COMMENTARY

Can Fenofibrate Prevent CVD in Type 2 Diabetes Patients?

Gregory A. Nichols, PhD

Disclosures

March 29, 2012

Benefits and Safety of Long-term Fenofibrate Therapy in People With Type 2 Diabetes and Renal Impairment: The FIELD Study

Ting RD, Keech AC, Drury PL, et al; FIELD Study Investigators
Diabetes Care. 2012;35:218-225

Study Summary

This analysis of the FIELD Study data investigated the effects of fenofibrate on cardiovascular disease (CVD) and end-stage renal disease (ESRD) events across levels of kidney function. Investigators calculated estimated glomerular filtration rate (eGFR) among patients with type 2 diabetes who were randomly assigned to receive placebo (n = 4900) or fenofibrate (n = 4895) at 200 mg/d for 5 years. For the current analysis, patients were stratified into 3 levels of eGFR: 90 mL/min/1.73 m2 or greater (n = 4058), 60-89 mL/min/1.73 m2 (n = 5218), and 30-59 mL/min/1.73 m2 (n = 519).

The primary outcome of FIELD was total cardiovascular events (composite of cardiovascular death, myocardial infarction, stroke, and coronary/carotid artery revascularization). Of particular interest in the current analysis were serious adverse events and ESRD, defined as a plasma creatinine level greater than 400 μmol/L, need for dialysis or renal transplant, or renal death.

Compared with placebo, fenofibrate reduced total CVD events by 11% (hazard ratio, 0.89; 95% confidence interval [CI], 0.80-0.99). The CVD risk reduction seemed to be greater at lower levels of eGFR (hazard ratio, 0.68 [95% CI, 0.47-0.97] for patients with eGFR 30-59 mL/min/1.73 m2 vs 0.85 [95% CI, 0.70-1.02] for those with eGFR > 90 mL/min/1.73 m2), but the interaction across groups was not statistically significant (P = .22).

Not surprisingly, the greatest rate of ESRD events occurred among patients with eGFR 30-59 mL/min/1.73 m2. However, there was no increase in ESRD events with fenofibrate use compared with placebo, either overall or in any eGFR group (P = .75 for interaction).

The extent of the increase in plasma creatinine level with fenofibrate did not predict the occurrence of ESRD events (P = .60 for interaction). Adverse event rates were no higher among patients receiving fenofibrate than those receiving placebo, including patients with eGFR 30-59 mL/min/1.73 m2.

Viewpoint

Despite a large trend in overall reduction of CVD risk, probably due to statin therapy, the residual risk for CVD in patients with type 2 diabetes remains greater than in the general population.[1] One reason may be that about one half of patients with diabetes have relatively low levels of high-density lipoprotein (HDL) cholesterol. Normalized levels of HDL cholesterol could potentially reduce CVD mortality by 42% in women and 23% in men.[2]

Although potent and safe HDL-raising drugs are not yet available, fenofibrates are known to raise HDL cholesterol level, although clinical trials of CVD risk reduction from fenofibrates have been inconclusive.[3,4] In the ACCORD trial, however, there seemed to be some CVD benefit among patients allocated to receive fenofibrate who had high triglyceride levels and low HDL cholesterol levels -- the very patients for whom the drug would be most indicated.

In any case, one of the main concerns with fenofibrate has been that it induces an increase in plasma creatinine,[5] which could increase risk for CVD and renal outcomes. Therefore, Ting and colleagues' study is important because it demonstrates that even with an increase in plasma creatinine level, patients who received fenofibrate had significant reductions in CVD risk and no indication of difference in risk for ESRD.

Of note, the mechanism by which CVD risk reduction was achieved with fenofibrate may not be related to increases in the HDL cholesterol level. In the FIELD Study, the overall difference in HDL cholesterol level between the fenofibrate and placebo groups was very small,[3] and large changes in HDL cholesterol level are probably necessary to generate CVD risk reduction.[6] Nevertheless, the take-away message is that there does not seem to be any reason to withhold fenofibrate treatment in patients with moderate renal impairment.

Abstract

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