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 HbA1c . 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 HbA1c 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 HbA1c , metformin was more effective in subjects with higher baseline HbA1c by RD, with metformin RD -1.03 cases/100 person-years with baseline HbA1c <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 HbA1c and women with a history of GDM.