New Diabetes Drugs Still Pose Liver Risks

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March 19, 2002 -- When 58-year-old Norma Culberson of Houston died in 1999, her family blamed her death on the diabetes drug Rezulin. A Houston jury disagreed, but the drug was linked to more than 60 liver failure deaths before being pulled from the market two years ago. Now, reports are linking a new version of the drug to liver damage -- although much less severe.

Rezulin was the first of the class of insulin-regulating drugs known as glitazones. Two newer glitazones -- Avandia and Actos -- are now commonly used by people with type 2 diabetes. These drugs are believed to be far safer than their predecessor, but several new reports question just how safe they are.

A report, published in the March 19 issue of the Annals of Internal Medicine, suggests that the newest of the three drugs, Actos, can also cause liver damage. And a separate study, reported this week, confirms that taking any of the glitazones increases a diabetic's risk of developing heart failure. That finding was announced at the annual meeting of the American College of Cardiology in Atlanta.

The report in the journal involved a 49-year-old electrician with a six-year history of diabetes. Although he had been treated with other diabetes drugs, the man had taken no other glitazones. After taking 15 mg of Actos daily for four months followed by 30 mg daily for two months, he developed abdominal pain, nausea, loss of appetite, and weight loss. When his blood sugar was found to be high, the dose of Actos was increased to 45 mg daily. Several days later, the whites of his eyes turned yellow and tests showed liver damage. The man was taken off the glitazone, but left on his other medications. Symptoms resolved within six weeks.

This is only the second reported case of liver injury linked to Actos, and it raises concerns that the drug may be more toxic than previously believed. But diabetes experts contacted by WebMD say it is already clear that the new-generation glitazone is far less damaging to the liver than Rezulin.

"With [Rezulin], otherwise healthy people were dying of [severe] liver failure within four to six months of being put on the drug," says Harvey Katzeff, MD, chief of endocrinology at New York's Long Island Jewish Medical Center. "The risk was still small -- approximately one in 20,000 -- but people who developed liver failure either had transplants or they died."

American Diabetes Association President Christopher D. Saudek, MD, says the two newer drugs have been watched very carefully in the wake of the Rezulin deaths, and only a handful of liver problems have been reported.

"These are reversible cases of liver inflammation, and the fact is that a great many drugs can cause some degree of liver inflammation," he says. Saudek is a professor of medicine at Baltimore's Johns Hopkins School of Medicine.

The heart disease study, conducted by researchers with Policy Analysis Inc., based in Brookline, Mass., compared more than 8,000 type 2 diabetics treated with either Rezulin, Avandia, or Actos, with more than 41,000 diabetics who did not receive a glitazone.

After nearly nine months, the risk of developing heart failure was almost double for those treated with the drugs -- 4.5% in the glitazone group vs. 2.6% for those not treated. Retaining too much fluid in the body is common among people taking glitazones, and this could pose a problem for diabetics who either have heart disease or who are at high risk.

"In people prone to congestive heart failure, fluid retention could tip them over into this condition," Saudek says. "This is not a big surprise, but it is a caution for people using these drugs."

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