Abstract Body (Do not enter title and authors here): Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are guideline-directed therapies for heart failure (HF), independent of left ventricular ejection fraction. Glucagon-like peptide-1 receptor agonists (GLP-1 RA), used primarily to treat type 2 diabetes mellitus (T2DM) and obesity, have demonstrated favorable cardiometabolic effects in obese patients with HF.

Research Question: Is adding a GLP-1 RA to SGLT2i therapy associated with improved HF outcomes compared to SGLT2i monotherapy in patients with HF?

Methods: We performed a retrospective cohort study using the TriNetX Global Research Network. Adults (≥18 years) with HF who initiated SGLT2i therapy between July 2020 and March 2024 were included. Patients receiving dual therapy with GLP-1 RA and SGLT2i were compared to those receiving SGLT2i monotherapy. There were 7,415 patients in each group after 1:1 propensity score matching for demographics, comorbid conditions, and medications. Outcomes were assessed from 30 to 365 days post-treatment initiation. We evaluated 1-year (1) all-cause mortality, (2) death or HF hospitalization (HFH), and (3) death or all-cause hospitalization (ACH). Kaplan-Meier analysis and Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).

Results: After matching, 7,415 patients per group were analyzed. Mean age was 63.6 ± 11.9 years, 56.4% were male, and 77.7% had T2DM. Obesity (body mass index over 30), hypertension and chronic kidney disease were present in 68.2%, 91.6%, and 36.6% of the cohort, respectively (Table 1). Compared to SGLT2i monotherapy, combination therapy was associated with significantly lower 1 year rates of all-cause mortality (2.6% vs. 6.7%; HR, 0.40; 95% CI, 0.35–0.48; p<0.001), death or HFH (7.5% vs. 12.7%; HR, 0.59; 95% CI, 0.53–0.66; p<0.001), and death or ACH (19% vs. 26.2%; HR, 0.70; 95% CI, 0.65–0.76; p<0.001)(Table 2, Figures 1-3).

Conclusion: In this large, real-world cohort, patients with HF treated with dual GLP-1 RA and SGLT2i therapy experienced lower risks of mortality, HF hospitalization, and all-cause hospitalization compared to SGLT2i monotherapy. These findings support the hypothesis of potential additive benefit via complementary cardiometabolic effects. Prospective randomized studies are needed to confirm these associations and guide future HF treatment strategies.