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) (1). Much remains unclear regarding their mechanism of action with current evidence implicating pathways involvement of inflammatory, autophagic and anti-fibrotic pathways (2). Purpose 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 cardiac 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. 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, a significant improvement in haematocrit (41.2+/-4.1 to 43.8+/-3.9%: p<0.001) and haemoglobin (140.5+/-13.9 to 147.9+/-13.6g/dL: p<0.001) were noted with no difference in NT-proBNP (p=0.441). Of the novel cardiac biomarkers assessed sSt2 fell significantly (mean difference -13.5pg/ml [95% CI: -17.9 to - 8.9: p<0.001]), with no significant change in IL1β, IL4, IL6 or IGFBP1 (all p=ns). Notably, a significant improvement in KCCQ-12 score was observed (mean improvement 9.3 points [95%CI: -12.6 to - 6.1: p<0.001]). Interestingly, delta change in IL-6 modestly correlated with delta change in global longitudinal strain (GLS) (%) (r=0.43, p=0.012); with a weak correlation also noted between delta change in LVEF (%) and sSt2 (r=0.314, p=0.06) and IL-6 (r=0.3, p=0.07). However, this did not reach significance. Additionally, when delineated by duration of treatment (≥/≤200days), improvement in GLS (%) was noted to be greater in the group with a longer duration of SGLT2i therapy (X2=4.3, p=0.037). 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. It is plausible that improvements in other markers of may become more pronounced with longer duration SGLT2i therapy, and as a corollary, this may explain the early signal of correlation noted between IL-6 and sSt2 with other markers of reverse cardiac remodeling. These data support the implication of SGLT2i in suppression of fibrotic and inflammatory pathways. More exploration of these associations are warranted.