Analysis of Long-term Follow-up of a Randomized Clinical Trial With Departures From Assigned Treatments: Estimation of Metformin Effects on Diabetes and Its Complications in the Diabetes Prevention Program Outcomes Study

The Diabetes Prevention Program (DPP) was a 3-year randomized clinical trial (RCT) with evaluation of lifestyle and metformin interventions compared with placebo for diabetes prevention in high-risk adults. Both interventions significantly reduced diabetes incidence, prompting the long-term Diabetes Prevention Program Outcomes Study (DPPOS) to assess the progression of diabetes and its complications over 22 years. During follow-up, departures from the original metformin or placebo assignment occurred primarily because of development of diabetes that, by protocol, was managed by clinicians outside the study, after participants developed diabetes with HbA1c ≥7.0%. Diabetes development led to changes in metformin treatment and addition of other glucose-lowering therapies. Using statistical methods designed to estimate intervention effects despite these deviations, we consistently found that metformin reduced diabetes incidence. However, using these methods to evaluate whether use of metformin for prediabetes confers continued benefits after diabetes diagnosis did not substantially change the conclusions from those of the simpler intention-to-treat analysis that did not account for treatment changes. All of the analytic methods used resulted in similar metformin effect estimates with 95% CIs for hazard ratios including 1.0 (no effect) for all outcomes except for diabetes incidence. Elucidating metformin's long-term role in mitigating diabetes-related complications beyond its effects on diabetes prevention is challenging.

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Diabetes Care
Published
2025-08-26
DOI
https://doi.org/10.2337/dci25-0032
Primary Topic
Diabetes, Cardiovascular Risks, and Lipoproteins
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article

Analysis of Long-term Follow-up of a Randomized Clinical Trial With Departures From Assigned Treatments: Estimation of Metformin Effects on Diabetes and Its Complications in the Diabetes Prevention Program Outcomes Study

Farida Rautaharju, Enrico Cagliero, Shihchen Kuo, Alafia Samuels et al.
Diabetes Care
Diabetes, Cardiovascular Risks, and Lipoproteins
article

Analysis of Long-term Follow-up of a Randomized Clinical Trial With Departures From Assigned Treatments: Estimation of Metformin Effects on Diabetes and Its Complications in the Diabetes Prevention Program Outcomes Study

Farida Rautaharju, Enrico Cagliero, Shihchen Kuo, Alafia Samuels, Ashley Guidi, Gina McAtee, Anna Bowers, Kathy Hattaway, Kenneth G. C. Smith, Kirsten Czech, Rosa Ruiz, Catherine Manus, Nancy J. Aronoff, Sharon M. Hall, John Reusing, Deborah Elsas, John C. Guare, Alan M. Jacobsen, Robin E. Yamamoto, Kali D’Anna, Susan Hagamen, Matthew J. O’Brien, Tara Dacawyma, Ysela Gonzales, Emily B. Schroeder, Sunder Mudaliar, William B. Applegate, Trevor J. Orchard, Wilfred Y. Fujimoto, Vanita R. Aroda, John Spandorfer, Maria Swift, Vickie L. Andre, Helen P. Hazuda, Mary A. Foulkes, Jennifer Arceneaux, Jonathan Scheindlin, Barbara Eberhardt, Vanessa Bradley, Dorothy Gohdes, Clara M. Smith, Asha K. Nair, Raed Imseis, Ellie Horse, Christopher Piromalli, Barbara Fargnoli, Alan R. Shuldiner, Narleen K. Baker-Ladao, Catherine Behrends, Diana Leos, Janet Sewenemewa, Holly Cohn, Darryl Tonemah, Sheila C. Steinke, Sameh Tadros, Beverly Tseng, Jonalle M. Dowden, Nicole Butler, Leslie F. 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article en

Abstract

The Diabetes Prevention Program (DPP) was a 3-year randomized clinical trial (RCT) with evaluation of lifestyle and metformin interventions compared with placebo for diabetes prevention in high-risk adults. Both interventions significantly reduced diabetes incidence, prompting the long-term Diabetes Prevention Program Outcomes Study (DPPOS) to assess the progression of diabetes and its complications over 22 years. During follow-up, departures from the original metformin or placebo assignment occurred primarily because of development of diabetes that, by protocol, was managed by clinicians outside the study, after participants developed diabetes with HbA1c ≥7.0%. Diabetes development led to changes in metformin treatment and addition of other glucose-lowering therapies. Using statistical methods designed to estimate intervention effects despite these deviations, we consistently found that metformin reduced diabetes incidence. However, using these methods to evaluate whether use of metformin for prediabetes confers continued benefits after diabetes diagnosis did not substantially change the conclusions from those of the simpler intention-to-treat analysis that did not account for treatment changes. All of the analytic methods used resulted in similar metformin effect estimates with 95% CIs for hazard ratios including 1.0 (no effect) for all outcomes except for diabetes incidence. Elucidating metformin's long-term role in mitigating diabetes-related complications beyond its effects on diabetes prevention is challenging.

Diabetes CareVol. 48(10)
Northwestern University (US), Milken Institute (US), Colorado School of Public Health (US), University of New Mexico (US), Columbia University Irving Medical Center (US), VA Puget Sound Health Care System (US), Michigan Medicine (US), University of Colorado Anschutz Medical Campus (US)
National Institute on Aging, National Institute of Diabetes and Digestive and Kidney Diseases
Openalex Percentile: Top 70%
Diabetes, Cardiovascular Risks, and Lipoproteins
DOIOpen Access PDFOpenAlex
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