Long-term Effects of Metformin on Diabetes Prevention: Identification of Subgroups That Benefited Most in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study

OBJECTIVE We examined the effects of metformin on diabetes prevention and the subgroups that benefited most over 15 years in the Diabetes Prevention Program (DPP) and its follow-up, the Diabetes Prevention Program Outcomes Study (DPPOS). RESEARCH DESIGN AND METHODS During the DPP (1996-2001), adults at high risk of developing diabetes were randomly assigned to masked placebo (n = 1,082) or metformin 850 mg twice daily (n = 1,073). Participants originally assigned to metformin continued to receive metformin, unmasked, in the DPPOS (2002-present). Ascertainment of diabetes development was based on fasting or 2-h glucose levels after an oral glucose tolerance test or on HbA(1c). Reduction in diabetes incidence with metformin was compared with placebo in subgroups by hazard ratio (HR) and rate differences (RDs). RESULTS During 15 years of postrandomization follow-up, metformin reduced the incidence (by HR) of diabetes compared to placebo by 17% or 36% based on glucose or HbA(1c) levels, respectively. Metformin's effect on the development of glucose-defined diabetes was greater for women with a history of prior gestational diabetes mellitus (GDM) (HR 0.59, RD -4.57 cases/100 person-years) compared with parous women without GDM (HR 0.94, RD -0.38 cases/100 person-years [interaction P = 0.03 for HR, P = 0.01 for RD]). Metformin also had greater effects, by HR and RD, at higher baseline fasting glucose levels. With diabetes development based on HbA(1c), metformin was more effective in subjects with higher baseline HbA(1c) by RD, with metformin RD -1.03 cases/100 person-years with baseline HbA(1c) <6.0% (42 mmol/mol) and -3.88 cases/100 person-years with 6.0-6.4% (P = 0.0001). CONCLUSIONS Metformin reduces the development of diabetes over 15 years. The subsets that benefitted the most include subjects with higher baseline fasting glucose or HbA(1c) and women with a history of GDM.