The High Cost of the Diabetes Controversy

The debate over Avandia's safety is creating a rift among doctors and leading to charges that patients are being put in danger

by Catherine Arnst

The news last week that GlaxoSmithKline's (GSK) popular diabetes drug Avandia may increase the risk of heart attacks is now causing a rift among doctors by specialty, leading to charges by each side that the other is endangering patients. Endocrinologists, who treat diabetics, tend to regard the data, which was published in The New England Journal of Medicine, with skepticism, pointing to weaknesses in the study, particularly when compared to more rigorous clinical trials. Cardiologists and drug safety experts, foremost among them study author Dr. Steven Nissen of the Cleveland Clinic, are more alarmed, though even they are recommending that patients not go off the drug without first consulting their physicians.

Caught in the middle are the diabetes patients already taking Avandia, which sensitizes the body to insulin. Doctors in the trenches say many patients are confused and scared, which raises concerns that they may stop taking the drug without medical consultation. "This kind of controversy really frustrates the average doctor," says Dr. Rob Lamberts, a primary-care physician with Evans Medical Group in Evans, Ga., who treats a number of diabetics. He finds the data in Nissen's study questionable and would prefer to wait for the results of the large, rigorously designed safety trial of Avandia which is scheduled to end in 2009.

"A Public Health Emergency"

He is now getting calls from worried patients who wonder whether they should stop taking Avandia. That would be a mistake, he says, because with diabetes, a progressive disease, controlling blood sugar levels is key to preventing complications. "All drugs have a lot of risks, and I try and convey that to my patients," he says. "But it is critically important that these patients maintain [blood sugar] control, and this is one of the drugs that can help."

The NEJM report that stirred up the trouble, a meta-analysis of 42 different clinical trials of Avandia, found that the drug raised the risk of heart attack by 43%. The report carries considerable weight because Nissen, one of the nation's foremost cardiologists, led the fight to have Merck's arthritis drug Vioxx withdrawn because of safety issues and is a leading advocate of drug safety. "My article serves as a first notice" of problems with Avandia, says Nissen. "I realize there are some real limitations in the analysis, but I felt this was a virtual public health emergency." (See BusinessWeek.com, 5/23/07, "Diabetes Drug Study in Doubt.")

Plenty of other doctors say Nissen has overreached this time because a meta-analysis, which combines the results of many different studies with disparate designs and objectives, generally is not considered very reliable. "The study poses an interesting hypothesis, but it was very poorly done," says Dr. Brian Strom, a professor of biostatistics and epidemiology at the University of Pennsylvania. "The New England Journal was wrong to publish it."

Clinicians Cite Study's Flaws

The controversial study, by Nissen and co-author Kathy Wolski, a statistician, combined 42 previous trials of Avandia, none of which were designed to look for heart attacks. Of the two large studies in the group, one showed a reduction in deaths from cardiovascular disease. However, the 40 small studies included tipped the statistical scales in the other direction.

The results: Among 15,560 patients taking Avandia, there were 86 heart attacks and 39 deaths from cardiovascular causes, while of the 12,283 diabetics on other drugs the corresponding numbers were 72 and 22. That makes for an extremely low overall risk. In addition, the authors excluded six trials of Avandia that showed no heart attacks. If those had been included, critics charge, the numbers would not have reached statistical significance.