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The purpose of the present article is to provide a detailed description of the highly successful lifestyle intervention administered to 1,079 participants, which included 45% racial and ethnic minorities and resulted in a 58% reduction in the incidence rate of diabetes (2). The two major goals of the Diabetes Prevention Program (DPP) lifestyle intervention were a minimum of 7% weight loss/weight maintenance and a minimum of 150 min of physical activity similar in intensity to brisk walking. Both goals were hypothesized to be feasible, safe, and effective based on previous clinical trials in other countries (3-7). The methods used to achieve these lifestyle goals include the following key features: 1) individual case managers or \"lifestyle coaches;\" 2) frequent contact with participants; 3) a structured, state-of-the-art, 16-session core-curriculum that taught behavioral self-management strategies for weight loss and physical activity; 4) supervised physical activity sessions; 5) a more flexible maintenance intervention, combining group and individual approaches, motivational campaigns, and \"restarts;\" 6) individualization through a \"toolbox\" of adherence strategies; 7) tailoring of materials and strategies to address ethnic diversity; and finally 8) an extensive network of training, feedback, and clinical support.

OBJECTIVE: Participants in the Diabetes Prevention Program (DPP) randomized to intensive lifestyle modification (ILS) or metformin had a significantly reduced incidence of diabetes compared with those randomized to placebo, yet most were still at risk because they had pre-diabetes. We explored the effect of baseline characteristics, weight change, ILS, and metformin on regression from pre-diabetes to the lowest-risk state of normal glucose regulation (NGR) defined by American Diabetes Association criteria. RESEARCH DESIGN AND METHODS: The DPP was a prospective randomized trial. Cox proportional hazards modeling was used to identify predictors of regression from pre-diabetes to NGR over 3 years of follow-up. RESULTS: Lower baseline fasting (hazard ratio 1.52, P < 0.01) and 2-h (1.24, P < 0.01) glucose predicted regression to NGR, as did younger age (1.07, P < 0.01) and greater insulin secretion (1.09, P = 0.04). ILS (2.05, P < 0.01) and weight loss (1.34, P < 0.01) had significant and independent effects on regression. A nonsignificant trend for regression was also observed for metformin (1.25, P = 0.06), male sex (1.17, P = 0.08), and insulin sensitivity (1.07, P = 0.09). In those entering the study with both impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), male sex and insulin sensitivity predicted regression to isolated IFG, whereas ILS, metformin, female sex, and greater insulin secretion predicted regression to isolated IGT. CONCLUSIONS: Insulin secretion, and other biologic processes retained with younger age, are key in restoring NGR in people with pre-diabetes. However, NGR may also be attained through weight loss and additional aspects of ILS.

Aims/hypothesis The Diabetes Prevention Program (DPP) lifestyle intervention successfully achieved its goal of increasing leisure physical activity levels. This current study examines whether the lifestyle intervention also changed time spent being sedentary and the impact of sedentary time on diabetes development in this cohort. Methods 3,232 DPP participants provided baseline data. Sedentary behaviour was assessed via an interviewer-administered questionnaire and reported as time spent watching television specifically (or combined with sitting at work). Mean change in sedentary time was examined using repeated measures ANCOVA. The relationship between sedentary time and diabetes incidence was determined using Cox proportional hazards models. Results During the DPP follow-up (mean: 3.2 years), sedentary time declined more in the lifestyle than the metformin or placebo participants ( p  < 0.05). For the lifestyle group, the decrease in reported mean television watching time (22 [95% CI 26, 17] min/day) was greater than in the metformin or placebo groups ( p  < 0.001). Combining all participants together, there was a significantly increased risk of developing diabetes with increased television watching (3.4% per hour spent watching television), after controlling for age, sex, treatment arm and leisure physical activity ( p  < 0.01), which was attenuated when time-dependent weight was added to the model. Conclusions/interpretation In the DPP, the lifestyle intervention was effective at reducing sedentary time, which was not a primary goal. In addition, in all treatment arms, individuals with lower levels of sedentary time had a lower risk of developing diabetes. Future lifestyle intervention programmes should emphasise reducing television watching and other sedentary behaviours in addition to increasing physical activity. Trial registration: ClinicalTrials.gov NCT00004992

