FRI607 SGLT2 Inhibition Improves Muscle Oxidative Capacity And Its Relationship With Cardiac Performance In Patients With T2D And Heart Failure
Authors: Qin Yuejuan , Sanchez Noah D , Moody Alexander J , Acosta Francisca M , Neppala Sivaram , Brown Marissa , Honka Henri , Todd Byron , Cruz Moreno Luis A , Stepanenko Allison R , Espinoza Sara E , Musi Nicolas , Triplitt Curtis , Clarke Geoffrey , Cersosimo Eugenio , Anthony DeFronzo Ralph , Solis-Herrera Carolina 
Published: October 2023

Disclosure: Y. Qin: None. N.D. Sanchez: None. A.J. Moody: None. F.M. Acosta: None. S. Neppala: None. M. Brown: None. H. Honka: None. B. Todd: None. L.A. Cruz Moreno: None. A.R. Stepanenko: None. S.E. Espinoza: None. N. Musi: None. C. Triplitt: None. G. Clarke: None. E. Cersosimo: None. R.A. DeFronzo: None. C. Solis-Herrera: None.

Cardioprotective benefits of SGLT2 inhibitors (SGLT2i) have been largely thought to be coupled to a physiologic increase in plasma ketones, with much interest in the role of adaptive changes in cardiac fuel source in subjects with T2D and HF. Given the changes in the global dynamics of bioenergetics with SGLT2i, and the proven pleiotropic effects of ketone bodies, suggest that, in addition to their cardioprotective function, SGLT2i may influence other organ systems. In particular, how skeletal muscle (SkM), or cardiopulmonary function, respond to these global bioenergetics changes remains largely unknown. A pilot randomized-controlled clinical study was designed to examine the effects of SGLT2i on SkM bioenergetics (31P MRS), & cardiopulmonary function (CPET), and its association with left ventricular cardiac function (MRI). Six subjects (Age=59±2.6, BMI=33.3±1.1, A1c=7.1±0.3) with T2D and HF (&lt;50%) were randomized empagliflozin 25mg/day (SGLT2i) vs. placebo (control) in a 2:1 fashion for 12 weeks. Imaging and clinical evaluations were performed pre- and post-intervention. The SGLT2i group improved EF (28.7 vs. 38.8, p=0.1). SkM 31P MRS at rest, measuring the relative intracellular concentrations of high-energy metabolites of phospholipid breakdown, reduced with SGLT2i, suggesting better energy utilization by the SkM. 31P MRS-after exercise, showed significant improvements in SkM oxidative capacity (KPCR*[PCr], 0.6 to 0.8, p=0.03), with SGLT2i.During CPET testing, the ventilatory anaerobic threshold (VT), with SGLT2i, showed a significant (p=0.05) increase in VT time, suggesting an increase in the time in aerobiosis in these subjects. The minute ventilation-to-carbon dioxide output slope (a strong predictor of cardiopulmonary complications/death) was improved in the SGLT2i group vs. placebo, which could be associated with the CV benefit observed with these agents. Additionally, patient self-reported outcomes (Promis) showed a trend of improvement in the SGLT2i group. In summary, we demonstrate novel and exciting preliminary findings that in patients with T2D & HF, SGLT2i-associated benefits are not isolated to the heart and may also expand to the SkM, including improved oxidative capacity, energy utilization, and SkM recovery post-exercise. With improvements in HF prognostic markers and patient self-reported outcomes. These original findings may represent novel mechanisms contributing to the cardiac benefits of SGLT2i.

Presentation: Friday, June 16, 2023