Fenofibrate Therapy in Diabetics

Abstract & Commentary

By Michael H. Crawford, MD, Professor of Medicine, Chief of Clinical Cardiology, University of California, San Francisco. Dr. Crawford is on the speaker's bureau for Pfizer.

Synopsis: Fenofibrate did not significantly reduce the risk of the primary outcome of coronary death or non-fatal MI. It did reduce total cardiovascular events, mainly due to fewer non-fatal myocardial infarctions and revascularizations.

Source: Keech A, et al. Effects of Long-Term Fenofibrate Therapy on Cardiovascular Events in 9795 People with Type 2 Diabetes Mellitus (the FIELD Study): Randomised Controlled Trial. Lancet. 2005;366:1849-1861.

Diabetics frequently have small dense LDL-cholesterol particles, low HDL-cholesterol, and high triglycerides. This lipid pattern can be corrected with fibrates. However, no large clinical trial of fibrates in diabetics has been done. Thus, the Fenofibrate Intervention and Event Lowering in Diabetics (FIELD) study was conducted in 63 centers in Australia, New Zealand, and Finland. This was a double-blind, placebo-controlled, randomized study of one daily dose of fenofibrate (200 mg). Patients had to have type 2 diabetes and no clear indication for lipid-lowering therapy, eg, total to HDL cholesterol ratio of > 4.0. Patients were followed for up to 5 years. Other treatment, including for abnormal lipids, was left to the primary physician's discretion. The primary end point was myocardial infarction (MI) or death. Several secondary and tertiary end points were assessed. Of over 14,000 patients evaluated, 4900 were randomized to placebo and 4895 to fenofibrate. In the study groups, 37% were women, 40% were > 65 years, and 22% had known coronary heart disease. At a median of 5 years follow-up, 10% on placebo and 11% on fenofibrate, dropped out for reasons that did not differ between the 2 groups. More patients on placebo (17%) as compared to fenofibrate (8%, P < .001) were put on other lipid-lowering therapies. Fenofibrate resulted in an 11% reduction in total cholesterol, 12% in LDL, 14% in apolipoprotein B, and 29% in triglyceride. HDL increased 5%. The primary end point was achieved in 5.9% on placebo and 5.2% on fenofibrate (HR, .89; CI, .75-1.05; P = NS). Nonfatal MI was reduced 24% (.76; .62-.94; P = .01), but death was increased from 6.6% to 7.3% on fenofibrate (1.19; .9-1.57; P = NS). Total cardiovascular events were reduced from 13.9 to 12.5% (.89;.80-.99; P < .04). Fenofibrate also resulted in less progression of albuminuria and retinopathy, but more pancreatitis and pulmonary embolism. There were no other significant adverse effects. The FIELD study investigators and colleagues concluded that fenofibrate did not reduce the primary combined end point of coronary heart disease death or nonfatal MI. The higher use of statins in the placebo group may have reduced the differences in treatment effects.

Commentary

Fenofibrate should be the ideal dyslipidemia drug in type 2 diabetics because it could correct their predominant lipid pattern of high triglycerides, low HDL, and small dense LDL particles. This is the first primary prevention trial to see if these beneficial effects translate into better clinical outcomes. This was a big trial that was not underpowered and, yet, it was largely negative. The FIELD study investigators and colleagues suggest several possibilities for the disappointing results. First, they did not control statin use, which was higher in the placebo group. In this study, LDL was lowered by fenofibrate 13%, but bigger effects would be expected from statins. Second, there was less HDL increase on fenofibrate (5%) than has been seen in non-diabetics in other studies. Also, the difference in HDL levels between the 2 groups decreased with time during the study. Finally, fenofibrate increased homocysteine levels. I would add that being in a clinical trial may select out patients who take better care of themselves. We know that tight glucose and blood pressure control reduces coronary events. Baseline HbA1c averaged 6.9 in both groups. So perhaps, better diabetes management narrowed the differences between the groups. Why nonfatal MI, revascularization, and microvascular complications were reduced on fenofibrate is unclear. The VA-HIT study showed improved outcomes with gemfibrozil in diabetics, but this was a secondary prevention trial. Interestingly, there was no difference in LDL in the VA-HIT study between the treatment and placebo groups. Perhaps, we are just seeing population differences. The combination of Australia, New Zealand, and Finland is interesting, and may be problematic. The relative isolation of these countries until modern times may have diverged their gene pools in unpredictable ways.

On the positive side, fenofibrate was well tolerated and can be used safely in diabetics. Perhaps the best use of fibrates is in combination with statins, but since HDL did not increase much on the fibrate you could argue that statins alone may be adequate in diabetics. Also, since triglyceride lowering was the biggest effect of fenofibrate (29%), you could argue that elevated triglycerides do not increase the risk for coronary events and their treatment is only of cosmetic value. Finally, this study raises the issue of what value niacin would be in this patient population, alone or in combination with other agents. Niacin is known to reduce LDL and triglycerides and raise HDL.