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.

项目摘要 阻塞性睡眠呼吸暂停（OSA）缺乏有效的，耐受性良好的治疗方法阻碍了研究 治疗对健康结果的影响，这意味着严重丧失了减少 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。 一个有前途的，新发现的途径需要进一步探索，是如何药理学钠葡萄糖 协同转运蛋白2抑制（SGLT 2 i）可能影响OSA。本项目的总体目标是进行2中心 在N=164名诊断为中度至重度肥胖的超重或肥胖成人（BMI 25-40 kg/m2）中进行的机制性临床试验 重度OSA（伴和不伴T2 D），随机接受厄托格列净15 mg每日一次vs安慰剂治疗6个月， 评价SGLT 2 i对OSA解剖、非解剖生理和临床特征的影响。我们将 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SGLT 2 i对解剖学OSA特征的影响。假设1：SGLT 2 i将由内脏 和颈部脂肪、上气道口径、上气道软组织结构体积和Pcrit/Vpass。次级目标1：探索 SGLT 2 i对功能失调性肥胖的血浆生物标志物的影响。 具体目标2：量化SGLT 2 i对非解剖学、生理学OSA特征的影响。假设2：SGLT 2 i 将导致LG和头尾流液转移。子目标2：探索SGLT 2 i对阿尔斯和Mresp的影响。 具体目的3：研究SGLT 2 i对OSA严重程度和睡眠不足临床结局的影响。 假设3：SGLT 2 i将改善OSA严重程度的临床指标（例如，睡眠不足（Sleep Deficiency）次级目标 3：进行正式的中介分析，以评估SGLT 2 i对OSA严重程度和睡眠的影响 缺陷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 对于所有目的，分析将考虑年龄、性别（作为生物学变量）、人种/种族、肥胖分类、2型 糖尿病状态和CPAP使用。这些目标的综合结果将为油井创造一个独特的机会。 有把握的机制试验，以明确阐明SGLT 2 i-OSA关系的机制。这 这些知识有可能为OSA的药理学治疗靶点提供新的见解， 哪些OSA患者表型可能对SGLT 2 i最有反应，并为确定性， 前瞻性III期试验，以测试药理学SGLT 2 i对OSA预防和治疗的疗效。