Empagliflozin does not change cardiac index nor systemic vascular resistance but rapidly improves left ventricular filling pressure in patients with type 2 diabetes: a randomized controlled study

Abstract

Background In the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial) treatment with the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin significantly reduced heart failure hospitalization (HHF) in patients with type 2 diabetes mellitus (T2D) and established cardiovascular disease. The early separation of the HHF event curves within the first 3 months of the trial suggest that immediate hemodynamic effects may play a role. However, hitherto no data exist on early effects of SGLT2 inhibitors on hemodynamic parameters and cardiac function. Thus, this study examined early and delayed effects of empagliflozin treatment on hemodynamic parameters including systemic vascular resistance index, cardiac index, and stroke volume index, as well as echocardiographic measures of cardiac function. Methods In this placebo-controlled, randomized, double blind, exploratory study patients with T2D were randomized to empagliflozin 10 mg or placebo for a period of 3 months. Hemodynamic and echocardiographic parameters were assessed after 1 day, 3 days and 3 months of treatment. Results Baseline characteristics were not different in the empagliflozin (n = 22) and placebo (n = 20) group. Empagliflozin led to a significant increase in urinary glucose excretion (baseline: 7.3 ± 22.7 g/24 h; day 1: 48.4 ± 34.7 g/24 h; p < 0.001) as well as urinary volume (1740 ± 601 mL/24 h to 2112 ± 837 mL/24 h; p = 0.011) already after one day compared to placebo. Treatment with empagliflozin had no effect on the primary endpoint of systemic vascular resistance index, nor on cardiac index, stroke volume index or pulse rate at any time point. In addition, echocardiography showed no difference in left ventricular systolic function as assessed by left ventricular ejections fraction and strain analysis. However, empagliflozin significantly improved left ventricular filling pressure as assessed by a reduction of early mitral inflow velocity relative to early diastolic left ventricular relaxation (E/eʹ) which became significant at day 1 of treatment (baseline: 9.2 ± 2.6; day 1: 8.5 ± 2.2; p = 0.005) and remained apparent throughout the study. This was primarily attributable to reduced early mitral inflow velocity E (baseline: 0.8 ± 0.2 m/s; day 1: 0.73 ± 0.2 m/sec; p = 0.003). Conclusions Empagliflozin treatment of patients with T2D has no significant effect on hemodynamic parameters after 1 or 3 days, nor after 3 months, but leads to rapid and sustained significant improvement of diastolic function. Trial registration EudraCT Number: 2016-000172-19; date of registration: 2017-02-20 (clinicaltrialregister.eu)

Effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on left ventricular remodelling and longitudinal strain: a prospective observational study

“…Furthermore, Global Longitudinal Strain (GLS) determined by Speckle Tracking technique is a surrogate of left ventricular systolic function [ 15 ]. Clinical studies of the effects of SGLT2 inhibitors on myocardial deformation parameters are scarce [ 16 , 17 ]. Although LV longitudinal strain was previously measured by cardiac magnetic resonance [ 18 ], to our knowledge, there are no studies estimating GLS by speckle tracking echocardiography in patients treated with SGLT2 inhibitors.…”

Human and mouse non‐targeted metabolomics identify 1,5‐anhydroglucitol as SGLT2‐dependent glycemic marker

“…In a placebo-controlled, randomized, double blind human trial (Figure 4A), 3 1,5-AG was significantly reduced by empagliflozin treatment , but not by placebo (Figure 4B). While at baseline (before empagliflozin), 1,5-AG showed a strong correlation to HbA1c and serum glucose, these correlations lost under conditions of empagliflozin treatment (Figure 4C,D).…”

“…2 A targeted analysis of 1,5-AG was performed in a placebo-controlled, randomized, double blind human trial with empagliflozin (n = 42). 3 We first explored serum metabolomics data of the MI cohort and Db/Db versus Db/+ mice (Figure 1A,B; Table S3 and Table S4). Considering the top 10 most significant metabolites by P-value, both data sets showed a clear separation of diabetes versus non-diabetes (Figure 1C,D; Tables S3 and S4).…”

“…Kirsten Thiele 1 Matthias Rau 1 Anna Artati 2 Jerzy Adamski 3,4,5 Bart Ghesquiere 6,7 Katharina Schuett 1 Francesco Romeo 8 Robert Stoehr 1 Nikolaus Marx 1 Massimo Federici 8,9,# Michael Lehrke 1,#…”

Cardioprotection by SGLT2 Inhibitors—Does It All Come Down to Na+?

“…Similar beneficial effects on diastolic function in patients with type II diabetes mellitus were reproduced in smaller trials using empagliflozin or canagliflozin [ 129 , 130 ]. In another interesting randomized, double-blind, and placebo-controlled study Rau et al demonstrated that empagliflozin improved diastolic function (E/e´) as early as one day after initiation in diabetic patients, while non-invasively assessed hemodynamic parameters (stroke volume index, cardiac index, vascular resistance index or pulse rate) were unchanged [ 131 ]. While the results from two large clinical trials investigating the effects of empagliflozin (EMPEROR-Preserved [ 132 ]) or dapagliflozin (DELIVER [ 133 ]) in reducing cardiovascular death and heart failure events in non-diabetic patients with HFpEF are awaited for late 2021 and early 2022, respectively, there is pre-clinical evidence for an SGLT2i-mediated attenuation of diastolic dysfunction irrespective of a diabetic condition.…”