Diabetes Prevention Program (DPP) 3,234 men and women with impaired glucose tolerance (fasting plasma glucose 95–125 mg/dL and 2-hr postload glucose 140–199 mg/dL) and BMI 24 kg/m2 45% from minority groups with increased prevalence of type 2 diabetes: African Americans, Hispanic Americans, Asian Americans, and American Indians 27 centers nationwide Randomization to lifestyle changes to include at least 7% weight loss and exercise 150 min/wk, metformin 850 mg b.i.d., or placebo Primary endpoint: development of diabetes Follow-up: designed for 3.5–5 years, but discontinued 1 year early because of conclusive results (mean 2.8 years) The Diabetes Prevention Program (DPP) studied the onset of diabetes in 3,234 men and women with impaired glucose tolerance, defined as fasting plasma glucose 95–125 mg/dL (125 mg/dL or less in American Indian centers) and 2-hour postload glucose 140–199 mg/dL. Patients were 25 years of age or older and had body mass index (BMI) of 24 kg/m2 or higher (22 kg/m2 or higher in Asian Americans). Patients were randomized to intensive lifestyle intervention (reduction in body weight of at least 7% through diet and exercise, physical activity of moderate intensity for at least 150 min/week), metformin 850 mg twice daily plus standard lifestyle recommendations (diet, weight reduction, exercise), or placebo plus standard lifestyle recommendations. The primary endpoint was development of diabetes. The study was conducted in 27 centers nationwide and was designed to have a follow-up period of 3.5–5 years. More than 45% of patients were racial or ethnic minorities: 20% were African American, 16% Hispanic, 5% American Indian, and 4% Asian American. The patient population was 68% female, and 20% of patients were aged 60 years or older (overall mean age at baseline, 51±11 years). Mean baseline BMI was 34.0±6.7 kg/m2; BMI was 30 kg/m2 or greater in 68% of patients (57% of men and 73% of women). Mean fasting plasma glucose was 106.5±8.3 mg/dL, and mean postload glucose was 164.6±17.0 mg/dL. Diabetes Prevention Program. Diabetes Care 1999;22:623-634. Diabetes Prevention Program. Diabetes Care 2000;23:1619-1629.

Trial was discontinued 1 year early because of clear results DPP: Reduction in Incidence of Diabetes with Lifestyle Intervention or Metformin Trial was discontinued 1 year early because of clear results 29 31% reduction 22 58% reduction Patients Developing Diabetes in Mean 3-Year Follow-up (%) 14 The study was stopped 1 year early (mean follow-up 2.8 years) because the data were already conclusive. Compared with placebo, patients randomized to intensive lifestyle intervention had a 58% reduction in onset of type 2 diabetes (by 1997 American Diabetes Association criteria), which was significantly greater than the 31% reduction in the metformin group. Mean weight loss with intensive lifestyle intervention was 12 lb; 50% achieved the weight loss goal of 7% by the end of the 24-week instruction period, and 74% met the physical activity goal at that time. Daily calorie intake in this group was reduced by 450 kcal (vs. 296 kcal in the metformin group and 249 kcal in the placebo group), and total fat intake was reduced by 6.6% (vs. 0.8% in both the metformin and placebo groups). Diet + Exercise Metformin Placebo 5-7% reduction in body weight; exercise 30 min/d Knowler WC, et al. N Engl J Med 2002;346:393-403.

DPP: Cumulative Incidence of Diabetes p<0.001 for Lifestyle vs. Metformin, Lifestyle vs. Placebo, Metformin vs. Placebo 40 Placebo 30 Metformin Cumulative incidence (%) 20 Lifestyle 10 Diabetes developed in 14% of the intensive lifestyle intervention group, 22% of the metformin group, and 29% of the placebo group; based on these rates, an estimated 7 patients would need to be treated with intensive lifestyle intervention for 3 years to prevent 1 case of diabetes, compared with 14 patients treated with metformin. Treatment effects on incidence rates and risk reductions did not differ significantly among subgroups categorized by sex or ethnicity. However, intensive lifestyle intervention had a significantly greater effect in older patients, reducing the incidence of diabetes among patients older than 60 years by 69% compared with metformin and 71% compared with placebo. Intensive lifestyle intervention was also significantly more effective in patients with lower postload glucose levels at baseline and in patients with a lower BMI. An estimated 10 million Americans are at high risk for type 2 diabetes, which accounts for 95% of the 16 million cases of diabetes in the United States. Prevalence of the disease is almost 20% in individuals aged 60 and older, and is 60% higher in blacks and 90% higher in Hispanics than in whites. The dramatic threefold increase in prevalence in the past 30 years is due in large part to the increase in obesity; individuals with BMI of 30 kg/m2 or greater have a fivefold greater risk for diabetes than individuals with BMI of 25 kg/m2 or less. The results of the DPP are encouraging because they indicate that this trend can be reversed through intensive lifestyle intervention aimed at reducing obesity, and that this intervention works particularly well in older patients, who are at high risk for developing diabetes. References Diabetes Prevention Program Research Group. The Diabetes Prevention Program: design and methods for a clinical trial in the prevention of type 2 diabetes. Diabetes Care 1999;22:623-634. Diabetes Prevention Program Research Group. The Diabetes Prevention Program: baseline characteristics of the randomized cohort. Diabetes Care 2000;23:1619-1629. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403. 1 2 3 4 Years from randomization Knowler WC, et al. N Engl J Med 2002;346:393-403. ©2002 Massachusetts Medical Society.