Insulin-sensitizing Drug Cut Diabetes Risk

When the DPP was launched in 1995, researchers sought to compare four approaches to preventing type 2 diabetes in 3,819 overweight people with higher-than-normal blood glucose levels: dietary changes and increased physical activity aimed at a 7-percent weight loss; treatment with the oral diabetes drug metformin; treatment with troglitazone; or placebo. The last three groups were also given standard medical advice about diet and weight loss.

In June 1998 the investigators halted DPP's troglitazone arm because the drug caused liver toxicity in some volunteers and was linked to one participant's death. In 2000, the Food and Drug Administration withdrew the drug from the U.S. market after receiving additional reports suggesting liver toxicity was more serious and widespread than initially appreciated. DPP researchers continued monitoring all 585 participants who had taken the drug.

The study's main results were announced in 2001 and reported in the New England Journal of Medicine in 2002: losing 5 to 7 percent of body weight through diet and a modest, consistent increase in physical activity (e.g., walking 5 days a week 30 minutes a day) lowered the incidence of type 2 diabetes by 58 percent. Treatment with metformin lowered the chances of developing diabetes by 31 percent. For more information, see the NIH announcement of the DPP results.

"The analysis of DPP participants who received troglitazone shows the value of treating insulin resistance as a way to prevent type 2 diabetes," said Dr. William Knowler of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), a study author and a DPP investigator. In insulin resistance, a condition that usually precedes type 2 diabetes, the cells in the body cannot use insulin effectively to convert glucose to energy and control blood glucose levels. "However, participants' exposure to troglitazone in the DPP was too short to draw firm conclusions about its long-term benefit in preventing or delaying type 2 diabetes," Knowler added. Analyzing the effects of the other treatment approaches for the same 11-month period, the researchers found that lifestyle changes reduced diabetes incidence by 58 percent, and treatment with metformin lowered it by 44 percent.

Troglitazone belongs to a class of drugs called the thiazolidinediones (TZDs), which make fat, muscle, and liver cells more sensitive to insulin. The TZDs currently approved by the FDA for the treatment of type 2 diabetes are Avandia (rosiglitazone) and Actos (pioglitazone), which have not been associated with the liver damage seen with troglitazone.

Industry-sponsored studies are currently looking at whether TZDs can prevent or delay type 2 diabetes in high-risk people. The NIH-funded TODAY study is comparing the combination of a TZD and metformin to other treatments in teens and children with type 2 diabetes.

"The good news from the DPP continues to be this: you can greatly lower the chances of getting type 2 diabetes by losing a modest amount of weight. Eating fewer calories and making physical activity a habit will help so many people stop or delay the disease before it becomes irreversible," said DPP study chair Dr. David Nathan of Massachusetts General Hospital, Boston.

About 40 percent of U.S. adults ages 40 to 74--41 million people--have abnormal blood glucose levels without having diabetes, which raises the risk of developing type 2 diabetes and cardiovascular disease. Many will develop type 2 diabetes in the next 10 years. (In the DPP, about 10 percent of participants in the placebo group developed diabetes each year.) Once a person has type 2 diabetes, the risk of heart and blood vessel disease is 2 to 4 times that of people without diabetes. (See tips on preventing type 2 diabetes developed by the National Diabetes Education Program, jointly sponsored by the National Institutes of Health and the Centers for Disease Control and Prevention.) About 18.2 million people-6.3 percent of the U.S. population-have diabetes. It is the main cause of kidney failure, limb amputations, and new onset blindness in adults and is a major cause of heart disease and stroke. Type 2 diabetes, the most common type of diabetes in adults, accounts for up to 95 percent of all diabetes cases. The prevalence of type 2 diabetes has risen dramatically in the last 30 years. In the last 10 years alone, the prevalence of diagnosed diabetes cases increased 50 percent, due mostly to the upsurge in obesity.

The DPP was funded by the following agencies of the U.S. Department of Health and Human Services: the NIDDK, the National Institute of Child Health and Human Development, the National Institute on Aging, the National Center on Minority Health and Health Disparities, the National Center for Research Resources, the Office of Research on Women's Health, and the Office of Behavioral and Social Science Research within the NIH as well as the Centers for Disease Control and Prevention and the Indian Health Service. The American Diabetes Association provided additional funding. Sources of corporate support included Bristol-Myers Squibb, Parke-Davis, Merck and Company, Merck Medco, Hoechst Marion Roussel, Sankyo, Lifescan, Lipha Pharmaceuticals, Slimfast, Nike, and Health-O-Meter.