Comparative Effectiveness of Metformin vs Sulfonylureas on Exceptional Longevity in Women with Type 2 Diabetes: Target Trial Emulation

Background The association of metformin with mortality has been mixed, and no prior study has determined whether metformin initiation is associated with exceptional longevity, defined as survival to ages 90 and older. Methods We performed a new-user, active comparator cohort study using the target trial emulation framework among the Women’s Health Initiative cohort to determine whether metformin versus sulfonylurea initiation was associated with exceptional longevity (survival to age 90). We identified participants ≥60 years with incident type 2 diabetes and no history of hypoglycemic agents or insulin prior to treatment initiation to perform intention-to-treat analyses. We used 1:1 propensity score matching on demographic characteristics, lifestyle behaviors, diabetes duration, comorbidities (hypertension, cardiovascular disease, chronic obstructive pulmonary disease, and cancer), body mass index, and concomitant medications to balance treatment groups on key confounders. Results Among 438 propensity score-matched women with type 2 diabetes, the incidence rate of death before age 90 per 100 person-years in women initiating metformin monotherapy was 3.7 (95% CI 3.1-4.4) compared with 5.0 (95% CI 4.2-5.8) for sulfonylurea monotherapy. The adjusted risk of death before age 90 was 30% lower for initiation of metformin monotherapy versus sulfonylurea monotherapy (HR, 0.70; 95% CI, 0.56-0.88). Conclusions In this first target trial emulation of metformin and exceptional longevity, we found that metformin initiation increased exceptional longevity compared with sulfonylurea initiation among women with type 2 diabetes. Because this comparison was not made to placebo in an RCT and given the observational design with potential for residual confounding, causality cannot be inferred.