The Effect of Empagliflozin on Left Ventricular Mass and Myocardial Extracellular Volume in Patients with Type 2 Diabetes and Cardiovascular Disease

Background: The sodium glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular (CV) outcomes in patients with type 2 diabetes (T2DM) and established CV disease (CVD) but the mechanism driving their cardio-benefit remains poorly understood. Specifically, whether SGLT2 inhibitors have direct cardiac effects remains unknown. Objective: To evaluate the effects of the SGLT2 inhibitor empagliflozin on left ventricular (LV) mass index (LVMi) and myocardial extracellular volume (ECV) in individuals with T2DM and CVD. Method: We randomized 97 participants with T2DM and CVD to receive empagliflozin 10 mg daily or placebo for 6 months in addition to standard of care therapy. The primary outcome was change in LVMi from baseline to 6 months determined by cardiac magnetic resonance. Other outcomes included change in indexed LV end diastolic volume (LVEDVi), end systolic volume (LVESVi) or ejection fraction (LVEF) and in circulating N-terminal pro B-type natriuretic peptide (NT-proBNP) and troponin I. For our sub-study with 74 participants we assessed ECV, indexed intracellular and extracellular compartment volume (iICV, iECV), the fibrosis biomarkers soluble suppressor of tumorgenicity (sST2) and matrix metalloproteinase-2 (MMP-2). Results: In the primary study, change in LVMi from baseline to 6-months was -2·6 (7·8) g/m2 for the empagliflozin group and -0·01 (5·7) g/m2 for placebo (adjusted difference between groups -3·4 g/m2; 95% Confidence Interval (CI), -5·9 to -0·8; P=0·01). There were no significant differences between groups for LVEDVi, LVESVi, LVEF nor in NT-proBNP and troponin I. In our sub-study, empagliflozin reduced ECV compared to placebo (adjusted difference: -1.4%; 95% CI, -2.6 to -0.14; P=0.03). This reduction in ECV in the empagliflozin group was observed after 6 months, alongside the reduction in LVMi. Empagliflozin therapy compared with placebo, also reduced iECV (adjusted difference: -1.5 mL/m2; 95% CI, -2.6 to -0.5; P=0.006) with a trend towards reduction in iICV (adjusted difference: -1.7 mL/m2; 95% CI, -3.8 to 0.3; P=0.09). Empagliflozin had no difference in impact upon circulating levels of MMP-2 or sST2 when compared to placebo. Conclusions: In patients with T2DM and CVD, empagliflozin therapy was associated with a reduction in ECV in parallel to a reduction in LVMi which may contribute to its CV benefits.Ph.D