DREAM: Study shows effective chemoprevention of diabetes

Rosiglitazone reduced new diabetes cases 62% in large randomized clinical study.

Issue: October 2006

ByAlan J. Garber, MD, PhD, MACE

Alan J. Garber, MD, PhD [photo]
Alan J. Garber

The results of the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication trial, or DREAM, were recently reported at the annual meeting of the European Association for the Study of Diabetes. These results were remarkable for multiple reasons and offer substantial hope for those at high risk for type 2 diabetes mellitus.

Prior to this study, the highest rates of diabetes prevention were achieved by intensive lifestyle modification including 7% weight loss and regular daily exercise. Although these numbers seem easily achievable, maintenance of such weight loss and daily exercise is highly difficult, and most patients readily regain the lost weight — and even more — within a few years. Thus, diabetes becomes almost inevitable.

In the NIH-sponsored Diabetes Prevention Program (DPP), it was found that metformin reduced the conversion of patients with impaired glucose tolerance (IGT) to overt diabetes by 31%. There was a strong bias toward efficacy in patients younger than 60 years old and against those older than 60. Since intensive lifestyle modification with personal trainers was twice as effective, little emphasis was placed on pharmacological assistance for diabetes prevention. Now, all that has changed.

Rosiglitazone (Avandia, Glaxo SmithKline) has double the efficacy of metformin without additional lifestyle modification efforts. It even regressed abnormal glucose levels in nearly half of those patients at entry with abnormal glycemia. Despite some small weight gain, the persistence of glycemic benefits seemed durable, suggesting a superiority to conventional weight loss treatments for diabetes prevention.

Of course there is no reason why rosiglitazone could not be combined with a lifestyle program to increase durability and efficacy, but that might not be a long-term vehicle for diabetes prevention. Instead, a combination therapy approach that combines rosiglitazone with metformin might be the optimal pharmacological approach for the present. Certainly this combination has been shown to have powerful effects on glycemic control in patients with pre-existing diabetes, and such effects were accompanied by no weight gain; a truly remarkable observation, suggesting that metformin efficacy on weight also might be reason enough for its inclusion with rosiglitazone in a long-term diabetes prevention strategy.

Some concern was raised at the meeting regarding the failure to observe a long-term cardiovascular benefit with rosiglitazone in the DREAM. Of course the study was not powered sufficiently to observe any benefit, and indeed none was observed.

There was a small increase in heart failure with these patients. This is not surprising, since diastolic dysfunction and left ventricular stiffness is common in diabetes and therefore likely in prediabetic patients. Volume expansion with 8 mg of rosiglitazone has the potential to express such early heart failure at an increased rate, and close observation in such patients is warranted. Doses less than 8 mg, such as the frequently prescribed 4-mg dose, may be quite useful in such patients, especially when combined with metformin to increase efficacy without necessarily increasing the small risk of heart failure. Nonetheless, this may be a point of little consequence when compared to the much larger benefit of the striking rates of diabetes prevention possible with rosiglitazone alone.

Finally, it should be noted that patients with impaired fasting glucose (100 mg/dL to 125 mg/dL), seemed to benefit as much from rosiglitazone chemoprevention as did IGT patients. This raises for the first time the recognition that IFG is a high-risk prediabetic state that can be dealt with effectively with rosiglitazone chemoprevention. This is clearly a paradigm shift for the average practitioner who can now easily diagnose and treat while monitoring high-risk patients for type 2 diabetes. Perhaps now, we can turn the corner on this exploding epidemic of diabetes.

For more information:

Alan J. Garber, MD, PhD, is a Professor in the Departments of Medicine, Biochemistry and Molecular Biology and Cellular and Molecular Biology at Baylor College of Medicine. He is the chief medical editor of Endocrine Today.