There is more evidence that sulfonylurea drugs, a mainstay for glucose control in type 2 diabetes for decades, increase the risk of mortality from cardiac events.
In a retrospective study, mortality risk showed a dose-dependent rise, which further suggests a causal link to adverse cardiac events for sulfonylureas, said Jeffrey A. Johnson, Ph.D., and colleagues at the University of Alberta.
Physicians have been concerned about a cardiovascular risk associated with sulfonylureas since publication of the University Group Diabetes Project study in Diabetes in 1970. This study found a higher rate of cardiovascular death in patients taking Orinase (tolbutamide) compared with placebo.
However, subsequent evidence has been conflicting, the researchers said. For example, the largest and longest study of glucose control in people with type 2 diabetes, the U.K. Prospective Diabetes Study, published in The Lancet in 1998, found no increased risk of death associated with sulfonylureas.
The current study retrospectively examined administrative data on nearly 5,800 patients in the Saskatchewan Health database. Participants were 30 or older and had received an oral anti-diabetic agent anytime during 1991 to 1996. To avoid confounding, participants who received insulin or oral anti-diabetic drugs from two or more classes were not included in the study.
Patients were placed into three groups. There were 120 who received a first-generation sulfonylurea, either Daibinese (chlorpropamine) or Orinase. A second group included 4,138 who received Diabeta (glyburide), and the third group included 1,537 who received the non-sulfonylurea drug metformin, which improves insulin sensitivity.
Each of these groups was further divided into a high-dose or low-dose group, with the median daily dose serving as the dividing line.
Participants were followed until death or termination of Saskatchewan Health coverage. Average follow up was about five years. The main outcomes were all-cause mortality and death from an acute ischemic event.
There were 1,503 deaths during the study period, of which 372 (about 25%) were attributable to an acute ischemic event. First-generation sulfonylurea users had the highest mortality (67.6 deaths per 1,000 person-years), compared with Diabeta users (61.4 deaths per 1,000 person-years) and metformin users (39.6 deaths per 1,000 person-years).
Compared with the low-dose patients, a greater risk of death was found in the high-dose patients receiving first-generation sulfonylureas (adjusted hazard ratio=2.1; 95% confidence interval=1.0-4.7) and Diabeta (HR=1.3; 95% CI= 1.2-1.4), but not metformin (HR=0.8; 95% CI=0.7-1.1).
The study also found an increased risk of death from ischemic event in the high-dose patients receiving first-generation sulfonylureas, though it was not statistically significant (HR=1.21; 95% CI=0.10-3.75). A significant association was found for Diabeta (HR=1.37; 95% CI=1.25-1.50). A slight and non-significant association was found for metformin (HR=1.10; 95% CI=0.75-1.30).
Sulfonylureas promote insulin release by binding to adenosine triphosphate (ATP)-sensitive potassium channels in pancreatic cells, thereby keeping these channels closed, the researchers noted. One likely mechanism to explain the link to cardiovascular risk is that this class of drugs also binds to the same channels in cardiac myocytes and smooth-muscle cells, interfering with these cells’ ability to withstand brief periods of ischemia, the researchers suggested.
"In conclusion, we observed a dose-response relation between sulfonylurea exposure and risk of death," the authors said "This evidence, taken within the context of observations collected over the last 30 years, suggests that clinicians should carefully assess the need for sulfonylurea therapy in subjects at high risk of cardiovascular events-particularly now, when several other classes of anti-diabetic oral medications are available,"
In an editorial, diabetes researcher David S. H. Bell, Ph.D., of the University of Alabama in Birmingham, said that the Canadian findings "add to the existing evidence that suggests that sulfonylureas increase the risk of cardiovascular events; furthermore, their study adds support to a causal link by demonstrating a dose-related effect on the risk of death." Dr. Bell advised that "sulfonylurea drugs should therefore be relegated to third-line agents (after metformin and thiazolidinedione drugs) for managing type 2 diabetes."
Study Note: Carefully assess the need for sulfonylurea therapy in patients with type 2 diabetes, weighing the possible cardiovascular risk suggested by this study with the potential benefit
In a related commentary, Dr. David S. H. Bell, from the University of Alabama at Birmingham, notes that sulfonylureas may raise the risk of death by directly affecting the myocardium. Even though these agents are still a popular treatment for diabetes, he believes that they should be relegated to third-line therapy, which is consistent with recently published guidelines.
Canadian Medical Association Journal, Jan 17, 2006 CMAJ 2006;174:169-174,185-186.