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Clinical Trial
. 2002 Feb 7;346(6):393-403.
doi: 10.1056/NEJMoa012512.

Reduction in the Incidence of Type 2 Diabetes With Lifestyle Intervention or Metformin

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Free PMC article
Clinical Trial

Reduction in the Incidence of Type 2 Diabetes With Lifestyle Intervention or Metformin

William C Knowler et al. N Engl J Med. .
Free PMC article

Abstract

Background: Type 2 diabetes affects approximately 8 percent of adults in the United States. Some risk factors--elevated plasma glucose concentrations in the fasting state and after an oral glucose load, overweight, and a sedentary lifestyle--are potentially reversible. We hypothesized that modifying these factors with a lifestyle-intervention program or the administration of metformin would prevent or delay the development of diabetes.

Methods: We randomly assigned 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concentrations to placebo, metformin (850 mg twice daily), or a lifestyle-modification program with the goals of at least a 7 percent weight loss and at least 150 minutes of physical activity per week. The mean age of the participants was 51 years, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 34.0; 68 percent were women, and 45 percent were members of minority groups.

Results: The average follow-up was 2.8 years. The incidence of diabetes was 11.0, 7.8, and 4.8 cases per 100 person-years in the placebo, metformin, and lifestyle groups, respectively. The lifestyle intervention reduced the incidence by 58 percent (95 percent confidence interval, 48 to 66 percent) and metformin by 31 percent (95 percent confidence interval, 17 to 43 percent), as compared with placebo; the lifestyle intervention was significantly more effective than metformin. To prevent one case of diabetes during a period of three years, 6.9 persons would have to participate in the lifestyle-intervention program, and 13.9 would have to receive metformin.

Conclusions: Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk. The lifestyle intervention was more effective than metformin.

Figures

Figure 1.
Figure 1.
Changes in Body Weight (Panel A) and Leisure Physical Activity (Panel B) and Adherence to Medication Regimen (Panel C) According to Study Group. Each data point represents the mean value for all participants examined at that time. The number of participants decreased over time because of the variable length of time that persons were in the study. For example, data on weight were available for 3085 persons at 0.5 year, 3064 at 1 year, 2887 at 2 years, and 1510 at 3 years. Changes in weight and leisure physical activity over time differed significantly among the treatment groups (P<0.001 for each comparison).
Figure 2.
Figure 2.
Cumulative Incidence of Diabetes According to Study Group. The diagnosis of diabetes was based on the criteria of the American Diabetes Association. The incidence of diabetes differed significantly among the three groups (P<0.001 for each comparison).
Figure 3.
Figure 3.
Fasting Plasma Glucose Concentrations (Panel A) and Glycosylated Hemoglobin Values (Panel B) According to Study Group. The analysis included all participants, whether or not diabetes had been diagnosed. Changes in fasting glucose values over time in the three groups differed significantly (P<0.001). Glycosylated hemoglobin values in the three groups differed significantly from 0.5 to 3 years (P<0.001). To convert the values for glucose to millimoles per liter, multiply by 0.05551.
Figure 4.
Figure 4.
Participants with Normal Plasma Glucose Values, According to Study Group. Panel A shows the proportions of participants with normal glucose values in the fasting state (<110 mg per deciliter [6.1 mmol per liter]), Panel B the proportions with normal values two hours after an oral glucose load (<140 mg per deciliter [7.8 mmol per liter]), and Panel C the proportions with normal values for both measurements. Persons in whom a diagnosis of diabetes had been made were considered to have abnormal values, regardless of the actual values at the time. By design, no participants had normal post-load glucose values at base line, but base-line fasting glucose values were normal in 67 percent of persons in the placebo group, 67 percent of those in the metformin group, and 68 percent of those in the lifestyle-intervention group. Metformin and lifestyle intervention were similarly effective in restoring normal fasting glucose concentrations, but lifestyle intervention was more effective in restoring normal post-load glucose concentrations.

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