Exercise Metabolic Flexibility in Type 2 Diabetes Treated With Empagliflozin: An Exploratory Analysis of the Randomised Trial <scp>EMPA</scp> ‐ <scp>HEART</scp>

AIM: Patients with type 2 diabetes (T2D) often develop metabolic inflexibility and reduced exercise capacity. We examined whether sodium-glucose cotransporter 2 inhibitors (SGLT2i) modify substrate oxidation during exercise. METHODS: As a pre-specified exploratory analysis, aimed at understanding the relevance of circulating lipid substrate availability in the effect of empagliflozin on cardiopulmonary function, we measured fasting plasma β-hydroxybutyrate (β(OH)B) and free fatty acids in 44 patients with T2D undergoing cardiopulmonary exercise tests (CPETs) before and after 6 months of randomised therapy with empagliflozin (n = 22) or sitagliptin (n = 22). We used indirect calorimetry to estimate the rates of fat (FATox) and glucose oxidation (CHOox) and identified maximal fat oxidation (MFO) and the exercise intensity at which MFO occurs (FATmax). RESULTS: at peak exercise) (p < 0.01). CONCLUSIONS: Empagliflozin treatment is associated with enhanced FATox during low-to-moderate intensity exercise with unchanged substrate oxidation at rest and at high-intensity exercise. This effect, if confirmed, has the potential to produce an improvement of exercise capacity in patients with T2D. TRIAL REGISTRATION: EudraCT Code: 2016-002225-10.