1 Diabetes Care Volume 44, June 2021

COMMENT ON NEELAND ET AL. Shay Brikman1 and Guy Dori2 The Impact of Empagliflozin on Obstructive and Cardiovascular and Renal Outcomes: An Exploratory Analysis of eth EMPA-REG OUTCOME Trial. Diabetes Care 2020;43:3007–3015 Diabetes Care 2021;44:1 | https://doi.org/10.2337/dc21-0310

We read with great interest the leading other causes of . Approxi- expected, with less CO2 to be removed article by Neeland et al. (1) highlighting mately 70–90% of patients with OHS also by the . the beneficial effects of empagliflozin have OSA. By doing so, SGLT2i decrease endog-

treatment on several metabolic end In these patients, CO2 removal is re- enous CO2 production and could po- points among participants with type 2 di- duced due to limited ventilation, causing tentially prevent the complications of abetes and chronic and (due hypercapnia. In addition to having (OSA) in the BI 10773 (Empagliflozin) Car- to obligatory reduction in alveolar other well-documented therapeutic ef- diovascular Outcome Event Trial in pressure, secondary to the increase in al- fects, SGLT2i might even change the Type 2 Diabetes Mellitus Patients (EMPA- veolar CO2 pressure). The combination of natural course of respiratory diseases REG OUTCOME). In addition, the authors chronic hypoxemia and hypercapnia indu- with CO2 retention (OSA and OHS). observed a lower frequency of new-onset ces pulmonary vaso-constriction, sympa- We conclude that further investiga- OSA, even when adjusting for baseline thetic activation, and increase in serum tion of the role of SGLT2 inhibition as a BMI. The authors provided few physiologi- catecholamine level (3), all of which could therapeutic strategy for patients with cal explanations for the favorable effects eventually contribute to development of type 2 diabetes and pulmonary diseases of empagliflozin, mainly attributing them systemic and pulmonary hypertension. causing CO retention is required. to the diuretic and natriuretic effects of It is important to segment the issue of 2 the drug. Among the latter effects were CO2 retention (hypercapnia) into endoge- 1) reduction of intrathoracic fluid reten- nous CO2 production and limited CO2 re- tion and rostral fluid shifts from the legs moval. It is hypothesized that SGLT2i Duality of Interest. No potential conflicts of and 2) interrupted sleep cycles and de- reduce the endogenous production of interest relevant to this article were reported. creased rapid eye movement sleep sec- CO2.SGLT2iforceglucosediuresisand ondary to nocturia. reduce the availability of glucose as an References We would like to suggest another ex- energy substrate for body cell metabo- 1. Neeland IJ, Eliasson B, Kasai T, et al.; EMPA- planation for the lower frequency of new- lism. Assuming that total body energy REG OUTCOME Investigators. The impact of onset OSA in patients in the empagliflozin expenditure remains constant and less empagliflozin on obstructive sleep apnea and

COMMENTS AND RESPONSES group.Inapreviouswork(2),wehypoth- glucose is available as substrate, other cardiovascular and renal outcomes: an exploratory — esized that sodium–glucose cotransporter substrates must be utilized. Thus, analysis of the EMPA-REG OUTCOME trial. Diabetes Care 2020;43:3007–3015 2 inhibitors (SGLT2i) might be therapeuti- SGLT2i medication potentially facilitates 2. Brikman S, Dori G. Sodium glucose cotrans- cally beneficial for patients with respirato- a preferential use of lipids (or proteins) porter2 inhibitor-possible treatment for e-LETTERS ry diseases and (CO2) as energy source for metabolism (for a patients with diabetes, pulmonary disease retention(e.g.,withOSAandwithobesity given amount of oxygen consumed, and CO2 retention. Med Hypotheses 2020; 139:109631 hypoventilation syndrome [OHS]). OHS is more CO2 is produced from the metab- 3. Furukawa S, Miyake T, Senba H, et al. a common pulmonary disease, defined by olism of carbohydrates compared with The effectiveness of dapagliflozin for sleep- > 2 thepresenceofobesity(BMI 30 kg/m ) that of lipids or proteins). Had such a disordered among Japanese patients associated with daytime hypercapnia shift in energy substrate occurred, less with obesity and type 2 diabetes mellitus. Endocr (pCO2 >45 mmHg) in the absence of endogenous CO2 production would be J 2018;65:953–961

1Department of Internal Medicine E, HaEmek Medical Center, Afula, Israel 2Ruth and Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, Haifa, Israel Corresponding author: Shay Brikman, [email protected] or [email protected] © 2021 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www.diabetesjournals.org/content/license. Diabetes Care Publish Ahead of Print, published online May 20, 2021