Effective treatment of sleep apnea in prediabetes to reduce cardiometabolic risk

有效治疗糖尿病前期的睡眠呼吸暂停以降低心脏代谢风险

• 批准号: 7822129
• 负责人: Esra Tasali
• 金额: $ 50万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7822129
• 关键词: Acute; Address; Adult; American; Area; Arts; Biological Markers; Blood Pressure; Body mass index; C-reactive protein; Cardiac; Cardiovascular Diseases; Cardiovascular system; Catecholamines; Clinical; Clinical Research; Clinical Trials; Continuous Positive Airway Pressure; Data; Development; Diabetes Mellitus; Disease; Disease Progression; Dissection; Economics; Electrocardiogram; Energy Intake; Energy Metabolism; Ensure; Epidemic; Future; Glucose; Glucose Intolerance; Glycosylated hemoglobin A; Goals; High Prevalence; Hour; Hypoglycemic Agents; Individual; Insulin; Insulin Resistance; Intervention; Knowledge; Laboratories; Leptin; Life Style; Link; Measures; Mediator of activation protein; Modification; Morbidity - disease rate; Nonesterified Fatty Acids; OGTT; Obesity; Obstructive Sleep Apnea; Oral Administration; Outcome; Overweight; Participant; Patients; Pharmacological Treatment; Placebos; Plasma; Prediabetes syndrome; Prevalence; Prevention; Public Health; Pulmonary Heart Disease; Randomized; Recommendation; Reporting; Research; Risk; Risk Factors; Role; Severities; Sleep; Sleep Apnea Syndromes; Sleep Disorders; Supervision; Tablets; Testing; Translating; Weight; blood glucose regulation; clinical practice; design; diabetes management; diabetes risk; diabetic; disorder risk; effective therapy; experience; glucagon-like peptide 1; glucose metabolism; glucose tolerance; glycemic control; heart rate variability; improved; indexing; insulin secretion; insulin sensitivity; intravenous glucose tolerance test; lifestyle intervention; mortality; non-diabetic; post intervention; prevent; response; secondary outcome

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (04) Clinical Research and specific Challenge Topic, 04-HL-101: Identify Mechanisms Linking Cardiopulmonary Disease Risk and Sleep-Disordered Breathing. Diabetes is increasing in epidemic proportions in the U.S. Cardiovascular disease is the leading cause of morbidity and mortality in diabetes. Despite the demonstrated efficacy of lifestyle interventions and the availability of multiple pharmacological treatment options, the economic and public health burden of diabetes remains enormous. Thus, the development of additional strategies to prevent or delay the onset of diabetes and its cardiovascular complications remains a critical public heath challenge. Recent estimates reveal that about 57 million of Americans have prediabetes, an intermediate state between normal glucose tolerance and overt diabetes, characterized by elevated glucose levels, insulin resistance and abnormalities in insulin secretion. Prediabetic state is a major risk factor for cardiovascular disease and progression to overt diabetes. Obstructive sleep apnea (OSA) is a treatable sleep disorder that is pervasive among overweight and obese individuals. OSA is well recognized as an important mediator of adverse cardiovascular outcomes. Numerous studies have also shown a robust association between OSA and insulin resistance, glucose intolerance and the risk of diabetes, independently of body mass index. In an analysis of over 2500 non- diabetic individuals, the presence of OSA was associated with a significantly higher prevalence of prediabetes and incident diabetes, independently of obesity. Four recent studies including a total number of nearly 900 patients have reported an OSA prevalence in diabetes averaging a staggering 73%. Findings from our group indicate that in diabetics, the presence of OSA is associated with poorer glucose control with effect sizes ranging from 1% to 2% increases in hemoglobin A1c depending on OSA severity. These effect sizes are comparable to and sometimes larger than those of widely used hypoglycemic drugs. Despite the overwhelming evidence to support a strong association between OSA and diabetes, it remains unclear today whether continuous positive airway pressure (CPAP) treatment of OSA can significantly improve glucose control. In