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/e') 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).

Keywords: Diabetes; Diastolic function; Hemodynamic parameters; SGLT2 inhibitors.

Conflict of interest statement

MR, KT, NUKH, AS and JM report no potential conflict of interest, EA did receive personal fees from AstraZeneca und Novartis and receive research grants from Bayer und Novartis, MB served as a consultant and gave talks for Abbott, Amgen, Astra-Zeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers-Sqibb, Cytokinetics, Medtronic, Novartis, Servier; NM has received support for clinical trial leadership from Boehringer Ingelheim, Novo Nordisk, served as a consultant to Boehringer Ingelheim, Merck, Novo Nordisk, AstraZeneca, BMS, received grant support from Boehringer Ingelheim, Merck, Novo Nordisk, and served as a speaker for Boehringer Ingelheim, Merck, Novo Nordisk, Lilly, BMS, and Astra Zeneca. NM declines all personal compensation from pharma or device companies. ML received grants and personal fees from Boehringer Ingelheim, MSD and Novo Nordisk, personal fees from Amgen, Sanofi, Astra Zeneca, Bayer and Lilly.

Figures

Fig. 1

Hemodynamic parameters. Systemic vascular resistance index (SVRI) (a), cardiac index (CI) (b), stroke volume index (SVI) (c), and heart rate (HR) (d) in patients with type 2 diabetes treated with empagliflozin (n = 20; black line) or placebo (n = 22; blue dotted line). Data are shown as mean ± standard error at baseline, after 1 day, 3 days, and 3 months. p-values are calculated from Wald tests for the intervention effect at each visit

Fig. 2

Metabolic parameters and renal function. Urinary glucose excretion (a), 24 h urinary volume (b), eGFR (c), and plasma cystatin C levels (d) in patients with type 2 diabetes treated with empagliflozin (n = 20; black line) or placebo (n = 22; blue dotted line). Data are shown as mean ± standard error at baseline, after 1 day, 3 days, and 3 months. p-values are calculated from Wald tests for the intervention effect at each visit

Fig. 3

Left ventricular diastolic function. Early mitral inflow velocity relative to early diastolic left ventricular relaxation (E/eʹ) in patients with type 2 diabetes treated with empagliflozin (n = 20; black line) or placebo (n = 22; blue dotted line). Data are shown as mean ± standard error at baseline, after 1 day, 3 days, and 3 months. p-values are calculated from Wald tests for the intervention effect at each visit