SGLT2 Inhibition Does Not Affect Myocardial Fatty Acid Oxidation or Uptake, but Reduces Myocardial Glucose Uptake and Blood Flow in Individuals With Type 2 Diabetes: A Randomized Double-Blind, Placebo-Controlled Crossover Trial

• Published in: Diabetes (New York, N.Y.) Vol. 70; no. 3; pp. 800 - 808
• Main Authors: Lauritsen, Katrine M, Nielsen, Bent R R, Tolbod, Lars P, Johannsen, Mogens, Hansen, Jakob, Hansen, Troels K, Wiggers, Henrik, Møller, Niels, Gormsen, Lars C, Søndergaard, Esben
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.03.2021
• Subjects: Acetic acid; Adenosine; Blood flow; Cardiovascular diseases; Computed tomography; Diabetes; Diabetes mellitus (non-insulin dependent); Double-blind studies; Fatty acids; Glucose; Heart; Hemodynamics; Ketogenesis; Morbidity; Na+/glucose cotransporter; Oxidation; Oxygen consumption; Palmitic acid; Perfusion; Placebos; Positron emission tomography
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db20-0921

Sodium-glucose cotransporter 2 (SGLT2) inhibition reduces cardiovascular morbidity and mortality in individuals with type 2 diabetes. Beneficial effects have been attributed to increased ketogenesis, reduced cardiac fatty acid oxidation, and diminished cardiac oxygen consumption. We therefore studied whether SGLT2 inhibition altered cardiac oxidative substrate consumption, efficiency, and perfusion. Thirteen individuals with type 2 diabetes were studied after 4 weeks' treatment with empagliflozin and placebo in a randomized, double-blind, placebo-controlled crossover study. Myocardial palmitate and glucose uptake were measured with C-palmitate and F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT). Oxygen consumption and myocardial external efficiency (MEE) were measured with C-acetate PET/CT. Resting and adenosine stress myocardial blood flow (MBF) and myocardial flow reserve (MFR) were measured using O-H O PET/CT. Empagliflozin did not affect myocardial free fatty acids (FFAs) uptake but reduced myocardial glucose uptake by 57% ( < 0.001). Empagliflozin did not change myocardial oxygen consumption or MEE. Empagliflozin reduced resting MBF by 13% ( < 0.01), but did not significantly affect stress MBF or MFR. In conclusion, SGLT2 inhibition did not affect myocardial FFA uptake, but channeled myocardial substrate utilization from glucose toward other sources and reduced resting MBF. However, the observed metabolic and hemodynamic changes were modest and most likely contribute only partially to the cardioprotective effect of SGLT2 inhibition.