Are cardiac risks of rosiglitazone legitimate?

July 23, 2007

Controversy surrounding rosiglitazone (Avandia) and cardiac risk prompted a special symposium at the annual scientific sessions of the American Diabetes Association.

Standing behind a meta-analysis showing excess cardiac risk associated with rosiglitazone was Steven E. Nissen, M.D., lead investigator of the meta-analysis (New England Journal of Medicine 2007;356:2457-2471). The 43% relative excess hazard of myocardial infarction (MI) found with rosiglitazone compared with controls in his analysis of 42 randomized trials, most of them unpublished, is in line with Glaxo's own meta-analysis provided to the Food & Drug Administration in 2006, and with an independent analysis conducted by the FDA, he said.

Subsequently, an observational study performed by Glaxo found no such excess cardiac risk with rosiglitazone, but Nissen pointed out several flaws in this study. It used an insurance claims database with an incomplete assessment of covariates, it followed patients for only one year, and it included no comparison with the other marketed thiazolidinedione, pioglitazone (Actos, Takeda). "In my view, this study was very weak," said Nissen, chairman of cardiovascular medicine at the Cleveland Clinic.

Based on these interim data, rosiglitazone should maintain a role in the glucose-lowering armamentarium, and "RECORD should continue to its planned end," which is a total of five years, said Home, professor of diabetes medicine, University of Newcastle upon Tyne, U.K.

"Major errors in design have rendered this study futile," said Nissen in enumerating the weaknesses of RECORD. The open-label design and the chosen endpoint, which did not include MI, are two such weaknesses. Another is that the annual event rate in RECORD was only 3.1%, which is far lower than the 11% annual event rate that the authors postulated, rendering the study underpowered to detect a difference between rosi-glitazone and its comparators. "The study has less than 1% power to detect a difference in mortality," he said.

In the end, Nissen believes that each agonist of a peroxisome proliferator-activated receptor (PPAR) needs to be evaluated individually, as each activates different genes. Pioglitazone, for example, has favorable effects on lipids, unlike rosiglitazone, and showed a trend toward a reduction in a composite of death, MI, and stroke in the Prospective Pioglitazone Clinical Trial in Macrovascular Events. Development of several PPAR agonists has already been stopped due to toxicity, he noted, many for direct cardiac toxicity.

In other news from the ADA meeting, Timothy Davis, M.D., Ph.D., reported that statins and fibrates lower the risk of peripheral neuropathy, independent of their effects on lipids. In his analysis of 531 patients with Type 2 diabetes who participated in the Fremantle Diabetes Study and were followed for at least five years, the use of statins reduced the adjusted risk of neuropathy by 35% and the use of fibrates reduced it by 48%.

"Statins and fibrates were independently predictive and the data suggest that they work to pre-vent neuropathy through different mechanisms," said Davis, professor of medicine, University of Western Australia. He therefore hypothesized that use of both drugs may produce greater benefit than either alone.

Another study showed that colesevelam HCl (WelChol, Daiichi Sankyo) not only lowers LDL cholesterol but reduces hemoglobin A1c in Type 2 patients who do not reach their glycemic target with metformin, said Harold Bays, M.D., medical director, Louisville Metabolic & Atherosclerosis Research Center.

In the study, 316 patients with A1c levels of 7.5% to 9.5% who were on a stable dose of metformin were randomized to colesevelam, 3.75 gm/ day, or placebo for 26 weeks. Among the 155 patients receiving metformin monotherapy, a mean reduction in A1c of 0.47% occurred in the colesevelam recipients relative to placebo. In the entire cohort of 316 patients, LDL cholesterol was reduced by 15.9% in patients assigned to colesevelam compared with placebo.

THE AUTHOR is a clinical writer based in the Cleveland area.