diabetics, only four studies including a total of a mere 86 patients, have addressed this important question. A major limitation of these studies is the insufficient CPAP use (roughly averaging 4.4 hours) or the lack of objective data on CPAP compliance. So far, not a single study has examined the effects of CPAP on glucose metabolism specifically in prediabetes, a potentially reversible state in which the development of overt diabetes and its cardiovascular complications could be prevented or delayed. Our overall goal is therefore to conduct over the next 2 years a "proof of concept" study to fill this major gap of knowledge and to rigorously test the hypothesis that effective CPAP treatment of OSA with all night optimum compliance can improve glucose metabolism in prediabetes and reduce cardiometabolic risk. We propose to study overweight or obese adults who have prediabetes and OSA at baseline and after randomization to either: (i) 2 weeks of effective CPAP treatment ("CPAP group") or (ii) 2 weeks of oral administration of a placebo tablet 30min before bedtime ("placebo group"). Both groups will spend each of the 14 nights in the laboratory with 8-hour bedtimes. In the CPAP group, optimum CPAP compliance during the entire night will be ensured by continuous supervision by a registered PSG technician. In all participants, we will perform at baseline and at the end of the intervention, an intravenous glucose tolerance test (ivGTT) to assess insulin sensitivity (SI), insulin secretion (i.e. acute insulin response to glucose; AIRg) and the disposition index (DI; a validated marker of diabetes risk) as well as an oral glucose tolerance test (OGTT) to translate ivGTT findings into end points commonly used in clinical practice. The findings from the ivGTT will allow for the dissection of the respective roles of improvements in SI and AIRg on diabetes risk. Blood pressure (BP) will be recorded continuously over 24hrs and cardiac sympathetic activity will be assessed by heart rate variability of ambulatory EKG recordings. For all cardiometabolic measures, post-intervention changes from baseline will be compared between the CPAP and placebo groups. Our specific aims are: 1) to test the hypothesis that effective CPAP treatment of OSA in prediabetics reduces diabetes risk, as assessed by the DI; 2) to test the hypothesis that CPAP treatment of OSA in prediabetics enhances the nocturnal dipping of BP and reduces daytime BP. We will also use state-of- the-art quantitative PSG analysis to identify potential biomarkers that may predict the cardiometabolic response to CPAP. Secondary outcomes will be plasma levels of catecholamines, free fatty acids, leptin and CRP. We will also collect daily data on weight, caloric intake, and energy expenditure. Today, nearly 50 million American adults have prediabetes or diabetes and have untreated OSA. The proposed research involves a focused "proof of concept" study that can be realistically completed within 2 years and that builds on our experience in clinical research on the cardiometabolic implications of sleep and its disorders. The results are expected to provide essential information for the design of future large clinical trials that will determine whether treatment of OSA, in addition to lifestyle modifications, could be a first line non-pharmacological intervention to prevent or delay the development of overt diabetes, or to improve glycemic control in overt diabetes. The findings thus have the potential to initiate a major reassessment of the clinical recommendations for the prevention, delay and management of diabetes and its cardiovascular complications for millions of Americans. Diabetes is increasing in epidemic proportions in the U.S. Cardiovascular disease is the leading cause of morbidity and mortality in diabetes. Despite the demonstrated efficacy of lifestyle interventions and the availability of multiple pharmacological treatments, the economic and public health burden of diabetes remains enormous. The results of this research may provide a better understanding of ways to prevent and/or treat diabetes and its cardiovascular complications for millions of Americans.