Effects of Withdrawal From Metformin on the Development of Diabetes in the Diabetes Prevention Program The Diabetes Prevention Program Research Group * From the Diabetes Prevention Program Coordinating Center, Biostatistics Center, George Washington University, Rockville, Maryland Abstract OBJECTIVE —In the Diabetes Prevention Program (DPP), metformin significantly reduced the risk of diabetes in individuals with impaired glucose tolerance. Diabetes status was assessed by oral glucose tolerance tests (OGTTs) performed while participants were still taking metformin or placebo. To determine whether the observed benefit was a transient pharmacological effect or more sustained, we performed a repeat OGTT after a short “washout” period during which medications (metformin or placebo) were withheld. RESEARCH DESIGN AND METHODS —All participants assigned to medication who had not developed diabetes at the end of the DPP were asked to have a repeat OGTT after discontinuing the study medication for 1–2 weeks. The predesignated outcome was the odds of diabetes in metformin versus placebo comparisons during the trial and washout combined RESULTS —There were 1,274 participants who participated in the washout study and 529 who did not because they had already developed diabetes. Before the washout, the odds of diabetes in the metformin group was lower than that in the placebo group (odds ratio 0.66, 95% CI 0.54–0.82, P < 0.001). After the washout, diabetes was somewhat more frequently diagnosed in the metformin participants (1.49, 0.93–2.38, P = 0.098). Combining diabetes conversions during the DPP and during the washout, diabetes was diagnosed significantly less frequently in the metformin than the placebo group (0.75, 0.62–0.92, P = 0.005). CONCLUSIONS —The primary analysis of the DPP demonstrated that metformin decreased the risk of diabetes by 31%. The washout study shows that 26% of this effect can be accounted for by a pharmacological effect of metformin that did not persist when the drug was stopped. After the washout the incidence of diabetes was still reduced by 25%. DPP, Diabetes Prevention Program FPG, fasting plasma glucose IGT, impaired glucose tolerance OGTT, oral glucose tolerance test Footnotes Address correspondence and reprint requests to Mark E. Molitch, MD, Diabetes Prevention Program Coordinating Center, Biostatistics Center, George Washington University, 6110 Executive Blvd., Suite 750, Rockville, MD 20852. E-mail: dppmail{at}biostat.bsc.gwu.edu . Received for publication 6 August 2002 and accepted in revised form 18 November 2002. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. See accompanying editorial, p. 1306. * ↵ * The members of the Diabetes Prevention Program Research Group are listed in reference 1. DIABETES CARE

OBJECTIVE—To describe the costs of the Diabetes Prevention Program (DPP) interventions to prevent or delay type 2 diabetes. RESEARCH DESIGN AND METHODS—We describe the direct medical costs, direct nonmedical costs, and indirect costs of the placebo, metformin, and intensive lifestyle interventions over the 3-year study period of the DPP. Resource use and cost are summarized from the perspective of a large health system and society. Research costs are excluded. RESULTS—The direct medical cost of laboratory tests to identify one subject with impaired glucose tolerance (IGT) was$139. Over 3 years, the direct medical costs of the interventions were $ 79 per participant in the placebo group,$2,542 in the metformin group, and $ 2,780 in the lifestyle group. The direct medical costs of care outside the DPP were$272 less per participant in the metformin group and $ 432 less in the lifestyle group compared with the placebo group. Direct nonmedical costs were$9 less per participant in the metformin group and $ 1,445 greater in the lifestyle group compared with the placebo group. Indirect costs were$230 greater per participant in the metformin group and $ 174 less in the lifestyle group compared with the placebo group. From the perspective of a health system, the cost of the metformin intervention relative to the placebo intervention was$2,191 per participant and the cost of the lifestyle intervention was $ 2,269 per participant over 3 years. From the perspective of society, the cost of the metformin intervention relative to the placebo intervention was$2,412 per participant and the cost of the lifestyle intervention was $ 3,540 per participant over 3 years. CONCLUSIONS—The metformin and lifestyle interventions are associated with modest incremental costs compared with the placebo intervention. The evaluation of costs relative to health benefits will determine the value of these interventions to health systems and society.

