Exercise Metabolic Flexibility in Type 2 Diabetes Treated With Empagliflozin: An Exploratory Analysis of the...

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.

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).

After treatment, during low-to-moderate intensity exercise (40% $\dot{V}$ O_2max), 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] % $\dot{V}$ O_2max, 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 ( $\dot{V}$ O₂ at peak exercise) (p < 0.01).

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.

EudraCT Code: 2016-002225-10.