The prevalence of type 2 diabetes is increasing in epidemic proportions throughout the world. It affects >7% of the adult U.S. population (or about 16 million individuals), approximately one-third to one-half of whom are undiagnosed (1,2). There are nearly 800,000 new cases in the U.S. each year (2). Once type 2 diabetes develops, normalization of glycemia is difficult to achieve or maintain. Over time, type 2 diabetes is accompanied by many severe complications, such as blindness, renal failure, lower-limb amputations, cardiovascular disease, and stroke. Total health care expenditure for diabetes has been estimated at ~$100 billion per year in the U.S. or ~12% of total health care costs (3,4). Prevention of type 2 diabetes would result in significant reductions in social and economic costs. Prevention of type 2 diabetes should be feasible because screening tests are available to identify individuals at high risk for the disease, there is a long asymptomatic period in the natural history of type 2 diabetes suitable for intervention, and there are potentially effective interventions available.

GOALS OF THE DIABETES PREVENTION PROGRAM — The principal objective of the Diabetes Prevention Program (DPP) is to prevent or delay the development of type 2 diabetes in those individuals who are at high risk by virtue of having impaired glucose tolerance (IGT). IGT affects nearly 21 million individuals in the U.S. The rate of progression from IGT to diabetes is 1–5% per year, depending on the specific population (10–13). Thus, individuals with IGT represent a large pool of subjects with the potential of developing diabetes in the U.S.

OVERALL STUDY DESIGN — The design and methods of the DPP are described in detail elsewhere (10). Briefly, the study is a randomized clinical trial with 1,000 participants in each of three intervention groups. Eligible volunteers are recruited and randomly assigned to one of the interventions over a 3-year period. After randomization, participants have quarterly clinical evaluations and in addition have a fasting plasma glucose at semi-annual visits and a 75-g oral glucose tolerance test (OGTT) at annual visits. All participants are followed for 3 years after the study-wide closing date for recruitment, resulting in 3–6 years (average of 4.5) of participant follow-up.

STUDY POPULATIONS — Volunteers are being recruited from populations known to be at high risk for IGT and type 2 diabetes. The study-wide goal is that ~50% of the study population will be composed of minorities (primarily African-Americans, Hispanic Americans, Asian Americans, Pacific Islanders, and Native Americans) and ~20% will be 65 years or older. Participants must have IGT diagnosed by a 75-g OGTT (14).

STUDY INTERVENTIONS — Originally, four intervention arms—lifestyle with a focus on dietary changes and physical activity to promote weight loss, the biguanide metformin, the thiazolidinedione troglitazone, and placebo—were included in the DPP. Unfortunately, after troglitazone was selected, hepatic dysfunction became apparent in a very small proportion of users of this medication. Although with increased frequency of monitoring of liver function tests, this was deemed to be an acceptable risk, one of the participants receiving troglitazone had severe hepatic damage that required liver transplantation and subsequently died. All participants were notified, the participants in the troglitazone arm were unmasked and the medication was stopped, and the troglitazone arm was discontinued. The 585 participants in the troglitazone arm were invited to continue in the DPP after confirmation of normal liver enzymes, and follow-up visits continued as originally scheduled. They have been offered quarterly lifestyle modification sessions addressing the principal educational components of the lifestyle intervention.

INTENSIVE LIFESTYLE INTERVENTION — The lifestyle intervention relies on training of participants in the use of a healthy diet and exercise. The goals are to attain and maintain >7% weight loss and expend >700 kcal per week through physical activity. This intervention is based on the premise that long-term changes in diet and exercise and sustained motivation to maintain behavior changes are most likely to occur in an intensive intervention that includes flexibility, a supportive staff, and sensitivity to cultural influences.

PHARMACOLOGICAL INTERVENTIONS — The drug intervention arms originally included 400 mg troglitazone q.d. or 850 mg metformin b.i.d., with corresponding placebos to achieve a randomized placebo-controlled double-blind study design. As already noted, however, the troglitazone arm was stopped in June 1998. Since then, metformin and the corresponding placebo have constituted the pharmacological interventions in the DPP.

OUTCOMES — The primary outcome of the DPP is the development of diabetes according to the revised American Diabetes Association criteria (14), confirmed with a repeat test. Development of diabetes is assessed by OGTT annually, by fasting plasma glucose measurements every 6 months, and by symptoms consistent with hyperglycemia. Secondary outcomes will focus on cardiovascular disease and its risk factors, and changes in glycemia, insulin secretion and sensitivity, obesity, physical activity and nutrient intake, quality of life, and occurrence of adverse events.

RECRUITMENT — It is anticipated that >150,000 individuals will have to be screened to end up with 3,000 participants—1,000 in each of the three arms of the study (lifestyle, metformin, and placebo). Recruitment, screening, and treatment are being done at 27 participating centers of the DPP. These centers represent the diverse subject population that the study seeks to recruit. Recruitment began in the summer of 1996 and concluded in the spring of 1999. The trial will be completed in 2002.

SUMMARY — Type 2 diabetes is an appropriate target for prevention because of the presence of identifiable risk factors for the disease, the availability of interventions to improve glucose tolerance, the difficulty of treating the disease, and the enormous human and financial costs associated with its development and treatment. The goals of the DPP are to prevent or delay type 2 diabetes, prevent cardiovascular disease, and ameliorate attendant cardiovascular risk factors. Recruitment of participants for the DPP has been highly successful—particularly the recruitment of individuals from ethnic minority groups in the U.S.