Effective Treatment of Sleep Apnea in Prediabetes to Reduce Cardiometabolic Risk

EFFECTIVE TREATMENT OF SLEEP APNEA IN PREDIABETES TO REDUCE CARDIOMETABOLIC RISK Diabetes is
increasing in epidemic proportions in the United States of America.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 24 hours
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 C-reactive protein, and GLP-1. 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.

Inclusion Criteria:

- Overweight or obese adults (age ≥45 yrs and BMI ≥25 kg/m2)

- prediabetes and OSA (AHI ≥ 5)

- regular life styles and schedules (no shift work in the past 6 months, no travel
across time zones during the past 4 weeks)

- habitual bedtimes of at least 6 hours but not exceeding 9 hours will be eligible.

- not to take any medications during the study period with the exception of
antihypertensives and lipid lowering agents

- not on hormone replacement therapy.

- have sedentary activities and no competitive athletes or subjects with high exercise
levels.

Exclusion Criteria:

- previous or current treatment with supplemental oxygen

- requirement of supplemental oxygen or bi-level positive airway pressure for OSA
treatment during titration

- presence of active infection, psychiatric disease or history of other significant
illness (e.g., myocardial infarction, congestive heart failure, stroke, arrhythmia,
chronic kidney or liver disease0

- clinical depression as evidenced by a score >16 in CES-D scale

- smoking, or routine alcohol use (more than 2 drinks per day), or excessive caffeine
intake (>300mg per day)