Both rosiglitazone (Avandia®) and metformin (Glucophage®, Fortamet® and others) already have an established market share for managing Type 2 diabetes. However, recent clinical trials provide evidence that the two may actually help prevent the disease in high-risk populations.
On Sept. 15, Dr. Hertzel Gerstein presented findings from the rosiglitazone arm of the multicenter DREAM Study (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) during the 42nd Annual Meeting of the European Association for the Study of Diabetes in Copenhagen.
While in the ramipril arm the blood pressure drug was not found to effectively reduce the risk of diabetes or death, the rosiglitazone trial showed much more promise.
The international study followed 5,269 people treated at 191 clinics for three years. Participants were either given 4 mg of rosiglitazone daily for four months and then 8 mg daily thereafter or received a placebo.
"We recruited patients who were at high risk for diabetes … who either had impaired fasting glucose or impaired glucose tolerance ... a term usually called 'pre-diabetes,'" explained Gerstein, director of the Division of Endocrinology and Metabolism and a professor in the Department of Medicine for McMaster University in Hamilton, Ontario, Canada.
Principal investigator for DREAM, Gerstein said rosiglitazone kept a statistically significant number of participants from progressing from pre-diabetes to a full diagnosis of diabetes mellitus or death.
"The relative risk reduction was 60 percent for those assigned to rosiglitazone as opposed to those assigned to placebo," he said.
Furthermore, those in the rosiglitazone group were 70-80 percent more likely to return to normal blood sugar levels as compared to the placebo group.
However, Gerstein notes, 14 patients in the rosiglitazone group, or 0.5 percent, did develop heart failure as compared to only two patients, or 0.1 percent, in the placebo arm.
"There was no difference in other cardiac events at all and no cases of fatal heart failure," he added. "All drugs have side effects, so this is one of the side effects we need to know more about."
Gerstein and co-principal investigator Dr. Salim Yusuf, director of the Division of Cardiology at McMaster, concluded that for every 1,000 people treated with rosiglitazone for three years, approximately 144 cases of diabetes would be prevented, but there would be an additional four or five cases of congestive heart failure.
All patients in the trial were counseled to incorporate exercise and sensible eating into their routine, but lifestyle choices were not closely monitored nor were they a participation requirement.
Despite the positive outcomes, Gerstein said adults should take a step-wise approach to diabetes prevention from first learning their personal risk factors to discerning their glucose levels to discussing options with their physician if those levels are high.
"What are all the other things we can do to reduce risk factors for diabetes? Before you start any drug therapy, physical activity, diet and exercise can reduce the risk of diabetes by about the same amount (as rosiglitazone) … about 60 percent," he continued.
However, Gerstein said for those for whom diet and exercise are not enough, the addition of rosiglitazone or metformin, which has been shown to have around a 38 percent risk reduction for diabetes in adherent populations, might be an option.
Dr. Larry C. Deeb, president of medicine and science for the American Diabetes Association, says he wasn't surprised either by the risk reduction or the side effects with rosiglitazone since fluid retention is an effect of Avandia, which in turn exacerbates heart failure.
As for the effectiveness in preventing diabetes, Deeb said, "The mechanism of improving insulin resistance, and therefore glucose tolerance, is pretty scientifically straightforward. If you intervene in the continuum from normal to diabetes, it will push things back towards normal."
Still, he said, in previous trials, patients were able to achieve a 58 percent risk reduction with a modest weight loss of 10-12 pounds coupled with 30 minutes of exercise five days a week.
"You can still argue for diet and exercise," he noted. "You should still do the things you know can't hurt you."
However, Deeb added that by the onset of diabetes, damage to other areas of the body has typically already occurred.
"That is why the study is important. We know that abnormal blood sugars begin to deteriorate the eyes, kidneys, vascular system … identifying people early keeps that clock from ticking," he said. "Preventing diabetes prevents complications."
Deeb added that he wants to emphasize that these drugs may be beneficial in carefully selected patients, "but they really do need to be secondary."
At this point, prescribing either drug in a preventative capacity is strictly an off-label use.
November 2006
