Cardiology Express Report

Publication date: 2002-07-23

Lipid Management with Fibrate and Statin Therapy: Comparative Efficacy and Combination Use in the Diabetic Patient

This report was reviewed for medical and scientific accuracy by Avedis K. Khachadurian, MD, Professor of Medicine, Division of Endocrinology, Metabolism and Nutrition, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey

Multiple large clinical trials have demonstrated that reducing levels of low-density lipoprotein cholesterol (LDL-C) significantly lowers morbidity and mortality associated with coronary atherosclerosis.^1-5 Ironically, most of the landmark trials of lipid-lowering pharmacotherapy included relatively few diabetic patients, a population recognized as possessing exceptionally high cardiovascular risk factors compared to the general population; particularly atherosclerotic coronary heart disease (CHD). However, the data from these studies have indicated that diabetic patients derived substantial benefit from treatment of dyslipidemia.⁶

At least part of the explanation for the lack of diabetic representation in major clinical trials of lipid-lowering pharmacotherapy relates to the focus on LDL-C. Diabetic dyslipidemia typically involves low levels of high-density lipoprotein cholesterol (HDL-C) with correspondingly elevated triglycerides indicating the presence of atherogenic triglyceride-rich intermediate-density lipoproteins.⁷ Type 2 diabetic patients typically have a preponderance of smaller, denser LDL particles, which possibly increases atherogenicity even if the absolute concentration of LDL-C is not significantly increased. Therefore, primary emphasis solely on LDL-C as it relates to the reduction of cardiovascular risk factors is inappropriate in the type 2 diabetic patient. The clinical trial focus on LDL-C has overshadowed the long-recognized fact that low HDL-C is a potent and independent coronary risk factor.⁸ Most major clinical trials employed HMG-CoA reductase inhibitors (statins) for lipid-lowering pharmacotherapy. However, statins act primarily on LDL-C and induce only modest increases in HDL-C.

The Veterans Affairs HDL Intervention Trial (VA-HIT) represented a new approach to clinical trials of lipid modification.⁹ The trial enrolled patients whose primary lipid abnormality was low HDL-C. The therapeutic agent employed was gemfibrozil (Lopid, Parke-Davis/Pfizer), a fibric acid derivative (fibrate). As a class, fibrates have a more robust impact on HDL-C, compared to statins, and induce substantial reductions in triglycerides. More than 30% of the VA-HIT patients were diabetic, including 25% at enrollment and an additional 6% who developed diabetes during the study. Many other patients had prediabetic characteristics, including elevated insulin levels, obesity, and hypertension.

VA-HIT tested the hypothesis that raising HDL-C levels, in the absence of an effect on LDL-C, would reduce the cardiovascular event rate in high-risk patients. The principal finding was a 22% reduction in cardiovascular events in patients treated with the fibrate, which compared favorably with results of the statin trials. Diabetic patients derived even greater benefit from treatment, a 27% overall reduction in events, including a 41% reduction in cardiovascular mortality.

The Diabetes Atherosclerosis Intervention Study (DAIS) went a step further and specifically limited enrollment to diabetic patients.¹⁰ This angiographic trial tested the ability of fenofibrate (Tricor, Abbott Laboratories) to slow the progression of atherosclerosis. At the end of the study, patients treated with fenofibrate had a 40% improvement in minimum lumen diameter, 43% improvement in minimum segment diameter, and 25% improvement in mean percentage stenosis, compared to patients randomized to placebo. Although not powered to show statistical significance, this trial showed a 23% reduction in cardiovascular events in the fenofibrate treatment arm.

The 2001 update to the National Cholesterol Education Program (NCEP) clinical guidelines has increased emphasis on both