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. Recent evidence has implicated inflammatory, autophagic and anti-fibrotic pathways as potentially being associated with their treatment effects. Aim We therefore sought to evaluate the patterns of biomarker response to SGLT2 and associations with 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 the patterns of novel cardiac biomarker response to SGLT2 inhibition and associations with 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+/-8.2 years: 30% 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 treated with SGLT2i, we found a significant decrease in levels of sSt2, a protein implicated in cardiac fibrosis. We noted no change in circulating levels of IL-1β, IL-4, IL-6 or IGFBP1. Interestingly, when compared to changes in LV GLS (%), we observed that decreasing levels of IL-6 correlated with improved LV GLS (%). More exploration of these novel associations are warranted.