Lifestyle and Metformin Interventions and Risk of Multimorbidity in Adults With Prediabetes

Importance: Studying how to prevent or delay not just 1 disease but multiple chronic conditions is of great importance for public health; however, few interventions have demonstrated success during long-term follow-up. Objective: To examine the association of lifestyle or metformin compared with placebo on long-term multimorbidity in adults with prediabetes. Design, Setting, and Participants: Observational follow-up cohort study of a randomized clinical trial conducted at 27 sites in the United States from June 1, 1996, to December 31, 2021. From June 1, 1996, through May 28, 1999, 3234 adults at high risk of diabetes enrolled in the 3-year Diabetes Prevention Program (DPP). They were subsequently enrolled in the DPP Outcomes Study (DPPOS). Of this cohort, Centers for Medicare & Medicaid Services (CMS) morbidity data were available through 2021 for 1173 participants who provided consent. Data were analyzed from June 5, 2024, to November 7, 2025. Exposures: Participants in DPP were randomly assigned to intensive lifestyle intervention, metformin, or placebo. During DPPOS, medications were unmasked with discontinuation of placebo; metformin was continued. Group booster classes were offered to the lifestyle group semiannually and all participants were offered lifestyle classes quarterly until 2014. Main Outcomes and Measures: The primary outcome was multimorbidity (presence of ≥2 of 15 prevalent conditions, defined in CMS' Chronic Condition Data Warehouse and adapted for Medicare Advantage encounters). Cox proportional hazard models were applied to estimate associations between randomized treatment groups and time to development of outcomes. Results: Of the 1173 participants (median age, 74 years [IQR, 70-80]; 795 [68%] were female), 997 (85%) experienced greater than or equal to 2 conditions (median, 5 [IQR, 3-7]) by the end of follow-up (316 of 385 [82%], 327 of 385 [85%], and 350 of 403 [87%], respectively, among lifestyle, metformin, and placebo groups). The risk of multimorbidity was lower among lifestyle compared with placebo participants (hazard ratio [HR], 0.79; 95% CI, 0.68-0.93) after adjustment for relevant covariates. There was no difference between participants in the metformin and placebo groups (HR, 0.91; 95% CI, 0.78-1.07). These relationships persisted when diabetes was excluded from the multimorbidity definition. When restricted to dyads of the costliest conditions, the association with lifestyle vs placebo yielded an HR of 0.57 (95% CI, 0.38-0.85). Conclusions and Relevance: Among adults with prediabetes at baseline, lifestyle intervention, but not metformin, was associated with a lower burden of multimorbidity. Lifestyle programs may persistently lower the development of chronic conditions. Trial Registration: ClinicalTrials.gov Identifier: DPP, NCT00004992; DPPOS, NCT00038727.