A Verdict for Glimepiride: Effective and Not Guilty of Cardiovascular Harm

Abstract

Amazingly, whether sulfonylureas pose unacceptable risks compared with other treatments for diabetes has been debated for nearly 50 years. Ever since increased mortality was associated with tolbutamide in the University Group Diabetes Program (UGDP) (1), a warning of potential cardiovascular risk for drugs in this class has been mandated. Their tendency to cause both nonsevere and severe hypoglycemia worries patients and providers alike, who fear that hypoglycemia may precipitate serious cardiovascular events. Despite these concerns, sulfonylureas continue to be widely used for type 2 diabetes because they reliably improve glycemic control, lack symptomatic side effects other than hypoglycemia, and are very inexpensive. A recent commentary in Diabetes Care questioned whether the modern drugs in this class—glimepiride and gliclazide—deserve the shadow of guilt cast over them by studies of older sulfonylureas (2). They are conveniently dosed once daily and are less likely to cause hypoglycemia than the older agents, especially glyburide (also called glibenclamide). Unlike glyburide, they do not oppose ischemic preconditioning, a cardioprotective mechanism (3), and meta-analytic evidence suggests they are associated with lower rates of cardiovascular events than glyburide (4).\n\nUp to now, high-quality evidence to resolve the risk-versus-benefit debate has been lacking. Epidemiologic analyses of clinical databases and meta-analyses of short-term clinical studies comparing a sulfonylurea with placebo or an active comparator have shown conflicting results (5–8). Some studies comparing sulfonylureas with metformin suggest higher cardiovascular risk with sulfonylureas (9), but it is unclear whether this is because sulfonylureas are harmful or metformin is protective. Experience in the UK Prospective Diabetes Study (UKPDS) favors the latter interpretation. Over 10 years of randomized comparison with a conventional lifestyle-based regimen in the UKPDS, basal insulin or a sulfonylurea did not alter cardiovascular outcomes, whereas metformin reduced cardiovascular and all-cause mortality (10). But because metformin is preferred as …