Sulfonylureas Show Higher Mortality Rates Than Metformin

Nancy A. Melville

June 29, 2012

June 29, 2012 (Houston, Texas) — The diabetes drugs glipizide, glyburide, and glimepiride each show a significantly higher risk for mortality compared with metformin, according to an analysis of more than 23,000 patients with type 2 diabetes presented here at ENDO 2012: The Endocrine Society 94th Annual Meeting.

The 3 drugs are all sulfonylureas, which have been shown in recent research to have safety profiles that are more varied between drugs than was previously believed, particularly in terms of issues such as hypoglycemic risks, sulfonylurea receptor selectivity, and the drugs' effects on myocardial ischemic preconditioning.

"There have been conflicting reports on whether these differences in pharmacological properties actually translate to differences in the risk of adverse cardiovascular outcomes and overall mortality," said lead author Kevin M. Pantalone, DO, an endocrinologist at Summa Western Reserve Hospital in Cuyahoga Falls, Ohio.

"These findings led us to ask 2 questions: Do these differences in pharmacological properties translate to differences in risk of overall mortality, and has it been inappropriate to analyze these medications as a class, as has historically been the case?"

In an effort to find the answers, Dr. Pantalone teamed up with researchers at the Cleveland Clinic in Ohio to identify 23,915 patients with type 2 diabetes in the center's electronic health record database. The study received funding from a grant from Astra Zeneca.

The participants included 12,774 patients with type 2 diabetes who had received monotherapy with metformin, 4325 patients receiving glipizide, 4279 patients receiving glyburide, and 2537 patients receiving glimepiride. Average age was 61 years, 69% were men, and the patients were both with and without a history of coronary artery disease.

At a median follow-up of 2.2 years, there were a total of 2546 deaths in the entire cohort, as well as 419 deaths among the subgroup of 2721 patients with coronary artery disease.

The results showed that compared with metformin, the overall mortality risk was increased with glipizide (hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.39 - 1.94), glyburide (HR, 1.59; 95% CI, 1.35 - 1.88), and glimepiride (HR, 1.68; 95% CI, 1.37 - 2.06).

Among patients with both diabetes and heart disease, only glimepiride did not increase the risk for death compared with metformin. Glipizide, however, was associated with a 41% increased risk for mortality among the patients with heart disease, and glyburide was associated with a 38% greater risk for death.

"The findings indicate that glipizide, glyburide, and glimepiride are all associated with an increased risk of overall mortality compared with metformin. Therefore, metformin, when not contraindicated, should be the first-line agent to prescribe to control glycemia," Dr. Pantalone said.

"If a sulfonylurea is required to obtain glycemic control in patients with type 2 diabetes, then glimepiride may be the preferred drug in those with underlying coronary artery disease."

He called for more prospective studies to determine the difference in pharmacologic properties inherent to individual sulfonylureas regarding the risk for adverse cardiovascular outcomes and overall mortality, particularly in patients with coronary artery disease.

"I believe this is very important because the American Diabetes Association recommends sulfonylureas as a tier 1, core validated therapy," Dr. Pantalone said.

"So if there is evidence that 1 sulfonylurea may be safer or potentially safer than others, then it would not make sense to use those agents that are potentially deleterious."

Although noting that the average follow-up period of just 2.2 years was a limitation of the study, endocrinologist Dace L. Trence, MD, who moderated the session, said the study's findings are in line with growing research showing important differences between sulfonylureas.

"The evidence continues to mount that there should be a consideration of the specific sulfonylurea that is used," said Dr. Trence, who is an assistant professor with the University of Washington's Department of Medicine in Seattle.

"The strength of this latest study is the number of individuals and medical records the researchers were able to access," she told Medscape Medical News.

Despite the growing evidence, there is not much awareness of the apparent distinctions between individual sulfonylurea drugs, she added.

"I don't think the differences between drugs in are appreciated in the primary care arena. I think endocrinologists are increasingly becoming aware of this issue, but I don't think it's widely known that not all sulfonylureas are created equal."

The study received funding from a grant from Astra Zeneca, and Dr. Pantalone disclosed that he has been a speaker on behalf of AstraZeneca. Dr. Trence has disclosed no relevant financial relationships.

ENDO 2012: The Endocrine Society 94th Annual Meeting: Abstract OR17-4. Presented June 24, 2012.