Adipose Dysfunction, Imaging, Physiology, and Outcomes with SGLT2i's for Sleep Apnea: The ADIPOSA Study

项目摘要 阻塞性睡眠呼吸暂停(OSA)缺乏有效、耐受性良好的治疗方法，阻碍了研究检查 治疗对健康结果的影响，它代表着严重丧失了减少 与阻塞性睡眠呼吸暂停相关的发病率和死亡率。代谢调节可能是预防和治疗阻塞性睡眠呼吸暂停综合征的主要靶点。 一个有希望的、需要进一步探索的新发现的途径是，药物葡萄糖钠如何 共转运蛋白2抑制(SGLT2i)可能影响OSA。这个项目的总体目标是进行一个双中心 超重或肥胖成人(BMI 25-40 kg/m2)诊断为中度到中度的机械性临床试验 重度阻塞性睡眠呼吸暂停(伴有和不伴有T2D)随机服用厄图格列酮15 mg，每日1次，与安慰剂对照，疗程6个月至 评估SGLT2i对阻塞性睡眠呼吸暂停综合征的解剖、非解剖生理和临床特征的影响。我们会 通过以下三个不同的具体目标实现这一目标： 特异性目的1：检测SGLT2i对OSA解剖性状的影响。假设1：SGLT2i意志发自内心 和颈部脂肪、呼吸道口径、上呼吸道软组织结构体积和Pcrit/VPass。次级目标1：探索 SGLT2i对功能性肥胖症血浆生物标志物的影响 具体目标2：量化SGLT2i对非解剖性、生理性OSA性状的影响。假设2：SGLT2i Lg和吻尾液体会发生移位。次目标2：探讨SGLT2i对ARTH和MRESP的影响。 具体目标3：研究SGLT2i对阻塞性睡眠呼吸暂停综合征严重程度和睡眠不足患者临床结局的影响。 假设3：SGLT2i将改善OSA严重程度(例如，AHI)和睡眠不足的临床测量。子目标 3：进行正式的中介分析，以评估SGLT2i对OSA严重程度和睡眠的影响 不足的临床结果通过个体解剖和非解剖生理特征和 功能性肥胖症的标志物。 对于所有目标，分析将考虑年龄、性别作为生物变量、种族/民族、肥胖类别、2型 糖尿病状况和CPAP使用情况。这些目标的综合发现将为油井创造一个独特的机会 动力性、机械性试验明确阐明SGLT2i-OSA关系的机制。这 知识有可能为阻塞性睡眠呼吸暂停综合征的药物治疗靶点产生新的见解，确定 哪些OSA患者的表型可能对SGLT2i最敏感，并为确定、 3期前瞻性试验，以测试药物SGLT2i预防和治疗OSA的疗效。

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.