GLP-1s Versus DPP-4s and Risk of Dementia in Patients Requiring Hemodialysis: A Target Trial Emulation Study.

OBJECTIVE: Glucagon-like peptide 1 agonists (GLP-1s) compared with dipeptidyl peptidase 4 inhibitors (DPP-4s) are associated with reduced risk of dementia in the general population with diabetes, but whether this association is true for patients requiring hemodialysis is unknown. RESEARCH DESIGN AND METHODS: Using the U.S. Renal Data System and Medicare Parts A, B, and D claims data from 2011 to 2021, we used the active comparator, new-user design to evaluate incident dementia comparing GLP-1s versus DPP-4s among individuals with both diabetes and hemodialysis dependence. We used inverse probability of treatment weights (IPTW) to balance baseline characteristics and Fine-Gray models to estimate subdistribution hazard ratios (sHRs) accounting for competing risks of death and kidney transplantation. We estimated intention-to-treat and as-treated effects. RESULTS: We identified 3,619 GLP-1 users and 11,502 DPP-4 users. After IPTW, the average individual was 63 years old, 63% were White, and mean BMI was 31 kg/m2. The median (interquartile interval) follow-up was 1.5 (0.6-2.9) years, and 2,014 patients received a dementia diagnosis. In the intention-to-treat analysis, the IPTW-sHR for dementia was 0.82 (95% CI 0.67-0.98), and after 2 years of follow-up, the cumulative incidence of dementia was 10.2% on GLP-1s vs 11.2% on DPP-4s. As-treated and subgroup analyses were consistent. GLP-1s were also associated with an increased risk of ketoacidosis (sHR 1.52, 95% CI 1.14-2.02; 2-year cumulative incidence: 3.1% vs. 2.2%). CONCLUSIONS: In patients with diabetes requiring hemodialysis, GLP-1s (vs. DPP-4s) may be a promising therapy to reduce the risk of dementia.