The Diabetes Prevention Program began in 1996 as an effort to prevent type 2 diabetes in adults at high risk. Twenty-five years later, the same cohort has yielded a finding that extends well beyond diabetes: intensive lifestyle modification cuts the risk of accumulating multiple chronic conditions, a phenomenon now tracked as multimorbidity.
The JAMA paper, led by the DPP Outcomes Study Group, followed 1,173 participants originally randomly assigned to intensive lifestyle intervention (n=380), metformin (n=390), or placebo (n=403) at 27 academic centers (NCT00004992, NCT00038727). At 25-year follow-up, lifestyle intervention reduced multimorbidity incidence compared with placebo (hazard ratio [HR], 0.79; 95% CI, 0.68–0.93) whereas metformin had no significant effect (HR, 0.91; 95% CI, 0.78–1.07).
Multimorbidity was defined as two or more of eight conditions: diabetes, hypertension, dyslipidemia, chronic kidney disease, heart failure, cardiovascular disease, peripheral artery disease, and neuropathy. The lifestyle arm succeeded in reducing diabetes onset (HR 0.57; 95% CI, 0.38–0.85), which likely cascaded into downstream protection against conditions like hypertension and renal disease.
That metformin failed to show the same benefit is the provocative finding. Metformin effectively reduced diabetes incidence in the original DPP; that protection did not translate into fewer cumulative conditions at 25 years. The authors propose that metformin’s mechanism—primarily reducing hepatic glucose output—does not address the inflammatory and metabolic pathways that drive multimorbidity beyond glucose control.
The implications for clinical practice are substantial. Metformin is among the most widely prescribed agents in the world, partly on the assumption that diabetes prevention confers broad health protection. The DPP 25-year data suggest that assumption needs reexamination. Lifestyle modification, despite its well-documented challenges in sustained implementation, showed durable protection against a composite of chronic disease burden that no medication in the trial could replicate.