Feature Article

A National Multicenter Study to Learn Whether Type II Diabetes

Can Be Prevented: The Diabetes Prevention Program

Wilfred Y. Fujimoto, MD, for the Diabetes Prevention Program Research Group

Type II diabetes mellitus, also known as non-insulin-dependent diabetes mellitus (NIDDM), is the predominant form of diabetes, comprising more than 90% of patients with diabetes in the United States. Type II diabetes affects more than 7% of the adult U.S. population, or about 16 million people. Approximately half of those with type II diabetes are undiagnosed. In many patients, the initial diagnosis of type II diabetes is delayed perhaps by as much as 10 years because symptoms are often absent or very mild during its early stages. There are 600,000 new cases of type II diabetes diagnosed in the United States each year.

Type II diabetes is particularly common among the elderly and in many minority populations, including African Americans, Hispanic Americans, American Indians, and Asian and Pacific Islander Americans, in whom it may occur in 10–50% of adults. Even if a person does not fall into any of these categories, the risk for type II diabetes increases with obesity, a family history of diabetes, and, in women, a history of gestational diabetes.

Over time, type II diabetes is accompanied by many severe complications, such as blindness, renal failure, lower- limb amputations, cardiovascular disease, and stroke. One estimate of the total health-care expenditures for diabetes in the United States is approximately $100 billion per year, or about 12% of all health-care expenditures.

In 1993, the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health issued a request for proposals for a multicenter study with the objective of preventing new cases of type II diabetes in adults. From among the many applications, 25 centers were selected to recruit 4,000 participants. The resulting study has been named the Diabetes Prevention Program (DPP) and is the result of nearly 2 years of planning and preparation.

The principal objective of the DPP is to prevent or delay the development of type II diabetes in those people who are at high risk by virtue of having impaired glucose tolerance (IGT), a stage of blood glucose abnormality that often precedes type II diabetes. IGT is diagnosed by an oral glucose tolerance test that shows glucose levels in an intermediate range between the normal and diabetic ranges. IGT affects nearly 21 million people in the United States, a large pool of potential patients with diabetes. The rate of progression from IGT to type II diabetes is 1–5% per year, depending upon the specific population.

The etiology of type II diabetes is complex, with both genetics and lifestyle playing roles. Moreover, many of the risk factors for this disease are interrelated through the pathophysiologic changes (weight gain, insulin resistance, and reduction of insulin secretion) that lead to glucose intolerance and type II diabetes. It has been hypothesized that it may be possible to prevent type II diabetes through interventions directed toward weight gain, insulin resistance, and insulin secretion. Unfortunately, relatively few controlled clinical trials have provided direct information on the effect of manipulating these risk factors on the development of type II diabetes.

The ability to identify through the relatively simple oral glucose tolerance test those people who are at high risk of developing type II diabetes and the availability of therapies that may ameliorate glucose intolerance encourage the initiation of a clinical trial to prevent type II diabetes. In order to maximize the chances of at least one treatment being effective, three interventions have been selected in the DPP. Economic analyses to examine the costs of interventions will also be done, allowing the determination of the cost-benefit ratio of preventing diabetes.

Overall Study Design and
Study Population
The DPP is a randomized, clinical trial. Eligible volunteers will be randomly assigned to one of four intervention groups during a 3-year recruitment

period. All participants are followed for 3 years after the closing date for recruitment, resulting in 3–6 years of participant follow-up depending on time of entry into the study.

Volunteers will be recruited from populations known to be at high risk for IGT and type II diabetes, including the following: people with a family history of diabetes, the elderly, overweight individuals, women with a history of gestational diabetes, and members of minority populations. The study-wide goal is that about 50% of the study population will be composed of minorities (primarily African Americans, Hispanic Americans, Asian and Pacific Islander Americans, and American Indians) and about 20% will be 65 years old or older. Participants must have IGT, defined in the DPP as a fasting plasma glucose (FPG) <140 mg/dl (7.8 mmol/L) but >100 mg/dl (5.5 mmol/L) and a 2-hour plasma glucose >140 mg/dl (7.8 mmol/L) but < 200 mg/dl (11.1 mmol/L). In addition, participants must have a body mass index of at least 24 kg/m² and must be at least 25 years old. There is no upper age limit.

Study Interventions
Three interventions were selected for the DPP. These include 1) lifestyle with a focus on dietary changes and physical activity to promote weight loss; 2) oral therapy with the biguanide metformin; and 3) oral therapy with the thiozlidinedione troglitazone. A placebo control arm will be the fourth group in the DPP.

Intensive lifestyle intervention. Life-style intervention relies upon training participants to use a healthy diet and exercise to attain and maintain weight loss and thereby reduce insulin resistance. 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. Although it is not possible to mask participants and investigators from knowing assignment to this treatment, the positive attributes of this intervention were considered to outweigh this shortcoming.

Pharmacologic interventions. There are two drug-intervention arms (metformin and troglitazone) and a placebo arm. Placebos are used to achieve a randomized, placebo-controlled, double-blind study design. Both metformin and troglitazone are investigational drugs for the treatment of IGT and will be used under an Investigative New Drug application with the Food and Drug Administration.

