Effect of empagliflozin on ectopic fat stores and myocardial energetics in type 2 diabetes: the EMPACEF study

Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that has demonstrated cardiovascular and renal protection in patients with type 2 diabetes (T2D). We hypothesized that empaglifozin (EMPA) could modulate ectopic fat stores and myocardial energetics in high-fat-high-sucrose (HFHS) d...

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Published in:	Cardiovascular diabetology Vol. 20; no. 1; pp. 57 - 14
Main Authors:	Gaborit, B, Ancel, P, Abdullah, A E, Maurice, F, Abdesselam, I, Calen, A, Soghomonian, A, Houssays, M, Varlet, I, Eisinger, M, Lasbleiz, A, Peiretti, F, Bornet, C E, Lefur, Y, Pini, L, Rapacchi, S, Bernard, M, Resseguier, N, Darmon, P, Kober, F, Dutour, A
Format:	Journal Article
Language:	English
Published:	England BioMed Central 01-03-2021 BMC
Subjects:	31P-MRS Adenosine triphosphate Adipose Tissue - drug effects Adipose Tissue - metabolism Adipose Tissue - pathology Animals Benzhydryl Compounds - adverse effects Benzhydryl Compounds - therapeutic use Biomarkers - blood Blood Glucose - drug effects Blood Glucose - metabolism Cardiac function Cardiology and cardiovascular system Cardiomyocytes Cardiovascular disease Diabetes Diabetes mellitus (non-insulin dependent) Diabetes Mellitus, Type 2 - drug therapy Diabetes Mellitus, Type 2 - metabolism Diabetes Mellitus, Type 2 - pathology Diet Disease Models, Animal Double-Blind Method Ectopic fat Ejection fraction Energy Metabolism - drug effects Epicardial adipose tissue France Glucose Glucose tolerance Glucosides - adverse effects Glucosides - therapeutic use Glycated Hemoglobin - metabolism Heart failure Hematocrit High fat diet Human health and pathology Humans Ketones Life Sciences Liver Liver - drug effects Liver - metabolism Liver - pathology Magnetic resonance imaging Metabolism Mice Mice, Inbred C57BL Myocardial energetics Myocardium - metabolism Myocardium - pathology Na+/glucose cotransporter Non-alcoholic Fatty Liver Disease - metabolism Non-alcoholic Fatty Liver Disease - pathology Non-alcoholic Fatty Liver Disease - prevention & control Nutrition research Original Investigation Pancreas Pcr/atp Placebos Proton Magnetic Resonance Spectroscopy SGLT2 inhibitors Sodium-Glucose Transporter 2 Inhibitors - adverse effects Sodium-Glucose Transporter 2 Inhibitors - therapeutic use Spectrum analysis Sucrose Time Factors Treatment Outcome Weight Loss - drug effects France Germany Pcr/atp Ectopic fat MRI Myocardial energetics 31P-MRS Epicardial adipose tissue SGLT2 inhibitors 31 P-MRS SGLT2 inhibitors.Epicardial adipose tissue.Ectopic fat.Myocardial energetics.Pcratp.P-31-MRS.MRI
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Summary:	Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that has demonstrated cardiovascular and renal protection in patients with type 2 diabetes (T2D). We hypothesized that empaglifozin (EMPA) could modulate ectopic fat stores and myocardial energetics in high-fat-high-sucrose (HFHS) diet mice and in type 2 diabetics (T2D). C57BL/6 HFHS mice (n = 24) and T2D subjects (n = 56) were randomly assigned to 12 weeks of treatment with EMPA (30 mg/kg in mice, 10 mg/day in humans) or with placebo. A 4.7 T or 3 T MRI with H-MRS evaluation-myocardial fat (primary endpoint) and liver fat content (LFC)-were performed at baseline and at 12 weeks. In humans, standard cardiac MRI was coupled with myocardial energetics (PCr/ATP) measured with P-MRS. Subcutaneous (SAT) abdominal, visceral (VAT), epicardial and pancreatic fat were also evaluated. The primary efficacy endpoint was the change in epicardial fat volume between EMPA and placebo from baseline to 12 weeks. Secondary endpoints were the differences in PCr/ATP ratio, myocardial, liver and pancreatic fat content, SAT and VAT between groups at 12 weeks. In mice fed HFHS, EMPA significantly improved glucose tolerance and increased blood ketone bodies (KB) and β-hydroxybutyrate levels (p < 0.05) compared to placebo. Mice fed HFHS had increased myocardial and liver fat content compared to standard diet mice. EMPA significantly attenuated liver fat content by 55%, (p < 0.001) but had no effect on myocardial fat. In the human study, all the 56 patients had normal LV function with mean LVEF = 63.4 ± 7.9%. Compared to placebo, T2D patients treated with EMPA significantly lost weight (- 2.6 kg [- 1.2; - 3.7]) and improved their HbA1c by 0.88 ± 0.74%. Hematocrit and EPO levels were significantly increased in the EMPA group compared to placebo (p < 0.0001, p = 0.041). EMPA significantly increased glycosuria and plasma KB levels compared to placebo (p < 0.0001, p = 0.012, respectively), and significantly reduced liver fat content (- 27 ± 23 vs. - 2 ± 24%, p = 0.0005) and visceral fat (- 7.8% [- 15.3; - 5.6] vs. - 0.1% [- 1.1;6.5], p = 0.043), but had no effect on myocardial or epicardial fat. At 12 weeks, no significant change was observed in the myocardial PCr/ATP (p = 0.57 between groups). EMPA effectively reduced liver fat in mice and humans without changing epicardial, myocardial fat or myocardial energetics, rebutting the thrifty substrate hypothesis for cardiovascular protection of SGLT2 inhibitors. Trial registration NCT, NCT03118336. Registered 18 April 2017, https://clinicaltrials.gov/ct2/show/NCT03118336.
ISSN:	1475-2840 1475-2840
DOI:	10.1186/s12933-021-01237-2