Overall Mortality in Patients With Type 2 Diabetes May Be Similar With Different Sulfonylureas

Laurie Barclay, MD

March 31, 2010

March 31, 2010 — The risk for overall mortality is similar in patients with type 2 diabetes receiving glipizide, glyburide, or glimepiride monotherapy, according to the results of a retrospective cohort study, reported online March 9 in Diabetes Care. However, the findings suggest that glimepiride may be the preferred sulfonylurea in patients with underlying coronary artery disease (CAD).

"Sulfonylureas have historically been analyzed as a medication class, which may be inappropriate given the differences in properties inherent to the individual sulfonylureas: hypoglycemic risk, sulfonylurea receptor selectivity and effects on myocardial ischemic preconditioning," write Kevin M. Pantalone, DO, from Cleveland Clinic in Cleveland, Ohio, and colleagues. "The purpose of this study was to assess the relationship of individual sulfonylureas and the risk of overall mortality in a large cohort of patients with type 2 diabetes."

Using an academic health center enterprise-wide electronic health record system, the investigators identified 11,141 patients with type 2 diabetes receiving sulfonylurea monotherapy who were at least 18 years old, with and without a history of CAD, and not taking insulin or a noninsulin injectable at baseline. Of these patients, 4279 had started monotherapy with glyburide, 4325 with glipizide, and 2537 with glimepiride. Mortality rate was determined from the electronic health record and Social Security Death Index, and cohorts were compared with multivariable Cox models.

In the entire cohort, these agents did not differ significantly in the risk for overall mortality. In patients with documented CAD, however, there was a trend towards increased overall mortality risk with glyburide vs glimepiride (hazard ratio [HR], 1.36; 95% confidence interval [CI], 0.96 - 1.91) and glipizide vs glimepiride (HR, 1.39; 95% CI, 0.99 - 1.96).

On the basis of these findings, the investigators concluded that no increased mortality risk among the individual sulfonylureas was identified. However, they did suggest that glimepiride may be the preferred sulfonylurea in patients with underlying CAD.

"This study deals with unsettled issues concerning the possible association between certain types of sulfonylureas and cardiovascular adverse events," Sameer A. Kassem, MD, PhD, from Endocrinology & Metabolism Service, Department of Internal Medicine at Hadassah Medical Center in Jerusalem, Israel, told Medscape Diabetes & Endocrinology when asked for independent comment. "The study leaves us with open questions rather than firm answers, partly due to study design and sample size. Although it included more than 11,000 participants, the [number of] patients with coronary artery disease [was] relatively small (341 glimepiride, 548 glipizide, and 580 glyburide)."

The authors acknowledge limitations of this study, including retrospective design; lack of randomization, causing possible selection bias; lack of documentation of compliance with the prescribed medication; and unknown medication exposure times after baseline. In addition, the medication groups were not balanced regarding baseline variables and risk factors, although the multivariable analysis adjusted for differences in relevant baseline variables and risk factors.

"Obviously, the study is not powered to show increased mortality with statistical significance," Dr. Kassem said. "Another aspect of this issue is the possible contribution of hypoglycemia per se (clearly associated with glyburide) to cardiovascular mortality rather than a direct effect of the drug on ischemia preconditioning in the heart."

Therefore, in future research, Dr. Kassem recommends a prospective, large, controlled trial comparing different classes of sulfonylureas, with sufficient power to show cardiovascular adverse events including cardiovascular mortality.

"Although not statistically significant, the data shown here and in previous studies emphasize the possible differences in cardiovascular adverse events between different sulfonylureas," Dr. Kassem concluded. "Precautions should be taken when prescribing glyburide to patients with CAD."

AstraZeneca supported this study. Some of the study authors have disclosed various financial relationships with AstraZeneca, Daiichi Sankyo, Merck, Pfizer, Novo Nordisk, and/or GlaxoSmithKline. Dr. Kassem has disclosed no relevant financial relationships.

Diabetes Care. Published online March 9, 2010. Abstract

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