Effect of Metformin and Lifestyle Interventions on Mortality in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study

Christine G Lee, Brandy Heckman-Stoddard, Dana Dabelea, Kishore M Gadde, David Ehrmann, Leslie Ford, Philip Prorok, Edward J Boyko, Xavier Pi-Sunyer, Amisha Wallia, William C Knowler, Jill P Crandall, Marinella Temprosa, Diabetes Prevention Program Research Group, Diabetes Prevention Program Research Group:

Abstract

Objective: To determine whether metformin or lifestyle modification can lower rates of all-cause and cause-specific mortality in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study.

Research design and methods: From 1996 to 1999, 3,234 adults at high risk for type 2 diabetes were randomized to an intensive lifestyle intervention, masked metformin, or placebo. Placebo and lifestyle interventions stopped in 2001, and a modified lifestyle program was offered to everyone, but unmasked study metformin continued in those originally randomized. Causes of deaths through 31 December 2018 were adjudicated by blinded reviews. All-cause and cause-specific mortality hazard ratios (HRs) were estimated from Cox proportional hazards regression models and Fine-Gray models, respectively.

Results: Over a median of 21 years (interquartile range 20-21), 453 participants died. Cancer was the leading cause of death (n = 170), followed by cardiovascular disease (n = 131). Compared with placebo, metformin did not influence mortality from all causes (HR 0.99 [95% CI 0.79, 1.25]), cancer (HR 1.04 [95% CI 0.72, 1.52]), or cardiovascular disease (HR 1.08 [95% CI 0.70, 1.66]). Similarly, lifestyle modification did not impact all-cause (HR 1.02 [95% CI 0.81, 1.28]), cancer (HR 1.07 [95% CI 0.74, 1.55]), or cardiovascular disease (HR 1.18 [95% CI 0.77, 1.81]) mortality. Analyses adjusted for diabetes status and duration, BMI, cumulative glycemic exposure, and cardiovascular risks yielded results similar to those for all-cause mortality.

Conclusions: Cancer was the leading cause of mortality among adults at high risk for type 2 diabetes. Although metformin and lifestyle modification prevented diabetes, neither strategy reduced all-cause, cancer, or cardiovascular mortality rates.

Trial registration: ClinicalTrials.gov NCT00004992 NCT00038727.

© 2021 by the American Diabetes Association.

Figures

Figure 1
Figure 1
Kaplan-Meier survival curves for metformin, lifestyle, and placebo groups. The figure shows the survival by randomization to metformin, lifestyle, and placebo.

