Sodium-glucose transporter 2 inhibitors may improve the prognosis of acute heart failure by correcting hypocapnia.

Abstract

We thank Guarnaccia et al.1 for their interest in our work and would like to respond to their comments regarding our study. We have demonstrated in the study that hypocapnia is an independent predictor of in-hospital all-cause mortality in acute heart failure (AHF).2 However, the value of hypocapnia in AHF seems to be still underestimated, especially its association with sodium-glucose transporter 2 inhibitors (SGLT2i). As outlined by Guarnaccia et al.,1 SGLT2i could reduce glucose utilization and promote fatty acid utilization to achieve higher ATP production, a process that increases CO2 production and an energy benefit. We agree with Guarnaccia et al. and would like to further explore whether the administration of SGLT2i improves the in-hospital prognosis of patients with hypocapnia. Based on 338 AHF patients in the study who presented with hypocapnia on admission, we used a 1:1 propensity score matching approach and assessed the prognosis of patients taking SGLT2i vs. those not taking SGLT2i utilizing Kaplan–Meier curves. Age, sex, heart failure course, body mass index, and chronic kidney dysfunction were matching variables for propensity score matching. The matched cohort consisted of 136 hypocapnic patients, with 68 patients taking SGLT2i and 68 patients not taking SGLT2i. The results showed that those hypocapnic patients taking SGLT2i had lower in-hospital mortality (11.2% vs. 67.6%, P < 0.001) than those not taking SGLT2i, suggesting that SGLT2i might improve the prognosis of AHF patients by correcting hypocapnia. Our previous work highlighted hypocapnia as a manifestation of cardiac and renal impairment during the progression of AHF.2 We showed that CO2 levels were significantly negatively correlated with B-type natriuretic peptide (r = −0.28, P < 0.001) and positively correlated with the estimated glomerular filtration rate (r = 0.20, P = 0.001) and left ventricular ejection fraction (r = 0.13, P < 0.001).2 Indeed, as suggested by Guarnaccia et al., hypocapnia could also form a vicious circle with lower circulating oxygen in the progression of AHF.3 This could cause a persistent lack of myocardial energy and deterioration of haemodynamics, ultimately leading to multi-organ damage, including kidney damage. SGLT2i have been reported to reprogram the energy metabolism of the myocardium, such as increasing fatty acid utilization to produce more ATP,3 a process accompanied by more CO2 production,1 so the up-regulation of CO2 levels could be a reflection of the energy benefits of SGLT2i. Besides, SGLT2i have a diuretic effect and could inhibit sodium-hydrogen exchangers of renal tubules,4 reducing the patient's circulating volume burden and then improving the acid-base profile to attenuate hypocapnia. SGLT2i also inhibit sympathetic nerve activity which could improve ventilation in patients with AHF, thereby increasing the patient's CO2 levels and alleviating hypocapnia.5, 6 Taken together, hypocapnia is a useful sign for assessing the short-term prognosis of AHF, and SGLT2i could improve the in-hospital prognosis of AHF patients through mechanisms related to the correction of hypocapnia.