Modern Sulfonylureas: Dangerous or Wrongly Accused?

Abstract

Except for insulin, sulfonylureas and biguanides are the best studied and most widely used glucose-lowering agents. However, neither class of drugs has had an easy life because of concern about safety. Phenformin, a biguanide, was associated with lactic acidosis and withdrawn from use (1) after causing increased mortality in the University Group Diabetes Program (UGDP) (2). The UGDP also found a sulfonylurea, tolbutamide, to be associated with increased mortality (3). Since then, a newer biguanide, metformin, has risen to its current place as the leading oral therapy for diabetes based on its relative lack of hazard from lactic acidosis and evidence, especially from a subgroup of participants in the UK Prospective Diabetes Study (UKPDS), that it can reduce cardiovascular risk and mortality (4,5). Even though the main randomized comparison in the UKPDS (sulfonylurea or insulin vs. lifestyle therapy) showed that cholorpropamide, glyburide, or glipizide also can reduce medical risks (5,6), the reputation of all sulfonylureas has remained tarnished. A warning of “increased risk of cardiovascular mortality” remains in their labeling information. Treatment guidelines and publications reporting effects of new drugs in other classes often emphasize the risk of hypoglycemia and weight gain from sulfonylureas. And yet, at least 25% of patients with type 2 diabetes are using sulfonylureas (7,8), presumably because they are very inexpensive, allow once-daily oral dosing, reliably reduce glucose, and rarely cause symptomatic side effects other than hypoglycemia. More than 40 years after the UGDP, their risks versus benefits are still debated (9–11). Statistical assessments of data pooled from randomized studies and clinical databases continue to be published, with conflicting …