Cardiovascular Disease Outcomes Associated with OSA in Diabetics

Cardiovascular Disease Outcomes Associated with OSA in Diabetics: History

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Subjects: Cardiac & Cardiovascular Systems

Contributor:

Prakasini Satapathy

Keerti Bhusan Pradhan

Zahraa Haleem Al-qaim

Jagdish Khubchandani

Ranjit Sah

Sanjit Sah

Ayush Anand

There is significant pathogenic and epidemiological overlap between diabetes and obstructive sleep apnea (OSA). There may be a possible association between OSA and diabetes and their impact on CVDs. Identifying and managing OSA in individuals with diabetes at an early phase could potentially reduce the risk of CVDs and its related complications.

sleep apnea
cardiovascular diseases
diabetes
stroke
comorbidity

1. Introduction

The global burden of diabetes is increasing, affecting nearly 500 million people in 2017 [1]. By 2025, diabetes is expected to contribute to the death of 1.59 million people globally [1]. One of the major contributors to diabetes-related mortality is CVDs affecting approximately one-third of people with diabetes [2,3]. Though the mortality due to CVDs has decreased over time due to effective secondary prevention strategies, the increasing prevalence of diabetes continues to contribute to the rising burden of CVDs [1,2,4]. OSA is a chronic condition that is increasingly becoming more prevalent. This rise in cases could be attributed to factors such as its potential connection to metabolic syndrome or an increased awareness of the OSA among people, leading to more diagnoses [5,6]. More than 900 million adults have been affected by OSA globally, with about two-fifths in the moderate to severe category [7]. The global prevalence ranges from 9% to 38%, with males (13% to 33%) more likely to be affected than females (6% to 19%) [5]. The elderly and obese individuals are also at higher risk. These latest estimates are higher than those reported in studies from the early 21st century and reflect an increasing prevalence globally [8]. The increased prevalence of OSA is of concern as the risk of obesity, dyslipidemia, diabetes, insomnia, and excessive daytime sleepiness is higher among individuals with OSA [9,10]. Also, OSA can adversely affect the hypoxia–reoxygenation system and sleep cycle, increasing several markers of inflammation, oxidative stress, endothelial dysfunction, and sympathetic activity, thereby increasing the risk of adverse cardiovascular events [11]. Numerous clinical studies have reported elevated levels of inflammatory biomarkers in individuals with OSA. Additionally, researchers have developed animal models of OSA and assessed the changes in biomarkers. Several of these experiments have provided evidence that intermittent hypoxia can activate inflammatory pathways, potentially leading to the development of cardiovascular or metabolic disorders [12]. Notably, moderate to severe OSA increases the risk of severe cardiovascular events such as stroke, heart attack, and heart failure (HF) [13]. One of the ways OSA can cause CVD is by inducing inflammation in the body. Studies have shown that OSA can result in systemic and local inflammation in patients. This inflammation can trigger the impairment of vascular endothelial cells and further modify the structure and function of vessels, leading to endothelial dysfunction. Endothelial dysfunction is a key factor in the development of various end-organ morbidities, such as CVD and metabolic dysfunction [12]. Also, in individuals with type 2 diabetes mellitus (T2DM), OSA is associated with a higher risk of retinopathy, dementia, chronic kidney disease (CKD), and decreased renal function [14,15,16]. Moreover, recent studies have found that nearly half of the people with diabetes had OSA, with a bidirectional association between OSA and diabetes [17,18,19].

2. Cardiovascular Disease Outcomes Associated with Obstructive Sleep Apnea in Diabetics

OSA is a prevalent sleep disorder characterized by repeated upper airway obstruction during sleep. This results in reduced oxygen intake by the lungs, increased carbon dioxide levels in the body, and frequent sleep pattern disruptions. It has been hypothesized to elevate the risk of various CVDs, including stroke, in affected individuals [38]. Although the specific biological processes that underlie the association between CVD and OSA are not entirely understood, some mechanisms have been postulated, such as changes in chest pressure, heightened activity in the sympathetic nervous system, inflammation, and oxidative stress in blood vessels due to cycles of oxygen deprivation and restoration during sleep [38]. The sympathetic nervous system is hypothesized to be activated due to heightened sympathetic drive induced by repeated episodes of apnea and hypopnea, resulting in lower amounts of oxygen in the blood and increased carbon dioxide levels. Recurrent upper airway collapse during sleep, which results in the partial or total cessation of airflow despite continued respiratory effort, is a defining feature of OSA. This can increase respiratory effort against the blocked upper airway, leading to negative intrathoracic pressure. Research has suggested that OSA may be linked to higher levels of inflammatory cytokines and metabolic dysregulation, which may contribute to the development of atherosclerosis. However, due to the complex and diverse nature of OSA, the precise mechanisms that link it to CVD remain somewhat unclear [39].

