Exploring the Synergistic Effect of Vitamin D and SGLT-2 Inhibitor on Cardio-metabolic Markers and the Renin Angiotensin Aldosterone System in CPAP-naive Obstructive Sleep Apnea Population

Obstructive sleep apnea (OSA) is a medical condition that occurs in 25% to 58% of men and 10% to 37% of women. Close to 50% of express bus drivers in Malaysia were diagnosed with OSA. The association between obesity and OSA is compelling. Approximately 70% of individuals with OSA are obese; whereas prevalence of OSA in people with obesity is 40%. Every 10-kg body weight increment increases OSA risk twofold. As Malaysia has the highest prevalence of adult with obesity in South East Asia with 50% of our adult population being overweight or obese, this makes OSA a very common medical condition in our population. Among patients with obesity undergoing bariatric surgery in our local population, the prevalence of OSA was found to be 80.5%.

The link between renin-angiotensin-aldosterone system (RAAS) and OSA could be bi-directional. It is hypothesized that aldosterone causes salt and water retention leading to edema of the parapharyngeal tissues resulting in obstruction of upper airway and worsening of OSA symptoms. Recurring upper airway collapse in OSA also causes intermittent hypoxia, which increases plasma levels of both renin and aldosterone in animal models, and stimulation of the receptor in the carotid body in rats. The association between OSA and hyperaldosteronism is also believed to be contributed by other factors, including endothelial dysfunction and sympathetic nervous system (SNS) derangement.

Vitamin D plays an important role in calcium homeostasis and metabolism. It is involved in maintenance of calcium and phosphorus levels in the blood, and bone content. Vitamin D is also implicated in several non-skeletal conditions, such as cardiovascular disease, cancer, autoimmune disorders and diabetes mellitus. Vitamin D deficiency has been associated with worse cardiovascular outcomes. Hypovitaminosis D is related to increased risks of cardiovascular diseases, metabolic dysfunctions, and elevated all-cause mortality in the general population. Vitamin D deficiency augments RAAS leading to elevated aldosterone and lowered renin. This is supported by a reduction in aldosterone and an increase in plasma renin in patients with heart failure, arterial hypertension and primary aldosteronism when repleted with vitamin D.

Sleep fragmentation in patients with OSA due to nocturnal hypoxia can lead to daytime drowsiness and fatigue, causing a decrease in outdoor activities and, hence, a decrease in vitamin D synthesis. Moreover, repeated aggravation of upper airway obstruction and hypopnea in these patients partly inhibit vagal nerve activity, affect gastrointestinal motility and secretion of gastrointestinal hormones. These affect absorption and metabolism of vitamin D. Besides, sleep disturbances, intermittent hypoxia, upper airway obstruction and chronic increased abdominal pressure could result in gastroesophageal reflux and gastric ischemia, affecting vitamin D absorption.

Vitamin D receptor-knockout-mice demonstrated a marked increase in angiotensin II and renin levels, whereas 1-alpha-hydroxylase (enzyme needed to synthesize active vitamin D) deficiency enhanced RAAS activity, which was attenuated with administration of active vitamin D. Besides, vitamin D receptors have been found in adrenocortical tissues. Vitamin D3 is demonstrated to decrease expression and activity of the gene which encodes the enzyme required for aldosterone synthesis.