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

脂肪功能障碍、影像学、生理学和 SGLT2i 治疗睡眠呼吸暂停的结果：ADIPOSA 研究

• 批准号: 10583864
• 负责人: Ian Jason Neeland
• 金额: $ 72.4万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-20 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583864
• 关键词: Abdomen; Adipose tissue; Adult; Age; Anatomy; Apnea; Arousal; Back; Biological; Biological Markers; Blood; Body Weight decreased; Body mass index; Caliber; Cardiovascular system; Clinical; Clinical Trials; Continuous Positive Airway Pressure; Data; Deposition; Development; Devices; Diagnosis; Diagnostic; Disease; Diuresis; Early Intervention; Equilibrium; Ethnic Origin; Fatty acid glycerol esters; Fluid Shifts; Functional disorder; Future; Glucose; Goals; Health; Heart failure; Hyperglycemia; Hypertension; Hypoxia; Image; Impairment; Individual; Intervention; Kidney; Knowledge; Measurable; Measures; Mediating; Mediation; Medical; Mental Depression; Metabolic; Monitor; Morbidity - disease rate; Muscle; Myocardial Infarction; Neck; Neurocognitive; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obstructive Sleep Apnea; Outcome; Overweight; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Placebos; Plasma; Polysomnography; Prevention; Prospective Studies; Public Health; Quality of life; Race; Randomized; Randomized, Controlled Trials; Research; Research Design; Research Personnel; Risk; Role; Severities; Sleep; Sleep Apnea Syndromes; Sleep Deprivation; Sleep Fragmentations; Sodium; Stroke; Structure; Surveys; Techniques; Tissues; Tongue; Translating; Viscera; Visceral; Wrist; actigraphy; adult obesity; anatomic imaging; bench to bedside; cost; cost estimate; efficacy testing; improved; indexing; insight; mortality; novel; pharmacologic; pharyngeal critical pressure; pharynx muscle; phase III trial; pressure; prevent; prospective; randomized, clinical trials; sex; symporter; therapeutic target; trait; vehicular accident

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.

项目概要 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验 治疗对健康结果的影响，并且它代表着严重失去减少减少的临床机会 与 OSA 相关的发病率和死亡率。代谢调节可能是预防和治疗 OSA 的主要目标。 一种有希望的、新发现的、需要进一步探索的途径是葡萄糖钠的药理作用 协同转运蛋白 2 抑制 (SGLT2i) 可能会影响 OSA 该项目的总体目标是进行 2 中心研究。 对 N=164 名超重或肥胖成人（BMI 25-40 kg/m2）进行的机械临床试验，诊断为中度至 严重 OSA（伴或不伴 T2D）随机接受 ertugliflozin 15 mg 每日一次与安慰剂组，为期 6 个月 我们将评估 SGLT2i 对 OSA 的解剖、非解剖生理和临床特征的影响。 通过以下三个单独的具体目标来实现这一目标： 具体目标 1：测量 SGLT2i 对 OSA 解剖特征的影响 假设 1：SGLT2i 会影响内脏。 和颈部脂肪、气道口径、 上气枪组织结构体积和 Pcrit/Vpass 子目标 1：探索。 SGLT2i 对功能失调性肥胖血浆生物标志物的影响。 具体目标 2：量化 SGLT2i 对非解剖、生理 OSA 特征的影响。假设 2：SGLT2i。 子目标 2：探索 SGLT2i 对 ArTh 和 Mresp 的影响。 具体目标 3：研究 SGLT2i 对 OSA 严重程度和睡眠不足的临床结果的影响。 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。 3：进行正式的中介分析，以评估 SGLT2i 是否对 OSA 严重程度和睡眠有影响 缺乏症的临床结果是通过个体解剖和非解剖生理特征介导的 功能失调性肥胖的标志物。 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、肥胖等级、2 型 这些目标的综合发现将为健康创造一个独特的机会。 明确阐明 SGLT2i-OSA 关系机制的强有力的机械试验。 知识有可能为 OSA 的药物治疗靶点提供新的见解，确定 哪些 OSA 患者表型可能对 SGLT2i 最敏感，并为确定性提供初步数据， 前瞻性 3 期试验旨在测试 SGLT2i 药物对 OSA 预防和治疗的功效。