HOUSTON – Glipizide, glyburide, and glimepiride were independently associated with 59%-68% greater all-cause mortality risks than metformin in a retrospective study of nearly 24,000 type 2 diabetic patients on monotherapy for control of blood sugar.
Notably, among the 2,721 subjects with documented coronary artery disease (CAD), glipizide and glyburide carried an increased overall mortality risk compared with metformin, but glimepiride did not, according to Dr. Kevin M. Pantalone of Summa Western Reserve Hospital in Cuyahoga Falls, Ohio.
Dr. Kevin M. Pantalone
"Metformin, when not contraindicated, should be the first-line agent used to control blood sugar levels in patients with type 2 diabetes. Our results suggest that if a sulfonylurea is required to control blood sugar levels, glimepiride may be the preferred sulfonylurea in those with known coronary artery disease," he said at the annual meeting of the Endocrine Society.
Given that this was a retrospective study, it has to be viewed as hypothesis generating. A prospective study is warranted to establish the causal mechanism for the observed increase in mortality risk associated with these three widely prescribed sulfonylureas.
"The Food and Drug Administration now requires all drugs for the treatment of diabetes to have a cardiovascular safety study. These older drugs, which are considered tier 1, core-validated therapies by the American Diabetes Association, appear to have been given a free pass in terms of their cardiovascular risk," the endocrinologist observed.
He reported on 23,915 patients with type 2 diabetes who began monotherapy with metformin or one of the three sulfonylureas. The study was conducted using data from the Cleveland Clinic’s electronic health record system. Patients were followed for a median of 2.2 years, during which 2,546 deaths occurred in 58,513 person-years of follow-up.
In a multivariate Cox regression analysis adjusted for 16 variables, glipizide was independently associated with a 64% greater relative risk of all-cause mortality than was metformin. Glyburide was linked to a 59% increased risk, and glimepiride was associated with a 68% increased risk.
Among 2,721 diabetic patients with documented baseline CAD, there were 419 deaths during 5,980 person-years of follow-up. In this subgroup with CAD, glipizide had a 41% increased overall mortality risk, and glyburide had a 38% greater risk than metformin.
Dr. Alvin Powers
The clinical implications of these study findings are huge, Dr. Pantalone said. An estimated 26 million Americans have diabetes, and most of them either have known CAD or are at elevated risk for it. The four antidiabetic drugs examined in the study are among the most widely prescribed agents for blood glucose control, and all four are available in generic versions at bargain basement prices.
Dr. Alvin Powers commented that controversy surrounding the safety of sulfonylureas dates back several decades. As far as he’s concerned the issue remains unresolved, given the limitations of Dr. Pantalone’s retrospective study design.
"I think we really need a prospective comparison. I think metformin remains the primary drug, and when we add a second-line drug, the studies would show that glipizide and glimepiride are probably preferred over glyburide because of the length of time they’ve been studied. But I think that because glycemic control is important, the second-line drug still can be a sulfonylurea," said Dr. Powers, professor of medicine at Vanderbilt University, Nashville, Tenn., and director of the Vanderbilt Diabetes Center.
Dr. Pantalone’s study was supported by a research grant from AstraZeneca.