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

Abstract

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.

Keywords: cardiac adipose tissue; empagliflozin; metabolism; type 2 diabetes.

FIGURE 1

Cardiac‐specific changes and changes in adipose tissue mass following short‐term empagliflozin treatment in patients with type 2 diabetes and established cardiovascular risk. Evidence suggests accumulation of cardiac adipose tissue has detrimental effects on cardiac remodelling through metabolic and inflammatory pathways. In the current substudy of the SIMPLE trial, a short regimen with 25 mg empagliflozin led to a decrease in cardiac adipose tissue [treatment effect: −12.41 ml 95% CI (−23.83 to −0.99), p = .034] and showed evidence of left ventricular mass regression indexed to body surface area [treatment effect: −2.47 g/m² 95% CI (−4.14 to −0.80), p = .004] as well as a change in body composition by a decrease in adipose tissue mass [treatment effect: −0.81 kg 95% CI (−1.40 to −0.22), p = .008] when comparing groups at week 13. However, changes in cardiac adipose tissue volume appeared mainly mediated by changes in weight, and were not correlated with changes in left ventricular mass, suggesting parallel phenomena rather than a direct of effect mediated by sodium‐glucose cotransporter 2 inhibitor (SGLT2‐i) treatment

FIGURE 2

Process of quantifying cardiac adipose tissue and left ventricular mass. (A) The fibrous layer of the pericardial sac was delineated automatically, resulting in a total cardiac volume. Adipose tissue contained therein was derived using the specific density of fat (−150 to −50 Hounsfield units), giving a volume including both paracardial and epicardial adipose tissue. (B) The epi‐ and endocardial border were delineated automatically to derive left ventricular mass, end‐diastolic and end‐systolic volume

FIGURE 3

Effect modification according to post‐hoc defined subgroups by baseline values. No significant effect modification was observed on the effect of sodium‐glucose cotransporter 2 inhibitor on the primary focus, cardiac adipose tissue