Project Summary Lack of effective, well-tolerated treatments for obstructive sleep apnea (OSA) has impeded research examining the impact of treatment on health outcomes, and it represents a serious lost clinical opportunity to reduce morbidity and mortality related to OSA. Metabolic modulation may be a prime target to prevent and treat OSA. One promising, newly identified pathway requiring further exploration is how pharmacologic sodium glucose co-transporter 2 inhibition (SGLT2i) may impact OSA. The overall goal of this project is to conduct a 2-center mechanistic clinical trial of N=164 overweight or obese adults (BMI 25-40 kg/m2) diagnosed with moderate to severe OSA (with and without T2D) randomized to ertugliflozin 15 mg once daily vs. placebo for 6 months to evaluate the impact of SGLT2i on anatomic, non-anatomic physiologic, and clinical traits of OSA. We will accomplish this by the following three separate specific aims: Specific Aim1: Measure the effects of SGLT2i on anatomic OSA traits. Hypothesis 1: SGLT2i will ¯ visceral and neck fat, airway caliber, ¯ upper airsoft tissue structure volumes, and ¯ Pcrit/Vpass. Sub-aim 1: Explore the effects SGLT2i on plasma biomarkers of dysfunctional adiposity. Specific Aim 2: Quantify the effects of SGLT2i on non-anatomic, physiologic OSA traits. Hypothesis 2: SGLT2i will ¯ LG and ¯ rostral-caudal fluid shifts. Sub-aim 2: Explore the effects SGLT2i on ArTh and Mresp. Specific Aim 3: Investigate the effects of SGLT2i on clinical outcomes of OSA severity and sleep deficiency. Hypothesis 3: SGLT2i will improve clinical measures of OSA severity (e.g., AHI) and sleep deficiency. Sub-aim 3: Perform formal mediation analysis to assess whether the effects of SGLT2i on OSA severity and sleep deficiency clinical outcomes is mediated through individual anatomic and non-anatomic physiologic traits and markers of dysfunctional adiposity. For all aims, analyses will account for age, sex as a biological variable, race/ethnicity, obesity class, type 2 diabetes status, and CPAP use. The integrated findings of these aims will create a unique opportunity for a well powered, mechanistic trial to definitively elucidate the mechanisms of the SGLT2i-OSA relationship. This knowledge has the potential to yield new insights for pharmacologic therapeutic targets for OSA, determine which OSA patient phenotypes may be most responsive to SGLT2i, and provide preliminary data for definitive, prospective phase 3 trials to test the efficacy of pharmacologic SGLT2i on OSA prevention and treatment.