Within-Trial Cost-Effectiveness of Lifestyle Intervention or Metformin for the Primary Prevention of Type 2 Diabetes Diabetes Prevention Program Research Group * From the Diabetes Prevention Program Coordinating Center, Biostatistics Center, Rockville, Maryland Address correspondence and reprint requests to the Diabetes Prevention Program Group, Diabetes Prevention Program Coordinating Center, George Washington University Biostatistics Center, 6110 Executive Blvd., Suite 750, Rockville, MD 20852. E-mail: dppmail{at}biostat.bsc.gwu.edu Abstract OBJECTIVE —The Diabetes Prevention Program (DPP) demonstrated that intensive lifestyle and metformin interventions reduced the incidence of type 2 diabetes compared with a placebo intervention. The aim of this study was to assess the cost-effectiveness of the lifestyle and metformin interventions relative to the placebo intervention. RESEARCH DESIGN AND METHODS —Analyses were performed from a health system perspective that considered direct medical costs only and a societal perspective that considered direct medical costs, direct nonmedical costs, and indirect costs. Analyses were performed with the interventions as implemented in the DPP and as they might be implemented in clinical practice. RESULTS —The lifestyle and metformin interventions required more resources than the placebo intervention from a health system perspective, and over 3 years they cost approximately $2,250 more per participant. As implemented in the DPP and from a societal perspective, the lifestyle and metformin interventions cost $24,400 and $34,500, respectively, per case of diabetes delayed or prevented and $51,600 and $99,200 per quality-adjusted life-year (QALY) gained. As the interventions might be implemented in routine clinical practice and from a societal perspective, the lifestyle and metformin interventions cost $13,200 and $14,300, respectively, per case of diabetes delayed or prevented and $27,100 and $35,000 per QALY gained. From a health system perspective, costs per case of diabetes delayed or prevented and costs per QALY gained tended to be lower. CONCLUSIONS —Over 3 years, the lifestyle and metformin interventions were effective and were cost-effective from the perspective of a health system and society. Both interventions are likely to be affordable in routine clinical practice, especially if implemented in a group format and with generic medication pricing. DPP, Diabetes Prevention Program IGT, impaired glucose tolerance NNT, number needed to treat QALY, quality-adjusted life-year QWB-SA, Self-Administered Quality of Well-Being Index Footnotes * ↵ * The members of the Diabetes Prevention Program Group are listed in reference 3 . A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. See accompanying editorial, p. 2693. Accepted April 27, 2003. Received February 20, 2003. DIABETES CARE

OBJECTIVE: The Diabetes Prevention Program (DPP) and its Outcomes Study (DPPOS) demonstrated that either intensive lifestyle intervention or metformin could prevent type 2 diabetes in high-risk adults for at least 10 years after randomization. We report the 10-year within-trial cost-effectiveness of the interventions. RESEARCH DESIGN AND METHODS: Data on resource utilization, cost, and quality of life were collected prospectively. Economic analyses were performed from health system and societal perspectives. RESULTS: Over 10 years, the cumulative, undiscounted per capita direct medical costs of the interventions, as implemented during the DPP, were greater for lifestyle ($4,601) than metformin ($2,300) or placebo ($769). The cumulative direct medical costs of care outside the DPP/DPPOS were least for lifestyle ($24,563 lifestyle vs. $25,616 metformin vs. $27,468 placebo). The cumulative, combined total direct medical costs were greatest for lifestyle and least for metformin ($29,164 lifestyle vs. $27,915 metformin vs. $28,236 placebo). The cumulative quality-adjusted life-years (QALYs) accrued over 10 years were greater for lifestyle (6.81) than metformin (6.69) or placebo (6.67). When costs and outcomes were discounted at 3%, lifestyle cost $10,037 per QALY, and metformin had slightly lower costs and nearly the same QALYs as placebo. CONCLUSIONS: Over 10 years, from a payer perspective, lifestyle was cost-effective and metformin was marginally cost-saving compared with placebo. Investment in lifestyle and metformin interventions for diabetes prevention in high-risk adults provides good value for the money spent.

