(A-147) Cardiovascular, Kidney, and Safety Outcomes following GLP-1 Receptor Agonist initiation in Adults with Alzheimer's Disease and Related Dementias: A Target Trial Emulation Study

Background: While previous evidence has shown well-established cardiovascular and renal benefits of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the general population with type 2 diabetes (T2D), their effectiveness and safety in individuals with Alzheimer's Disease and Related Dementias (ADRD) remain largely unexplored.

Objectives: This target trial emulation aimed to evaluate the effectiveness and safety of GLP-1RAs in adults with T2D and ADRD.

Methods: Using TriNetX electronic health records from January 2014 to January 2025, we conducted a target trial emulation involving adults (≥50 years) with T2D and ADRD who initiated either a GLP-1RA or dipeptidyl peptidase-4 inhibitor (DPP4i). Outcomes of interest included major adverse cardiovascular events (MACE: myocardial infarction, stroke, heart failure, ventricular arrhythmia, and sudden cardiac death), end-stage renal disease (ESRD)/dialysis, all-cause mortality, hypoglycemia, hyperglycemic crises, and gastrointestinal symptoms. Propensity score matching (1:1) was used to balance baseline characteristics, and Cox proportional hazards regression was employed to estimate hazard ratios (HRs) with 95% confidence intervals (CIs).

Results: Among 8,234 adults initiating GLP-1RAs and 20,107 initiating DPP4is, 7,041 remained in each group after matching. Over a median follow-up of 1.87 years, GLP-1RAs were associated with a reduced risk of all-cause mortality (HR,0.76; 95%CI, 0.70, 0.82) and ESRD/Dialysis (HR, 0.71; 95%CI, 0.57 – 0.90), compared to DPP4is. No association was observed between GLP-1RA use and risk of MACE (HR, 0.97; 95%CI, 0.88 – 1.08). However, GLP-1RAs were associated with an increased risk of hypoglycemia (HR, 1.18; 95%CI, 1.04 – 1.33) and gastrointestinal symptoms (HR, 1.14; 95%CI, 1.04 – 1.26), but not hyperglycemic crises (HR, 1.11;95%CI, 0.93 – 1.04).

Conclusions: In adults with T2D and ADRD, GLP-1RAs were associated with a lower risk of all-cause mortality and ESRD/dialysis compared to DPP4is, but no significant cardiovascular benefits were observed. The increased risks of hypoglycemia and gastrointestinal symptoms warrant careful consideration in this population. Further research is needed to validate these findings.