Abstract Body (Do not enter title and authors here): Background: Heart failure with reduced ejection fraction (HFrEF) is characterized by impaired systolic function and invariably presents with co-existing diastolic dysfunction, creating a complex pathophysiological state that contributes to poor outcomes. While sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated cardiovascular benefits in HFrEF, the effectiveness of combination glucagon-like peptide-1 receptor agonist (GLP-1 RA) and SGLT2 inhibitor therapy in this population remains unclear.
Objective: To compare clinical outcomes in HFrEF patients receiving combination therapy of GLP-1 RAs and SGLT2 inhibitors versus SGLT2 inhibitors alone.
Methods: We conducted a multicenter retrospective cohort study from January 2021 to December 2024. Cohort 1: 1,376 patients with HFrEF (ejection fraction ≤40%) on combination therapy. Cohort 2: 3,711 patients with HFrEF on SGLT2 inhibitors only. Primary endpoint was the composite of hospital admissions or death. Secondary endpoints included rate of intravenous diuretic use (as surrogate marker of acute cardiac decompensation), improvement to normal ejection fraction (EF ≥50%), hypoglycemia, and acute kidney injury. Outcomes were analyzed 365 days post-treatment initiation with mean follow-up of 268 days.
Results: After propensity score matching, cohorts (1,118 pairs) demonstrated well-balanced baseline characteristics including other HFrEF guideline directed therapies. Mean age at index was 63.6 vs 64.0 years (p=0.410), with 66.3% vs 66.9% male (p=0.754). Combination therapy significantly reduced the primary composite endpoint (39.1% vs 52.8%, HR 0.664, 95% CI 0.587-0.752, p<0.001) with improved survival probability at the end of follow-up. Rate of intravenous diuretic use was significantly lower with the combination therapy (12.3% vs 20.8%, HR 0.563, 95% CI 0.456-0.695, p<0.001). Rate of improvement to normal EF was similar between groups (10.0% vs 10.3%, HR 0.991, 95% CI 0.764-1.285, p=0.944). Hypoglycemia rates were low and similar (1.3% vs 1.7%, HR 0.799, 95% CI 0.406-1.572, p=0.515). Combination therapy was associated with significantly lower rates of acute kidney injury (19.1% vs 27.8%, HR 0.671, 95% CI 0.564-0.799, p<0.001).
Conclusion: Combination GLP-1 RA and SGLT2 inhibitor therapy was associated with reduced rate of admissions and death compared to SGLT2 inhibitor monotherapy in patients with HFrEF, with improved safety profile including reduced acute kidney injury and similar hypoglycemia rates.