Safety Study of Pioglitazone Compared To Glyburide on Liver Function

Type 2 diabetes generally arises from an initial state of insulin resistance that coincides with a gradual decline in insulin secretion due to beta-cell dysfunction. Together, these factors contribute to impaired glucose tolerance and eventually hyperglycemia. Thiazolidinediones are selective agonists for the nuclear receptor peroxisomal proliferator-activated receptor gamma. These receptors are found in tissues with insulin action including adipose tissue, skeletal muscle and the liver. Thiazolidinediones reduce insulin resistance by enhancing insulin sensitivity in adipose tissue, muscle cells and hepatic cells without directly affecting insulin secretion. These effects improve glycemic control and result in reduced levels of circulating insulin. Pioglitazone is a thiazolidinedione developed by Takeda Chemical Industries, Ltd., and depends on the presence of insulin for its mechanism of action. Glyburide is an oral antidiabetic agent of the sulfonylurea class, and impacts glycemic control by stimulating the pancreas to release insulin, an effect that is dependent upon beta-cells in the pancreatic islets. Elevated levels of hepatic enzymes, hepatocellular inflammation, and viral susceptibility are known to occur with increased frequency in individuals with type 2 diabetes mellitus regardless of the type of antidiabetic therapy used. Subject to the approval of pioglitazone, the Food and Drug Administration requested a 3-year outcome study evaluating the occurrence of serious liver disease in subjects treated with pioglitazone. The present study was designed to fulfill this phase 4, postmarketing commitment to the Food and Drug Administration, pursuant to demonstrating the long-term hepatic safety of pioglitazone. This study was designed to determine whether pioglitazone is associated with a difference in the incidence of elevated levels of alanine aminotransferase, a marker of hepatocellular inflammation or injury, when compared with glyburide. Glyburide is used for treatment of patients with type 2 diabetes mellitus; its use in this study as a comparator should provide a basis for evaluating whether pioglitazone is associated with an increased risk of hepatocellular inflammation or injury.