Metformin vs. Sulfonylureas for Diabetes

Study Shows Sulfonylureas Have Higher Heart Failure Risk Than Metformin

By Salynn Boyles
WebMD Health News

Reviewed By Louise Chang, MD

Dec. 4, 2009 -- Concerns that the diabetes drugs Avandia and Actos raise the risk for heart failure led the FDA to require label changes warning of the potential risk two years ago.

Now a new study suggests this concern might be unfounded, but it also raises questions about a different class of oral diabetes drugs that have been used since the 1950s: sulfonylureas.

Researchers reported that diabetes patients who used sulfonylureas had a higher risk of death from all causes and a higher risk of heart failure than diabetes patients who used the most widely prescribed diabetes drug, metformin.

Compared with metformin, also known as Glucophage, single-drug treatment with first- and second-generation sulfonylureas was associated with up to a 61% increased risk for death. Users of second-generation sulfonylureas had up to a 30% higher risk for congestive heart failure.

Patients treated with Actos or Avandia did not appear to have a greater risk for heart attacks than those treated with metformin.

Treating Diabetes

As many as 180 million people worldwide have type 2 diabetes, and heart attacks and heart failure are among the major killers associated with the disease.

Over the past two decades, a host of drugs have been approved to treat diabetes. The drugs improve blood sugar control, but there have also been concerns that some may raise the risk of cardiovascular events in people who are already at high risk.

In an effort to explore the issue, researchers in the U.K. examined the treatment records of more than 91,000 diabetes patients enrolled in a national database between 1990 and 2005.

During the follow-up, almost 36,000 patients had heart attacks, 6,900 developed congestive heart failure, and just over 18,500 died.

Metformin was the most widely prescribed drug, followed by second-generation sulfonylureas. Many patients took more than one diabetes drug.

Among the major findings:

  • Compared with metformin, single-drug treatments with first- or second-generation sulfonylureas was associated with a 24% to 61% increased risk for death from all causes.
  • Compared to metformin, second-generation sulfonylurea use was associated with an 18% to 30% increased risk for heart failure.
  • Compared to metformin, treatment with Actos was associated with a 31% to 39% decreased risk for death.

Metformin as a First-Line Treatment

First-generation sulfonylureas in this study include the drugs acetohexamide (Dymelor), chlorpropamide (Diabinese), tolbutamide, and tolazamide (Tolinase).

Second-generation versions from the study include glipizide (Glucotrol), gliclazide, glimepiride (Amaryl), and glyburide (Diabeta, Micronase, Glycron, Glynase).

Study researcher Ionna Tzoulaki, PhD, of the Imperial College London, tells WebMD the findings are consistent with current recommendations by the American Diabetes Association (ADA) and other diabetes groups designating metformin as the first-line oral treatment for type 2 diabetes.

ADA president-elect for medicine and science Richard M. Bergenstal, MD, agrees.

"A decade ago it was something of a toss-up as to whether a new patient would be given metformin or a sulfonylurea," he tells WebMD. "But metformin has earned the right to be the first-line oral drug."

The bigger issue, he says, is whether aggressive glucose control is really as important as has been widely believed in managing type 2 diabetes.

Bergenstal is executive director of the International Diabetes Center in Minneapolis, Minn.

"Recent studies have failed to confirm that glucose control really benefits the heart," he says. "And since 80% of diabetes deaths are heart related, it is clear that controlling cardiovascular risk factors like blood pressure and cholesterol should be a major focus."

Bergenstal says that a sulfonylurea may still be a good option for individual patients who can't take metformin or need additional medication. Patients and their doctors have to weigh individual risks and benefits.

No one should stop taking their medications based on this study, Tzoulaki tells WebMD.

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SOURCES: Tzoulaki, I. BMJ Online First, Dec. 3, 2009.

Ioanna Tzoulaki, PhD, lecturer, department of epidemiology and public health, Imperial College London.

Richard M. Bergenstal, MD, president-elect for medicine and science, American Diabetes Association.

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