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OSA and diabetes-related complications
Recently, there has been increasing interest in the association between OSA and diabetes-related complications. There is one cross-sectional published study regarding the association between OSA and macrovascular complications in T2DM, but several studies have examined the association between microvascular complications and OSA in T2DM. Most of these studies are cross-sectional in nature but more recently prospective studies proving causality have been published. Many of these studies fail to adjust for many of the possible confounders.
The hypothesis that OSAc an cause micro- (as well as macro-) vascular complications in T2DM is based on the observation that OSA and intermittent hypoxia result in similar molecular consequences in patients without T2DM to those caused by hyperglycemia and result in diabetes-related complications; including increased oxidative stress and advanced glycation end-products, production and activation of the protein kinase C pathway and its molecular perturbations resulting in micro- and macrovascular disease and endothelial dysfunction (Figure 22.3) [118]. Recent work has shown that OSA in patients with T2DM is associated with increased oxidative stress and nitrosative stress and impaired microvascular and endothelial function despite adjustment for a wide range of confounders [118]. OSA has also been shown to be associated with poly (ADP ribose) polymerase (PARP) activation in patients with T2DM (Tahrani, unpublished data).
One cross-sectional analysis from the Look AHEAD study showed that AHI is associated with stroke (adjusted OR 2.57; 95% CI 1.03–6.42), but there was no association with coronary artery disease [133]. Cardiovascular disease (CVD) in this study was self-reported.
Three studies have examined the association between OSA and diabetic retinopathy (DR). In the first study, Shiba et al. used a highly selected population of 219 Japanese patients who were undergoing vitreous surgery and used pulse oximetry to diagnose OSA [134]. Patients with proliferative DR had higher ODI compared to those with nonproliferative DR. After adjustment for age, HbA1c, and hypertension, higher oxygen saturations were found to be protective against proliferative DR [134]. The same investigation has also shown that OSA is associated with angle neovascularization in proliferative DR [135]. Another study included 118 men from primary and secondary care in the UK [136] and found that OSA was independently associated with DR and maculopathy after adjusting for age, BMI, diabetes duration, and hypertension [136].
Another cross-sectional study from the UK that included 226 patients recruited from a secondary care diabetes clinic and used multichannel respiratory devices to diagnose OSA, found that patients with OSA are 3–4 times more likely to have sight-threatening retinopathy, preproliferative/proliferative retinopathy or maculopathy after adjustment for a wide range of confounders, such as age, obesity, diabetes duration, glycemic control and medications amongst others [137]. Furthermore, a longitudinal follow-up of the last mentioned cross-sectional study showed that patients with OSA are more likely to develop preproliferative or proliferative DR despite adjustment for confounders (OR 6.6; 95% CI 1.2–35.1, p=0.03) [137]. In an uncontrolled, hypothesis-generating study of 28 patients with clinically significant macular edema, 6 months of treatment with CPAP was associated with improvement in visual acuity without an impact on macular edema [138].
The association between OSA and diabetic peripheral neuropathy (DPN) has been examined in one cross-sectional study that included South Asians and white Caucasians with T2DM recruited from the diabetes clinic of a secondary care hospital in the UK. This study used portable multichannel respiratory devices to diagnose OSA, the Michigan Neuropathy Screening Instrument to diagnose DPN, and the 10 g monofilament perception to diagnose foot insensitivity. Patients with OSA were three times (OR 2.82; 95% CI 1.44–5.52) and four times (OR 3.97; 95% CI 1.80–8.74) more likely to have DPN and foot insensitivity, respectively, compared to those without OSA [118]. OSA patients were also more likely to have reduced vibration perception and absent ankle jerk reflex [118]. OSA and nocturnal hypoxemia severity were associated with DPN and its severity [118]. Unpublished data from the same study showed that OSA was also associated with lower intra-epidermal nerve fiber density in skin biopsies (Tahrani, unpublished data) suggesting that OSA may cause large as well as small nerve fiber Dysfunction.
The association between OSA and diabetic nephropathy has been examined in two studies. In one study of 237 patients, snoring (as a surrogate marker of OSA) was found to be independently associated with microalbuminuria [139]. Another study showed that OSA was associated with diabetic nephropathy (defined as microalbuminuria, microalbuminuria and/or reduced eGFR) in patients with T2DM after adjustment for a wide range of confounders; patients with end-stage renal disease were excluded from this study [140]. A 2.5 year follow-up of the latest study showed that the decline in eGFR was greater in patients with T2DM and OSA compared to those with OSA alone (−6.8% [−16.1–2.2%] vs. −1.6% [−7.7–5.3%], p=0.002) and that OSA was a predictor of study-end eGFR despite adjustment for confounders [140].
OSA is also associated with autonomic neuropathy and increased sympathetic activity [141]. It is likely that both recurrent hypoxia [95] and recurrent arousals [96] contribute to the activation of the sympathetic system. Obese subjects with autonomic neuropathy develop more frequent and more prolonged hypopnea/apnea in comparison to obese subjects without autonomic dysfunction whether or not they had T2DM [142].