Novel Drug Might Prevent New-Onset Diabetes

BY BRUCE JANCIN

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NEW ORLEANS -- Succinobucol, a novel antioxidant with anti-inflammatory properties, achieved a 64% reduction in new-onset diabetes in patients with a recent acute coronary syndrome in the phase III Aggressive Reduction of Inflammation Stops Events (ARISE) trial.

Use of the investigational agent also was linked to significant reductions in cardiovascular death, MI, and stroke, compared with optimal current therapy in the 6,144-patient double-blind randomized trial, Dr. Jean-Claude Tardif reported at the annual meeting of the American College of Cardiology.

But these were prespecified secondary outcome measures.

Succinobucol failed to achieve a significant impact on the primary end point, a composite of "hard" atherosclerotic outcomes and the "soft" end points of coronary revascularization and hospitalization for unstable angina, said Dr. Tardif, professor of medicine at the University of Montreal and director of research at the Montreal Heart Institute.

That failure was severely punished by a single-day 60% nosedive in the stock price of AtheroGenics Inc., the trial sponsor, as some observers dismissed ARISE as a negative study. That's not how the ARISE investigators see it, though.

"I'm pretty bullish," added Dr. Marc A. Pfeffer, ARISE co-principal investigator. "We're all looking for the next step [in cardiovascular risk reduction], and I think this is as promising as anything I've seen in terms of developments."

"We didn't hit our primary end point, but we're the ones who established that primary. We made it more inclusive. We wish we hadn't, we wish we'd made it the firmer one, but there it is.

"The firm end points are there, and the diabetes effect was pretty profound. If we can come back here with another study aiming specifically at those end points and we can show positive results, then that would be the highest compliment for a clinical trial--it would change the practice of medicine. That's our aim," said Dr. Pfeffer, professor of medicine at Harvard Medical School, Boston.

The 6,144 ARISE participants were randomized to 300 mg/day of succinobucol or placebo for an average of 2 years starting shortly after hospitalization for an acute MI or unstable angina.

All were deemed at high risk for further atherosclerotic events. Rates of utilization of secondary preventive therapies were extremely high: 90% of patients were on a statin at baseline, 80% on a ?-blocker, 92% on aspirin, and 74% on an ACE inhibitor or angiotensin receptor blocker.

A total of 37% of subjects had diabetes at baseline, with a mean HbA1c of 7.2%. Among the other nearly 4,000 participants, the incidence of new-onset diabetes was 4.2% with placebo and 1.6% with succinobucol, a 64% relative risk reduction. Consistent with this benefit, succinobucol resulted in a mean 0.5% lower HbA1c than placebo did at 12 months in patients with diabetes at entry, and an improvement in fasting blood glucose as well.

The combined "hard" secondary atherosclerotic end point of cardiovascular death, cardiac arrest, MI, or stroke occurred in 8.2% of the placebo group and 6.7% with succinobucol, for a significant 19% relative risk reduction.

The chief side effect when using succinobucol was diarrhea, reported by 23% of patients, although only one in seven of those affected discontinued the study. The incidence of liver function abnormalities was similar to that with placebo.

Discussant Dr. Robert A. Harrington, director of cardiovascular clinical trials at the Duke Clinical Research Institute, Durham, N.C., said ARISE sends mixed signals, including unwelcome trends toward increased heart failure hospitalizations, lower HDL, and increased LDL.

Succinobucol, a potent lipophilic antioxidant, is the monosuccinic acid ester of probucol. The drug's appeal, Dr. Pfeffer said, lies in the fact that it operates by mechanisms beyond modification of the conventional risk factors such as blood pressure and lipids.

Officials at the AtheroGenics company indicated they plan to back a large confirmatory trial.

Dr. Tardif and Dr. Pfeffer disclosed that their financial relationship with AtheroGenics is limited to research grants.

"Although the market may have reacted unfavorably, this study is one of many that are demonstrating a fundamental link between diseases of lipid, glucose metabolism and vascular inflammation," said Dr. Russell H. Samson when asked to comment on this article.

"Other pharmaceuticals such as the PPAR agonists have also been shown to help control diabetes while improving lipid metabolism and possibly atherosclerosis," he added.

Dr. Samson is an editorial advisor for VASCULAR SPECIALIST, and a physician of Samson Showalter Lapore--Vascular Specialists, and is the director of the noninvasive lab at Sarasota Memorial Hospital, Sarasota, Fla.

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