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

      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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          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.


          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.


          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).


          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.


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

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          Most cited references 31

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          A new equation to estimate glomerular filtration rate.

          Equations to estimate glomerular filtration rate (GFR) are routinely used to assess kidney function. Current equations have limited precision and systematically underestimate measured GFR at higher values. To develop a new estimating equation for GFR: the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Cross-sectional analysis with separate pooled data sets for equation development and validation and a representative sample of the U.S. population for prevalence estimates. Research studies and clinical populations ("studies") with measured GFR and NHANES (National Health and Nutrition Examination Survey), 1999 to 2006. 8254 participants in 10 studies (equation development data set) and 3896 participants in 16 studies (validation data set). Prevalence estimates were based on 16,032 participants in NHANES. GFR, measured as the clearance of exogenous filtration markers (iothalamate in the development data set; iothalamate and other markers in the validation data set), and linear regression to estimate the logarithm of measured GFR from standardized creatinine levels, sex, race, and age. In the validation data set, the CKD-EPI equation performed better than the Modification of Diet in Renal Disease Study equation, especially at higher GFR (P < 0.001 for all subsequent comparisons), with less bias (median difference between measured and estimated GFR, 2.5 vs. 5.5 mL/min per 1.73 m(2)), improved precision (interquartile range [IQR] of the differences, 16.6 vs. 18.3 mL/min per 1.73 m(2)), and greater accuracy (percentage of estimated GFR within 30% of measured GFR, 84.1% vs. 80.6%). In NHANES, the median estimated GFR was 94.5 mL/min per 1.73 m(2) (IQR, 79.7 to 108.1) vs. 85.0 (IQR, 72.9 to 98.5) mL/min per 1.73 m(2), and the prevalence of chronic kidney disease was 11.5% (95% CI, 10.6% to 12.4%) versus 13.1% (CI, 12.1% to 14.0%). The sample contained a limited number of elderly people and racial and ethnic minorities with measured GFR. The CKD-EPI creatinine equation is more accurate than the Modification of Diet in Renal Disease Study equation and could replace it for routine clinical use. National Institute of Diabetes and Digestive and Kidney Diseases.
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            Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.

            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. 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. 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. 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.
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              Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance.

              Type 2 diabetes mellitus is increasingly common, primarily because of increases in the prevalence of a sedentary lifestyle and obesity. Whether type 2 diabetes can be prevented by interventions that affect the lifestyles of subjects at high risk for the disease is not known. We randomly assigned 522 middle-aged, overweight subjects (172 men and 350 women; mean age, 55 years; mean body-mass index [weight in kilograms divided by the square of the height in meters], 31) with impaired glucose tolerance to either the intervention group or the control group. Each subject in the intervention group received individualized counseling aimed at reducing weight, total intake of fat, and intake of saturated fat and increasing intake of fiber and physical activity. An oral glucose-tolerance test was performed annually; the diagnosis of diabetes was confirmed by a second test. The mean duration of follow-up was 3.2 years. The mean (+/-SD) amount of weight lost between base line and the end of year 1 was 4.2+/-5.1 kg in the intervention group and 0.8+/-3.7 kg in the control group; the net loss by the end of year 2 was 3.5+/-5.5 kg in the intervention group and 0.8+/-4.4 kg in the control group (P<0.001 for both comparisons between the groups). The cumulative incidence of diabetes after four years was 11 percent (95 percent confidence interval, 6 to 15 percent) in the intervention group and 23 percent (95 percent confidence interval, 17 to 29 percent) in the control group. During the trial, the risk of diabetes was reduced by 58 percent (P<0.001) in the intervention group. The reduction in the incidence of diabetes was directly associated with changes in lifestyle. Type 2 diabetes can be prevented by changes in the lifestyles of high-risk subjects.

                Author and article information

                Role: (Chair)
                Lancet Diabetes Endocrinol
                Lancet Diabetes Endocrinol
                The lancet. Diabetes & endocrinology
                8 October 2015
                13 September 2015
                November 2015
                01 November 2016
                : 3
                : 11
                : 866-875
                [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@

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


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



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