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About DPP: Executive Summary


Background

Non-insulin-dependent diabetes mellitus (NIDDM) is rapidly becoming the most common chronic disease in the United States, with more than 7% of the adult population affected and 600,000 new cases per year. NIDDM is even more common in the elderly and in minority populations including African Americans, Hispanic Americans, Asian and Pacific Island Americans, and Native Americans. In these populations, NIDDM may be present in 10% to as much as 50% of the adult population. Diabetes is accompanied by a multitude of severe long-term complications that ultimately cause more adult cases of blindness, renal failure, and amputations than any other disease in the United States (U.S.). In addition, persons with NIDDM have a 2 to 4 fold increased risk for cardiovascular disease and stroke. Owing largely to the high costs of caring for NIDDM and its attendant long-term complications, total health care expenditure for diabetes has been estimated at approximately 100 billion dollars per year, or 12% of total U.S. health care expenditures.

The enormous human and financial costs that accompany NIDDM, and the difficulty in treating it effectively once it has developed, make it an appropriate target for prevention. In 1993, the National Institute of Diabetes and Digestive and Kidney Diseases, issued a request for proposals for a study with the objective of preventing the development of NIDDM in adults, with a major emphasis on the minority communities in which NIDDM is so prevalent. Clinical centers were selected to participate in recruiting a target cohort comprising approximately 50% minorities from the populations mentioned above.

The investigators of the Diabetes Prevention Program (DPP) designed the following consensus protocol between August, 1994 and November, 1995.

Objective

The principal objective of the DPP is to prevent or delay the development of NIDDM in those persons who are at high risk for its development by virtue of having impaired glucose tolerance. Impaired glucose tolerance represents a less severe stage of blood glucose abnormalities that often precedes NIDDM.

Study Populations

Volunteers will be recruited from populations known to be at particularly high risk for impaired glucose tolerance and NIDDM including the following: persons with a family history of NIDDM, the elderly, overweight individuals, women with a history of diabetes during pregnancy ("gestational diabetes"), and minority populations including African Americans, Hispanic Americans, Asian and Pacific Island Americans, and Native Americans. In order to be eligible, persons who are older than 25 years will have to demonstrate impaired glucose tolerance with plasma glucose levels 95-125 mg/dL (5.3-6.9 mmol/L) fasting and 140- 199 mg/dL (7.8 - 11.0 mmol/L) two hours after a 75 gram oral glucose tolerance test. The study-wide goal is that approximately 50% of the study population be composed of minorities and approximately 20% be 65 years of age or older.

Study Interventions

Three interventions were selected based on their potential efficacy in ameliorating abnormal glucose metabolism in IGT and on their safety and tolerable profile of side-effects. The interventions include an intensive lifestyle intervention and two pharmacological intervention. The intensive lifestyle intervention focuses on a healthy diet to achieve and maintain at least a 7% loss of body weight and to achieve at least 150 min/week of moderate intensity exercise, and maintain this level of physical activity throughout the DPP. Attempts to modify diet and exercise are flexible and sensitive to cultural differences and acceptable to the specific communities in which they are implemented. Standard lifestyle recommendations, which include conventional instructions regarding diet and exercise, will be provided to all participants, including a placebo treated group which will serve as the control group for the study. The pharmacological interventions include the biguanide metformin and the thiazolidinedione troglitazone.

Randomization to the troglitazone pharmacological intervention was suspended on May 27, 1998, and discontinued by the NIDDK on June 3, 1998. The NIDDK, with input from the DPP Data Monitoring Board, decided to discontinue use of troglitazone in the DPP based on liver toxicity with hepatic failure (see section 5.3.1).

Outcomes

The primary outcome is the development of diabetes according to American Diabetes Association criteria (fasting plasma glucose level =126 mg/dL [7.0 mmol/L] or 2-hour plasma glucose =200 mg/dL [11.1 mmol/L], after a 75 gram OGTT, and confirmed with a repeat test). 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 the occurrence of adverse events.

Design and Power

The study is a randomized clinical trial. Eligible volunteers will be stratified according to center and assigned to one of three treatment groups during a two and two-thirds year recruitment period. The pharmacological interventions are double blinded and placebo controlled. After randomization, participants have quarterly clinical evaluations and have, in addition, a fasting plasma glucose at semi-annual visits and a 75 gram oral glucose tolerance test at annual visits. All participants will be followed for three and one-third years after the study-wide closing date for recruitment, resulting in 3 1/3 to 6 years of participant follow-up.

Three thousand participants (one thousand per group) will provide 90% power to detect a 33% reduction in the progression to diabetes, assuming an annual rate of progression to diabetes in the control group of at least 6.5% and a level of significance of 5% (two-sided) with adjustment for pairwise comparisons of the three treatment groups.

Analyses

For the primary outcome, time to development of diabetes, product-limit life-table distributions of each intervention group and the control group will be compared using the log-rank test statistic. The primary analyses will include all participants in their randomly assigned treatment group, regardless of adherence to the assigned treatment (intention-to-treat principle).