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      Long-term Effects of Lifestyle Intervention or Metformin on Diabetes Development and Microvascular Complications: the DPP Outcomes Study

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      Diabetes Prevention Program Research Group, , M.D. 1 , , M.D. 2 , , M.D. 3 , , Sc.M. 4 , , M.D. 5 , , M.D. 6 , , M.D., Dr.P.H. 7 , , M.D. 8 , , M.D. 9 , , M.D. 10 , , M.D. 11 , , Ph.D. 4
      The lancet. Diabetes & endocrinology

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          Abstract

          Background

          The worldwide epidemic of type 2 diabetes requires effective prevention. We determined the long-term extent of beneficial effects of lifestyle intervention and metformin on diabetes prevention, originally demonstrated during the 3-year Diabetes Prevention Program (DPP), and whether diabetes-associated microvascular complications are reduced.

          Methods

          The DPP (1996–2001) was a randomized trial comparing an intensive lifestyle intervention or masked metformin with placebo in a cohort selected to be at very high risk to develop diabetes. All participants were offered lifestyle training at DPP-end. 2776 (88%) of the surviving DPP cohort were followed in the DPP Outcome Study (DPPOS 2002–2013) and analyzed by intention-to-treat based on original DPP assignment. During DPPOS, the lifestyle group was offered lifestyle reinforcement semi-annually and the metformin group received unmasked metformin.

          Findings

          During 15 years of average follow-up, lifestyle intervention and metformin reduced diabetes incidence rates by 27% (p<0.0001) and 18% (p=0.001), respectively, compared with the placebo group, with declining between group differences over time. At year 15, the cumulative incidences of diabetes were 55, 56 and 62%, respectively. The prevalences at study-end of the aggregate microvascular outcome, composed of nephropathy, neuropathy, and retinopathy, were not significantly different among the treatment groups (11–13%) in the total cohort. However, in women (n=1887) lifestyle intervention was associated with a lower prevalence (8.7%) than in the placebo (11%) and metformin (11.2%) groups, with 21% (p=0.03) and 22% (p=0.02) reductions with lifestyle compared with placebo and metformin, respectively. Compared with participants who progressed to diabetes, those who didn’t progress had a 28% lower prevalence of microvascular complications (p<0.0001).

          Interpretation

          Lifestyle intervention or metformin significantly reduce diabetes development over 15 years. There were no overall differences in the aggregate microvascular outcome among treatment groups; however, those who did not progress to diabetes had a lower prevalence of microvascular complications than those who progressed.

          Funding

          National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

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          Most cited references20

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          Longitudinal data analysis for discrete and continuous outcomes.

          Longitudinal data sets are comprised of repeated observations of an outcome and a set of covariates for each of many subjects. One objective of statistical analysis is to describe the marginal expectation of the outcome variable as a function of the covariates while accounting for the correlation among the repeated observations for a given subject. This paper proposes a unifying approach to such analysis for a variety of discrete and continuous outcomes. A class of generalized estimating equations (GEEs) for the regression parameters is proposed. The equations are extensions of those used in quasi-likelihood (Wedderburn, 1974, Biometrika 61, 439-447) methods. The GEEs have solutions which are consistent and asymptotically Gaussian even when the time dependence is misspecified as we often expect. A consistent variance estimate is presented. We illustrate the use of the GEE approach with longitudinal data from a study of the effect of mothers' stress on children's morbidity.
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            Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study.

            Individuals with impaired glucose tolerance (IGT) have a high risk of developing NIDDM. The purpose of this study was to determine whether diet and exercise interventions in those with IGT may delay the development of NIDDM, i.e., reduce the incidence of NIDDM, and thereby reduce the overall incidence of diabetic complications, such as cardiovascular, renal, and retinal disease, and the excess mortality attributable to these complications. In 1986, 110,660 men and women from 33 health care clinics in the city of Da Qing, China, were screened for IGT and NIDDM. Of these individuals, 577 were classified (using World Health Organization criteria) as having IGT. Subjects were randomized by clinic into a clinical trial, either to a control group or to one of three active treatment groups: diet only, exercise only, or diet plus exercise. Follow-up evaluation examinations were conducted at 2-year intervals over a 6-year period to identify subjects who developed NIDDM. Cox's proportional hazard analysis was used to determine if the incidence of NIDDM varied by treatment assignment. The cumulative incidence of diabetes at 6 years was 67.7% (95% CI, 59.8-75.2) in the control group compared with 43.8% (95% CI, 35.5-52.3) in the diet group, 41.1% (95% CI, 33.4-49.4) in the exercise group, and 46.0% (95% CI, 37.3-54.7) in the diet-plus-exercise group (P or = 25 kg/m2). In a proportional hazards analysis adjusted for differences in baseline BMI and fasting glucose, the diet, exercise, and diet-plus-exercise interventions were associated with 31% (P < 0.03), 46% (P < 0.0005), and 42% (P < 0.005) reductions in risk of developing diabetes, respectively. Diet and/or exercise interventions led to a significant decrease in the incidence of diabetes over a 6-year period among those with IGT.
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              The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial.

