Abstract Body (Do not enter title and authors here): Introduction
Metabolic pharmacotherapies [Glucagon-like peptide-1 receptor agonists (GLP1RA) and sodium-glucose cotransporter type 2 inhibitors (SGLT2i)] have shown benefit in patients with heart failure and preserved ejection fraction (HFpEF). It remains unclear whether the two classes would have additive effects.

Methods
We performed a retrospective study using a de-identified federated database with 89 contributing health care organizations (HCO), including over 126 million patients (TriNetX Research Network, Cambridge, MA; date of data access: May 23, 2024). TriNetX regularly aggregates clinical data directly from participating HCOs, and performs extensive data quality and accuracy assessment. While TriNetX obfuscates institutional information relating to participating HCOs, a typical HCO includes a large academic health center with inpatient, outpatient, and specialty care services. We identified all patients with a diagnosis of Heart failure with preserved ejection fraction (HFpEF, ICD-10: I50.3), and SGLT2i usage. We then categorized this patient population into two cohorts, including patients with concomitant GLP1RA use, and patients without GLP1RA use. For both cohorts, we collected data on patient demographics, and the outcomes of all-cause mortality, and all-cause hospitalization, occurring up to 10-years after the index diagnosis. We evaluated differences in outcome risk using hazards ratios and 95% confidence intervals.
Results
Prior to propensity score matching, we identified 114,329 patients, with 7931 patients receiving SGLT2i +GLP1RA vs 106398 receiving SGLT2i-alone. Majority (55.7%) identified as white and 24.4% as African Americans and >90% of the patients had a diagnosis of type 2 diabetes mellitus. After propensity matching, the rate of all-cause hospitalization within the combination group was lower than SGLT2i group (29.6% vs 32.4%, HR 0.76 [0.73- 0.79], P<0.001). All-cause mortality for the combination group was 6.8% versus 10.6% within the SGLT2i-alone group (HR 0.52 [0.47-0.56], P<0.001)).

Conclusion
In this propensity-matched cohort, patients with HFpEF receiving GLP1RA and SGLT2i had lower rates of hospitalizations and all-cause mortality compared with those receiving SGLT2i alone. Large randomized controlled trials are warranted to corroborate these findings.