Fibrates in the prevention of cardiovascular disease in patients with type 2 diabetes mellitus – A pooled meta-analysis of randomized placebo-controlled clinical trials

Abstract

Objective

Fibrates are thought to be useful anti-dyslipidemic agents particularly in patients with diabetes mellitus and dyslipidemia characterized by high triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) levels. We conducted a systematic review and meta-analysis of long-term randomized controlled trials to evaluate the role of fibrates in the prevention of cardiovascular events in patients with type 2 diabetes mellitus.

Data sources

English-language journals indexed in Index Medicus/MEDLINE and the Cochrane Collaboration databases (through December 2007), unpublished data from selected clinical trials.

Data extraction and analysis

A total of 11,590 patients from 6 published randomized placebo-controlled trials were analyzed using pooled meta-analysis techniques. Relative risks were computed for various cardiovascular outcomes and mortality, and statistical significance was tested using the z-test statistic (two-sided alpha error < 0.05).

Results

The use of fibrates did not significantly affect the risk of all-cause mortality or cardiac mortality, and also did not affect the risk of stroke, unstable angina, or invasive coronary revascularization. However, the relative risk of non-fatal myocardial infarction was significantly reduced by about 21% (pooled relative risk 0.79, p = 0.006) with the use of fibrates.

Conclusions

Long-term use of fibrates in patients with type 2 diabetes mellitus significantly reduces the risk of non-fatal myocardial infarction, but has no significant effect on mortality or on other adverse cardiovascular outcomes.

Introduction

The risk of coronary heart disease is about 3–4 fold higher in patients with diabetes mellitus, and heart disease death rates in adults with heart disease and diabetes are about 2–4 times higher than adults without diabetes [1]. Recent epidemiologic data show that in terms of risk for adverse cardiovascular events, the presence of diabetes mellitus requiring glucose-lowering therapy in adults > 30 years of age is a coronary artery disease equivalent [2]. Dyslipidemia in patients with type 2 diabetes mellitus is characterized by high triglyceride (TG) levels, low high-density lipoprotein cholesterol (HDL-C) levels, and a preponderance of small, dense, low-density lipoprotein cholesterol (LDL-C) particles [3], [4]. Although the 3-hydroxy-3-methylglutaryl coenzyme A (HMG coA) reductase inhibitors or ‘statins’ have been shown to significantly reduce LDL-C levels and change the LDL-C subclass distribution towards larger particles, they do not specifically address the high TG levels and low HDL-C levels observed in diabetic patients, both of which have been shown to be independent predictors for occurrence of adverse cardiovascular events [5], [6], [7].

Since the serendipitous discovery of clofibrate as an effective anti-lipidemic agent in the mid-1960s [8], the fibrate class of agents has been the subject of scientific inquiry both in the laboratory as well as in large randomized clinical trials. The fibrates significantly reduce TG levels and raise HDL-C levels, and have a variable effect on LDL-C levels [9], [10]. They have also been shown to alter the LDL-C subclass distribution towards larger, more buoyant particles, especially in patients with diabetes [4]. These data suggest that fibrates would be ideal agents for the management of dyslipidemia in patients with type 2 diabetes. In the late 1980s, the fibrates were shown to have agonist effects on the peroxisome proliferator-activated receptor alpha (PPARα) group of nuclear receptors, which control the expression of key elements in cholesterol transport and lipid metabolism, as well as endothelial function, vascular inflammation and remodeling [11], [12], [13], [14]. However, in spite of the plethora of molecular [15], [16], [17] and in vivo data (both in animals and in human studies) [18], [19], [20], [21], [22] suggesting the potential for fibrates in reducing the cardiovascular risk in patients, including those with features associated with the metabolic syndrome and ‘diabetic dyslipidemia’ [23], results from large randomized clinical trials have yielded conflicting results. We therefore conducted a systematic review and pooled meta-analysis of randomized, placebo-controlled clinical trials to define the role of fibrates in the prevention of cardiovascular events in patients with type 2 diabetes mellitus – the subpopulation in which fibrates are thought to have the greatest potential.