              The metabolic syndrome is a high-risk state for diabetes and cardiovascular disease. Little is known about its prevalence and prevention in those with impaired glucose tolerance. To determine the prevalence of the metabolic syndrome at baseline in the Diabetes Prevention Program and the effect of intensive lifestyle intervention and metformin therapy on the syndrome's incidence and resolution. Randomized, controlled clinical trial. Research and community-based centers. Participants had impaired glucose tolerance (World Health Organization criteria plus fasting plasma glucose level >or=5.3 mmol/L [>or=95 mg/dL]) and were followed for a mean of 3.2 years after random assignment to intensive lifestyle intervention, metformin therapy, or placebo. Metformin, 850 mg twice daily, or intensive lifestyle intervention designed to achieve and maintain a 7% weight loss and 150 minutes of exercise per week. The metabolic syndrome was defined as having 3 or more characteristics (waist circumference; blood pressure; and levels of high-density lipoprotein cholesterol, triglycerides, and fasting plasma glucose) that met criteria from the National Cholesterol Education Program Adult Treatment Panel III. Fifty-three percent of participants (n = 1711) had the metabolic syndrome at baseline; incidence did not vary substantially by age. However, low levels of high-density lipoprotein cholesterol predominated in younger participants (age 25 to 44 years), and high blood pressure predominated in older participants (age 60 to 82 years). In life-table analyses (log-rank test), incidence of the metabolic syndrome was reduced by 41% in the lifestyle group (P < 0.001) and by 17% in the metformin group (P = 0.03) compared with placebo. Three-year cumulative incidences were 51%, 45%, and 34% in the placebo, metformin, and lifestyle groups, respectively. There was no significant heterogeneity by ethnic group. The study involved a volunteer group with impaired glucose tolerance, which limits generalizability. The metabolic syndrome affected approximately half of the participants in the Diabetes Prevention Program at baseline. Both lifestyle intervention and metformin therapy reduced the development of the syndrome in the remaining participants.
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                Author and article information

                Contributors
                Role: (Chair)
                Journal
                101618821
                41837
                Lancet Diabetes Endocrinol
                Lancet Diabetes Endocrinol
                The lancet. Diabetes & endocrinology
                2213-8587
                2213-8595
                8 October 2015
                13 September 2015
                November 2015
                01 November 2016
                : 3
                : 11
                : 866-875
                Affiliations
                [1 ]Massachusetts General Hospital, Boston, MA
                [2 ]University of California, San Diego, San Diego, CA
                [3 ]Albert Einstein College of Medicine, Bronx, NY
                [4 ]George Washington University, Biostatistics Center, Rockville, MD
                [5 ]University of Miami, Miami, FL
                [6 ]Joslin Diabetes Center, Boston, MA
                [7 ]National Institutes of Health, NIDDK, Phoenix, AZ
                [8 ]Indiana University School of Medicine, Indianapolis, IN
                [9 ]University of Pittsburgh, Pittsburgh, PA
                [10 ]Columbia University, New York, NY
                [11 ]University of New Mexico, Albuquerque, NM
                Author notes
                Corresponding author: David M. Nathan, M.D. c/o: Diabetes Prevention Program Coordinating Center, The Biostatistics Center, George Washington University, 6110 Executive Blvd, Suite 750, Rockville, MD 20852, USA dppmail@ 123456bsc.gwu.edu
                [*]

                A complete listing of the Diabetes Prevention Program Research Group can be found in Supplement 1.

                Article
                NIHMS726663
                10.1016/S2213-8587(15)00291-0
                4623946
                26377054
                f7eb32ac-00cd-46de-8a1d-852d99a5a24d

                This manuscript version is made available under the CC BY-NC-ND 4.0 license.

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