TCF7L2 variants have been associated with type 2 diabetes, body mass index (BMI), and deficits in proinsulin processing and insulin secretion. Here we sought to test whether these effects were apparent in high-risk individuals and modify treatment responses. We examined the potential role of the TCF7L2 rs7903146 variant in predicting resistance to weight loss or a lack of improvement of proinsulin processing during 2.5-years of follow-up participants (N = 2,994) from the Diabetes Prevention Program (DPP), a randomized controlled trial designed to prevent or delay diabetes in high-risk adults. We observed no difference in the degree of weight loss by rs7903146 genotypes. However, the T allele (conferring higher risk of diabetes) at rs7903146 was associated with higher fasting proinsulin at baseline (P<0.001), higher baseline proinsulin:insulin ratio (p<0.0001) and increased proinsulin:insulin ratio over a median of 2.5 years of follow-up (P = 0.003). Effects were comparable across treatment arms. The combination of a lack of impact of the TCF7L2 genotypes on the ability to lose weight, but the presence of a consistent effect on the proinsulin:insulin ratio over the course of DPP, suggests that high-risk genotype carriers at this locus can successfully lose weight to counter diabetes risk despite persistent deficits in insulin production.

OBJECTIVE:--The Diabetes Prevention Program (DPP) was a large, multicenter, randomized clinical trial testing interventions to prevent or delay type 2 diabetes. A major challenge was to identify eligible high-risk adults, defined by DPP as having both impaired glucose tolerance (IGT) (2-h glucose 140-199 mg/dl) and elevated fasting plasma glucose (EFG) (95-125 mg/dl). RESEARCH DESIGN AND METHODS--We analyzed how screening yields would be affected by the presence of established risk factors such as age, sex, ethnicity, BMI, and family history of diabetes, and how much yields would be enhanced by preselecting individuals with elevated capillary blood glucose levels. Of 158,177 contacted adults, 79,190 were potentially eligible (no history of diabetes, age 25 years and older, BMI [>/=]24 kg/m²). We focus on the 30,383 participants who completed an oral glucose tolerance test (OGTT). RESULTS:--Based on OGTT, 27% had IGT with EFG, meeting DPP eligibility criteria for being at high risk of diabetes, and 13% had previously undiagnosed diabetes based on OGTT. Older age and higher BMI increased yield of high-risk individuals and those with newly discovered diabetes in most ethnic groups (whites, African Americans, Hispanics, and American Indians). In Asian Americans, age but not BMI predicted high risk and diabetes. Independent of age and BMI, the preliminary fasting capillary glucose predicted screening yield in all ethnic groups, with an inverted-U pattern defining DPP eligibility alone (IGT-EFG) and a steep curvilinear pattern defining either IGT-EFG or newly discovered diabetes. Fasting capillary glucose did not attenuate the affects of other participant characteristics in predicting IGT-EFG or the combination of IGT-EFG and newly discovered diabetes. CONCLUSIONS:--The DPP screening approach identified adults with or at high risk for type 2 diabetes across various ethnic groups and provided guidance to more efficient use of OGTTs. Fasting capillary glucose is a useful adjunct in screening programs combined with data on age and adiposity.

OBJECTIVE: Metformin produced weight loss and delayed or prevented diabetes in the Diabetes Prevention Program (DPP). We examined its long-term safety and tolerability along with weight loss, and change in waist circumference during the DPP and its long-term follow-up. RESEARCH DESIGN AND METHODS: The randomized double-blind clinical trial of metformin or placebo followed by a 7–8-year open-label extension and analysis of adverse events, tolerability, and the effect of adherence on change in weight and waist circumference. RESULTS: No significant safety issues were identified. Gastrointestinal symptoms were more common in metformin than placebo participants and declined over time. During the DPP, average hemoglobin and hematocrit levels were slightly lower in the metformin group than in the placebo group. Decreases in hemoglobin and hematocrit in the metformin group occurred during the first year following randomization, with no further changes observed over time. During the DPP, metformin participants had reduced body weight and waist circumference compared with placebo (weight by 2.06 ± 5.65% vs. 0.02 ± 5.52%, P < 0.001, and waist circumference by 2.13 ± 7.06 cm vs. 0.79 ± 6.54 cm, P < 0.001 in metformin vs. placebo, respectively). The magnitude of weight loss during the 2-year double-blind period was directly related to adherence (P < 0.001). Throughout the unblinded follow-up, weight loss remained significantly greater in the metformin group than in the placebo group (2.0 vs. 0.2%, P < 0.001), and this was related to the degree of continuing metformin adherence (P < 0.001). CONCLUSIONS: Metformin used for diabetes prevention is safe and well tolerated. Weight loss is related to adherence to metformin and is durable for at least 10 years of treatment.