Sulfonylureas for diabetes increase risk of heart disease and death, study finds

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Sulfonylureas, the first family of oral drugs used for treating type 2 diabetes, increase the risk of death from all causes by as much as 61% compared with the newer drug metformin, British researchers have found. Some researchers have suspected that the drugs carry an increased risk, but the new study reported online in BMJ.com is the first to quantify the risks. BMJ.com is the website of BMJ, formerly the British Medical Journal.

The good news from the study is that the new family of drugs called thiazolidinediones is not associated with an increased risk and that one of them, pioglitazone, actually reduces risk by as much as 39% compared with metformin.

Type 2 diabetes has reached epidemic status, with more than 180 million victims worldwide and nearly 24 million in the United States. It is most common among the elderly and is associated with obesity, but the growing incidence of obesity in youth is causing the disease to appear in an ever-younger population. Diabetes by itself doubles the risk of heart disease, which complicates the task of identifying increased risks from drugs. U.S. guidelines call for using metformin as first-line therapy for type 2 diabetes, and the new results support that recommendation.

The sulfonyureas, which include Glucotrol, Diabeta, Glipizide, Gliclazide, glyburide, Amaryl, chlorpropamide, tolbutamide and tolazamide, have been marketed in the United States since 1955 and are taken once or twice daily before meals. They stimulate the release of insulin by the pancreas and may help sensitize cells to the action of the hormone.

Dr. Paul Elliott, an epidemiologist at Imperial College London, and his colleagues studied health records of 91,521 diabetic men and women (with an average age of 65) in the U.K. General Practice Database between 1990 and 2005. Among that group, in an average follow-up period of seven years, there were 3,588 myocardial infarctions (heart attacks), 6,900 cases of congestive heart failure and 18,548 deaths.

Compared with metformin, the team observed a 24% to 61% excess risk for deaths from all causes among users of first- and second-generation sulfonylureas and an 18% to 30% excess risk of congestive heart failure for users of the second-generation drugs. The thiazolidinediones rosiglitazone (Avandia) and pioglitazone (Actos) were not associated with an increased risk of heart attacks. Actos was associated with a 31% to 39% decrease in risk of all-cause mortality compared with metformin. Comparing the two thiazolidinediones to each other, the team found that Avandia was linked to a 34% to 41% higher risk of death, but the team concluded the increased risk was not statistically significant when other factors were taken into account.

Experts cautioned, however, that the study suffers from a problem characteristic of all such retrospective studies -- researchers cannot know what diagnosis prompted physicians to describe specific drugs. High-risk patients with high blood levels of creatine, for example, are not likely to be prescribed metformin and would probably receive a sulfonylurea instead. Because the high creatine levels increase the risk of death by themselves, an increased risk might inappropriately be blamed on the drugs.

-- Thomas H. Maugh II