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.

RC1HL100046

2009-09-30

2012-08-31