Pathophysiology

A variety of lipid disorders can occur as a primary event or an event that is related to some underlying disease. Dyslipidemia can result from genetic disorders, concomitant disease states, or environmental factors. Alterations in lipoprotein metabolism are complex and often multifactorial. The primary dyslipidemias are associated with overproduction or impaired removal of lipoproteins. Primary dyslipidemias and their associated abnormalities are listed in Table 24-1. Often, the cause of primary dyslipidemia is not identified and plays little or no role in the diagnosis and treatment of most patients.

Table 24-2 provides a list of causes that contribute to secondary hyperlipidemia. If the clinician determines that a patient’s hyperlipidemia may be related to another process, correction or modification of this process should be sought before pharmacologic treatment is provided for the hyperlipidemia. Not mentioned in Table 24-2 is obesity, which may also produce lipoprotein alterations. In diabetes, triglyceride levels are related to the degree of glycemic control. In hypothyroidism, lipid abnormalities are corrected with thyroxine replacement. In uremia, an elevated triglyceride and low HDL level is observed. Elevated total cholesterol and triglycerides are seen in patients with nephrotic syndrome. In drug-induced hyperlipidemia, estrogens may increase HDL, whereas β-blockers, progestins, and anabolic steroids may decrease HDL.

Disease Process

Overwhelming scientific evidence supports a causal relationship between hyperlipidemia and CHD. Premature coronary atherosclerosis, leading to manifestations of CHD, is the most common and important consequence of hyperlipidemia. Elevated LDL cholesterol is a significant and positive predictor of CHD. Although cholesterol likely contributes to CHD in multiple ways, a major mechanism is LDL oxidation. Oxidation causes the lipoproteins to become “sticky” and facilitates their adhesion to the endothelium of blood vessels, thus causing atherosclerosis. An inverse correlation has been noted between HDL and CHD risk, so that elevated HDL cholesterol is considered protective against the development of CHD. Roughly 50% of Americans have cholesterol levels that place them at increased risk of CHD.

Most data point to an association between elevated triglycerides as an independent risk factor for CHD, although data are conflicting. Obesity, inactivity, cigarette smoking, excess alcohol, high carbohydrate intake, diseases (e.g., type 2 diabetes, renal failure, nephrotic syndrome), and drugs (e.g., corticosteroids, estrogens, retinoids) are known to be risk factors for elevated triglycerides.

Assessment

As a screening measure, a fasting lipoprotein profile should be obtained every 5 years in adults, beginning at the age of 20 years. Serum cholesterol should be assessed more frequently in patients who have risk factors for CHD. Lipid profiles should be obtained in the fasting state (>12 hours since last meal) for an accurate measurement of triglycerides and LDL. Patients should be evaluated for common secondary causes of hyperlipidemia (i.e., diseases and drugs). Assessment of the patient’s lifestyle, including diet and exercise, is crucial.

Fibric Acid Derivatives

Despite our lengthy experience with gemfibrozil, several uncertainties surround its precise mechanism of action. Its primary lipoprotein effect is to decrease triglyceride and raise HDL concentrations. The ability of gemfibrozil to lower triglycerides is attributed to an increase in lipoprotein lipase activity, which results in increased catabolism of VLDL. Gemfibrozil also may suppress lipolysis in adipose tissue, decrease free fatty acid flux, and lower the rate of triglyceride synthesis. The increase in HDL observed with gemfibrozil may result from increased synthesis of apolipoprotein A-1, or it may be indirectly related to the drug’s ability to lower VLDL. Gemfibrozil exerts a variable and minor effect on LDL levels.

Fenofibrate is a prodrug that is converted to its active metabolite, fenofibric acid. Fenofibric acid inhibits triglyceride synthesis and accelerates the removal of lipoproteins.

Bile Acid Sequestrants

Bile acid sequestrants are unique among the antihyperlipidemics because they are not absorbed systemically, and they are the safest drugs available for the treatment of hypercholesterolemia. Although they differ in their chemical structure, all are large copolymers that function as anion-exchange resins in the intestinal lumen. Here they bind to bile acids, forming an insoluble complex and producing a large increase in the fecal excretion of bile acids. The pathways involved in cholesterol and bile acid metabolism are intertwined and closely related. Although the resin agents are sequestering bile acids and are interrupting their enterohepatic recirculation, a 3- to 10-fold increase has been noted in the diversion of cholesterol into bile acid synthesis. This resultant decline in intracellular cholesterol concentrations leads to two compensatory changes: acceleration of HMG-CoA reductase activity, and upregulation of LDL cell surface receptors. The two homeostatic changes increase intracellular cholesterol concentrations for conversion to bile acids, either by increased cholesterol synthesis or by increased uptake and removal of LDL from plasma. Therefore, bile acid sequestrants increase the diversion of cholesterol to bile acid synthesis, lower intracellular stores of cholesterol, and result in increased catabolism of LDL by the liver.

