Exercise Metabolic Flexibility in Type 2 Diabetes Treated With Empagliflozin: An Exploratory Analysis of the Randomised Trial EMPA-HEART

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: After treatment, during low-to-moderate intensity exercise (40% (Formula presented.) O2max), FATox increased (+32 [5/65]%, p = 0.02) and CHOox decreased (−30 [−45/−1]%, p = 0.04), in the empagliflozin group only. Also, MFO (empa +0.66 [0/1.31] vs. sita −0.59 [−1.49/0.31] mg/min/kg fat-free mass, p = 0.0249) and FATmax (empa +5 [2/8] vs. sita 0 [−4/3] % (Formula presented.) O2max, p = 0.0433) increased in the empagliflozin group. Plasma β(OH)B concentrations increased with empagliflozin (+51 [21/81] μmol/L, p = 0.012) and correlated both with MFO and with FATmax (p < 0.05). In the whole population, the improvements in FATox correlated with changes in cardiopulmonary fitness ((Formula presented.) O2 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.