ATLANTA -- Results from the large, government-funded ACCORD study reinforce the idea that taking Abbott's fibrate TriCor along with statins is only appropriate for a minority of diabetes patients at high risk for cardiovascular events.

The triglyceride-lowering TriCor (fenofibrate) goes off-patent in 2011 and Abbott, with U.S. marketing partner AstraZeneca, has been looking to switch patients to its next-generation TriLipix , the only fibrate cleared for use with a statin (Also see "TriLipix Approval Strengthens Abbott’s Cholesterol Franchise" - Pink Sheet, 22 December, 2008.).

TriCor/TriLipix sales have been sliding in recent quarters and global sales for the whole of 2009 were down 0.3 percent to $1.3 billion. The drugs are similar apart from Trilipix's indication for use with a statin, so negative findings for TriCor have potential to damage the follow-on (Also see "TriCor Data Close At Hand; Will It Strike ACCORD With Physicians?" - Pink Sheet, 14 October, 2009.). Certriad , a combination of TriLipix and the statin Crestor (rosuvastatin) which is awaiting FDA approval, could also suffer.

Results from the Action to Control Cardiovascular Risk in Diabetes lipid trial testing TriCor with simvastatin (Merck's Zocor and generics) in about 5,000 patients with type 2 diabetes and pre-existing cardiovascular disease and at least two more cardiovascular risk factors were presented at the American College of Cardiology meeting in Atlanta on March 14.

Based on an analysis at 4.7 years follow-up, the TriCor combination was safe but it did not significantly reduce the primary outcome in terms of reducing combined rates of death, nonfatal heart attack or nonfatal stroke, investigators reported during a late-breaking trials session. Nor did it reduce these rates on an individual basis.

"The ACCORD lipid trial does not support the use of combination of fenofibrate and simvastatin compared to simvastatin alone to reduce cardiovascular events in the majority of patients with type 2 mellitus who are at high risk for CV disease," said investigator Henry Ginsberg, who presented the results.

TriLipix is currently indicated for use in combination with statins to reduce triglycerides and increase HDL cholesterol in patients with mixed dyslipidemia and chronic heart disease or risk equivalent who are on optimal statin therapy to achieve their LDL cholesterol goals. TriCor is only approved as a monotherapy for treating high cholesterol, mixed dyslipidemia and high triglycerides.

Subgroup analyses from the ACCORD trial suggest that the TriCor/statin combination affected patients differently, said Ginsberg, director of the Irving Institute for Clinical and Translational Research at Columbia University College of Physicians and Surgeons in New York.

For instance, the study indicated that women may be harmed by the addition of another drug, while men could benefit.

Furthermore, the results suggest a positive effect for those with a high baseline level of triglycerides and low HDL cholesterol. In such patients, with high triglycerides (at or above 204 mg/dL) and low HDL (at or below 34 mg/dL), there was a 31 percent lower rate of cardiovascular events in the fibrate-plus-statin arm compared to the statin-only arm (p=0.057 for interaction).

Results Were Disappointing, But Not Surprising

The ACCORD findings are not that surprising given that the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, published in 2005, reached similar conclusions.

Based on that research and treatment guidelines, clinicians mainly use TriCor in higher-risk populations. Ginsberg estimates that 15 percent of the general diabetes population fall into this category, but that only 5 percent of patients are actually treated with a fibrate and statin. So ironically, at least in his view, the ACCORD results suggest that TriCor is presently underused.

After the session, panelist Paul Thompson, director of cardiology at Hartford Hospital in Connecticut, said that while the media headlines are likely to focus on "fibrate failure," doctors are best advised to "read the fine print" of the study, which shows a benefit for some patients. The potential benefit is worthy of further study, he said.

Thompson added that the study doesn't address benefits of TriCor as a monotherapy and that cardiovascular benefits for the combination might not be evident at five years follow-up. "I don't want to be an apologist for the pharmaceutical industry, but is 4.7 years long enough?" he said.

Patients care a lot more about long-term benefits than what will happen in five years' time, he added.

In a statement Abbott said: "The results of ACCORD Lipid were widely expected and not surprising given that two-thirds of patients in the trial would not be treated with fibrates under current guidelines."

The primary endpoint of the study was not met, but the pre-specified subgroup of patients with high triglycerides and low HDL showed potential benefit, the company noted.

"The average triglyceride level of a patient that starts fenofibrate in the United States is 302 mg/dL, according to medical claims data. The median triglyceride level in ACCORD Lipid was 162 mg/dL. The subgroup of patients in this study with triglycerides at or above 204 mg/dL reflects real-world fibrate usage."

However, there was a negative tone to the buzz amongst attendees after the release of the ACCORD study, as well as other late-breaking trials in the same session that also suggested a failure of drugs to impact CV outcomes in randomized controlled setting.

In general the studies showed that more treatment is not necessarily better treatment, though it does cost more, said Raymond Gibbons, a Mayo Clinic cardiologist and former president of the American Heart Association. Gibbons questioned whether more than 5 percent of the diabetes population is using fenofibrate with statins.

"Certainly they are pushing it," he said.

What ACCORD Could Mean For Promotional Push...

Abbott reports that the discussions between its sales force and physicians center around treatment guidelines for fibrates - specifically the National Cholesterol Education Project's Adult Treatment Panel III recommendation that fibrates be added for patients already on statins to reduce LDL cholesterol if their triglycerides are greater than 200 mg/dL.

Abbott could still find some positive take-home messages from ACCORD that could further the promotional efforts behind the fenofibrate franchise, according to Decision Resources analyst Nikhil Mehta. "There is an apparent benefit in the pre-specified subgroup with high triglycerides and low HDL cholesterol... Tricor/TriLipix users in the real-world are more likely to have high TGs and low HDL-C than the average values seen in ACCORD," Mehta said.

"But I think Abbott has braced itself for a negative efficacy results from ACCORD and the company was probably not pinning homes on expanding use on the back of this study," he noted.

Mehta's conclusion is that the ACCORD-Lipid findings mean that the Tricor/TriLipix franchise is unlikely to significantly expand beyond use in the 5 percent of patients now treated in the high TG/low HDL category. "Overall, we're not expecting prescribing practices to change materially on the basis of the ACCORD Lipid study," he said.

- Emily Hayes ( e.hayes@elsevier.com )

Abbott's Fibrate Franchise Will Likely Remain Limited To High-Risk Patients After ACCORD

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