The High Cost of the Diabetes Controversy
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weight because Nissen, one of the nation's foremost cardiologists, led the fight to have Merck's arthritis drug Vioxx withdrawn because of safety issues and is a leading advocate of drug safety.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.
"People heard 43% and they think it is a very big number, but if you look at the actual number of heart attacks on Avandia it's an increase of only 0.1% in absolute risk," says Dr. Sue Kirkman, vice-president for clinical affairs at the American Diabetes Assn.
Nissen also charges that there is no proof that Avandia has any benefit beyond controlling blood sugar levels and says that many other drugs are available for that purpose. But to endocrinologists, such control is critically important to avoid the many complications of diabetes, such as foot ulcers and heart disease, and they want as many drugs in their arsenal as possible in case a patient is resistant to one. "It is well established that lowering blood sugar makes a huge difference in outcomes for diabetics," says Dr. Robert Rushakoff, a professor at the University of California at San Francisco's endocrinology department. "If I have a patient who is on the drug and they are doing well, I am not going to take them off." Dr. Samuel Andrews, director of the clinical diabetes center at Ochsner Health System in New Orleans, says the meta-analysis is not a true scientific study. "I don't use a lot of Avandia because it can cause weight gain, but it does have value in some patients. I think it would be premature to take it off the market."
Glaxo Awaits New Study
Nissen dismisses such criticism as self-serving. "The diabetes specialists have a very big problem with cognitive dissonance," he says, in that they have to justify why they have been prescribing Avandia. "A cardiologist tells them this drug is dangerous, and no doubt that there is some pushback. But I believe the results we have reported will stand the test of time."
Nissen points out that Glaxo, in its own meta-analysis, found a 30% increase in the risk of heart attack from Avandia and reported those results to the Food & Drug Administration last August. The agency, however, decided there was too much conflicting data to take action. Although it did issue a safety alert on Avandia after the report was published in the NEJM, FDA officials have no plans to withdraw the drug. They want to wait for the results of a 4,400-patient, eight-year clinical trial called RECORD, which is designed to look for cardiovascular outcomes in Avandia. Those results won't be out until 2009, and Nissen says that's too long to wait: "If we are right and there is a 43% increase, then waiting for results of the RECORD trial to warn people is just not acceptable."
But Glaxo, which is vigorously defending its $3 billion a year drug, says an independent board's interim analysis of the trial found no signs that safety concerns warrant halting production. It also says a database of some 30,000 patients revealed no increased risk of heart attack. British medical journal The Lancet has also urged caution in interpreting the results of Nissen's meta-analysis.
Behind all this back-and-forth is a larger issue about how the FDA regulates drugs. Senator Chuck Grassley (R-Iowa) has already scheduled congressional hearings for June 6 to investigate why the FDA did not take a tougher stand on Avandia, and observers expect the agency to be far more cautious, at least for the near term. Then there are those doctors who deal every day with diabetes, one of the nation's biggest killers. "It's easy for an academic or a politician to sit on a soapbox and make declarations about this drug because they have an axe to grind, but I don't think that is doing the patient any good," says Lamberts, of Evans Medical Group.