targets have been reached (9 Treatment references Dyslipidemia is elevation of plasma cholesterol, triglycerides (TGs), or both, or a low high-density lipoprotein cholesterol (HDL-C) level that contributes to the development of atherosclerosis... read more ). Treatments for LDL-C and TG reduction often increase HDL-C, and the 3 objectives can sometimes be achieved simultaneously.

No guidelines specifically address treatment of low HDL-C in children.

Treatment includes lifestyle changes such as an increase in exercise and weight loss. Alcohol raises HDL-C but is not routinely recommended as a therapy because of its many other adverse effects. Drugs may be successful in raising levels when lifestyle changes alone are insufficient, but it is uncertain whether raising HDL-C levels reduces mortality.

Nicotinic acid (niacin) is the most effective drug for increasing HDL-C. Its mechanism of action is unknown, but it appears to both increase HDL-C production and inhibit HDL-C clearance; it may also mobilize cholesterol from macrophages. Niacin also decreases TGs and, in doses of 1500 to 2000 mg a day, reduces LDL-C. Niacin causes flushing, pruritus, and nausea; premedication with low-dose aspirin may prevent these adverse effects. Extended-release preparations cause flushing less often. However, most over-the-counter slow-release preparations are not recommended; an exception is polygel controlled-release niacin. Niacin can cause liver enzyme elevations and occasionally liver failure, insulin resistance, and hyperuricemia and gout. It may also increase homocysteine levels Hyperhomocysteinemia Hyperhomocysteinemia may predispose to arterial and venous thrombosis. (See also Overview of Thrombotic Disorders.) Hyperhomocysteinemia may predispose to arterial thrombosis and venous thromboembolism... read more . The combination of high doses of niacin with statins may increase the risk of myopathy. In patients with average LDL-C and below-average HDL-C levels, niacin combined with statin treatment may be effective in preventing cardiovascular disorders. In patients treated with statins to lower LDL-C to < 70 mg/dL (< 1.8 mmol/L), niacin does not appear to have added benefit and may cause increased adverse effects, including ischemic stroke Ischemic Stroke Ischemic stroke is sudden neurologic deficits that result from focal cerebral ischemia associated with permanent brain infarction (eg, positive results on diffusion-weighted MRI). Common causes... read more .

Fibrates increase HDL-C. Fibrates may decrease cardiovascular risk in patients with TGs > 200 mg/dL (> 2.26 mmol/L) and HDL-C < 40 mg/dL (< 1.04 mmol/L).

The usual approach in patients with elevated Lp(a) is to lower LDL-C aggressively. LDL apheresis has been used to lower Lp(a) in patients with high Lp(a) levels and progressive vascular disease.

The upper limit of normal for Lp(a) is about 30 mg/dL (75 nmol/L), but values in African Americans tend to be higher. Few data exist to guide the treatment of elevated Lp(a) or to establish treatment efficacy. Niacin is the only drug that directly decreases Lp(a); it can lower Lp(a) by > 20% at higher doses. There are several RNA-based therapies that lower Lp(a) levels in clinical development.

Treatment of diabetic dyslipidemia should always involve lifestyle changes and statins to reduce LDL-C. To decrease the risk of pancreatitis, fibrates can be used to decrease TGs when levels are > 500 mg/dL (> 5.65 mmol/L). Metformin lowers TGs, which may be a reason to choose it over other oral antihyperglycemic drugs when treating diabetes. Some thiazolidinediones (TZDs) increase both HDL-C and LDL-C. Some TZDs also decrease TGs. These antihyperglycemic drugs should not be chosen over lipid-lowering drugs to treat lipid abnormalities in patients with diabetes but may be useful adjuncts. Patients with very high TG levels and less than optimally controlled diabetes may have a better response to insulin than to oral antihyperglycemic drugs.

Treatment of dyslipidemia in patients with hypothyroidism Hypothyroidism Hypothyroidism is thyroid hormone deficiency. Symptoms include cold intolerance, fatigue, and weight gain. Signs may include a typical facial appearance, hoarse slow speech, and dry skin. Diagnosis... read more , chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more , liver disease, or a combination of these disorders involves treating the underlying disorders primarily and lipid abnormalities secondarily. Abnormal lipid levels in patients with low-normal thyroid function (high-normal TSH levels) improve with hormone replacement. Reducing the dosage of or stopping drugs that cause lipid abnormalities should be considered.

Lipid levels should be monitored periodically after starting treatment. No data support specific monitoring intervals, but measuring lipid levels 2 to 3 months after starting or changing therapies and once or twice yearly after lipid levels are stabilized is common practice.

Liver and severe muscle toxicity with statin use occurs in 0.5 to 2% of all users. Routine monitoring of liver enzyme levels is not necessary, and routine measurement of creatine kinase (CK) is not useful to predict the onset of rhabdomyolysis Rhabdomyolysis Rhabdomyolysis is a clinical syndrome involving the breakdown of skeletal muscle tissue. Symptoms and signs include muscle weakness, myalgias, and reddish-brown urine, although this triad is... read more . Muscle enzyme levels need not be checked regularly unless patients develop myalgias or other muscle symptoms. If statin-induced muscle damage is suspected, statin use is stopped and CK may be measured. When muscle symptoms subside, a lower dose or a different statin can be tried. If symptoms do not subside within 1 to 2 weeks of stopping the statin, another cause should be sought for the muscle symptoms (eg, polymyalgia rheumatica Polymyalgia Rheumatica Polymyalgia rheumatica is a syndrome closely associated with giant cell arteritis (temporal arteritis). It affects adults > 55. It typically causes severe pain and stiffness in proximal muscles... read more ).