Abou Warda Ahmed Essam, Flohr Rylie M, Sarhan Rania M, Salem Mohamed Nabil, Salem Heba F, Moharram Ayman N, Alanazi Abdullah S, Lteif Christelle, Gawronski Brian E, Dumeny Leanne, Alsahli Tariq G, Elenizi Khaled, Zarif Bassem, Sarhan Neven, Duarte Julio D
Department of Clinical Pharmacy, Faculty of Pharmacy, October 6 University, Giza, Egypt.
Center for Pharmacogenomics and Precision Medicine and Department for Pharmacotherapy and Translational Research, University of Florida, Gainesville, FL, United States.
Front Pharmacol. 2025 Apr 28;16:1539870. doi: 10.3389/fphar.2025.1539870. eCollection 2025.
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have emerged as promising therapeutics for heart failure (HF). Nevertheless, evidence supporting the mechanism of SGLT2i efficacy in HF patients is currently limited. Genetic variation in (encoding SGLT2) may influence HF progression and SGLT2i response, as well as inform potential SGLT2i mechanisms. Thus, this study investigated associations between variation and clinical outcomes in SGLT2i-naïve and dapagliflozin-treated HF cohorts.
We analyzed two HF cohorts to identify variants associated with SGLT2i response pathways. Adjusted Cox proportional-hazard regression models were used to assess the effect of variation on a primary composite outcome of cardiovascular (CV) hospitalization or all-cause mortality in SGLT2i-naïve patients, and HF hospitalization or CV death in dapagliflozin-treated patients. The initial cohort comprised 327 American HF patients naïve to SGLT2i throughout the study. Subsequently, a prospective cohort study of 190 Egyptian SGLT2i-naïve HF patients treated with dapagliflozin was analyzed. In this cohort, SNPs in and were also investigated. Changes in NT-proBNP levels, KCCQ-12 scores, echocardiographic parameters, and eGFR throughout 6-month follow-up were tested with linear regression models as secondary outcomes.
In SGLT2i-naïve patients, rs3813008 (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 dapagliflozin-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).
Our study suggests that variation is associated with clinical outcomes in SGLT2i-naïve and treated HF patients, warranting further investigation of and SGLT2i interactions.
钠-葡萄糖协同转运蛋白2抑制剂（SGLT2i）已成为治疗心力衰竭（HF）的有前景的疗法。然而，目前支持SGLT2i在HF患者中疗效机制的证据有限。编码SGLT2的基因变异可能影响HF进展和SGLT2i反应，以及揭示潜在的SGLT2i机制。因此，本研究调查了在未使用SGLT2i和使用达格列净治疗的HF队列中基因变异与临床结局之间的关联。
我们分析了两个HF队列，以确定与SGLT2i反应途径相关的变异。采用校正的Cox比例风险回归模型，评估基因变异对未使用SGLT2i患者的心血管（CV）住院或全因死亡的主要复合结局，以及使用达格列净治疗患者的HF住院或CV死亡的影响。初始队列包括在整个研究期间未使用SGLT2i的327例美国HF患者。随后，分析了一项对190例接受达格列净治疗的未使用SGLT2i的埃及HF患者的前瞻性队列研究。在该队列中，还研究了编码SGLT2的基因和其他基因中的单核苷酸多态性（SNP）。在6个月的随访期间，用线性回归模型测试NT-proBNP水平、KCCQ-12评分、超声心动图参数和估算肾小球滤过率（eGFR）的变化作为次要结局。
在未使用SGLT2i的患者中，rs3813008（SLC5A2）与全因死亡或住院的复合结局风险降低显著相关（风险比[HR]=0.65，95%置信区间[CI]：0.47-0.89，P=0.008）。在使用达格列净治疗的队列中，rs3813008也与死亡或住院相关，但在治疗患者中风险增加（HR=3.38，95%CI：1.35-8.42，P=0.008）。
我们的研究表明，基因变异与未使用SGLT2i和已使用SGLT2i治疗的HF患者的临床结局相关，需要进一步研究编码SGLT2的基因与SGLT2i的相互作用。