Metformin has been used in the management of type II diabetes in more than 90 countries for over 30 years. It was approved for use in diabetes patients in the United States in 1995. Metformin reduces the excessive hepatic glucose production that characterizes type II diabetes. With reduced hyperglycemia, glucose uptake by peripheral tissues is enhanced while insulin levels remain stable or decline. Metformin also has hypolipidemic effects, particularly the lowering of serum levels of triglycerides. Frequency of adverse effects is low at the doses needed to obtain the desired metabolic effect.

Troglitazone is a member of a new class of drugs that are “insulin sensitizers.” It was selected on the basis of its effect to lower glycemia without increasing insulin levels, its ability to improve lipid levels, absence of signficiant side effects or adverse events in short-term human studies, potential for translation into non-research settings, and availability of placebo.

The placebo-treated group will serve as the control group. The drug arms and the placebo group will all receive standard lifestyle recommendations, which include conventional instructions regarding diet and exercise.

Outcomes
The primary outcome of the DPP is the development of diabetes according to World Health Organization criteria (FPG >140 mg/dl or 7.8 mmol/L or 2-hour plasma glucose > 200 mg/dl or 11.1 mmol/L) during a 75-g oral glucose tolerance test and confirmed with a repeat test. This is assessed by oral glucose tolerance testing annually, by FPG measurements every 6 months, and by the presence or absence of symptoms consistent with hyperglycemia. Secondary outcomes will focus upon 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.

Call for Recruitment
It is anticipated that more than 100,000, and perhaps as many as 200,000, people may have to be screened in order to identify 4,000 participants. Recruitment, screening, and treatment will be done at the 25 participating centers of the DPP. Recruitment started in 1996 and will continue through 1999. The trial will be completed in 2002.

Volunteers and physicians may get further information about the DPP by calling 1-888-377-5646, or the nearest center (Appendix 1). Volunteers may also access information on the internet ( www.niddk.nih.gov/DPPbrochure/DPPbrochure.html ).

Recommended Reading

American Diabetes Association: Diabetes 1996: Vital Statistics. Alexandria, Va., American Diabetes Association, 1996.

Bourn DM, Mann JI, McSkimming BJ, Waldron MA, Wishart JD: Impaired glucose tolerance and NIDDM: does lifestyle intervention program have an effect? Diabetes Care 17:1311-19, 1994.

Eriksson KF, Lindgarde F: Prevention of type II (non-insulin-dependent) diabetes mellitus by diet and physical exercise: the 6-year Malmo feasibility study. Diabetologia 34:891-98, 1991.

Harris MI: Classification, diagnostic criteria, and screening for diabetes. In: Diabetes in America, 2nd edition. Bethesda, Md., NIDDK, NIH, 1995, p. 15-36.

Jarrett RJ, Keen H, Fuller H, McCartney M: Worsening to diabetes in men with impaired glucose tolerance (“borderline diabetes”). Diabetologia 16:25-30, 1979.

Keen H, Jarrett RJ, McCartney P: The 10-year follow-up of the Bedford survey (1962-1972): glucose tolerance and diabetes. Diabetologia 22:73-78, 1982.

Kenny SJ, Aubert RE, Geiss LS: Prevalence and incidence of non-insulin-dependent diabetes. In: Diabetes in America, 2nd edition. Bethesda, Md., NIDDK, NIH, 1995, p. 47-67.

Knowler WC, Narayan KMV, Hanson RL, Nelson RG, Bennett PH, Tuomilehto J, Schersten B, Pettitt DJ: Preventing non-insulin-dependent diabetes. Diabetes 44:483-88, 1995.

Nolan JJ, Ludvik B, Beerdsen P, Joyce M, Olefsky J: Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med 331:1188-93, 1994.

Rewers M, Hamman RF: Risk factors for non-insulin-dependent diabetes. In: Diabetes in America, 2nd edition. Bethesda, Md., NIDDK, NIH, 1995, p. 179-220.

Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Charles MA, Bennett PH: A two-step model for development of non-insulin-dependent diabetes. Am J Med 90:229-35, 1991.

Sartor G, Schersten B, Carlstrom S, Melander A, Norden A, Persson G: Ten-year follow-up of subjects with impaired glucose tolerance: prevention of dibetes by tolbutamide and diet regulation. Diabetes 29:41-44, 1980.

Tomilehto J, Knowler WC, Zimmet P: Primary prevention of non-insulin-dependent diabetes mellitus. Diabetes Metab Rev 8:339-53, 1992.

Yudkin JS, Alberti KG, McLarty DG, Swai AB: Impaired glucose tolerance. Brit Med J 301:397-402, 1990.

Zimmet PZ: Kelly West Lecture 1991. Challenges in diabetes epidemiology—from west to the rest. Diabetes Care 15:232-52, 1992.

Wilfred Y. Fujimoto, MD, is a professor of medicine at the University of Washington School of Medicine, Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, in Seattle, Wash., and a co-investigator and chair of the Recruitment and Retention Subcommittee of the DPP.

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