Diabetic Veterans Started on Sulfonylureas Had More Cardiac Events

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By Brenda L. Mooney

NASHVILLE–While metformin generally is considered first-line treatment for diabetes, many recently-diagnosed patients are started on sulfonylureas, often because of side-effect issues. A new study of more than a quarter million veterans calls that practice into question, however, citing a surprising increase in risk of acute myocardial infarction, stroke or death.

Researchers from the Nashville VAMC and Vanderbilt University reviewed data on 253,690 veterans beginning diabetes treatment between 2001 and 2008 to compare the effects of therapy selection on cardiovascular disease outcomes or death.

In the study, published this week in the Annals of Internal Medicine, 98,665 patients began treatment with sulfonylureas, while 155,025 started with metformin.

Researchers found that sulfonylurea use was associated with a 21% increased risk of acute myocardial infarction, stroke or death.

In 2007, more than 10.1 million Americans (approximately 34% of patients with treated diabetes) used a sulfonylurea as part of their diabetes treatment, according to the study.

“The reason for the difference in risk between metformin and sulfonylurea users remains unknown,” according to the researchers who say they could not conclude whether sulfonylureas themselves are harmful, or if metformin is protective. They also could not determine if differences in patient characteristics contributed to varying rates of cardiovascular events and death.

“Compared with metformin, sulfonylureas are associated with increases in weight and lipid levels and greater risk for hypoglycemia but similar glycemic control,” the authors write. ”Thus, metformin is recommended as first-line therapy for patients without contraindications. Nonetheless, sulfonylureas are sometimes preferred because they require little titration and have fewer gastrointestinal adverse effects than metformin.”

Steven E. Nissen, MD, a cardiologist from the Cleveland Clinic, called the findings “credible and important” in an accompanying editorial.

 “How might sulfonylureas increase adverse CV outcomes? One theory focuses on their adverse effects on ischemic preconditioning, an adaptive mechanism that allows the myocardium to resist necrosis after intermittent periods of ischemia,” Nissen writes. “Another hypothesis relates to sulfonylurea-induced hypoglycemia, which theoretically may result in myocardial ischemia.”

“Regardless of mechanism, this scientific question demands a definitive answer,” he adds. “In the absence of an industry-sponsored study, public health authorities should conduct such a clinical trial. With more than two thirds of diabetic patients dying of CV causes and millions of patients currently receiving sulfonylureas, this question must be resolved with high-quality evidence.”

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