Personalized Response to Empagliflozin in Heart Failure: Association of BDNF and ATP2A2 Variants in a South Asian Cohort

<b>Background:</b> Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, improves outcomes in heart failure (HF) patients, yet inter-individual variability in response remains unclear. Genetic variants in Brain-Derived Neurotrophic Factor <i>BDNF</i> (rs6265) and ATPase Sarcoplasmic/Endoplasmic Reticulum Ca²⁺ Transporting 2 ATP2A2 (rs1860561) may influence the treatment efficacy. <b>Objective:</b> To assess the association of <i>BDNF</i> and <i>ATP2A2</i> polymorphisms with the response to low-dose empagliflozin (10 mg) in Pakistani patients with heart failure and a reduced ejection fraction (HFrEF). <b>Methods:</b> In this prospective study, 120 HF patients with an ejection fraction of 25-45% who had been on stable standard heart failure therapy for at least 3 months were initiated on 10 mg of empagliflozin. The brain natriuretic peptide (BNP) and LVEF left ventricular ejection fraction (LVEF) were assessed at 6 and 12 months. Genotyping for rs6265 and rs1860561 was performed via Sanger sequencing. A response was defined as a ≥5% EF increase or ≥20% BNP reduction. Associations were analyzed using chi-square and logistic regression. <b>Results:</b> Among 99 genotyped patients, <i>BDNF</i> T allele carriers (CT/TT) had a significantly lower EF (<i>p</i> = 0.028) and BNP (<i>p</i> < 0.001) response. The CC genotype was associated with improved outcomes (BNP OR: 7.70; EF OR: 5.97). For <i>ATP2A2</i>, the GG genotype showed a strong association with EF improvement (OR: 5.97; <i>p</i> = 0.001), with no BNP association. Variant allele frequencies were higher among Punjabis and Kashmiris than Pathans. <b>Conclusions:</b> BDNF rs6265 and ATP2A2 rs1860561 polymorphisms appear to influence the individual response to empagliflozin in HFrEF patients. These findings underscore the potential of pharmacogenetic profiling to guide personalized therapy and optimize treatment outcomes in heart failure.