Prevention of Cardiovascular Events
Gemfibrozil is used to reduce the risk of developing coronary heart disease (CHD) in patients with type IIb hyperlipoproteinemia without clinical evidence of CHD (primary prevention) who have an inadequate response to dietary management, weight loss, exercise, and drugs known to reduce low-density lipoprotein (LDL)-cholesterol and increase high-density lipoprotein (HDL)-cholesterol (e.g., bile acid sequestrants) and who have low HDL-cholesterol concentrations in addition to elevated LDL-cholesterol and triglyceride concentrations. Although gemfibrozil has been used effectively in patients with types IIa and IIb hyperlipoproteinemia to decrease elevated total or LDL-cholesterol concentrations, the drug appears to be more effective in reducing the incidence of serious coronary events in patients with type IIb hyperlipoproteinemia who have elevations of both LDL-cholesterol and triglyceride concentrations. Therefore, the manufacturers state that because of potential toxicity, including malignancy, gallbladder disease, abdominal pain leading to appendectomy and other abdominal surgeries, and an increased incidence of noncardiovascular and all-cause mortality associated with the chemically and pharmacologically similar drug, clofibrate (no longer commercially available in the US), the potential benefit of gemfibrozil in treating patients with type IIa hyperlipoproteinemia and elevations of LDL-cholesterol only is unlikely to outweigh the risks of such therapy.
(See Cautions: Precautions and Contraindications.)Gemfibrozil is not indicated for use in the management of patients with low HDL-cholesterol as their only lipid abnormality (isolated low HDL-cholesterol).
The American College of Cardiology (ACC)/American Heart Association (AHA) guideline for management of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults states that nondrug therapies (i.e., lifestyle modifications), which include adherence to a heart-healthy diet, regular exercise, avoidance of tobacco products, and maintenance of a healthy weight, are the foundation of atherosclerotic cardiovascular disease (ASCVD) prevention. For additional details on lifestyle modifications, consult the most recent AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk (available at http://www.cardiosource.org or http://my.americanheart.org).
The ACC/AHA cholesterol management guideline states that nonstatin therapies (e.g., fibric acid derivatives) do not provide acceptable ASCVD risk reduction benefits compared to their potential for adverse effects in the routine prevention of ASCVD. The guideline states that nonstatin drugs may be useful as adjuncts to statin therapy in certain high-risk patients (e.g., patients with ASCVD, patients with LDL-cholesterol concentrations of 190 mg/dL or higher, patients with diabetes mellitus) who have a less-than-anticipated response to statins, are unable to tolerate even a less-than-recommended intensity of a statin, or are completely intolerant to statin therapy. When combination therapy with a fibric acid derivative and statin is required, fenofibrate is considered the drug of choice; gemfibrozil should not be used in combination with statin therapy because of an increased risk of adverse muscle effects and rhabdomyolysis. However, it should be noted that the addition of fenofibrate to simvastatin therapy in patients with diabetes mellitus has not been shown to substantially reduce the rate of major adverse cardiovascular events compared with statin monotherapy. For additional details on prevention of ASCVD, and also consult the most recent ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (available at http://www.cardiosource.org or http://my.americanheart.org).
In the Helsinki Heart Study (a large, multicenter, placebo-controlled study), long-term (up to 5 years) gemfibrozil (1200 mg daily) therapy in asymptomatic males with elevated pretreatment LDL- and/or VLDL-cholesterol concentrations (primary dyslipidemia, including types IIa, IIb, and IV hyperlipoproteinemia) who received dietary management was shown to reduce the risk of CHD. Average serum concentrations of total, LDL-, and non-HDL-cholesterol and triglycerides were decreased and HDL-cholesterol was increased in patients in this study and such changes were associated with a 34% reduction in CHD-associated end points (mainly fatal or nonfatal myocardial infarction and other death attributable to CHD), a 37% reduction in nonfatal myocardial infarction, and a 26% reduction in definite coronary death; however, overall mortality rate was similar for the gemfibrozil-treated and placebo groups. Subsequent analysis revealed that gemfibrozil therapy was associated with a substantial reduction in Q-wave but not non-Q-wave myocardial infarction. Subsequent detailed analyses of the serum lipid alterations in patients in the Helsinki Heart Study also indicated that reductions in LDL-cholesterol or increases in HDL-cholesterol were independently associated with reductions in coronary heart disease risk, while reductions in triglyceride concentrations had relatively little effect on CHD incidence. In a proportional hazards analysis in which risk factors such as age, blood pressure, smoking and drinking habits, baseline lipid concentrations, exercise, and relative weight were controlled, estimated reductions in CHD incidence of 23% or 15% were associated with mean HDL-cholesterol increases of 8% or mean LDL-cholesterol reductions of 7%, respectively, for the 2-year period immediately preceding a CHD end point. Reductions in the incidence of CHD-associated end points compared with placebo were observed among gemfibrozil-treated patients of all 3 lipoprotein types. However, reductions were greatest in patients with type IIb hyperlipoproteinemia and smallest in those with type IIa hyperlipoproteinemia; the number of CHD end points in patients with type IV hyperlipoproteinemia was insufficient for analysis. Substantial changes in triglyceride concentrations (mean reduction: 35%) in patients receiving gemfibrozil in this study had only a small effect (not statistically significant) on CHD incidence. While there is epidemiologic evidence to suggest that each 1-mg/dL increase in HDL-cholesterol may be associated with a 2-4% reduction in the incidence of CHD, it remains to be established whether HDL or one of its subfractions is responsible for protection against CHD or whether such protection is indirectly related to the relationship of HDL to other CHD risk factors such as obesity, smoking, exercise, or alcohol consumption.
