Investigation of Biomarker Response to SGLT2 Inhibition in Heart Failure (SiN-HF)

Introduction Following several landmark trials, sodium glucose co-transport (SGLT) 2 inhibitors, have been established as a guideline directed therapy for heart failure (HF). Moreover, their benefit has been established across the spectrum of left ventricular (LV) dysfunction. Much remains unclear regarding their mechanism of action with current evidence implicating pathways involvement of inflammatory, autophagic and anti-fibrotic pathways. Aim We therefore sought to evaluate the effects of SGLT2 inhibition on cardiac biomarkers, myocardial remodelling and patient reported outcomes in heart failure. Methods This was a 26-week, single-arm prospective evaluation of the effects of SGLT2 inhibition on novel biomarkers, myocardial remodeling and patient reported outcomes in patients with heart failure. Baseline echocardiography, serum analysis (standard care and novel biomarkers) and quality of life (QoL) metrics were assessed prior to SGLT2i therapy and at 26-week follow-up. Novel biomarkers were analysed using enzyme-linked immunosorbent assays. Data were analysed using SPSS (IBM SPSS Statistics, Version 28.0). Clinical Trials.gov identifier: NCT06140251 . Results Forty-six patients were recruited with forty patients undergoing biomarker analysis (mean age 67.2+/-8.2years: 68.3% female). Mean LV ejection fraction (LVEF) at baseline was 45.3+/9.8% (ischaemic aetiology: 40.0%, diabetic: 5%). At a median follow-up of 196 days, soluble suppression of tumorigenicity 2 (sSt2) fell significantly (mean difference − 13.5pg/ml [95% CI: -17.9 to − 8.9: p < 0.001]), with no significant change in interleukin (IL)1-β, IL-4, IL-6 or insulin growth factor binding protein 1 (IGFBP-1) (all p = ns). Interestingly, delta change in IL-6 modestly correlated with change in global longitudinal strain (GLS) (%) (r=-0.43, p = 0.012). Change in GLS (%) was not correlated with other novel cardiac biomarkers. Conclusion In our cohort we found that sSt2, a protein implicated in cardiac fibrosis, was suppressed by SGLT2i. Additionally, we observed that suppression of IL-6, a marker of inflammation, correlated with reverse cardiac remodeling. These data support the implication of SGLT2i in suppression of fibrotic and inflammatory pathways. More exploration of these associations is warranted.