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The ACCORD Lipid Study: Fenofibrate Doesn't Help

Summary and Comment |
March 14, 2010

The ACCORD Lipid Study: Fenofibrate Doesn't Help

  1. Harlan M. Krumholz, MD, SM

Although triglyceride levels improved markedly with fenofibrate, incidence of adverse cardiovascular events was not affected.

  1. Harlan M. Krumholz, MD, SM

Interventions that improve lipid profiles do not always improve patient outcomes. A common strategy in diabetic patients — who often have low HDL and elevated triglyceride levels — is to add fibrate therapy, despite mixed results in previous studies. In the government-funded ACCORD Lipid Study, researchers evaluated whether adding fenofibrate to statin therapy prevents adverse cardiovascular events in patients with type 2 diabetes.

More than 5000 diabetic adults (mean age, 62; 31% women; glycosylated hemoglobin, ≥7.5%; LDL cholesterol, 60–180 mg/dL; HDL cholesterol, <55 mg/dL for women and blacks and <50 mg/dL for all others) were enrolled. All participants received simvastatin and also were assigned to daily fenofibrate (160 mg) or placebo. Mean follow-up was 4.7 years.

In both groups, mean LDL levels dropped from ≈100 mg/dL to ≈80 mg/dL. Mean HDL levels increased from 38.0 mg/dL to 41.2 mg/dL in the fenofibrate group and to 40.5 mg/dL in the placebo group. Median triglyceride levels decreased from about 160 mg/dL to 122 mg/dL in the fenofibrate group and to 144 mg/dL in the placebo group. The primary endpoint, adverse cardiovascular events, occurred with similar frequency in the two groups (2.2% vs. 2.4% per year; hazard ratio, 0.92; P=0.32). No subgroup analysis was strongly positive, although women assigned to fenofibrate had higher adverse event rates than did women assigned to placebo. Fenofibrate recipients were significantly more likely than placebo recipients to leave the study (2.4% vs. 1.1%) because of a decrease in glomerular filtration rate.

Comment

This important negative trial indicates that fenofibrate should not be used for high-risk diabetic patients. Although it improved triglyceride profiles, no clinical benefit was seen. Moreover, worsening of renal function occurred more often with fenofibrate. The burden of proof is firmly on advocates of this drug to justify the cost and risk to patients.

Citation(s):

Reader Comments (6)

Indah Widyastuti, S.Farm., Apt Other, Other, Pt. Pharos Indonesia

how combination simvastatin and fenofibrate used for treatment patient on some case treatment artherosclerosis wit diabetes mellitus?

Harlan Krumholz

Great discussion. What I can say is that someone is using fenofibrate since sales in the US are $1.3 billion a year - and its use has grown recently. The drug did little to raise HDL - and HDL subgroups and TG subgroups were not significant. The low HDL and high TG subgroup was also not significant, with a P value for the interaction of 0.06. In the context of many subgroup comparisons this finding does not add amount to much support for the hypothesis that the drug is effective in this subgroup. The subgroup was pre-specified but so were many others -- and I could not find a place where the specific subgroup analysis was described before the trial was published (either in clinicaltrials.gov or in their Methods paper). This is the second negative trial for fenofibrate -- there are no positive trials. It would be nice to see a trial of the high TG/low HDL subgroup -- but until that time there really is no strong evidence available to treat this group. And certaintly this trial does not provide that. The only subgroup, by the way, that was significant was sex -- with women doing much worse on fenofibrate.

Competing interests: None declared

Alfonso E. Sierra

How important was the decrease in the GFR? 1?, 5? 10?, 20?, was it consistent?

Competing interests: None declared

Eliot Brinton

Despite Professor Krumholz’s statement to the contrary, it is not “a common strategy in diabetic patients… to add fibrate therapy” to a statin. Even among diabetics with low HDL and high TG, only about 10% receive fibrates, and it is rarely used in those without that dyslipidemia.

So, what did we know about CVD effects of fibrates in high TG and low HDL-C before ACCORD? In 1992, a post-hoc analysis of the Helsinki Heart Study showed that gemfibrozil reduced CVD in subjects with high TG and low HDL-C. Later, the VA-HIT showed that subjects recruited for low HDL-C had CVD reduction with gemfibrozil, especially insulin-resistant diabetics. A subanalysis of BIP then showed that bezafibrate reduced CVD in subjects with high TG. In 2009, a post-hoc analysis of the FIELD showed that CVD benefit with fenofibrate was confined to subjects with high TG and low HDL -C.

A pre-specified subgroup analysis of ACCORD confirms the above by showing a statistically significant one-third reduction in CVD in diabetic subjects with high TG and low HDL-C. Although no single trial absolutely proves that fibrates reduce CVD in the setting of high TG and low HDL-C, ACCORD is the 5th fibrate trial to strongly suggest this benefit.

It is reasonable to add fenofibrate in diabetic (and perhaps non- diabetic) patients when high TG and low HDL-C persist after statin monotherapy!

Competing interests: Speaker's Bureau and Research Grants from Abbott, GSK and Merck; speaker's bureau for AstraZeneca.

Brunel Bredy, MD

Does this study look at those diabetics who have higher triglyceride levels, and the benefit of fenofibrate use in these high risk patients? I often see diabetics with triglycerides levels much higher than the mean starting triglyceride levels in this study, well above 250 mg/dl. Would we also expect there to be no benefit at higer levels of triglycerides?

Competing interests: None declared

Lisa W Martin

The enrollment criteria in this study is very important. The subgroup analysis showed benefit for those patients with the dyslipidemia profile. I feel that this outcome should not be ignored, and will need further study.

Competing interests: None declared

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