Lessons From the Avandia Controversy: A new paradigm for the development of drugs to treat type 2 diabetes

Sulfonylureas used to be the only oral agents available in the U.S. to treat patients with type 2 diabetes. The biguanide phenformin had been used widely in the 1950s and 1960s but was removed from the market in 1977 because of lactic acidosis (1). Other biguanides, including metformin, were felt to be safer and had been used extensively elsewhere in the world. But a biguanide did not become available in the U.S. until 1995 (2). The year 1995 marked a sea change in availablilty of drugs to treat type 2 diabetes. The approval of metformin, a biguanide, was followed by the approval of acarbose, a galactosidase inhibitor that, like metformin, had been widely used in Europe. A new drug application for acarbose had been rejected by the Food and Drug Administration (FDA) 3 years earlier, but in 1995 the regulatory environment had become friendlier, owing in large part to the finding of the Diabetes Control and Complications Trial (DCCT) that aggressive treatment of hyperglycemia prevented or delayed complications of diabetes (3). Approval of the thiazolidinedione (TZD) troglitazone and the non-sulfonylurea insulin secretagog repaglinide followed soon after, along with additional members of the newly approved classes. In 2005, the uninterrupted succession of new drug approvals came to an end. Muraglitazar was a dual peroxisome proliferator–activated receptor agonist. It was different chemically from the TZDs and fibrates but was believed to combine the desirable pharmacological effects of both. Muraglitazar was highly effective in lowering A1C and had favorable effects on serum lipids. But contrary to what one might expect, muraglitazar appeared to increase the risk of adverse events related to cardiac ischemia (4). This might have been considered an isolated event were it not for the recent brouhaha that rosiglitazone (Avandia) also increased the risk of cardiac ischemia. The Avandia affair …