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Rebuttal from Craig L. Phillips, Camilla M. Hoyos, Brendon J. Yee and Ronald R. Grunstein

Most of the case argued by Vgontzas and colleagues is based on one component of metabolic syndrome (MetS), namely abdominal obesity, causing obstructive sleep apnoea (OSA) rather than MetS overall or any of the remaining components. Whilst insulin resistance is core to MetS, in referring to MetS components we note that hyperglycaemia was omitted. We agree that it is irrefutable that obesity exacerbates OSA and weight loss alleviates the condition (to some extent). This does not, however, disprove the hypothesis that a reciprocal or bidirectional interaction exists between obesity and OSA (Ong et al. 2013). Regardless, the proposal by Vgontzas et al. that obesity and MetS precede the development of OSA, which would support a causal argument, is not supported by any published studies. Even in their original longitudinal study (Bixler et al. 2016), the link between abdominal visceral fat and OSA was based on cross-sectional analyses, which negates any causal inference. In contrast, we propose that the evidence (in terms of a ‘chicken and egg’ argument) suggests that OSA precedes weight gain before any reciprocal interaction evolves. In support of this, we provided evidence including that poor sleep and symptoms of sleep apnoea predict the development of MetS (Troxel et al. 2010) and that the severity of OSA seems to independently predict both weight gain (Brown et al. 2011) and decreased weight and visceral fat loss (Borel et al. 2012). Whilst we acknowledge the potential link between neck fat accumulation and OSA, it is unclear how close this relationship really is since we have found that as part of overall weight loss, upper airway fat loss does not predict a reduction in OSA severity (Sutherland et al. 2011). The role of leptin in human respiratory control and collapse of the upper airway is very speculative given there are major differences between leptin deficiency in rodents and leptin resistance in humans. Moreover the authors quote a paper (Piper et al. 1994) in which leptin was never measured. It is also argued that the prevalence of metabolic syndrome declines with older age along with the cardio-metabolic effects of OSA. However, it is well established that the prevalence of OSA itself does not decline in older age. In fact in a recent population study, moderate-to-severe sleep-disordered breathing prevalence was increased significantly in participants aged over 60 years compared to younger people (Heinzer et al. 2015). This effectively argues against rather than for the direction of causality going from MetS to OSA. An increase in mortality in people where OSA has caused MetS could explain the decrease in MetS prevalence in older age. Finally, Vagontzas and colleagues (2016) propose that inflammation may mediate the association between MetS and OSA. However there are two recent meta-analyses which both consistently suggest that inflammatory markers including tumour necrosis factor α (TNFα) and C-reactive protein (CRP) are reduced with continuous positive airway pressure therapy (CPAP) treatment of OSA (Baessler et al. 2013; Xie et al. 2013). In summary, we propose that the ‘weight’ of evidence supports OSA as a cause of MetS and its components rather than the opposing view that MetS causes OSA.