Effect of Empagliflozin on Left Ventricular Mass and Diastolic Function in Individuals With Diabetes: An Important Clue to the EMPA-REG OUTCOME Trial?

Amid the excitement over the results of the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial (1), the potential mechanisms through which empagliflozin produced a rapid and profound reduction in hospitalization for heart failure and cardiovascular (CV) death in subjects with type 2 diabetes remain entirely unexplained. Importantly, the effects of empagliflozin on objective measures of cardiac structure and function are unknown (2).We report the first systematic analysis of echocardiograms of 10 patients with type 2 diabetes and established CV disease in whom empagliflozin 10 mg/day was initiated as per approved clinical indication, without any other concurrent changes in medications. Transthoracic echocardiograms, performed before and 3 months after initiation of empagliflozin, were analyzed by an experienced cardiac echocardiographer not involved in the clinical care of the patients and blinded to identity of the patients and the study order (pre vs. post). Informed patient consent and ethics approval were obtained. Baseline patient characteristics were as follows: 80% were men, age was mean (SD) 67.6 (6.6) years, 40% had a previous myocardial infarction, 90% had undergone vascularization, and estimated glomerular filtration rate was 77.5 (21.3) mL/min/1.73 m. Background medications included the following: eight patients on metformin, five patients on dipeptidyl peptidase-4 inhibitors, one patient on a sulfonylurea, three patients on insulin, nine patients on statins, six patients on ACE inhibitors or angiotensin receptor blockers, two patients on diuretics, eight patients on b-blockers, and three patients on calcium channel blockers. Mean (SD) treatment duration was 151.8 (21.8) days. Empagliflozin treatment modestly improved glycemic control [HbA1c 7.30% (0.84) [56 mmol/mol (9.3)] vs. 6.81% (0.49) [51 mmol/mol (5.4)], P 5 0.024, and fasting blood glucose 6.3 (1.12) vs. 6.0 (0.95) mmol/L, P 5 0.668]. There were no significant changes in blood pressure [117 (18)/68 (11) vs. 126 (13)/74 (11) mmHg, P . 0.05]. Body weight did not change after treatment [74.4 (9.7) vs. 74.1 (11.7) kg, P5 0.821]. Strikingly, short-term empagliflozin treatment was associated with a significant reduction in left ventricular (LV) mass index [mean (SD) 88 (21) vs. 75 (19) g/m, P 5 0.01] (a wellestablished CV surrogate end point) and improved diastolic function per the early lateral annular tissue Doppler velocity [8.5 (1.6) vs. 9.6 (1.3) cm/s, P5 0.002 (e9; Fig. 1)]. There were numerical but not significant differences in ratio of early to late mitral inflow [0.90 (0.20) vs. 1.04 (0.20), P 5 0.101] and early diastolic deceleration time [229.90 (45.06) vs. 205.60 (26.03) ms, P 5 0.112]. There were no differences in LV systolic function [63% (8) vs. 66% (6), P 5 0.41], LV end diastolic volume [47 (15) vs. 46 (15) mL/m, P5 0.93], and LV endsystolic volume [18 (9) vs. 16 (7)mL/m, P5 0.54]. These observations, albeit preliminary, suggest the potential of empagliflozin to favorably promote LV reverse remodeling and improve diastolic function in subjects with type 2 diabetes and established CV disease. The rapid cardiac benefits are consistent with the early separation of the Kaplan-Meier curves for heart failure–associated hospitalization and CV mortality in the EMPA-REG OUTCOME trial (1). Whether the improvement in diastolic function is secondary to a reduction in LV mass or through another distinct mechanism remains