Evidence-Based Recommendations

Dyslipidemia is a major treatable risk factor for coronary artery disease. Lowering LDL results in significant decreases in coronary events, including transient ischemic attacks and stroke. As primary prevention, lipid-lowering therapies decrease risk of CHD events and mortality in patients without a history of CHD (1A). In persons with diabetes, LDL reduction produces a more substantial decrease in cardiovascular disease than does blood glucose control (1A). Patients without coronary artery disease should be evaluated with respect to their global cardiac risk to determine whether lipid-lowering therapy is indicated. Statin therapy should be considered as secondary prevention for all patients with coronary heart disease, peripheral vascular disease, or history of stroke. These medications have been shown to decrease coronary heart disease and mortality even if baseline LDL is <100 mg/dl (1A). Statins reduce 5-year overall mortality and cardiovascular morbidity and mortality; the greatest reductions occur in patients at greatest risk (1A). A new “black box” warning has been mandated by the FDA for statins because of the increased occurrence of muscle pain, diabetes, and memory loss in patients. In addition, the side effects and potential “harm” of statins are often minimized and not adequately discussed or addressed with patients. Also, the benefit of lowering cholesterol or LDL in older people and primary prevention in women are of questionable value. Little substantial data exist to support primary prevention in women, but this is rarely stated, and women and men are often classed together in discussions about prevention.

Cardinal Points of Treatment

The most widely recognized treatment guidelines for hyperlipidemia, those of the NCEP, were most recently updated in 2004, although it is anticipated that another update will be released in 2013. An important tenet of these guidelines is that the intensity of evaluation and treatment depends on the patient’s overall risk status for CHD (Box 24-1)—that is, those patients with preexisting CHD or with CHD risk equivalents or those who are at high risk (more than two risk factors) for CHD in the near future are treated more aggressively. Next, patients with two or more risk factors should be further classified into 10-year risk groups based on their Framingham point scores. (See Framingham tables at www.nhlbi.nih.gov/guidelines/cholesterol/risk.) Framingham scores are based on age, total cholesterol level, smoking status, HDL cholesterol, and systolic blood pressure. They are used to assess the individual’s 10-year risk of developing CHD. Three levels of 10-year risk are identified: >20%, 10% to 20%, and <10%. Those found to have a risk >20% are categorized as if they had a CHD risk equivalent (for further information, see NCEP guidelines).

A second important feature of the NCEP guidelines is that dietary and drug treatment decisions are based on LDL cholesterol levels (Table 24-3). For example, an individual whose blood pressure is 150/95 mm Hg who currently smokes and has a 10-year risk of 8% would have lifestyle changes initiated at an LDL level 130 mg/dl. According to the recommendations, this individual would initiate drug therapy with an LDL level ≥160 mg/dl. In contrast, an individual with the risk factors listed earlier and a 10-year risk of 12% would initiate therapeutic lifestyle changes and drug therapy at an LDL ≥130 mg/dl. Alternatively, the current guidelines would consider drug therapy “optional” for LDL values between 100 and 129 mg/dl in such an individual.

Nonpharmacologic Treatment

The importance of dietary therapy and exercise is often overlooked, and their effectiveness is often underappreciated. Readers are advised to review the NCEP guidelines for further discussion of dietary strategies. Consider referring the patient to a dietitian for further instruction on low–saturated fat and low-cholesterol diets. Try to improve CHD risk factors that can be modified, such as smoking, hypertension, diabetes, inactivity, and obesity.

Pharmacologic Treatment

Treatment of patients with elevated LDL cholesterol and no prior history of CHD is considered primary prevention in men only. The clinical evidence supporting the benefit of statins for primary prevention in women is scant to nonexistent. This is even more true for elderly women. Treatment of patients with CHD is called secondary prevention. Although therapeutic lifestyle changes are a mainstay of primary prevention, recent evidence shows that lipid-lowering drugs reduce the risk for developing CHD. In the case of secondary prevention, it is clear that antihyperlipidemic drugs reduce major coronary artery events, coronary artery procedures, stroke, and coronary and total mortality.

Although achieving the goal LDL value is the first and primary goal, triglycerides and HDL should be considered in drug selection (Table 24-4). If triglycerides are >200 mg/dl after the LDL goal is reached, NCEP recommends setting a goal for non-HDL cholesterol (total cholesterol − HDL cholesterol) that is 30 mg/dl higher than the LDL goal. Once the LDL goal has been reached and triglycerides are <200 mg/dl, the focus should turn to the patient’s HDL. The first step in treatment is to increase physical activity and lose weight if overweight. Drug therapy, nicotinic acid, or fibric acid derivatives may be used if the patient’s HDL level remains below 40 mg/dl.

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