The presence of diabetes with OSA enhances CVD risk. This is possible because OSA is associated with repetitive episodes of hypoxia–reoxygenation, triggering a cascade of metabolic and inflammatory changes that exacerbate pre-existing metabolic and cardiovascular risk factors in diabetes [11]. One potential mechanism involves insulin resistance, which is common in diabetes and known to promote inflammation and oxidative stress [40]. OSA is linked with impaired glucose metabolism and increased insulin resistance, leading to further inflammation, endothelial dysfunction, and the development of atherosclerosis and CVDs [41]. Another potential mechanism involves activating the renin–angiotensin–aldosterone system (RAAS), associated with maintaining blood pressure (BP). OSA activates the RAAS system, leading to an increase in BP and causing volume overload, contributing to the development of hypertension and CVDs [42]. Additionally, OSA is associated with increased sympathetic nervous system activity, which can further exacerbate hypertension and CVD risk in diabetes. Sympathetic activation can increase heart rate and vasoconstriction, leading to arrhythmias [43]. Overall, the mechanisms linking CVD and OSA in diabetics are likely multifactorial and involve a complex interplay between metabolic and inflammatory pathways.

Few studies explored the relationship with individual CVDs. For example, a cohort study conducted by Adderly et al. revealed that people with DM who developed OSA were at a greater risk of developing CVDs by over 50% [21]. Individuals with diabetes who developed OSA face a greater risk of peripheral neuropathy (PN), AF, diabetic foot disease (DFD), CKD, and all-cause mortality when compared with diabetics without OSA, even after adjusting for potential confounding factors [21]. This study also found that the newly diagnosed DM and OSA patients were at high risk of composite PN, DFD, CVD, and albuminuria [21]. However, the secondary analysis found no significant association between the individual factors of composite CKD, AF, CVD outcome, and all-cause death. This difference may be due to the shorter diabetes duration or better prevention in the OSA group before diabetes diagnosis. Similarly, another observational study found that individuals undergoing coronary artery bypass grafting (CABG) had a relatively higher prevalence of developing OSA and DM [20].The study also found that individuals with both OSA and DM had an elevated probability of emerging MACCEs and were more likely to be hospitalized for HF [20]. Findings further demonstrated that the presence of OSA and DM is independently related to the risk of MACCEs and hospitalization for HF following CABG, even after controlling for left ventricular ejection fraction and medication use [20]. However, it should be mentioned that this study had a few limitations, such as the possibility of unknown or unmeasured confounding variables, and the generalizability of the findings to emergency CABG or major non-cardiac-related surgeries may be limited. Also, the predominantly Asian study population had a limited representation of women subjects [20].

A prospective cohort study by Wang et al. demonstrated a link between OSA and DM, where patients with both conditions were at greater risk of MACCE following an ACS episode, compared to those with DM alone [22]. Interestingly, the prevalence of MACCE among non-DM patients was comparable between individuals with and without OSA. The high risk of adverse effects was mainly observed in patients with OSA and poor glucose control, which was further exacerbated in the presence of prolonged hypoxia, particularly if accompanied by DM [22]. A cross-sectional study by Rice et al. found a positive association between the apnea-hypopnea index (AHI) and stroke risk among obese individuals with type 2 DM, indicating that moderate and severe OSA can elevate the risk of stroke [23]. Notably, no significant association was observed between OSA and baseline CHD. These findings also suggest that identifying and addressing OSA may be crucial for mitigating stroke risk among obese individuals with DM [20,21,22,23].

These findings highlight the importance of considering the link between OSA and diabetes and not overlooking its potential impact on the occurrence of cardiovascular diseases. It is crucial to suggest regular screening for CVDs in patients with both OSA and diabetes to catch any issues early and manage them appropriately. Clinicians need to stay vigilant and well-informed about the potential effects of OSA when it coexists with diabetes, as it can lead to various negative cardiovascular outcomes. However, more research is needed to strengthen our understanding of this connection and how it affects clinical practice.

In conclusion, these studies emphasize the significance of acknowledging the association between OSA and diabetes and its potential influence on CVDs. Clinicians must remain vigilant and informed about the possible cardiovascular risks when OSA coexists with diabetes. The early detection and treatment of OSA in patients with diabetes may lower healthcare utilization and CVD risk in this population. The results of the studis emphasize the necessity for future research to gain a more comprehensive understanding of the intricate connection between OSA, diabetes, and CVD, thereby establishing efficient interventions for the prevention and management of these conditions in clinical practice.

This entry is adapted from the peer-reviewed paper 10.3390/diseases11030103

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