Randomized Study of Metformin and Intensive Lifestyle Intervention on Cancer Incidence over 21 Years of Follow-up in the Diabetes Prevention Program

Meta-analyses have reported a decrease in overall cancer incidence of approximately 10% to 40% with metformin use among individuals with diabetes. Lifestyle change could potentially reduce cancer incidence. The objective was to determine whether metformin or intensive lifestyle (ILS) intervention reduces the risk of cancer among adults at high risk of diabetes. The Diabetes Prevention Program (1996–2001) randomized 3,234 participants to ILS, metformin (850 mg twice daily), or blinded placebo. During follow-up through the Diabetes Prevention Program Outcomes Study, all participants were offered a modified lifestyle intervention, and metformin continued in an open-label metformin group. Participants reported cancer cases annually. Medical records were adjudicated for all reported events. The primary endpoint was total cancer incidence, comparing metformin versus placebo, with ILS versus placebo as a secondary objective. After a median follow-up of 21 years, 546 participants (173 metformin, 182 ILS, and 191 placebo) were diagnosed with a first incident cancer. Incidence rates of cancer were 9.8, 10.5, and 10.8 per 1,000 person-years in metformin, ILS, and placebo, respectively, with a HR of 0.90 (95% confidence interval, 0.73–1.10) for metformin compared with placebo and 0.96 (95% confidence interval, 0.79–1.18) for ILS compared with placebo. There were no differences between any treatment groups for obesity-related cancer or in sex-specific analyses. Neither assignment to metformin nor ILS reduced cancer incidence among adults at high risk of diabetes. These results may be impacted by increased nonstudy metformin usage over time due to the development of diabetes and reduced intensity of the ILS intervention over time.