Effect of empagliflozin on left ventricular contractility and peak oxygen uptake in subjects with type 2 diabetes without heart disease: results of the EMPA-HEART trial

Abstract

Background The mechanism through which sodium-glucose cotransporter 2 inhibitors (SGLT2i) prevent the incidence of heart failure and/or affect cardiac structure and function remains unclear. Methods The EMPA-HEART trial is aimed at verifying whether empagliflozin improves myocardial contractility (left ventricle global longitudinal strain, LV-GLS) and/or cardiopulmonary fitness (peak oxygen uptake, VO2peak) in subjects with type 2 diabetes (T2D) without heart disease. Patients with T2D, normal LV systolic function (2D-Echo EF > 50%), and no heart disease were randomized to either empagliflozin 10 mg or sitagliptin 100 mg for 6 months and underwent repeated cardiopulmonary exercise tests with echocardiography and determination of plasma biomarkers. Results Forty-four patients completed the study, 22 per arm. Despite comparable glycaemic control, modest reductions in body weight (− 1.6; [− 2.7/− 0.5] kg, p = 0.03) and plasma uric acid (− 1.5; [− 2.3/− 0.6], p = 0.002), as well as an increase in haemoglobin (+ 0.7; [+ 0.2/+ 1.1] g/dL, p = 0.0003) were evident with empagliflozin. No difference was detectable in either LV-GLS at 1 month (empagliflozin vs sitagliptin: + 0.44; [− 0.10/+ 0.98]%, p = 0.11) and 6 months of therapy (+ 0.53; [− 0.56/+ 1.62]%), or in VO2peak (+ 0.43; [− 1.4/+ 2.3] mL/min/kg, p = 0.65). With empagliflozin, the subgroup with baseline LV-GLS below the median experienced a greater increase (time*drug p < 0.05) in LV-GLS at 1 month (+ 1.22; [+ 0.31/+ 2.13]%) and 6 months (+ 2.05; [+ 1.14/+ 2.96]%), while sitagliptin induced a modest improvement in LV-GLS only at 6 months (+ 0.92; [+ 0.21/+ 0.62]%). Conclusions Empagliflozin has neutral impact on both LV-GLS and exercise tolerance in subjects with T2D and normal left ventricular function. However, in patients with subclinical dysfunction (LV-GLS < 16.5%) it produces a rapid and sustained amelioration of LV contractility. Trial registration EUDRACT Code 2016-002225-10

Oral ketone esters acutely improve myocardial contractility in post-hospitalized COVID-19 patients: A randomized placebo-controlled double-blind crossover study

“…It has been suggested that ketone bodies might have a direct metabolic cardioprotective effect ( 38 ). In patients with T2D without heart disease, treatment with SGLT2 inhibitors increase GLS but only in the group with subclinical myocardial dysfunction (GLS < 16.5%) ( 39 ). This supports the proposed hypothesis that the effect of ketone esters on myocardial contractility depends on the degree of cardiac dysfunction.…”

Distinct effects of type 2 diabetes and obesity on cardiopulmonary performance

“…Breath‐by‐breath minute ventilation, carbon dioxide production (VCO 2 ), and VO 2 were measured using a dedicated cardiopulmonary diagnostic device (Blue Cherry; Geratherm Respiratory GmbH). We defined VO 2peak as the highest median value of the two 30‐s intervals of the last minute of exercise, as previously validated and used 1,21,22 . An automatic procedure determined the anaerobic threshold (AT) based on the V‐slope, ventilatory equivalents and end‐tidal partial pressure methods; AT was verified visually and, if necessary, recalculated 1 .…”

“…Cardiac output was calculated as the multiplication of SV and HR. Peripheral extraction, or arteriovenous oxygen difference (Δ(a‐v)O 2 ) was estimated indirectly with a validated approach 1,5,21,22 . Images were acquired concurrently with breath‐by‐breath gas exchange measurements at both baseline and peak of exercise.…”

“…We defined VO 2peak as the highest median value of the two 30-s intervals of the last minute of exercise, as previously validated and used. 1,21,22 An automatic procedure determined the anaerobic threshold (AT) based on the V-slope, ventilatory equivalents and end-tidal partial pressure methods; AT was verified visually and, if necessary, recalculated. 1 The chronotropic response was calculated as the change in HR from rest to peak exercise, divided by the difference between the age-predicted maximal HR and the resting HR (i.e.…”

“…Peripheral extraction, or arteriovenous oxygen difference (Δ(a-v)O 2 ) was estimated indirectly with a validated approach. 1,5,21,22 Images were acquired concurrently with breath-by-breath gas exchange measurements at both baseline and peak of exercise. All measurements were reported as the average of three beats.…”