Gemfibrozil has been used in men with clinical evidence of CHD who have low HDL-cholesterol and moderately elevated LDL-cholesterol concentrations to reduce the risk of recurrent coronary events (secondary prevention), including death from coronary causes, myocardial infarction, and stroke. In the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) in men with a history of CHD (e.g., myocardial infarction), low HDL-cholesterol concentrations (40 mg/dL or less), and moderately elevated LDL-cholesterol concentrations (140 mg/dL or less), therapy with gemfibrozil (1200 mg daily) was associated with a 22% reduction in CHD mortality or nonfatal myocardial infarction compared with placebo. Therapy with gemfibrozil also reduced the risk of stroke by 25%.
Gemfibrozil is used as an adjunct to dietary therapy for the management of severe hypertriglyceridemia in patients at risk of developing pancreatitis (typically those with serum triglyceride concentrations exceeding 2000 mg/dL and elevated concentrations of VLDL and fasting chylomicrons) who do not respond adequately to dietary management. Gemfibrozil also may be used in patients with triglyceride concentrations of 1000-2000 mg/dL who have a history of pancreatitis or of recurrent abdominal pain typical of pancreatitis; however, efficacy of the drug in patients with type IV hyperlipoproteinemia and triglyceride concentrations less than 1000 mg/dL who exhibit type V patterns subsequent to dietary or alcoholic indiscretion has not been adequately studied. The manufacturer states that gemfibrozil is not indicated for use in patients with type I hyperlipoproteinemia who have elevated triglyceride and chylomicron concentrations but normal VLDL-cholesterol concentrations.
The Third Report of the National Cholesterol Education Program (NCEP) (Adult Treatment Panel [ATP] III) stated that initiation of therapy and target goals in the management of hypertriglyceridemia depend on initial risk status and preexisting triglyceride concentrations. As in primary or secondary prevention of CHD, LDL-cholesterol is considered the primary target of therapy in most patients with borderline high (150-199 mg/dL) or high (200-499 mg/dL) triglyceride concentrations; in those with high triglyceride concentrations, non-HDL-cholesterol (sum of VLDL-cholesterol plus LDL-cholesterol, calculated as total cholesterol minus HDL-cholesterol) becomes a secondary target of therapy. The principal aim of therapy in patients with very high triglyceride concentrations (500 mg/dL or greater) is to prevent acute pancreatitis through triglyceride lowering; principal and secondary targets similar to those used in patients with borderline high or high triglycerides may be considered in these patients when triglyceride levels are reduced to less than 500 mg/dL.
ATP III stated that nondrug therapies and measures (i.e., weight reduction, increased physical activity, smoking cessation, restriction of excessive alcohol use, avoidance of high-carbohydrate [more than 60% of calories] diets) are considered the initial treatments of choice in the management of patients with borderline high or high triglyceride concentrations. Drug therapy, in addition to nonpharmacologic measures, also may be considered (after LDL-lowering therapy) in patients with high triglyceride concentrations to achieve the non-HDL-cholesterol goal. In these patients, ATP III recommended one of several options: intensifying therapy with an LDL-lowering drug (i.e., statin), initiating therapy with a triglyceride-lowering drug (i.e., fibric acid derivative or, preferably, niacin), or combining moderate doses of statins and triglyceride-lowering drugs. AHA states that although statins have consistently shown benefit in subgroups with or without high triglyceride concentrations, fibric acid derivatives have more commonly been shown to provide greater benefit in subgroups with increased triglyceride concentrations. Concomitant use with a fibric acid derivative (i.e., fenofibrate) requires reduction in the daily dosage of the statin and should be used with extreme caution to minimize the potential risk of myopathy and/or rhabdomyolysis. In addition, such combined regimens generally should be avoided in geriatric patients, in patients with acute or serious chronic illnesses (especially chronic renal disease), in those undergoing surgery, and in patients receiving certain interacting medications. (See
Cautions: Precautions and Contraindicationsand see Drug Interactions: HMG-CoA Reductase Inhibitors [Statins].)
