FDA Tells Advisors to Focus on ACCORD for Fenofibrate Review

Reed Miller

May 17, 2011

May 17, 2011 (Silver Spring, Maryland) — When it convenes May 19, an FDA advisory panel will consider whether to recommend that the agency narrow the approved indication for fenofibrate (Trilipix, Abbott) to reflect the findings of trials showing that adding the drug to statins does not reduce the risk of adverse events in diabetic patients [1].

As reported by heartwire , fibrates are a guideline-recommended treatment for the reduction of elevated triglyceride levels in diabetic patients, and the FDA approved fenofibrate as an adjunct to a statin to reduce triglycerides and increase HDL cholesterol in patients with mixed dyslipidemia and coronary heart disease or risk for coronary heart disease. The drug is also FDA approved as a monotherapy to reduce triglycerides in patients with severe hypertriglyceridemia or to reduce elevated LDL cholesterol, total cholesterol, triglycerides, and apolipoprotein B and to increase HDL cholesterol in patients with primary hyperlipidemia or mixed dyslipidemia.

However, the 2005 Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial showed no significant difference in cardiovascular morbidity and mortality in diabetics with fenofibrate vs placebo, and the lipid arm of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, completed last year, found fenofibrate plus statins did not reduce cardiovascular events more than statins alone. Over an average of nearly five years, the rate of major adverse events, including fatal cardiovascular events, nonfatal MI, or nonfatal stroke in patients randomized to simvastatin plus placebo was 11.3% compared with 10.5% in patients randomized to simvastatin plus fenofibrate (p=0.32).

According to meeting briefing materials released today, reviewers for the FDA's Center for Drug Evaluation and Research expect the May 19 meeting of the Endocrinologic and Metabolic Drugs Advisory committee to focus on the lipid arm of the ACCORD trial and whether those results should prompt a change in fenofibrate's approved indication for coadministration with a statin. The FDA wants the panelists to vote for one or more of the following options:

Allow the drug to stay on the market with its current indication for coadministration with a statin.

Withdraw approval of fenofibrate's indication for coadministration with a statin.

Allow continued marketing of fenofibrate's indication for coadministration with a statin but somehow revise the labeling to reflect the principal findings of ACCORD.

Require Abbott to sponsor a new clinical trial that will determine whether adding fenofibrate to statin therapy significantly lowers the risk of major adverse events compared with placebo in high-risk patients at their goal LDL cholesterol with residually high triglycerides and low HDL cholesterol.

The panel will also discuss the importance of some of the subgroup analysis from ACCORD. In the subgroup of women, major adverse events were less frequent in the simvastatin-plus-placebo group vs the simvastatin-plus-fenofibrate group (6.6% vs 9.1%, interaction p=0.01 vs men).

In patients with baseline levels of triglycerides >204 mg/dL and HDL cholesterol <34 mg/dL, the incidence of adverse events was 17.3% in the placebo group compared with 12.4% fenofibrate group (interaction p=0.06 vs all others). But, as reported by heartwire , some experts have argued that other agents, such as niacin, are a better option to try first in these severely hypertriglyceridemic patients.

According to its meeting briefing document, Abbott maintains that trials finished before ACCORD show that fenofibrate reduces cardiovascular risk in patients with elevated triglycerides and low HDL cholesterol and that the risk of cardiovascular events increases with increasing levels of triglycerides and/or decreasing levels of HDL cholesterol in patients whose LDL cholesterol is already well-controlled by a statin.

The company will also argue that ACCORD confirms previous trials showing that coadministration of fenofibrate with a statin reduces the risk of cardiovascular adverse events in patients with elevated triglycerides and low HDL cholesterol compared with statin monotherapy. Abbott will also argue that the safety of fenofibrate is both predictable and consistent with the drug's current FDA-approved labeling.

Read theheart.org on May 19 for complete coverage of the FDA advisory committee discussion. For up-to-the-minute updates, follow theheart.org on Twitter.