Major Finding: In patients with type 2 diabetes and a high risk for cardiovascular disease, 2,765 treated with fenofibrate in addition to standard medical therapy had a 2.24%-per-year rate of major fatal or nonfatal cardiovascular events during an average 4.7 years of follow-up. The 2,753 patients randomized to placebo in addition to standard medical therapy had a 2.41%-per-year incidence rate of the end point. The difference in rates between the two groups was not statistically significant.
Data Source: ACCORD, a randomized, controlled lipid trial conducted at 77 sites in the United States and Canada during January 2001–July 2009.
Disclosures: Dr. Ginsberg has financial relationships with several pharmaceutical companies, including Merck and Abbott, which donated the simvastatin and fenofibrate/placebo but had no involvement in ACCORD. The trial was funded by the National Heart, Lung, and Blood Institute.
Atlanta — The failure to significantly reduce the cardiovascular event rate with fenofibrate treatment in a large trial of high-risk type 2 diabetes patients probably occurred because the study enrolled too many of the wrong types of patients to clearly show a benefit from this drug, several experts said.
Instead of focusing on patients with diabetes and dyslipidemia, an elevated serum level of triglycerides, and depressed HDL cholesterol, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial enrolled a representative sampling of 5,518 patients with diabetes and a range of triglyceride and HDL cholesterol levels, proving that fibrate treatment, on top of the moderate statin dosage, could not further help most of these patients.
The ACCORD investigators decided to enroll a wide spectrum of patients “to see if [fenofibrate] could apply generally. It's important that we found that fenofibrate on top of a statin will not benefit the majority” of patients with diabetes, Dr. Henry N. Ginsberg said at the annual meeting of the American College of Cardiology.
Existing cholesterol-treatment guidelines from the National Heart, Lung, and Blood Institute—the Adult Treatment Panel III—call for adding a fibrate drug to statin treatment when triglyceride levels are high and HDL cholesterol is low. “I think that's the role for this drug, in patients with the most significant dyslipidemia,” said Dr. Ginsberg, professor of medicine and director of the Irving Institute for Clinical and Translational Research at Columbia University, New York.
In ACCORD, 17% of enrolled patients fell into the subgroup with a plasma triglyceride level of at least 204 mg/dL and a plasma HDL cholesterol that was 34 mg/dL or less. Within this subgroup, fenofibrate treatment produced an improvement in the study's primary end point, the combination of major fatal or nonfatal cardiovascular events, that just missed statistical significance. Tr. Ginsberg said. Concurrently with his report at the meeting, the results were posted online (N. Engl. J. Med. 2010 Mar 14 [doi:10.1056/NEJMoa1001282
“They tested the drug on the wrong patients,” said Dr. Prakash C. Deedwania, a cardiologist at the University of California, San Francisco, in Fresno, Calif. The trial results could potentially have been positive if enrollment had been more focused, he said in an interview.
“The message is that the majority of patients with diabetes don't need a fibrate added,” said Dr. Roger S. Blumenthal, professor of medicine and director of preventive cardiology at Johns Hopkins University in Baltimore. “There was good reason to think the results might have been positive, but in ACCORD it was added to a statin, and a statin by itself is hard to beat.”
In ACCORD, all patients received standard medical therapy for type 2 diabetes and cardiovascular disease risk, including statin therapy with simvastatin. Randomization assigned half the patients to also receive fenofibrate, at a target dosage of 160 mg/day. Although fenofibrate effectively cut triglyceride and HDL cholesterol levels, the incidence of all cardiovascular disease end points examined was similar between the treatment groups: 2.24% per year for the finofibrate group, 2.41% per year for the placebo group.
Dr. Deedwania has been a consultant to or received honoraria from AstraZeneca and Pfizer. Dr. Blumenthal had no relevant disclosures.
My Take
Design Worked Against Fenofibrate
I think of fenofibrate as a triglyceride drug, or possibly as an HDL drug. The median triglyceride level in the ACCORD lipid patients was 162 mg/dL, so it's not very surprising that the overall group did not benefit. It is interesting that patients with high triglycerides and low HDL had some suggestion of benefit, with a P value of .06. Another limitation of the study was that fenofibrate was used on top of a statin.