We conducted an observational cohort study examining the impact of sleep apnea on the development of type II diabetes mellitus. Our results show that a) sleep apnea is a risk factor for the development of diabetes; b) increasing severity of sleep apnea is associated with an increasing risk for the development of diabetes; and, c) among patients with moderate to severe sleep apnea (upper 2 quartiles of severity), regular use of positive airway pressure is associated with an attenuated risk for the development of incident diabetes.
Our findings are consistent with previous cross-sectional data showing an association between sleep apnea and insulin resistance, glucose intolerance, and diabetes.8, 11, 13, 14, 23-25
The causal direction of these associations, however, has been questioned.26-28
The few studies assessing longitudinal associations between sleep apnea and diabetes have had limitations. For example, sleep apnea was associated with development of diabetes during a 10-year follow-up period, but sleep apnea was determined by a self-report of snoring as a surrogate for a confirmed diagnosis.29, 30
In addition, a longitudinal analysis of the Wisconsin Cohort found an association between sleep apnea and diabetes, but the impact of sleep apnea was not statistically significant when adjusted for BMI.24
Finally, a recent longitudinal analysis of the Busselton Health Study detected an association between moderate-severe sleep apnea and diabetes using portable monitoring, but the small sample size, limited distribution of sleep apnea severity, and few incident cases of diabetes resulted in a wide confidence interval.31
Our study is novel in that it used a longitudinal design that was powered to demonstrate an independent association between confirmed sleep apnea and diabetes, used the gold standard test for diagnosis, assessed a broad range of sleep apnea severity, and examined the impact of sleep apnea treatment.
Several potential mechanistic pathways may explain how sleep apnea and its physiologic sequelae (intermittent hypoxemia and recurrent arousals) ultimately lead to metabolic abnormalities. Previous studies found that severity of hypoxemia is related to the degree of glucose intolerance and insulin resiatnce.8, 32, 33
Although insulin levels were not available in the current study, hypoxemia (T90, defined as a greater than 2% of the night spent with an oxygen saturation less than 90%) was significantly associated with the outcome of diabetes (data not shown); intermittent hypoxemia may act through mechanisms of oxidative stress to mediate alterations in glucose metabolism.34-35
We also observed that the arousal index was associated with development of diabetes. Recurrent arousals (and sleep loss) may act through sympathetic activation and subsequent alterations in hypothalamic-pituitary-adrenal axis, leading to altered cortisol levels, decreased pancreatic beta-cell activity, elevated growth hormone levels, and alterations in neuroendocrine control of appetite.35-39
Our findings suggest an increased risk of diabetes among patients with sleep apnea, despite “usual care” administration of various therapies, primarily positive airway pressure. A few explanations might account for this finding. First, it is likely that our population had untreated sleep apnea for years before seeking diagnosis and treatment, resulting in prolonged exposure to an associated metabolic risk. Second, diabetes may develop even if patients receive effective therapy for sleep apnea. Finally, reduced compliance with positive airway pressure and limited efficacy of other treatments may have played a role in reducing the potential benefit of therapy.
We observed that regular use of positive airway pressure among patients in the upper two quartiles of severity was associated with a significant attenuation of incident diabetes, even after adjusting for subsequent weight loss. These findings are consistent with several treatment studies that have demonstrated improvements in insulin sensitivity and postprandial glucose with airway pressurization therapy. 40-42
In contrast, others studies, including 2 short-term randomized controlled trials, have not shown a benefit.23, 25
Future longitudinal and randomized studies examining the impact of treatment in various patient populations (e.g. sleepy and non-sleepy patients) are needed.
Several methodologic issues should be considered in the interpretation of our results. First, as with any observational study, it is possible that residual confounding affected our adjusted hazard ratios, despite our attempts to control for major risk factors. For example, family history of diabetes could not be reliably ascertained through electronic medical record extraction and was not included in our analysis. In addition, BMI may not fully adjust for visceral obesity, known to be associated with components of the metabolic syndrome.47,48 Our comparison group also consisted of mainly obese males referred for suspected sleep apnea, however, thereby reducing the potential for residual confounding, given that similar risk factors were prominent in the comparison group. Change in BMI was also accounted for, to exclude the possibility that differential weight gain in one group may account for the difference in incident diabetes during the study.
Second, tracking of positive airway pressure treatment status was done through documentation in the electronic record, based on clinical assessment by treating physicians in conjunction with documentation of equipment and supply orders. Although the possibility of misclassification of treatment status exists (with a bias towards the null hypothesis), this scenario would not explain our observed findings of the attenuation of incident diabetes conferred by positive airway pressure use among our patients in the upper 2 quartiles of sleep apnea severity. In addition, our moderate long-term rates (~60%) of regular CPAP use are similar to those described using direct data card measures that track hours of use.43
Third, treatment status in this observational cohort study was not randomly assigned. Patients who complied with positive airway pressure may have also been leading healthier lifestyles and complying with other therapies for the prevention of diabetes (e.g., diet and exercise). Yet, this possibility would not explain the attenuation of incident diabetes among patients in the upper 2 quartiles of severity that was observed even after adjustment for weight loss.
Finally, the relatively low observed values for the Epworth Sleepiness Scale (mean <9; see ) may prompt questions regarding thresholds for initiating CPAP in the context of risk of future diabetes. Virtually all patients in our study were symptomatic, however, with episodes such as gasping during sleep, loud habitual snoring, or a bed-partner noting witnessed apneas; many of these patients also had coexistent cardiovascular risk factors and some had prevalent cardiovascular disease. Thus, caution is warranted in extrapolating our findings to healthier populations.
In summary, sleep apnea is significantly associated with the risk of type II diabetes, independently of other risk factors, including age, race, gender, baseline fasting glucose, and BMI, and changes in BMI. Increased severity of sleep apnea is associated with an increased risk of diabetes, and the risk may be partially explained by hypoxemia and arousals. As a treatable condition, sleep apnea may represent a modifiable risk factor for development of diabetes.