ACCORD: Fenofibrate No Benefit to Statin Therapy in High-Risk Diabetic Patients

March 14, 2010

Updated March 14, 2010 (Atlanta, Georgia) – Combination therapy with fenofibrate and simvastatin failed to reduce the risk of fatal cardiovascular events, nonfatal MI, or nonfatal stroke, according to results from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial [1]. There was a suggestion of benefit observed among patients with dyslipidemia, those with high triglyceride and low HDL-cholesterol levels.

Dr Henry Ginsberg

Presented today at the American College of Cardiology (ACC) 2010 Scientific Sessions, the ACCORD investigators, led by Dr Henry Ginsberg (Columbia University, New York), conclude that the "findings do not support the use of combination fibrate-statin therapy, rather than statin therapy alone, to reduce cardiovascular risk in the majority of patients with type 2 diabetes who are at high risk for cardiovascular disease."

Speaking during the morning press conference, Ginsberg said the results reinforce the importance of lifestyle in the treatment of type 2 diabetes. "Clearly, many of the problems we have been addressing pharmacologically would be significantly [affected] by weight loss in all of our patients," he said.

Commenting on the results of the study for heartwire , Dr Rury Holman (Churchill Hospital, Oxford, UK) said that fenofibrate is used sparingly in the UK and Europe, mainly in those patients with high triglyceride levels at risk of pancreatitis.

"The concern is that there are always people with diabetes who have all of their risk factors treated as well as you can, and they still have some residual risk," he said. "People are looking for that magical additional risk-factor reduction, and fibrates have been around for a long time. The [Fenofibrate Intervention and Event Lowering in Diabetes]FIELDtrial suggested there wasn't much benefit to be had, and I think ACCORD has finally shown that adding fenofibrate for this particular add-on risk reduction is probably not worthwhile."

In an editorial accompanying the published study [2], Dr Peter Nilsson (University Hospital, Malmö, Sweden) writes that standards of diabetes care have improved considerably in the past decade, with clinicians paying attention to not only glucose levels but also cardiovascular risk factors. The results from ACCORD, however, highlight the need for flexible targets regarding the treatment of hyperglycemia, blood pressure, and dyslipidemia in patients with type 2 diabetes mellitus, "taking into account individual clinical factors of importance."

The ACCORD study, along with the editorial, is published online in the New England Journal of Medicine to coincide with the ACC presentation.

The ACCORD Study

The ACCORD trial, reported extensively by heartwire , was conducted in 10 251 high-risk patients with type 2 diabetes who were randomly assigned to either intensive or standard glycemic control. In addition, 4733 of the participants were also randomized to either intensive or standard blood-pressure control, the results of which were presented today at the ACC and also reported by heartwire , and 5518 patients were randomly assigned to simvastatin plus fenofibrate or simvastatin plus placebo.

The glycemic-control ACCORD study was stopped early, in February 2008, because of higher mortality in the intensive-glycemic-control group. All patients, whether they were participating in the ACCORD blood-pressure study or the ACCORD lipid study, were then transferred to a standard glycemia-control regimen, and the studies continued for their planned durations of approximately five years.

After an average follow-up of 4.7 years, there were 291 major fatal or nonfatal cardiovascular events in the fenofibrate-statin-therapy study arm and 310 events in the statin-therapy-alone arm, translating into an annualized rate of 2.2 and 2.4 events per year, respectively, in the two treatment arms. The difference in events was not statistically significant. Among the secondary end points, there was also no statistically significant difference between the two treatments.

Prespecified Primary and Secondary Outcomes

Outcome Fenofibrate (n=2765), Rate/year Placebo (n=2753), Rate/year Hazard ratio (95% CI)
Primary outcome (major fatal and nonfatal cardiovascular events) 2.24 2.41 0.92 (0.79–1.08)
Primary outcome plus revascularization or hospitalization for congestive heart failure 5.35 5.64 0.94 (0.85–1.05)
Major coronary disease event 2.58 2.79 0.92 (0.79–1.07)
Nonfatal MI 1.32 1.44 0.91 (0.74–1.12)
Any stroke 0.38 0.36 1.05 (0.71–1.56)
Nonfatal stroke 0.35 0.30 1.17 (0.76–1.78)
Death from any cause 1.47 1.61 0.91 (0.75–1.10)
Death from cardiovascular causes 0.72 0.83 0.86 (0.66–1.12)
Fatal or nonfatal congestive heart failure 0.90 1.09 0.82 (0.65–1.05)

"We don't consider the trial negative," Ginsberg told the media. "We didn't show benefit above standard care, but those are important positive findings."

Benefits in Different Subgroups

Dr Paul Thompson (Hartford Hospital, CT), the scheduled discussant during the late-breaking clinical-trials session, said the results of ACCORD are unlikely to affect clinical practice, because the drug is not routinely used in diabetic patients. He said he considers fenofibrate a triglyceride-lowering agent, while others might consider it an HDL-raising drug, and that it is typically used in patients with low HDL cholesterol and elevated triglycerides. In ACCORD, the mean triglyceride level in the overall study was just 162 mg/dL.

One clinician surprised by the results, however, is Dr Roger Blumenthal (Johns Hopkins Medical Center, Baltimore, MD).

"In clinical practice, most people wouldn't add a fibrate until a patient's triglyceride levels were higher than 200 [mg/dL]," he told heartwire . "But a lot of us in the cardiology community who manage high-risk diabetic patients thought we were doing patients a favor, thinking we were decreasing events at five years. So it was a bit of a surprise." Blumenthal said the ACCORD trial shows the value of testing these add-on therapies in a clinical-trial setting.

Ginsberg told the audience that the researchers faced a conundrum when starting the trial, questioning whether it would be best to test the addition of fenofibrate to statin therapy in patients with dyslipidemia, those with low HDL cholesterol and high triglyceride levels, or in a broader spectrum of patients, in this case, all high-risk diabetic patients, so that the results could be extrapolated to more patients. Choosing the latter, they prespecified a number of subgroups, including patients with dyslipidemia.

In this subgroup analysis, there was a suggestion that patients with higher baseline triglycerides and lower HDL-cholesterol levels benefited from fenofibrate therapy in addition to simvastatin. Among these dyslipidemic patients, baseline triglyceride levels were 284 mg/dL, about 120 mg/dL higher than the rest of cohort, and HDL levels were 29.5 mg/dL, about 10 mg/dL lower that the full cohort. Among these dyslipidemic patients, triglyceride levels decreased and HDL-cholesterol levels increased more with fenofibrate therapy than in the overall cohort of patients.

These findings, according to the ACCORD investigators, are similar to post hoc subgroup analyses performed in the Helsinki Heart Study and Bezafibrate Infarction Prevention (BIP) and FIELD studies.

Ginsberg said that fenofibrate should be added as the ATP III clinical guidelines indicate--that is, used in statin-treated patients with high triglyceride levels and low HDL-cholesterol levels. He also noted there was a significant interaction with gender, with men seeming to benefit and a trend toward harm among women.

To heartwire , Holman said the findings from the subgroup analyses are interesting, but further research is likely to be directed toward HDL-raising therapies in these high-risk diabetic patients. In his editorial, Nilsson notes that the "role of fibrates for correcting dyslipidemia in high-risk patients with diabetes is still not settled."

Disclosures for the ACCORD authors are listed online . Nilsson has acted as a consultant to Merck and Novartis; as a speaker for Merck, Novartis, Lilly, GlaxoSmithKline, Pfizer, AstraZeneca, and Novo Nordisk; and has received honoraria from Berlin-Chemie and Menarini.

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