LB-007 - GENETIC POLYMORPHISMS IN SLC5A2 ARE ASSOCIATED WITH CLINICAL OUTCOMES AND SGLT2I RESPONSE IN HEART FAILURE PATIENTS.

A. Abou Warda¹, R. Flohr², R. M. Sarhan³, M. Nabil Salem³, H. F. Salem³, A. N. Moharram⁴, A. S Alanazi⁵, C. Lteif², B. Gawronski², L. Dumeny², T. G. Alsahli⁵, K. Elenizi⁶, B. Zarif⁷, N. Sarhan⁸, J. Duarte⁹; ¹October 6 University, Giza, Egypt, ²University of Florida, Gainesville, FL, United States, ³Beni-Suef University, Beni-Suef, Egypt, ⁴Cairo University, Cairo, Egypt, ⁵Jouf University, Jouf, Saudi Arabia, ⁶Prince Sattam bin Abdulaziz University, Alkharj, Saudi Arabia, ⁷National Heart Institute, Giza, Egypt, ⁸Misr International University, Cairo, Egypt, ⁹University of Florida, Gainesville, FL, USA.

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have recently gained much attention in the management of heart failure (HF). However, current findings do not adequately address the precise mechanism through which SGLT2i exerts its beneficial effects in HF patients. Potential SGLT2i mechanisms, HF development, and SGLT2i response can be influenced by genetic diversity in SLC5A2 (the gene that encodes SGLT2). Thus, this study investigated associations between SLC5A2 variation and clinical outcomes in SGLT2i-naïve and SGLT2i-treated HF cohorts.

Methods: Two HF cohorts were analyzed to identify genetic variants associated with SGLT2i response. The first cohort comprised 327 American HF patients naïve to SGLT2i, where the effect of 30 SNPs in SLC5A2 variation on a primary composite outcome of cardiovascular (CV) hospitalization and all-cause mortality were evaluated by adjusted Cox proportional-hazard regression models. Consequently, a prospective cohort study of 190 Egyptian SGLT2i-naïve HF patients treated with SGLT2i was conducted from February 2023 to May 2024. SGLT2-treated patients were also followed for HF hospitalization or CV death. Genotyping was performed for the SLC5A2 SNPs found significant in the first cohort, and clinical outcomes were analyzed in relation to these genetic variations.

Results: In SGLT2i-naïve patients, rs3813008 in SLC5A2 was significantly associated with reduced risk of the composite outcome of all-cause death or hospitalization (HR = 0.65, 95% CI: 0.47-0.89, P = 0.008). In the SGLT2i-treated cohort, rs3813008 was also associated with death or hospitalization, but with increased risk in treated patients (HR = 3.38, 95% CI: 1.35–8.42, P = 0.008).

Conclusion: Our study suggests that SLC5A2 variation is associated with clinical outcomes in SGLT2i-naïve and treated HF patients, warranting further investigation of SLC5A2 and SGLT2i interactions.