Metformin: We need to either put it in our drinking water or rethink how we study it

Powell, M.; Clark, C.; Alyakin, A.; Vogelstein, J.; Hart, B. B.

Objectives - To expose the potential impact of residual confounding in common observational study designs investigating metformin using a type 2 diabetes cohort; to propose a more robust study design for future observational studies of metformin. Design - Retrospective cohort studies using a prevalent user design conducted in two distinct cohorts: individuals with type 2 diabetes and individuals with prediabetes. Setting - Insurance claims database for Medicare Advantage beneficiaries in the United States, 2018-2019. An identical analysis of commercial insurance beneficiaries appears in the supplement. Participants - 404,765 individuals with type 2 diabetes, 81,791 individuals with prediabetes. Main outcome measures - Total inpatient admission days in 2019, total medical spend (excluding prescription drugs) in 2019. Each of these measures is treated as a binary outcome: greater than zero inpatient days and top 10% medical spend. Results - We implement a common observational study design and observe a strong metformin effect estimate associated with reduced inpatient admissions and reduced medical expenditures; we also implement a more robust study design that suggests any estimated effect is attributable to residual confounding related to individuals' overall health. Conclusions - Common observational study designs examining metformin in a type 2 diabetes population are likely impacted by significant residual confounding. By additionally considering numerous negative control outcomes and a complementary prediabetes cohort, the study design proposed here demonstrates efficacy at exposing residual confounding related to overall health, nullifying the claim derived from a standard study design. Trial registration - Preregistration available at https://osf.io/qf49p.