Diabetes adversely affects many major organs, including heart, blood vessels, nerves, eyes and kidneys. The complications related to these organs develop gradually, but they can eventually be disabling or even life threatening. Treatment of diabetes can prevent some of these devastating complications but does not eliminate all of them. Prevention is thus more preferable than treatment. Previous studies (,  and ) indicated that type 2 diabetes can be prevented by changes in the lifetyles of high risk subjects. However, these studies have not demonstrated that medications used to treat diabetes are effective for its prevention. The Diabetes Prevention Program (DPP) was developed to compare several strategies to prevent or delay type 2 diabetes, including both lifestyle intervention and the diabetes medication metformin. Our goal here is to describe this study and use this example to illustrate characteristics of a randomized controlled experiment.
The study design of the DPP was described in detail in  and the findings were published in . Information can also be found in the Diabetes Prevention Program Study Repository.
The primary objective is a comparison of the effectiveness and safety of the three interventions (an intensive lifestyle intervention, metformin or placebo with standard lifestyle recommendations) in preventing or delaying the development of type 2 diabetes among adults in the United States who are at high risk of developing type 2 diabetes.
There are three treatment groups, one lifestyle intervention, two pharmacological. They are:
- An intensive lifestyle intervention.
- Metformin (850 mg twice daily) with standard lifestyle recommendations.
- Placebo (twice daily) with standard lifestyle recommendations.
The intensive lifestyle intervention group consisted of the following components:
- To achieve and maintain a weight loss of at least 7% of initial body weight through healthy eating and physical activity.
- To achieve and maintain a level of physical activity of at least 150 minutes per week through moderate intensity activity such as brisk walking or bicycling.
- To attend a 16-lesson curriculum covering diet, exercise and behavior modification that was designed to help participants to achieve the goals of weight loss and physical activity. The curriculum, taught by case managers on a one-on-one basis during the first 24 weeks after enrollment, was flexible, culturally sensitive and individualized. Behavioral changes were reinforced in subsequent monthly follow-up sessons with case managers.
The standard lifestyle recommendations for the pharmacological treatment groups were presented in the form of written information and in an annual 20 to 30 minute individual sessions with case managers that emphasized the importance of a healthy lifestyle. Participants were encouraged to follow the Food Pyramid guidelines, to consume the equivalence of a National Cholesterol Education Program Step 1 diet, to lose 5 to 10% of initial weight through diet and exercise, to increase physical activity, to avoid excessive alcohol intake and to stop smoking.
The Diabetes Prevention Program (DPP) is a randomized clinical trial funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), which is a part of the National Institute of Health of the U.S. Department of Health and Human Services. The DPP was conducted in 27 clinical centers around the United States.
The subjects of the study were overweight adults who were at least 25 years of age with body mass index at least 24 (22 or higher for Asian Americans) and had pre-diabetes according to the 1997 criteria of the American Disbetes Association: a fasting plasma glucose concentration of 95 to 125 mg/dL or a plasma glucose of 140 to 199 mg/dL after a 75-g oral glucose load. These blood glucose levels are higher than normal but not high enough for a diagnosis of diabetes. The participants included both men and women. Approximately half of the subjects were from minority groups and approximately 20% were 65 years or older.
A total of 3234 subjects were randomly assigned to the three treatment groups (1079 to the intensive lifestyle intervention, 1073 to metformin and 1082 to placebo). The randomization to treatment groups was not performed over all subjects. Instead it was performed separately within each of the 27 clinical centers (such a randomization scheme is called stratified randomization). Assignment to the metformin group and the placebo group was double-blind. Figure 1 is an outline of this experimental design.
The primary outcome was the development of diabetes on the basis of an annual oral glucose treatment test or a semiannual fasting plasma glucose test according to the 1997 criteria of the American Diabetes Association (a fasting plasma glucose concentration of at least 126 mg/dL or a plasma glucose of at least 200 mg/dL after a 75-g oral glucose load).
The DPP found that type 2 diabetes can be prevented or delayed in high risk population for the disease. The incidence of diabetes was reduced by 58% in the intensive lifestyle intervention group and by 31% in the metformin group, as compared with the placebo group. The results were similar in men and women and across all racial and ethnic groups.
Intensive lifestyle intervention worked particularly well for subjects aged 60 and older (incidence of diabetes was reduced by 71%). The metformin treatment was the most effective in the subjects aged 44 or younger (the incidence of diabetes was reduced by 44%) and in the most overweight subjects, i.e., BMI 35 or higher (the incidence of diabetes was reduced by 53%). However, the metformin treatment was the least effective in the older age groups (aged 45 or older).
About 5% of the intensive lifestyle intervention group and about 7.8% of the metformin group developed diabetes each year of the study as compared with 11% of the placebo group.
All three intervention groups experienced similar rates of adverse events with the exceptions that the metformin group had the highest rate of gastrointestinal symptoms (diarrhea, flatulence, nausea, and vomiting) and the intensive lifestyle intervention group had the highest rate of musculoskeletal symptoms. Overall, all three treatments were safe in addition to being effective.
The participants were followed up for an average of 2.8 years. The double-blind phase of the study was terminated one year early in May 2001, based on the advice of the data monitoring board, becasue the researchers had obtained sufficient evidence of efficacy for the interventions.
Diabetes is not inevitable even among people with pre-diabetes. The investigators in the DPP concluded that lifestyle modifications such as weight loss and physical activity and treatment with metformin were highly effective ways to prevent or delay the development of type 2 diabetes among people at high risk for the disease. The lifestyle changes were more effective than metformin. Implementation of these interventions can reduce the personal cost and the public burden of diabetes.
- Knowler W C, Narayan K M, Hanson R L, et al, Preventing non-insulin-dependent diabetes, Diabetes, 1995, 44 (5), 483-488. Abstract.
- Pan X R, Li G W, Hu Y H, et al, Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: the Da Qing IGT and Diabetes Study, Diabetes Care, 1997, 20 (4), 537-544. Abstract.
- The 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 (4), 623-634. PDF.
- The Diabetes Prevention Program Research Group, Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin, N Engl J Med, 2002, 346 (6), 393-403. PDF.
- Tuomilehto J, Lindstrom J, Eriksson J G, et al, Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance, N Engl J Med, 2001, 344 (18), 1343-1350. PDF.