Hyperlipidemia is a major cause of atherosclerosis and atherosclerosis-induced conditions, such as coronary heart disease (CHD), ischemic cerebrovascular disease, and peripheral vascular disease. These conditions cause morbidity or mortality in a majority of middle-aged or older adults. Dyslipidemias, including hyperlipidemia (hypercholesterolemia) and low levels of high-density-lipoprotein cholesterol (HDL-C), are major causes of increased atherogenic risk; both genetic disorders and lifestyle contribute to the dyslipidemias seen in countries around the world.
Classes of drugs that modify cholesterol levels include:
Statins, inhibitors of 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase
Bile acid–binding resins
Nicotinic acid (niacin)
Fibric acid derivatives
Ezetimibe, an inhibitor of cholesterol absorption
These drugs provide benefit in patients across the entire spectrum of cholesterol levels, primarily by reducing levels of low-density-lipoprotein cholesterol (LDL-C). Drug regimens that reduce LDL-C levels moderately (30-40%) can reduce fatal and nonfatal CHD events and strokes by as much as 30-40%. In patients with low HDL-C and average LDL-C levels, appropriate drug therapy reduces CHD endpoint events by 20-35%. Because two-thirds of patients with CHD in the U.S. have low HDL-C levels (<40 mg/dL in men, <50 mg/dL in women), low-HDL-C patients should be treated for dyslipidemia, even if their LDL-C levels are in the normal range.
Severe hypertriglyceridemia (i.e., triglyceride levels of >1000 mg/dL) requires therapy to prevent pancreatitis. Moderately elevated triglyceride levels (150-400 mg/dL) are of concern because they often occur as part of the metabolic syndrome, which includes insulin resistance, obesity, hypertension, low HDL-C levels, a procoagulant state, and substantially increased risk of CVD. Atherogenic dyslipidemia in patients with metabolic syndrome also is characterized by lipid-depleted LDL (sometimes referred to as "small, dense LDL"). Metabolic syndrome affects ~25% of adults and is common in CVD patients; hence, identification of moderate hypertriglyceridemia in a patient, even if the total cholesterol level is normal, should trigger an evaluation to identify insulin-resistant patients with this disorder.
PLASMA LIPOPROTEIN METABOLISM
Lipoproteins are macromolecular assemblies that contain lipids and proteins. The lipid constituents include free and esterified cholesterol, triglycerides, and phospholipids. The protein components, known as apolipoproteins or apoproteins, provide structural stability to the lipoproteins and also may function as ligands in lipoprotein–receptor interactions or as cofactors in enzymatic processes that regulate lipoprotein metabolism. The major classes of lipoproteins and their properties are summarized in Table 31–1. Apoproteins have well-defined roles in plasma lipoprotein metabolism (Table 31–2).
Table 31–1Characteristics of Plasma Lipoproteins ||Download (.pdf) Table 31–1 Characteristics of Plasma Lipoproteins
|LIPOPROTEIN CLASS ||DENSITY (g/mL) ||MAJOR LIPID CONSTITUENT ||TG:CHOL ||SIGNIFICANT APOPROTEINS ||SITE OF SYNTHESIS ||CATABOLIC PATHWAY |
|Chylomicrons and remnants ||<<1.006 ||Dietary triglycerides and cholesterol ||10:1 ||B-48, E, A-I, A-IV, C-I, C-II, C-III ||Intestine ||Triglyceride hydrolysis by LPL, apoE-mediated remnant uptake by liver |
|VLDL ||<1.006 ||"Endogenous" or hepatic triglycerides ||5:1 ||B-100, E, C-I, C-II, C-III ||Liver ||Triglyceride ...|