The effects of empagliflozin on measured glomerular filtration rate and estimated extracellular and plasma volumes in patients with type 2 diabetes.

AIMS: To investigate the effects of empagliflozin on measured glomerular filtration rate (mGFR), estimated plasma volume (PV) and estimated extracellular volume (ECV) in a cohort of patients with type 2 diabetes (T2D) and high risk of cardiovascular events. MATERIALS AND METHODS: In this prespecified substudy of the randomized, placebo-controlled SIMPLE trial, patients with T2D at high risk of cardiovascular events were allocated to either empagliflozin 25 mg or placebo once daily for 13 weeks. The prespecified outcome was between-group change in mGFR, measured by the 51 Cr-EDTA method after 13 weeks; changes in estimated PV and estimated ECV were included. RESULTS: From April 4, 2017 to May 11, 2020, 91 participants were randomized. Of these, 45 patients from the empagliflozin group and 45 patients from the placebo group were included in the intention-to-treat analysis. Treatment with empagliflozin reduced mGFR by -7.9 mL/min (95% confidence interval [CI] -11.1 to -4.7; P < 0.001), estimated ECV by -192.5 mL (95% CI -318.0 to -66.9; P = 0.003) and estimated PV by -128.9 mL (95% CI -218.0 to 39.8; P = 0.005) at Week 13. CONCLUSIONS: Treatment with empagliflozin for 13 weeks reduced mGFR, estimated ECV and estimated PV in patients with T2D and high risk of cardiovascular events.

Reduction of cardiac adipose tissue volume with short-term empagliflozin treatment in patients with type 2 diabetes: A substudy from the SIMPLE randomized clinical trial.

OBJECTIVE: Ectopic accumulation of cardiac adipose tissue volume (CAT) has been associated with cardiac remodelling and cardiac dysfunction in type 2 diabetes and may be a future therapeutic target. In this substudy from the SIMPLE-trial, we investigated short-term empagliflozin therapy's effects on CAT in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Between 4 April 2017 and 11 May 2020, we randomized 90 patients with type 2 diabetes and established or high risk of cardiovascular disease to 25 mg empagliflozin or placebo for 13 weeks. The substudy focused on change in CAT evaluated by images acquired during 82 Rubidium-positron emissions tomography/computed tomography. The analysis included 78 patients who had at least one scan. Furthermore, we report on the relation to the concurrent effects on left ventricular mass, end-diastolic volume and end-systolic volume, body composition and glucometabolic status. RESULTS: Mean ± SD baseline CAT was 258.5 ± 117.9 ml. Empagliflozin reduced CAT after 13 weeks by 12.41 ml [95% CI (-23.83 to -0.99), p = .034] as compared with placebo. Similarly, left ventricular mass [-5.16 g, 95% CI (-8.80 to -1.52), p = .006], end-diastolic volume and end-systolic volume decreased with empagliflozin. In addition, significant improvements were observed in body composition, with reduced total fat mass, and in measures of glucose and lipid metabolism. However, no correlation was observed between changes in CAT and changes in cardiac parameters and change in CAT appeared mediated primarily by concurrent change in weight. CONCLUSIONS: Empagliflozin provides an early reduction of CAT; however, no association was observed with concurrent changes in cardiac volumetrics.

Randomized Controlled Trial of the Hemodynamic Effects of Empagliflozin in Patients With Type 2 Diabetes at High Cardiovascular Risk: The SIMPLE Trial.

Treatment with the sodium-glucose cotransporter 2 inhibitor (SGLT-2i) empagliflozin significantly reduces cardiovascular events in patients with type 2 diabetes (T2D); however, the mechanisms behind the reduction in cardiovascular (CV) events are unknown. We investigated whether SGLT-2i treatment affected central hemodynamics during rest and exercise in 34 patients with diabetes in this investigator-initiated, randomized, placebo-controlled, double-blinded trial. The primary end point was change in pulmonary capillary wedge pressure (PCWP) at a submaximal ergometer workload (25 W) after 13 weeks of SGLT-2i treatment (25 mg once daily) compared with placebo. Secondary end points included changes in resting hemodynamics. Baseline and follow-up hemodynamic assessments were performed at rest, submaximal exercise (25 W), and peak exercise using right heart catheterization. Treatment with empagliflozin for 13 weeks in patients with T2D at high CV risk did not reduce left heart filling pressure more than placebo at submaximal exercise. At rest, we observed that empagliflozin reduced PCWP at a magnitude of clinical significance.

Effect of empagliflozin on myocardial structure and function in patients with type 2 diabetes at high cardiovascular risk: the SIMPLE randomized clinical trial.

