Key result
The SLC5A2 rs3813008 variant was associated with a reduced risk of death or hospitalization in SGLT2i-naïve heart failure patients (HR 0.65) but an increased risk in dapagliflozin-treated patients (HR 3.38).
Why the study?
Evidence supporting the mechanism of SGLT2i efficacy in heart failure is limited, and genetic variation in SLC5A2 may influence HF progression and treatment response.
Does SLC5A2 genetic variation influence clinical outcomes in SGLT2i-naïve and dapagliflozin-treated heart failure patients?
Cohort (n=517)
Yes
Does SLC5A2 genetic variation influence clinical outcomes in SGLT2i-naïve and dapagliflozin-treated heart failure patients?
Hazard Ratio: 0.65 (95% CI 0.47–0.89)
p-value: p=0.008
Genetic variation in SLC5A2 (rs3813008) may influence clinical outcomes differently in SGLT2i-naïve versus dapagliflozin-treated heart failure patients, highlighting a potential gene-drug interaction.
rs3813008 may modify HF outcomes by dapagliflozin exposure; leaves open gene-drug interaction hypothesis, no practice change yet.
Background 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 SLC5A2 (encoding SGLT2) may influence HF progression and SGLT2i response, as well as inform potential SGLT2i mechanisms. Thus, this study investigated associations between SLC5A2 variation and clinical outcomes in SGLT2i-naïve and dapagliflozin-treated HF cohorts. Methods 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 SLC5A2 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 UGT2B4 and SLC2A1 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. Results 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). 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.
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Warda et al. (2025) conducted a cohort in Heart failure (n=517). SLC5A2 rs3813008 polymorphism vs. Reference genotype was evaluated on Composite of cardiovascular hospitalization or all-cause mortality (HR 0.65, 95% CI 0.47-0.89, p=0.008). The SLC5A2 rs3813008 variant was associated with a reduced risk of death or hospitalization in SGLT2i-naïve heart failure patients (HR 0.65) but an increased risk in dapagliflozin-treated patients (HR 3.38).
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