Sodium-glucose Cotransporter-2 Inhibitor Initiation and Incident Dementia in Heart Failure With Diabetes: A Population-based Cohort Study.

Background: Heart failure often coexists with important dementia-risk factors, such as diabetes, atrial fibrillation and hypertension. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been associated with a lower dementia risk in general diabetes populations, but evidence is limited, specifically in heart failure with comorbid diabetes.

Objective: To investigate the association of SGLT2 inhibitors with incident dementia in people with heart failure and diabetes.

Methods: This target trial emulation cohort study used linkable administrative databases from Ontario, Canada. New users of SGLT2 inhibitors or dipeptidyl peptidase-4 (DPP4) inhibitors aged ≥ 66 years with diabetes and heart failure (July 2016-December 2020) entered this cohort. A 180-day lag time was implemented to mitigate reverse causality. The primary analysis used an intention-to-treat exposure definition. Cause-specific hazard ratios (HRs), with death as a competing risk, were estimated by using Cox models with propensity-score fine stratification weights. Weighted incidence-rate differences (IRDs) per 1000 person-years were also estimated.

Results: Among 4402 SGLT2 inhibitor and 6319 DPP4 inhibitor new users, over a median follow-up of 3.95 years from treatment initiation, SGLT2 inhibitor vs DPP4 inhibitor initiation was associated with lower dementia risk (HR 0.73, 95% confidence interval [CI] 0.60-0.87; IRD -8.1, 95% CI -12.7 to -3.5). The secondary as-treated analysis showed greater risk reduction (HR 0.53, 95% CI 0.39-0.70; IRD -14.2, 95% CI -20.1 to -8.4) than the primary intention-to-treat analysis.

Conclusions: SGLT2 inhibitor initiation was associated with dementia risk reduction in heart failure and diabetes, a population at a high risk of developing dementia.