To investigate the effects of 13 weeks treatment with empagliflozin in patients with high-risk type-2 diabetes mellitus on echocardiographic measures of left ventricular (LV) structure and function compared to placebo. A total of 91 patients were randomized to treatment with empagliflozin (25 mg/day, n = 45) or matching placebo (n = 45) for 13 weeks. Left ventricular (LV) mass, volumes and geometry as well as measures of LV systolic and diastolic function were measured using echocardiography at baseline and follow up. Mean LV mass index (LVMi) was reduced by - 11.5 g/m2 (95% CI - 56.4; 33.4, p = 0.03) with empagliflozin compared to - 1.4 g/m2 (95% CI - 36.5; 33.8, p = 0.63) for placebo. The proportion of patients with LV hypertrophy was reduced by 16.3% (p = 0.04) in the empagliflozin group compared to 1.1% in the placebo group (p = 1.00). The proportion of patients with left atrial volume index > 34 mL/m2 was reduced by 20.0% (p = 0.02) with empagliflozin compared to 9.5% for placebo (p = 0.45) and the E/e' ratio decreased (∆-0.8 (1.9) vs. ∆0.5 (2.0), p < 0.01). 13 weeks empagliflozin treatment in patients with type-2 diabetes at high CV risk significantly reduced LV mass, improved LV geometry and improved diastolic function compared to placebo.

Effects of Empagliflozin on Myocardial Flow Reserve in Patients With Type 2 Diabetes Mellitus: The SIMPLE Trial.

Background Sodium-glucose cotransporter 2 inhibitors reduce hospitalizations for heart failure and cardiovascular death, although the underlying mechanisms have not been resolved. The SIMPLE trial (The Effects of Empagliflozin on Myocardial Flow Reserve in Patients With Type 2 Diabetes Mellitus) investigated the effects of empagliflozin on myocardial flow reserve (MFR) reflecting microvascular perfusion, in patients with type 2 diabetes mellitus at high cardiovascular disease risk. Methods and Results We randomized 90 patients to either empagliflozin 25 mg once daily or placebo for 13 weeks, as add-on to standard therapy. The primary outcome was change in MFR at week 13, quantified by Rubidium-82 positron emission tomography/computed tomography. The secondary key outcomes were changes in resting rate-pressure product adjusted MFR, changes to myocardial flow during rest and stress, and reversible cardiac ischemia. Mean baseline MFR was 2.21 (95% CI, 2.08-2.35). There was no change from baseline in MFR at week 13 in either the empagliflozin: 0.01 (95% CI, -0.18 to 0.21) or placebo groups: 0.06 (95% CI, -0.15 to 0.27), with no treatment effect -0.05 (95% CI, -0.33 to 0.23). No effects on the secondary outcome parameters by Rubidium-82 positron emission tomography/computed tomography was observed. Treatment with empagliflozin reduced hemoglobin A1c by 0.76% (95% CI, 1.0-0.5; P<0.001) and increased hematocrit by 1.69% (95% CI, 0.7-2.6; P<0.001). Conclusions Empagliflozin did not improve MFR among patients with type 2 diabetes mellitus and high cardiovascular disease risk. The present study does not support that short-term improvement in MFR explains the reduction in cardiovascular events observed in the outcome trials. Registration URL: https://clinicaltrialsregister.eu/; Unique identifier: 2016-003743-10.

Design of a randomised controlled trial of the effects of empagliflozin on myocardial perfusion, function and metabolism in type 2 diabetes patients at high cardiovascular risk (the SIMPLE trial).

INTRODUCTION: A diagnosis of type 2 diabetes (T2D) more than doubles the risk of cardiovascular disease (CVD), with heart failure (HF) being one of the most common complications with a severe prognosis. The landmark Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Paitients (EMPA-REG OUTCOME) study demonstrated that treatment with the sodium glucose cotransporter-2 (SGLT-2) inhibitor empagliflozin rapidly and significantly reduces CVD mortality and admission rates for HF. However, the mechanisms behind this reduction in clinical events are unknown.This study was designed to investigate the effects of the SGLT-2 inhibitor empagliflozin on myocardial perfusion and function in patients with T2D and high CVD risk. METHODS AND ANALYSIS: In this investigator-initiated, randomised, double-blind controlled clinical trial, 92 patients with T2D and established CVD or high CVD risk will be randomised to treatment with empagliflozin 25 mg or a matching placebo for 13 weeks. The primary outcome measure is change in myocardial flow reserve measured quantitatively by Rubidium-82 position emission tomography. In a substudy, invasive haemodynamics at rest and during exercise will be measured at baseline and following the intervention, using right heart catheterisation. ETHICS AND DISSEMINATION: The study protocol (v7, 02/08/2018) has been approved by the Ethics Committee of the Capital Region, Danish Data Protection Board and the Danish Medicines Agency, and it will be monitored according to the Good Clinical Practice regulations from the International Conference on Harmonization. The results be submitted to international peer-reviewed journals and be presented at conferences. The data will be made available to the public via EudraCT and www.clinicaltrials.gov. TRIAL REGISTRATION NUMBER: NCT03151343.