Abstract / Summary
Background Following the publication of several landmark trials, sodium glucose co-transport 2 (SGLT2) inhibitors have been demonstrated to reduce all-cause mortality, cardiovascular (CV) mortality and heart failure (HF) hospitalisations, in patients with HF. Unique to this new drug class, is there efficacy in exerting these effects across the spectrum of left ventricular (LV) dysfunction. This has culminated in their rapid incorporation as a class IA guideline directed therapy in both HF with reduced and preserved ejection fractions. Despite this, much remains unclear regarding their mechanism of action with emerging theories that they may exert their effects via mechanisms beyond that of traditional HF pharmacotherapies. In brief the following body of work will address several key questions with respect to the role of SGLT2 inhibition in patients with HF. The arc of these questions will encompass three papers which will broadly address the following. Methods The body of this work that comprises this thesis seeks to examine the effects of SGLT2 inhibition in patients with HF across three key areas, summarised as follows: 1. The impact of SGLT2 inhibition on reverse cardiac remodeling in patients with HF. 2. The effect of SGLT2 inhibition in patients with HF on novel and standard care biomarkers. 3. The effect of SGLT2 inhibition in patients with HF on proteomic expression. The central clinical study was a 26-week, single-arm prospective evaluation of the effects of SGLT2 inhibition on cardiac biomarkers, proteomic shift, myocardial remodeling and patient reported outcomes in patients with heart failure. Results In this thesis by publication, across the collective series of papers presented, we have demonstrated that SGLT2 inhibition in patients with heart failure produces several notable effects. In our meta-analysis we demonstrated SGLT2 inhibition promotes improvements in several cardiac imaging markers of reverse cardiac remodeling. Furthermore, in our clinical study, we found that SGLT2i suppresses markers associated with cardiac fibrosis and inflammation in addition to modulation of proteins/pathways involved in regulation of oxidative stress, cardiac repair, vascular homeostasis and autophagy. Conclusion These results add to the growing body of evidence that SGLT2i may promote cardiac remodeling via modulation of several pathways, distinct to conventional HF therapy. Thesis embargoed until 31st July 2028.