REZULIN: Drug’s Effect on Heart Stirs New Controversy

      In yet "another unsettling chapter" in the Rezulin saga, previously undisclosed FDA documents show that the diabetes medication may contribute to heart failure, the Los Angeles Times reports. The new findings come on the heels of the FDA's decision last week to pull Rezulin from the market, citing potentially fatal liver toxicity. According to the Times, researchers investigating Rezulin as far back as the mid-1990s expressed concern about the drug's propensity to cause "[d]iscolored, overweight hearts" in animal experiments. FDA pharmacologists wrote, "These changes were drug-related, and were responsible for the early mortality in both sexes." And, those findings were consistent with previous animal research on that medication and Actos, a diabetes treatment belonging to the same class of drugs. Dr. John Gueriguian, a retired FDA researcher who studied the drugs, said, "In rats, in dogs, in monkeys -- I've never seen a class of drug that had such a consistent pattern of cardiopulmonary toxicity." The revelation now brings into question the safety of the two diabetes drugs, Actos and Avandia, both of which were hailed by the FDA last week as "safer alternatives" to Rezulin.

Heart of the Matter
      When the heart irregularities were initially discovered, FDA officials scrambled to investigate possible complications in humans prior to Rezulin's anticipated approval. In an October 1996 e-mail to Gueriguian, FDA diabetes specialist Dr. Robert Misbin wrote, "My primary concern about (Rezulin) is related to its potential for cardiac toxicity." In a subsequent e-mail, Misbin said that specialists reviewing Rezulin were seeking "some measure of assurance that the cardiac events in animals were not also observed in patients." The potential for a diabetes drug to have adverse effects on the heart was particularly concerning to officials, as many patients with adult onset Type II diabetes are prone to be overweight, adding additional stress on the heart. The problem "elevated the significance" of an earlier 1994 study by Rezulin manufacturer Warner-Lambert, which was designed to assess Rezulin's affect on cardiac functioning. Testing 154 patients in five sites, the study evaluated whether the drug contributed to a change in the strength of the heart's left ventricle -- the chamber that pumps blood through the aorta -- over a 48-week period. None of the patients experienced heart failure, but FDA officials expressed concern when the data revealed that 26% of the participants had dropped out of the study.

Officials Made Concessions
      In January 1997, three weeks prior to the scheduled approval date for Rezulin, the FDA sent an official to scrutinize the data gathered at two sites -- one in Omaha, Neb., and the other in Buffalo, N.Y. Following the official's report, Dr. Solomon Sobel, director of the FDA's endocrine drug division, said it was "disturbing" that interpretation of the results in the Warner-Lambert study varied from site to site. Further, it was discovered that Warner-Lambert excluded the Buffalo data "due to poor local technique," despite results that indicated that some patients experienced a thickening of the ventricular wall. Documents show that in both instances, top FDA officials "made concessions in Warner-Lambert's favor," indicating that the drugmaker had "bad luck" with some of the sites chosen for the study. When Warner-Lambert submitted Rezulin for approval in late 1996, it stated that the drug "does not increase cardiac mass or impair cardiac function." Still, when the FDA approved the drug in January 1997, it negotiated a non-binding pledge from Warner-Lambert that the company would conduct a new study examining the cardiac affects of Rezulin. That study was never completed. According to FDA documents, some patients taking Rezulin have died of heart failure. However, experts contend that it would be hard to pin those deaths on Rezulin since many diabetes patients have pre-existing heart conditions and many have taken a host of previous medications (Willman, 3/26).