Effects of Fibrates on Cardiovascular Outcomes

Abstract & Commentary

By Harold L. Karpman, MD, FACC, FACP, Clinical Professor of Medicine, UCLA School of Medicine. Dr. Karpman reports no financial relationship to this field of study.

Synopsis: Fibrates can reduce the risk of major cardiovascular events predominantly by prevention of coronary events, and might have a role in treating individuals who are at especially high risk of cardiovascular events and in those with combined dyslipidemia.

Source: Jun M, et al. Effects of fibrates on cardiovascular outcomes. Lancet 2010;375:1875-1884.

As is well known, cardiovascular (CV) disease is the leading cause of premature morbidity and mortality worldwide.1 For many years it had been clearly proven that lipids have a significant effect on the causation of coronary artery disease (CHD) and, therefore, pharmacotherapy with statin drugs,2,3 which primarily target LDL cholesterol, has proven to be a particularly effective intervention strategy, substantially reducing the risks of CHD, stroke, and mortality. However, an extremely high residual risk for these illnesses persists, drawing attention to the need for additional effective preventive therapies. Several studies have demonstrated associations of low HDL cholesterol and/or high triglyceride concentrations with increased vascular risk, and numerous studies beneficially altering HDL and triglyceride levels have proven to be of great value.4,5 Fibrates have been demonstrated to significantly raise HDL, lower triglycerides, and reduce LDL;6 however, the ACCORD study suggested no overall benefit for fenofibrate,7 raising a significant question as to the clinical benefit of this class of drugs.

Jun and colleagues attempted to determine the overall efficacy of fibrates on CV risk and outcomes by systematically searching multiple databases published between 1950 and March 2010. They identified and analyzed 18 prospective, randomized, controlled trials providing data on 45,058 participants. Outcomes analyzed included major CV events, coronary events, stroke, heart failure, coronary revascularization, all-cause mortality, CV death, non-vascular death, sudden death, new-onset albuminuria, and drug-related adverse events. Fibrate therapy reduced the risk of CV disease by reducing the number of coronary events; however, the magnitude of this effect was only moderate. Meaningful reductions in outcome risk, however, were achieved particularly in high-risk individuals and in those with combined dyslipidemia. Also, fibrate therapy appears safe and well tolerated in the modern era.

Commentary

There is an increasing awareness that even after achieving beneficial results with statin therapy, CV risk remains high, especially in patients with diabetes and even in those receiving optimum statin therapy resulting in excellent control of the LDL cholesterol values. Fibrates have consistently been demonstrated to be efficacious, but appear to be most useful in patients with combined dyslipidemia. The analysis by Jun et al demonstrated no increase in adverse events (including rhabdomyolysis) with fibrate therapy, which is very reassuring in view of the previously reported severe drug-drug interaction of gemfibrozil with statins, which precipitated several reports of life-threatening myopathy. They concluded that there's reason to suspect that fibrate therapy would have an added benefit in patients with CHD and they attributed the negative results in the ACCORD trial to the limited power of that study.7

In summary, it appears that the new generation of fibrate drugs will be useful in managing certain groups of patients with CV disease, providing safety is maintained. The greatest benefit of fibrate therapy appears to be in the 20% of diabetic patients who have high triglyceride and low HDL cholesterol levels. A carefully controlled, randomized study in this subset of patients at high CV risk and with combined dyslipidemia is the next step needed to permit what appears to be appropriate application of targeted therapy. The results of such a study will possibly provide the data needed to formulate therapy for those patients at high residual risk of CHD and other CV events after effective statin therapy and even in patients who have been "successfully" treated with statin therapy alone.

References

1. Murray CJ, Lopez AD. Mortality by cause for eight regions of the world. Lancet 1997;349:1269-1276.

2. Packard C. Improving outcomes through statin therapy. Eur Heart J 2004;6(suppl A):A28-31.

3. LaRosa C, et al. Effect of statins on risk of coronary disease. JAMA 1999;282:2340-2346.

4. Gordon T, et al. Lipoproteins, cardiovascular disease, and death. Arch Intern Med 1981;141:1128-1131.

5. Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level. J Cardiovasc Risk 1996;3:213-219.

6. Birjmohun RS, et al. Efficacy and safety of high-density lipoprotein cholesterol-increasing compounds. J Am Coll Cardiol 2005;45:185-197.

7. For the ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-1574.