Obstructive sleep apnea and the metabolic syndrome: The road to clinically-meaningful phenotyping, improved prognosis, and personalized treatment

Abstract

Obstructive sleep apnea (OSA) is an increasingly prevalent sleep disorder characterized by upper airway obstruction during sleep, resulting in breathing pauses, intermittent hypoxia, and fragmented sleep. In parallel, the constellation of adverse health outcomes associated with prolonged obesity, such as insulin resistance, elevated blood pressure, triglycerides, and reduced high-density lipoprotein cholesterol - termed metabolic syndrome -raises the risk of cardiovascular morbidity and mortality, type 2 diabetes, and all-cause mortality. Affecting 35-40% of U.S. adults, risk factors for metabolic syndrome, including obesity, middle age, sedentary behavior, and genetics, share considerable overlap with those for OSA. Thus, it has been difficult to disentangle cause, effect, and whether certain treatments, such as CPAP, can improve these outcomes. In this paper, we provide an update to our 2005 review which explored the association between OSA and metabolic syndrome, highlighting visceral obesity as the common etiological factor of both conditions. This update includes (a) recent data on physiological and biochemical mechanisms, (b) new data in nonobese men and women as well as children and adolescents, (c) insight from the latest treatment studies, (d) the role of aging in understanding clinically-meaningful phenotypes of the disorder, and (e) the potential diagnostic/prognostic utility of biomarkers in identifying OSA patients with the strongest cardiometabolic risk.

Keywords: Biomarkers; Inflammation; Metabolic syndrome; Obesity; Obstructive sleep apnea; Phenotypes.

Figure 1.

A heuristic model of the feedforward associations between visceral fat, insulin resistance, inflammatory cytokines, stress hormones, excessive daytime sleepiness (EDS) and fatigue, and obstructive sleep apnea (OSA). Adapted from Vgontzas et al., 2005 [8].

Figure 2.

The prevalence of clinically-defined OSA in men and women (A), and metabolic syndrome in U.S. men and women (B; National Health and Nutrition Examination Survey [NHANES] 1988–1994). From Ford et al., 2002 and Vgontzas et al., 2005 [8, 11].

Figure 3.

Model (A) for the association between visceral adiposity and moderate OSA, as mediated by IL-6 and CRP, in adolescents with incident OSA. Scatterplot (B) depicting the association of increased CRP from childhood to adolescence (∆CRP) with adolescent AHI in boys. Adapted from Gaines et al., 2016 and Gaines et al., 2017a [25, 45].

Figure 4.

Probabilities of hypertension and hyperglycemia in “typical” obese, middle-aged men (A) and women (B) with mild-to-moderate OSA when CRP levels are in the healthy (0.5 mg/L) vs. “at-risk” (3.0 mg/L) range. From Gaines et al., 2017b [108].