References

    1. Huang Y, Cai X, Chen P, et al. . Associations of prediabetes with all-cause and cardiovascular mortality: a meta-analysis. Ann Med 2014;46:684–692
    1. Huang Y, Cai X, Mai W, Li M, Hu Y. Association between prediabetes and risk of cardiovascular disease and all cause mortality: systematic review and meta-analysis. BMJ 2016;355:i5953.
    1. Zhou XH, Qiao Q, Zethelius B, et al. .; DECODE Study Group . Diabetes, prediabetes and cancer mortality. Diabetologia 2010;53:1867–1876
    1. Knowler WC, Barrett-Connor E, Fowler SE, et al. .; Diabetes Prevention Program Research Group . Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393–403
    1. Mercken EM, Carboneau BA, Krzysik-Walker SM, de Cabo R. Of mice and men: the benefits of caloric restriction, exercise, and mimetics. Ageing Res Rev 2012;11:390–398
    1. Johnson JA, Majumdar SR, Simpson SH, Toth EL. Decreased mortality associated with the use of metformin compared with sulfonylurea monotherapy in type 2 diabetes. Diabetes Care 2002;25:2244–2248
    1. Johnson JA, Simpson SH, Toth EL, Majumdar SR. Reduced cardiovascular morbidity and mortality associated with metformin use in subjects with Type 2 diabetes. Diabet Med 2005;22:497–502
    1. Campbell JM, Bellman SM, Stephenson MD, Lisy K. Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis. Ageing Res Rev 2017;40:31–44
    1. Bergmark BA, Bhatt DL, McGuire DK, et al. .; SAVOR-TIMI 53 Steering Committee and Investigators . Metformin use and clinical outcomes among patients with diabetes mellitus with or without heart failure or kidney dysfunction: observations from the SAVOR-TIMI 53 trial. Circulation 2019;140:1004–1014
    1. Vistisen D, Witte DR, Brunner EJ, et al. . Risk of cardiovascular disease and death in individuals with prediabetes defined by different criteria: the Whitehall II study. Diabetes Care 2018;41:899–906
    1. Gandini S, Puntoni M, Heckman-Stoddard BM, et al. . Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders. Cancer Prev Res (Phila) 2014;7:867–885
    1. Landman GW, Kleefstra N, van Hateren KJ, Groenier KH, Gans RO, Bilo HJ. Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16. Diabetes Care 2010;33:322–326
    1. Han Y, Xie H, Liu Y, Gao P, Yang X, Shen Z. Effect of metformin on all-cause and cardiovascular mortality in patients with coronary artery diseases: a systematic review and an updated meta-analysis. Cardiovasc Diabetol 2019;18:96.
    1. Cao X, Wu Y, Wang J, Liu K, Wang X. The effect of metformin on mortality among diabetic cancer patients: a systematic review and meta-analysis. JNCI Cancer Spectr 2017;1:pkx007.
    1. Williamson DF, Thompson TJ, Thun M, Flanders D, Pamuk E, Byers T. Intentional weight loss and mortality among overweight individuals with diabetes. Diabetes Care 2000;23:1499–1504
    1. Gregg EW, Gerzoff RB, Thompson TJ, Williamson DF. Intentional weight loss and death in overweight and obese U.S. adults 35 years of age and older. Ann Intern Med 2003;138:383–389
    1. Murphy RA, Patel KV, Kritchevsky SB, et al. . Weight change, body composition, and risk of mobility disability and mortality in older adults: a population-based cohort study. J Am Geriatr Soc 2014;62:1476–1483
    1. UK Prospective Diabetes Study (UKPDS) Group . Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854–865
    1. Kritchevsky SB, Beavers KM, Miller ME, et al. . Intentional weight loss and all-cause mortality: a meta-analysis of randomized clinical trials. PLoS One 2015;10:e0121993.
    1. Li G, Zhang P, Wang J, et al. . Cardiovascular mortality, all-cause mortality, and diabetes incidence after lifestyle intervention for people with impaired glucose tolerance in the Da Qing Diabetes Prevention Study: a 23-year follow-up study. Lancet Diabetes Endocrinol 2014;2:474–480
    1. Gong Q, Zhang P, Wang J, et al. .; Da Qing Diabetes Prevention Study Group . Morbidity and mortality after lifestyle intervention for people with impaired glucose tolerance: 30-year results of the Da Qing Diabetes Prevention Outcome Study. Lancet Diabetes Endocrinol 2019;7:452–461
    1. Huang Y, Cai X, Qiu M, et al. . Prediabetes and the risk of cancer: a meta-analysis. Diabetologia 2014;57:2261–2269
    1. Di Angelantonio E, Bhupathiraju ShN, Wormser D, et al. .; Global BMI Mortality Collaboration . Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents. Lancet 2016;388:776–786
    1. Rao Kondapally Seshasai S, Kaptoge S, Thompson A, et al. .; Emerging Risk Factors Collaboration . Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med 2011;364:829–841
    1. Rubin RR, Fujimoto WY, Marrero DG, et al. .; DPP Research Group . The Diabetes Prevention Program: recruitment methods and results. Control Clin Trials 2002;23:157–171
    1. The Diabetes Prevention Program . The Diabetes Prevention Program. Design and methods for a clinical trial in the prevention of type 2 diabetes. Diabetes Care 1999;22:623–634
    1. Diabetes Prevention Program Research Group . Long-term safety, tolerability, and weight loss associated with metformin in the Diabetes Prevention Program Outcomes Study. Diabetes Care 2012;35:731–737
    1. Grafféo N, Latouche A, Le Tourneau C, Chevret S. ipcwswitch: an R package for inverse probability of censoring weighting with an application to switches in clinical trials. Comput Biol Med 2019;111:103339.
    1. Orchard TJ, Temprosa M, Barrett-Connor E, et al. .; Diabetes Prevention Program Outcomes Study Research Group . Long-term effects of the Diabetes Prevention Program interventions on cardiovascular risk factors: a report from the DPP Outcomes Study. Diabet Med 2013;30:46–55
    1. Knowler WC, Fowler SE, Hamman RF, et al. .; Diabetes Prevention Program Research Group . 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 2009;374:1677–1686
    1. Gregg EW, Cheng YJ, Srinivasan M, et al. . Trends in cause-specific mortality among adults with and without diagnosed diabetes in the USA: an epidemiological analysis of linked national survey and vital statistics data. Lancet 2018;391:2430–2440
    1. Kim D, Li AA, Cholankeril G, et al. . Trends in overall, cardiovascular and cancer-related mortality among individuals with diabetes reported on death certificates in the United States between 2007 and 2017. Diabetologia 2019;62:1185–1194
    1. Sun X, Du T. Trends in cardiovascular risk factors among U.S. men and women with and without diabetes, 1988-2014. BMC Public Health 2017;17:893.
    1. Pearson-Stuttard J, Bennett J, Cheng YJ, et al. . Trends in predominant causes of death in individuals with and without diabetes in England from 2001 to 2018: an epidemiological analysis of linked primary care records. Lancet Diabetes Endocrinol 2021;9:165–173
    1. Data and Statistics (WISQARS) , 2018. Accessed 13 October 2020. Available from
    1. Diabetes Prevention Program Research Group . Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study. Lancet Diabetes Endocrinol 2015;3:866–875
    1. Uusitupa M, Peltonen M, Lindström J, et al. .; Finnish Diabetes Prevention Study Group . Ten-year mortality and cardiovascular morbidity in the Finnish Diabetes Prevention Study--secondary analysis of the randomized trial. PLoS One 2009;4:e5656.
    1. Eriksson KF, Lindgärde F. No excess 12-year mortality in men with impaired glucose tolerance who participated in the Malmö Preventive Trial with diet and exercise. Diabetologia 1998;41:1010–1016
    1. Pan XR, Li GW, Hu YH, et al. . Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 1997;20:537–544
    1. Lesko CR, Edwards JK, Cole SR, Moore RD, Lau B. When to censor? Am J Epidemiol 2018;187:623–632

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel