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Hyperlipidaemia is a major cause of atherosclerosis and atherosclerosis-associated conditions, such as coronary heart disease (CHD), ischemic cerebrovascular disease, and peripheral vascular disease. Although the incidence of these atherosclerosis-related events has declined in the United States, these conditions still account for the majority of morbidity and mortality among middle-aged and older adults.

The incidence and absolute number of annual events will likely increase over the next decade because of the epidemic of obesity and the aging of the U.S. population. Dyslipidemias, including hyperlipidaemia (hypercholesterolemia) and low levels of high-density-lipoprotein cholesterol (HDL-C), are major causes of increased atherogenic risk; both genetic disorders and lifestyle (sedentary behavior and diets high in calories, saturated fat, and cholesterol) contribute to the dyslipidaemias seen in developed countries around the world.
Recognition that dyslipidemia is a risk factor has led to the development of drugs that reduce cholesterol levels. These drugs provide benefit in patients across the entire spectrum of cholesterol levels, primarily by reducing levels of low-density lipoprotein cholesterol (LDL-C). In well-controlled clinical trials, fatal and nonfatal CHD events and strokes were reduced by as much as 30% to 40%.

Clinical trial data support extending lipid-lowering therapy to high-risk patients whose major lipid risk factor is a reduced plasma level of HDL-C, even if their LDL-C level does not meet the existing threshold values for initiating hypolipidemic drug therapy. In patients with low HDL-C and average LDL-C levels, appropriate drug therapy reduced CHD endpoint events by 20% to 35%. Since two-thirds of patients with CHD in the United States have low HDL-C levels (<40 mg/dl), it is important to include low-HDL patients in management guidelines 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 to 400 mg/dl) also are of concern because they often occur as part of the metabolic syndrome, which includes insulin resistance, obesity, hypertension, low HDL-C levels, and substantially increased CHD risk. The atherogenic dyslipidemia in patients with the metabolic syndrome is characterized by moderately elevated triglycerides, low HDL-C levels, and lipid-depleted LDL (sometimes referred to as “small, dense LDL”). The metabolic syndrome affects ~25% of adults and is common in CHD patients; hence, identification of moderate hypertriglyceridemia in a patient, even if the total cholesterol level is normal, should trigger an evaluation to identify this disorder.

Hyperlipidaemia (elevated levels of triglycerides or cholesterol) and reduced HDL-C levels occur as a consequence of several interrelated factors that affect the concentrations of the various plasma lipoproteins. These factors may be lifestyle or behavioural (e.g., diet or exercise), genetic (e.g., mutations in a gene regulating lipoprotein levels), or metabolic (e.g., diabetes mellitus or other conditions that influence plasma lipoprotein metabolism). An understanding of these factors requires a brief description of lipoprotein metabolism. A more detailed description can be found elsewhere.

Despite a continuing decline in the incidence of atherosclerosis-related deaths in the past 39 years, deaths from CHD, cerebrovascular disease, and peripheral vascular disease accounted for 38.5% of the 2.4 million deaths in the United States during 2001. Two-thirds of atherosclerosis deaths were due to CHD. About 85% of CHD deaths occurred in individuals over 65 years of age. Among the 15% dying prematurely (below age 65), 80% died during their first CHD event. Among those dying of sudden cardiac death in 1997, 50% of the men and 64% of the women had previously been asymptomatic. It is estimated that an average of 11.5 years of life are lost as a consequence of having a myocardial infarction.

These statistics illustrate the importance of identifying and managing risk factors for CHD. The major conventional risk factors are elevated LDL-C, reduced HDL-C, cigarette smoking, hypertension, type 2 diabetes mellitus, advancing age, and a family history of premature (men <55 years; women <65 years) CHD events in a first-degree relative. Control of the modifiable risk factors is especially important in preventing premature CHD. Observational studies suggest that modifiable risk factors account for 85% of excess risk (risk over and above that of individuals with optimal risk-factor profiles) for premature CHD. The presence of one or more conventional risk factors in 90% of patients with CHD belies claims that a large percentage of CHD, perhaps as much as 50%, is not attributable to conventional risk factors.

Furthermore, these studies indicate that, when total cholesterol levels are below 160 mg/dl, CHD risk is markedly attenuated, even in the presence of additional risk factors. This pivotal role of hypercholesterolemia in atherogenesis gave rise to the almost universally accepted cholesterol-diet-CHD hypothesis: elevated plasma cholesterol levels cause CHD; diets rich in saturated (animal) fat and cholesterol raise cholesterol levels; and lowering cholesterol levels reduces CHD risk. Although the relationship between cholesterol, diet, and CHD was recognized nearly 50 years ago, proof that cholesterol lowering was safe and prevented CHD death required extensive epidemiological studies and clinical trials.

More effective lipid-lowering agents and a better understanding of atherogenesis have helped to prove that aggressive lipid-lowering therapy has many beneficial effects over and above those obtained by simply decreasing lipid deposition in the arterial wall. Arteriographic trials have shown that, although aggressive lipid lowering results only in very small increases in lumen diameter, it promptly decreases acute coronary events. Lesions causing less than 60% occlusion are responsible for more than two-thirds of the acute events. Aggressive lipid-lowering therapy may prevent acute events through its positive effects on the arterial wall; it corrects endothelial dysfunction, corrects abnormal vascular reactivity (spasm), and increases plaque stability.

Atherosclerotic lesions containing a large lipid core, large numbers of macrophages, and a poorly formed fibrous cap are prone to plaque rupture and acute thrombosis. Aggressive lipid lowering appears to alter plaque architecture, resulting in fewer lipids, fewer macrophages, and a larger collagen and smooth muscle cell-rich fibrous cap. Stabilization of plaque susceptibility to thrombosis appears to be a direct result of LDL-C lowering or an indirect result of changes in cholesterol and lipoprotein metabolism or arterial wall biology.

Drug therapy: 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors¾the statins¾which are the most effective and best tolerated drugs currently in use for treating dyslipidemia, bile acid-binding resins, nicotinic acid (niacin), fibric acid derivatives, and the cholesterol absorption inhibitor ezetimibe. Despite the efficacy of drug therapy, alterations in lifestyle have a far greater potential for reducing vascular disease risk and at a lower cost.

By: Ammarah Khan