描述（由申请人提供）：本申请涉及广泛的挑战领域（04）临床研究和具体挑战主题，04- hl -101：识别连接心肺疾病风险和睡眠呼吸障碍的机制。糖尿病在美国的流行比例正在上升，心血管疾病是糖尿病发病率和死亡率的主要原因。尽管生活方式干预已证明有效，而且有多种药物治疗方案可供选择，但糖尿病的经济和公共卫生负担仍然巨大。因此，制定预防或延迟糖尿病及其心血管并发症发病的其他战略仍然是一项重大的公共卫生挑战。最近的估计显示，大约有5700万美国人患有前驱糖尿病，这是一种介于正常葡萄糖耐量和显性糖尿病之间的中间状态，其特征是葡萄糖水平升高、胰岛素抵抗和胰岛素分泌异常。糖尿病前期状态是心血管疾病和进展为显性糖尿病的主要危险因素。阻塞性睡眠呼吸暂停（OSA）是一种可治疗的睡眠障碍，在超重和肥胖人群中普遍存在。阻塞性睡眠呼吸暂停被认为是心血管不良结局的重要中介。大量研究也表明，与体重指数无关，OSA与胰岛素抵抗、葡萄糖耐受不良和糖尿病风险之间存在密切关联。在对2500多名非糖尿病个体的分析中，OSA的存在与糖尿病前期和糖尿病发生率的显著升高相关，与肥胖无关。最近的四项研究，包括近900名患者，报告了糖尿病患者的睡眠呼吸暂停患病率平均达到惊人的73%。本研究小组的研究结果表明，在糖尿病患者中，OSA的存在与较差的血糖控制有关，根据OSA的严重程度，糖化血红蛋白升高的效应大小为1%至2%。这些效应大小与广泛使用的降糖药相当，有时甚至更大。尽管有大量证据支持OSA与糖尿病之间的密切联系，但目前尚不清楚持续气道正压通气（CPAP）治疗OSA是否能显著改善血糖控制。在糖尿病患者中，只有四项研究（总共86名患者）解决了这个重要的问题。这些研究的一个主要限制是CPAP使用不足（大约平均4.4小时）或缺乏关于CPAP依从性的客观数据。到目前为止，还没有一项研究检验CPAP对葡萄糖代谢的影响，特别是对糖尿病前期的影响，糖尿病前期是一种潜在的可逆状态，在这种状态下，显性糖尿病及其心血管并发症的发展可以被预防或延迟。因此，我们的总体目标是在未来2年内进行一项“概念验证”研究，以填补这一重大知识空白，并严格检验CPAP治疗OSA的有效治疗和整夜最佳依从性可以改善前驱糖尿病患者的葡萄糖代谢并降低心脏代谢风险的假设。我们建议研究超重或肥胖的前驱糖尿病和OSA的成年人，在基线和随机分组后：(i) 2周有效的CPAP治疗（“CPAP组”）或（ii） 2周睡前30分钟口服安慰剂片（“安慰剂组”）。两组都将在实验室度过14个晚上，每晚睡8小时。在CPAP组中，在一名注册的PSG技术员的持续监督下，将确保整个晚上最佳的CPAP依从性。在所有参与者中，我们将在基线和干预结束时进行静脉葡萄糖耐量试验（ivGTT），以评估胰岛素敏感性（SI）、胰岛素分泌（即急性胰岛素对葡萄糖的反应；AIRg）和处置指数（DI，一种有效的糖尿病风险标志物），以及口服葡萄糖耐量试验（OGTT），将ivGTT的结果转化为临床实践中常用的终点。ivGTT的研究结果将允许对SI和AIRg改善对糖尿病风险的各自作用进行解剖。在24小时内连续记录血压（BP），并通过动态心电图记录的心率变异性评估心脏交感神经活动。对于所有的心脏代谢指标，将比较CPAP组和安慰剂组干预后的基线变化。我们的具体目的是：1)验证糖尿病前期OSA患者CPAP治疗有效降低糖尿病风险的假设，正如DI评估的那样；2)验证CPAP治疗前驱糖尿病OSA可提高夜间血压下降，降低日间血压的假设。我们还将使用最先进的定量PSG分析来识别可能预测CPAP心脏代谢反应的潜在生物标志物。次要结果将是儿茶酚胺、游离脂肪酸、瘦素和CRP的血浆水平。我们还将收集关于体重、热量摄入和能量消耗的每日数据。今天，近5000万美国成年人患有前驱糖尿病或糖尿病，并且没有得到治疗。拟议的研究包括一个重点的“概念验证”研究，可以在2年内实际完成，并建立在我们在睡眠及其紊乱的心脏代谢影响的临床研究经验的基础上。该结果有望为未来大型临床试验的设计提供重要信息，这些试验将确定除了改变生活方式外，OSA治疗是否可以作为预防或延缓显性糖尿病发展或改善显性糖尿病血糖控制的一线非药物干预措施。因此，这些发现有可能对数百万美国人预防、延迟和管理糖尿病及其心血管并发症的临床建议进行重大重新评估。糖尿病在美国的流行比例正在上升，心血管疾病是糖尿病发病率和死亡率的主要原因。尽管生活方式干预的有效性已得到证实，多种药物治疗方法也可获得，但糖尿病的经济和公共卫生负担仍然巨大。这项研究的结果可能为数百万美国人提供更好地了解预防和/或治疗糖尿病及其心血管并发症的方法。