Abstract 4368981: Early GLP-1 Receptor Agonist Initiation Reduces Major Cardiac and Renal Events in Older Adults with Type 2 Diabetes Without Prior Cardiovascular or Renal Disease: A Target Trial Emulation

Background: GLP-1 receptor agonists (GLP-1 RAs) are known to reduce cardiovascular risk in type 2 diabetes. However, their effectiveness in primary prevention, particularly among older adults who were underrepresented in landmark trials, remains uncertain. Research Question: Does early GLP-1 RA initiation reduce the risk of major adverse cardiac and renal events (MACRE) in older adults with type 2 diabetes and no baseline cardiovascular or renal disease? Method: Using a target trial emulation framework, we conducted a retrospective cohort study within the TriNetX Global Research Network. We included patients aged ≥75 years with type 2 diabetes with baseline metformin between December 5, 2017, and December 5, 2024. Patients with prior heart failure (HF), myocardial infarction (MI), coronary revascularization, acute kidney injury (AKI), chronic kidney disease (CKD), or dialysis dependence were excluded to ensure a primary prevention cohort. We also excluded those on other glucose-lowering agents prior to metformin or with contraindications or barriers to GLP-1 RA access. Patients were assigned to either (1) GLP-1 RA initiation or (2) initiation of other non-GLP-1 RA medications within 6 months of their first metformin. Propensity score matching (1:1) was used to balance covariates. The primary outcome was MACRE: all-cause mortality, incident HF, MI, AKI, CKD, or dialysis dependence. Secondary outcomes included the individual MACRE components and HF hospitalization. Safety outcomes included gastroparesis, nutritional deficiency, sarcopenia, or falls. Follow-up extended up to 3 year or until an outcome event, death, or loss to follow-up. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, with P< 0.05 considered significance. Results: A total of 1,835 GLP-1 RA users were matched to 1,835 non-users, with balanced covariates (mean age: 78.7 vs. 78.6 years; male: 45.2% vs. 46.7%; BMI: 32.2 vs. 31.7 kg/m 2 ; HbA1c: 7.6% vs. 7.9%). Early GLP-1 RA initiation was associated with a 33% lower risk of MACRE compared to non-use (HR: 0.67; 95% CI: 0.58–0.78) (Table) . Subgroup analyses showed consistent reductions in MACRE across comparisons with other glucose-lowering therapies (Figure) . All secondary outcomes were also significantly lower among GLP-1 RA users (Table) . Conclusion: In a primary prevention cohort of older adults with type 2 diabetes, early initiation of GLP-1 RA was associated with significantly lower risk of MACRE.