Patients with very high triglyceride concentrations should be treated more intensively to prevent development of acute pancreatitis. However, before initiating antilipemic therapy, patients with triglyceride concentrations of 500 mg/dL or greater should be evaluated to rule out secondary causes of hyperlipidemia. ATP III recommended elimination of alcohol from diet and identification and, preferably, discontinuance of drugs that increase triglyceride concentrations. In addition, insulin or oral antidiabetic therapy may be initiated (or dosage increased) in patients with hyperglycemia. In patients with triglyceride concentrations exceeding 1000 mg/dL, a very low-fat diet (less than 15% of total daily calories as fat) should be initiated immediately to improve chylomicronemia that contributes to hypertriglyceridemia. Weight reduction and increased physical activity as components of lifestyle modifications should be emphasized. Pharmacologic therapy with triglyceride-lowering drugs (i.e., niacin or, preferably, a fibric acid derivative) usually is required in patients with very high triglyceride concentrations and often can prevent acute pancreatitis. Because niacin may worsen hyperglycemia (and thus increase triglyceride concentrations), high doses (greater than 2 g daily) of the drug generally should be used with caution in patients with elevated serum glucose concentrations. For most patients with very high triglyceride concentrations, therapy is considered successful if triglyceride concentrations are reduced to less than 500 mg/dL; triglyceride concentrations often cannot be normalized in these patients. The principal aim of therapy is to prevent acute pancreatitis; efforts to modify CHD risk (by lowering LDL- and/or non-HDL-cholesterol concentrations) may be considered once triglyceride concentrations have been reduced to less than 500 mg/dL.
The AHA and some clinicians recommend that therapy with a fibric acid derivative or niacin be considered in patients with type III hyperlipoproteinemia in whom hyperlipidemia persists despite weight control; restricted intake of total fats, saturated fatty acids, and cholesterol; and an appropriate program of physical activity.
Patients with very high triglyceride and chylomicron concentrations usually have a genetic form of the disease and generally are unresponsive to triglyceride-lowering drugs. Treatment for these patients includes very low-fat diets, which may be supplemented with medium-chain triglycerides to minimize production of chylomicrons.
Several studies have compared the efficacy of gemfibrozil and clofibrate in hyperlipoproteinemia. Studies in patients with type IIa, IIb, or IV hyperlipoproteinemia comparing 400 mg of gemfibrozil twice daily (200-mg capsules were used in initial drug trials) with 750 mg of clofibrate twice daily showed that these drugs were equally effective in decreasing serum cholesterol and triglyceride concentrations. Other studies in healthy males and patients with types IIa, IIb, and IV hyperlipoproteinemia indicate that 600 mg of gemfibrozil twice daily or 1 g of clofibrate twice daily produces similar decreases in serum cholesterol and triglycerides. A gemfibrozil dosage of 1.6 g daily produces a greater decrease in total serum triglyceride and VLDL-triglyceride concentrations and a greater increase in HDL-cholesterol than does 2 g of clofibrate daily. Some patients who do not have an adequate therapeutic response to gemfibrozil may respond to clofibrate and vice versa. However, some patients with type IIa, IIb, or IV hyperlipoproteinemia may not respond adequately to either drug even when dosage is increased. Studies that adequately compare gemfibrozil with niacin, probucol (no longer commercially available in the US), or bile acid sequestrants such as cholestyramine are limited.
Gemfibrozil has been used effectively in a very limited number of patients with type III hyperlipoproteinemia to decrease elevated triglyceride and cholesterol concentrations associated with this disorder.
Because therapy with gemfibrozil or other antilipemic agents (i.e., bile acid sequestrants, statins, niacin) has been shown to reduce mortality and nonfatal coronary events (e.g., myocardial infarction) in patients with or without CHD who have normal or elevated cholesterol concentrations, ACC and AHA currently recommend initiation of antilipemic therapy in combination with aspirin, nitrates, and β-adrenergic blockers for the management of chronic stable angina in patients with documented or suspected CHD who have LDL-cholesterol concentrations greater than 130 mg/dL. The ACC and AHA state that the decision to initiate antilipemic therapy in patients with CHD and LDL-cholesterol concentrations of 100-129 mg/dL must be individualized based on clinical judgment of the risks and benefit of such therapy.
For further information on the role of antilipemic therapy in the treatment of lipoprotein disorders, the prevention of cardiovascular events, and other conditions, see General Principles of Antilipemic Therapy in the HMG-CoA Reductase Inhibitors General Statement 24:06.08.