Fibrates: What Have We Learned in the Past 40 Years?

James M. Backes, Pharm.D.; Cheryl A. Gibson, Ph.D.; Janelle F. Ruisinger, Pharm.D.; Patrick M. Moriarty, M.D.

Disclosures

Pharmacotherapy. 2007;27(3):412-424. 

In This Article

Major Trials of Fibrate Therapy

The safety and efficacy of fibrates have been assessed in six major outcome studies during the past 30 years ( Table 3 ).[2,8,50,51,52,53] The results of these studies have produced mixed findings when evaluating overall mortality, cardiovascular events, and adverse effects. The inconsistent outcomes may be a result of differences among individual fibrates and highly varied study populations.

Coronary Drug Project

The Coronary Drug Project (CDP) was one of the first major lipid trials with key findings; its results were published in 1975.[50] The primary objective of the trial was to determine safety and efficacy of several lipid-altering agents in preventing a recurrent CHD event among men with a previous myocardial infarction. Three arms of the study, using varying doses of estrogen and also dextrothyroxine, were discontinued prematurely secondary to excess mortality compared with the placebo group. However, a remaining treatment group, in which patients were randomly assigned to receive clofibrate, continued until the end of this approximately 5-year study. Overall mortality rates and cancer deaths were nearly identical between the clofibrate and placebo groups. The rate of CHD events was reduced 9% in the clofibrate group, but the difference between groups failed to reach statistical significance. The CDP raised concern regarding clofibrate because of a lack of efficacy on overall mortality and a significantly higher rate of cholelithiasis (3.0% vs 1.3%, zc = 3.63) compared with placebo. The authors concluded that the CDP results provided no evidence with which to recommend the use of clofibrate among men with CHD.

Two smaller trials published 4 years earlier produced similar results to those of the CDP. The Scottish (717 patients) and Newcastle (497 patients) studies each evaluated the effects of clofibrate on cardiovascular events among patients with CHD.[54,55] These trials yielded contrasting results with clofibrate and its effects on CHD death but showed a nonsignificant (40%) reduction in nonfatal myocardial infarction with clofibrate compared with placebo. In addition, subgroup analyses of these studies suggested clofibrate-treated patients with a previous history of angina, rather than myocardial infarction, experienced lower rates of CHD death and myocardial infarction. These effects were not observed with clofibrate in the CDP.

World Health Organization Study

With the publication in 1978 of results from the World Health Organization (WHO) cooperative trial in the primary prevention of ischemic heart disease using clofibrate came more uncertainty.[51] Middle-aged men (age range 30-59 yrs) with hypercholesterolemia, but free of cardiovascular disease, were randomly assigned to receive clofibrate or placebo and were followed for an average of 5.3 years. The treatment group experienced a 25% reduction (p<0.05) in nonfatal myocardial infarction compared with the control group. However, overall mortality and the rate of cholelithiasis and cholecystectomy were significantly higher with clofibrate than placebo. Subjects receiving clofibrate experienced a 9% reduction in total cholesterol concen-trations, considerably less than the expected 15%. The excess mortality rates were due in part to a higher rate of malignant neoplasms of the liver, gallbladder, and intestines. However, death rates among the treatment group for cancer were similar to the official mortality statistics for individuals from the same area. The authors stated the excess mortality may have been exaggerated because of unexpectedly low death rates among subjects receiving placebo. Individuals who received the greatest benefit with clofibrate had higher baseline cholesterol concentrations and greater reductions in total cholesterol levels, or experienced a substantial reduction in serum cholesterol levels and exhibited other cardiovascular risk factors (e.g., hypertension and tobacco use). Regardless, the results of the WHO trial and CDP caused sub-stantial stigma with clofibrate, and subsequent prescribing of the agent decreased dramatically. Investigators of the WHO trial stated that clofibrate cannot be recommended as a lipid-lowering agent among healthy men for prevention of ischemic heart disease.

Helsinki Heart Study

The next major trial evaluating the long-term safety and efficacy of a fibrate was the Helsinki Heart Study (HHS), published 9 years later in 1987.[52] This double-blind, placebo-controlled trial used gemfibrozil and enrolled middle-aged men free of CHD. After 5 years, significant reductions (34%, p<0.02) in CHD events (i.e., fatal and nonfatal myocardial infarction, CHD death) were observed among those in the treatment group. The greatest reductions were noted for nonfatal myocardial infarction (37%, p<0.05); however, the rate of overall mortality was comparable to that with placebo. In addition, the HHS provided reassurance regarding the safety of fibrates, as cases of newly diagnosed cancer and the rates of cholecys-tectomy were not statistically significantly different among the groups.

Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial

Another randomized, placebo-controlled trial using gemfibrozil was the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT).[53] Men with a previous history of CHD and low HDL levels were randomly assigned to receive gemfibrozil or placebo for 5 years. Gemfibrozil was specifically chosen to evaluate long-term clinical effects when lipoproteins other than LDL (i.e., HDL, plasma triglyceride concentrations) are favorably altered. Compared with placebo, gemfibrozil produced significant changes in HDL and plasma triglyceride concentrations, whereas LDL concentrations remained similar between groups. In terms of clinical events, those receiving treatment were 22% (p=0.006) less likely to experience CHD death or a nonfatal myocardial infarction. Although the study was not designed to evaluate overall mortality, the investigators assessed the number of deaths and reported an 11% reduction in mortality with gemfibrozil compared with placebo (p=0.23). No significant differences were noted in the need for revascularizations (i.e., coronary artery bypass graft [CABG] and percutaneous transluminal coronary angioplasty [PTCA]) between groups. However, significant reductions in transient ischemic attacks (59%), investigator-designated strokes (29%), and carotid endarterectomies (65%) occurred with gemfibrozil therapy. Further analyses of VA-HIT data suggested that the increase in HDL levels from gemfibrozil was the major reason for the reduction in clinical events.[56] Similar to HHS, VA-HIT provided reassurance regarding the long-term safety of fibrates, as the incidence of newly diagnosed cancer and gallbladder disease were not statistically significantly different between treatment and placebo groups.

Bezafibrate Infarction Prevention Study

The Bezafibrate Infarction Prevention (BIP) study was another randomized, placebo-controlled outcome trial evaluating the effects of a fibrate (bezafibrate) among men and women with CHD.[8] Bezafibrate therapy produced significant reductions in LDL and plasma triglyceride concentrations and fibrinogen while markedly increasing HDL levels. However, at the end of the 6-year trial, bezafibrate was associated with only a 9% reduction (p=0.26) in the composite end point of fatal and nonfatal myocardial infarction and sudden death. Further, no differences were seen in secondary end points (i.e., CABG, PTCA, and unstable angina) between groups. Overall mortality rates and frequency of newly diagnosed cancer were similar among the groups. Bezafibrate proved to be safe among adults with CHD but had no significant effect on the frequency of major coronary events.

Fenofibrate Intervention and Event Lowering in Diabetes Study

The recently published Fenofibrate Interven-tion and Event Lowering in Diabetes (FIELD) study provided additional information on the long-term safety and efficacy of fibrates.[2] Men and women who were not receiving statin therapy at study entry were randomly assigned to fenofibrate or placebo for 5 years. All subjects had type 2 diabetes mellitus, and 37% experi-enced a previous cardiovascular event. Fenofibrate therapy resulted in significant changes in lipoproteins, including reductions in total choles-terol levels, plasma triglyceride concentrations, and LDL levels, compared with placebo. With regard to HDL level, fenofibrate produced a 5% increase early in the study; however, this decreased to only 2% by study close. Individuals receiving fenofibrate experienced an 11% (p=0.16) reduction in coronary events (CHD death and nonfatal myocardial infarction) but also a nonsignificant increase in overall mortality (19%, p=0.22), compared with the placebo group. The lower rate of coronary events was primarily due to a significant reduction (24%, p=0.01) in nonfatal myocardial infarction. In addition, a reduction in total cardiovascular events (11%, p=0.035) was observed with the fenofibrate group. Other important measures associated with fenofibrate were significantly lower rates in the progression of albuminuria and less need for laser therapy in the treatment of retinopathy. However, compared with the placebo group, those receiving active treatment were more likely to experience pancreatitis (0.5 vs 0.8%, p=0.031) and pulmonary embolism (0.7 vs 1.1%, p=0.022). Results of the FIELD study were highly anticipated, and many practitioners were hoping it would help elucidate the role of these agents in the treatment of cardiovascular disease. Unfortunately, with only modest reductions in cardiovascular events and no significant changes in overall mortality, the FIELD study did little to further define the role of these agents.

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