Metformin and Sulfonylurea Use and Risk of Incident Dementia

Abstract

Background: Diabetes is associated with a 70% increased risk of dementia. With increasing diabetes prevalence, determining if first choice anti-diabetic medications are associated with reduced risk of dementia is a clinical and public health priority. The objective was to compare risk of incident dementia among patients who initiated diabetes treatment with either metformin or a sulfonylurea. Analysis used data from Veterans Health Affairs (VHA) patients with replication in Kaiser Permanente Washington (KPW) patients. Secondary outcomes included effect modification by age and average glycemic burden. Methods: We conducted a new user, active comparator cohort study. The cohorts contained patients ≥50 years of age who initiated monotherapy with metformin or a sulfonylurea and were free of dementia diagnoses and any diabetes treatment for 2 years prior to cohort entry. We identified 75,187 eligible VHA patients and 10,866 eligible KPW patients. Electronic health data from VHA (1999-2015) and KPW (1996-2015) including diagnosis codes, pharmacy data, laboratory values and demographics were used to define variables. Propensity scores and inverse probability of treatment weighting controlled for confounding. Findings: VHA patients were 60·8 years (SD, ±6·8) of age on average and in KPW, 63·1 years (SD, ±9·5) of age. In the VHA sample, 96·8% were male and in KPW 50·4% were male. In primary analyses adjusted for potential confounding factors, metformin initiation was associated with a significantly lower risk of dementia in VHA (HR=0·93; 95%CI: 0·87-0·99) and a similar point estimate was observed in KPW (HR=0·89; 95%CI: 0·74-1·07). Metformin was not associated with dementia among patients ≥75 years of age. Interpretations: Existing epidemiological studies of metformin and incident dementia have been inconsistent. Using a similar study design in two patient populations that differed on clinical and demographic characteristics, our results provide robust evidence that metformin use is associated with lower risk of incident dementia. Funding: National Institute on Aging R21 AG055604 Declaration of Interest: All authors report no conflicts of interest that could inappropriately influence this work. Ethical Approval: The project was approved with a waiver of consent by the Institutional Review Boards of participating institutions.