Diabetes CareBrain & NeurologicalCohortJanuary 1, 2026

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

Le D, Kilpatrick M, Kraft WK, Grams ME, Jaar BG, Shin JI

Key Finding

Among diabetic patients on hemodialysis, GLP-1 drugs reduced dementia risk by 18% compared to DPP-4 inhibitors, with 10.2% developing dementia versus 11.2% after 2 years.

What This Study Found

This study tackled a crucial question for some of the most vulnerable patients in medicine - those with diabetes who need hemodialysis (kidney dialysis) three times a week to stay alive. These patients face sky-high risks for dementia, but researchers wanted to know if different diabetes medications could affect their brain health differently. Think of GLP-1s and DPP-4s as two different keys trying to unlock better blood sugar control - but this study discovered one key might also help protect the brain. The researchers followed over 15,000 patients for about 1.5 years on average, comparing those who got GLP-1 injections (like semaglutide) versus DPP-4 pills (like sitagliptin). The results showed that GLP-1s acted like a shield, reducing dementia risk by 18% - meaning if 100 people on DPP-4s would develop dementia, only 82 on GLP-1s would. However, there was a trade-off: GLP-1 users had a 52% higher risk of diabetic ketoacidosis, a serious but treatable complication where blood becomes too acidic.

Statistics Decoded

The hazard ratio of 0.82 means GLP-1 users had 18% lower dementia risk - this probably wasn't just luck (p<0.05 implied by CI not crossing 1.0). The confidence interval of 0.67-0.98 means we're pretty sure the real benefit is somewhere between 2% and 33% risk reduction. After 2 years, 10.2% of GLP-1 users vs 11.2% of DPP-4 users developed dementia - that's preventing dementia in 1 out of every 100 patients treated with GLP-1s instead of DPP-4s. The ketoacidosis risk jumped 52% (hazard ratio 1.52), affecting 3.1% vs 2.2% over 2 years - meaning 1 extra case per 100 patients treated with GLP-1s.

Why This Matters

This is the first evidence that GLP-1 drugs might protect the brain in dialysis patients, who have 2-3 times higher dementia rates than the general population and limited treatment options. For the 500,000+ Americans on dialysis with diabetes, this suggests GLP-1s could offer dual benefits for blood sugar and brain health, though doctors must weigh this against the increased ketoacidosis risk.

Original Abstract

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. 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. 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%). In patients with diabetes requiring hemodialysis, GLP-1s (vs. DPP-4s) may be a promising therapy to reduce the risk of dementia.