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

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00038727 NCT00004992.

Figure 1

Forest plot of diabetes HRs and hazard RDs with diabetes defined by glucose levels for metformin vs. placebo over 15 years by subgroups defined at DPP baseline. Point estimates and 95% CIs shown. Highlighted rows show significant treatment-by-group interactions. Group interactions were tested using continuous values for baseline values of age (years), BMI (kg/m²), FPG and 2-h glucose (2hrPG) (mg/dL), and HbA_1c (%). Statistically significant (P < 0.05) interactions of metformin treatment by subgroup are indicated by shading and as follows: *FPG-by-treatment interaction P = 0.02, GDM-by-treatment interaction P = 0.01; ‡FPG-by-treatment interaction P < 0.001, GDM-by-treatment interaction P = 0.02. Afr Am, African American; Am Indn, American Indian; eth, ethnicity; GDM, history of prior GDM; NHW, non-Hispanic white.

Figure 2

Forest plot of diabetes HRs and hazard RDs with diabetes defined by HbA_1c levels for metformin vs. placebo over 15 years by subgroups defined at DPP baseline. Point estimates and 95% CIs shown. Highlighted rows show significant treatment-by-group interactions. Group interactions were tested using continuous values for baseline values of age (years), BMI (kg/m²), FPG and 2-h glucose (2hrPG) (mg/dL), and HbA_1c (%). Statistically significant (P < 0.05) interactions of metformin treatment by subgroup are indicated by shading and as follows: *HbA_1c-by-treatment interaction P = 0.001; ‡FPG-by-treatment interaction P = 0.04. Afr Am, African American; Am Indn, American Indian; eth, ethnicity; GDM, history of prior GDM; NHW, non-Hispanic white.