Effects of empagliflozin on functional capacity, LV filling pressure, and cardiac reserves in patients with type 2 diabetes mellitus and heart failure with preserved ejection fraction: a randomized controlled open-label trial

Abstract

Background: Clinical trials have established the prognostic benefits of sodium‒glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus (T2DM) and heart failure (HF) with preserved ejection fraction (HFpEF), although the underlying mechanisms are not clearly understood. The purpose of this study was to determine the effects of the SGLT2 inhibitor empagliflozin on functional capacity, left ventricular (LV) diastolic function/filling pressure, and cardiac reserves in patients with HFpEF and T2DM.

Methods: In the present prospective single-center trial, we enrolled 70 diabetic patients with stable HF according to the New York Heart Association functional class II-III criteria, an LV ejection fraction ≥ 50%, and increased LV filling pressure at rest and/or during exercise (determined by echocardiography). The patients were randomly assigned in an open-label fashion to the empagliflozin group (10 mg a day, n = 35) or the control group (n = 35) for 6 months. Echocardiography (at rest and during exercise), the 6-min walk test distance (6MWD), blood levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), and the profibrotic biomarker sST2 were analysed at baseline and 6 months after randomization. The primary endpoint was the change in the 6MWD, and the secondary endpoints included the change in the left atrial (LA) volume index, early mitral inflow to mitral annulus relaxation velocity (E/e') ratio both at rest and during exercise, key cardiac reserves and biomarkers in the blood from baseline to 6 months.

Results: After 6 months of empagliflozin therapy, the 6MWTD significantly increased, whereas the LA volume index and the E/e' ratio both at rest and during exercise decreased compared with those of the control group (P < 0.05 for all). LV diastolic, LA reservoir and contractile, and chronotropic reserves also improved in the empagliflozin group compared with those in the control group (P < 0.05 for all). Furthermore, treatment with empagliflozin led to improvements in NT-proBNP and ST2 blood levels compared with those in the control group (P < 0.05 for both).

Conclusions: In diabetic patients with HFpEF, empagliflozin treatment improved exercise capacity, which appeared to be the result of favourable effects on LV diastolic dysfunction and key cardiac reserves: LV diastolic, LA reservoir and contractile, and chronotropic. These haemodynamic mechanisms may underline the benefits of SGLT2 inhibitors in large-scale HFpEF trials.

Trial registration: URL: https://www.

Clinicaltrials: gov . Unique Identifier NCT03753087.

Keywords: Cardiac reserve; Diastolic dysfunction; Empagliflozin; Heart failure with preserved ejection fraction; Type 2 diabetes.

Fig. 1

Flow chart of patient enrolment. T2DM, type 2 diabetes mellitus; HFpEF, heart failure with preserved ejection fraction

Fig. 2

Individual and mean changes from baseline (95% CI) in the 6-min walk distance a bicycle exercise duration b and the Minnesota Living with Heart Failure Questionnaire (MLHFQ) total score c in both study groups. Individual changes are represented by circles, the squares indicate the means, and the error bars indicate the 95% CIs

Fig. 3

Individual and mean changes from baseline (95% CI) in the left atrial volume index (LAVI, a), pulmonary artery systolic pressure (PASP, b), annulus relaxation velocity (e′, c), and tricuspid annular plane systolic excursion (TAPSE, d) in both study groups. Individual changes are represented by circles, the squares indicate the means, and the error bars indicate the 95% CIs

Fig. 4

The mean and individual changes in the mitral E/e′ ratio (a–c), left atrial reservoir strain (LASr, d–f), and heart rate (g–i) at rest and during cycle exercise at baseline and after 6 months in both study groups. The bars and squares indicate the means, and the markers (error bars) indicate the standard deviations or 95% confidence intervals

Fig. 5

Correlations between changes in the 6-min walk test distance (6MWTD, from baseline values to 6-month values) and changes in the mitral E/e′ ratio during exercise a mitral annular relaxation velocity (e′) at rest b or during exercise c in patients treated with empagliflozin for 6 months

Fig. 6

Correlations between changes in NT-proBNP levels (from baseline values to 6-month values) and changes in exercise-induced annular a′ velocity increase (LA reserve, a), exercise-induced e′ velocity increase (diastolic reserve, b), and hsCRP blood levels in the entire empagliflozin group (c) and in the subgroup of patients with baseline hsCRP > 2.1 mg/L (above the median, d). a Average annular relaxation velocity, ε Average annular relaxation velocity, hsCRP High-sensitivity C-reactive protein, LASr Left atrial strain during the reservoir phase, NT-proBNP N-terminal pro–brain natriuretic peptide, sST2 Soluble interleukin 1 receptor-like 1