Abstract Body (Do not enter title and authors here): Introduction:
Sodium-Glucose Cotransporter 2 (SGLT-2) inhibitors have shown mortality and morbidity benefit in patients with heart failure with reduced ejection fraction (HFrEF). However, there is limited evidence regarding their safety profile and impact on cardiovascular outcomes in frail older adults with HF.

Aim: To evaluate cardiovascular outcomes and safety profile of SGLT-2 inhibitors in frail octogenarians.

Methods:
This retrospective cohort study used the TriNetX Global Collaborative Network to analyze outcomes of SGLT-2 use in frail patients aged ≥ 80 with HFrEF between January 2014 and May 2025. Patients were divided into two cohorts: one group consisted of frail octogenarians with HFrEF on SGLT-2 inhibitors, while the control group included matched frail patients with HFrEF not on SGLT-2 inhibitors. Primary and secondary outcomes included all-cause mortality, hospitalization, HF events, urinary tract infections (UTI), hypotension, and composite of falls/syncope. Risk ratio (RR) was calculated using TrinetX platform with 95% confidence interval (CI) and p-values. Survival analysis was conducted using Kaplan-Meier curves, and p-values were derived through the log-rank test.

Results:
A total of 8612 patients were studied with 3406 in each cohort. After propensity score matching, the mean age of the patients at index diagnosis was 86 years (female 45%, male 49%, unknown gender 15%). All-cause mortality was significantly lower in the SGLT-2 inhibitor group compared to the control group (RR 0.648, 95% CI 0.612-0.687, p-value< 0.0001). There was no difference between two cohorts for hospitalization (RR 0.829, 95% CI: 0.544–1.263, p = 0.3811), HF events (RR 0.97, 95% CI: 0.742–1.268, p = 0.8234), UTI (RR 0.946, 95% CI: 0.777–1.153, p = 0.5830), hypotension (RR 0.942, 95% CI: 0.802–1.105, p = 0.4615) and syncope/falls (RR 0.902, 95% CI: 0.743–1.095, p = 0.2977).

Conclusion:
Overall, treatment with SGLT-2 inhibitors was associated with significant reduction in all-cause mortality in frail octogenarians with HFrEF without an increase in adverse events including UTI, hypotension, and syncope/falls. These results suggest that SGLT-2 inhibitor therapy should not be withheld from frail older adults due to fear of adverse events.