Obstructive Sleep Apnea and Medical Comorbidities in the Asian Population: Evidence From a Nationwide Healthcare System Data in South Korea
Article information
Abstract
Objective
Obstructive sleep apnea (OSA) is a breathing disorder characterized by recurrent airway obstruction during sleep. Previous western studies have investigated the link between medical disorders and the pathophysiology of OSA. The prevalence and comorbidity rates of OSA; however, vary across different countries and racial groups. This study aimed to delve into medical comorbidities in patients with OSA using a large nationwide healthcare database in Korea.
Methods
This nationwide study used the Korean National Health Insurance claims database (2010–2019). The effect of OSA on the incidence of medical disorders was estimated using the Cox proportional hazard ratio (HR) model. The results were reported as crude and adjusted HRs with 95% confidence intervals (CI). Subgroup analysis was conducted by sex and age.
Results
In total, 103,785 patients with OSA and 207,570 patients without OSA were included. OSA group had significantly higher HRs for ischemic heart disease and stroke even after adjusting for hypertension, dyslipidemia, and diabetes. The OSA group also showed an increased risk of metabolic syndrome-related diseases, chronic kidney disease, and gastroesophageal reflux disease. Female patients with OSA exhibited notably higher rates of comorbid liver cirrhosis, chronic obstructive pulmonary disease, and asthma. The cardiovascular burden of patients increased in accordance with the patients’ age.
Conclusion
Korean patients with OSA have a significantly increased risk of cardio-cerebrovascular diseases, which aligns with the previous studies conducted in the western countries. This result holds particular significance as it represents the first nationwide, population-based study conducted in Asia.
INTRODUCTION
Obstructive sleep apnea (OSA) is a breathing disorder characterized by recurrent episodes of partial or complete airway obstruction during sleep, which results in hypoxemia and hypercapnia [1]. Repeated effort to maintain normal ventilation through upper airway reopening is often accompanied by frequent arousals and stimulation of the sympathetic nervous system. These phenomena are believed to be the primary mechanisms underlying the various medical comorbidities associated with OSA [2].
OSA is one of the most prevalent sleep disorders affecting an estimated one billion patients worldwide [3]. The prevalence of OSA is higher in African Americans, Native Americans, and Hispanics compared to other racial groups. Asians seem to exhibit rates of OSA that are comparable to those of Caucasians despite significantly lower obesity levels [4]; the prevalence of OSA in the United States has been estimated to be about 15% [5], and the prevalence of OSA in Korea was up to 15.8% in 2020 [6].
Previous studies in Western countries suggest that OSA not only poses an elevated risk for metabolic diseases such as hypertension, diabetes, and dyslipidemia but also increases the likelihood of cardiovascular diseases. A notable difference in the prevalence of cardiovascular comorbidities is observed when analyzed by race. For instance, among African Americans, the prevalence of severe hypertension is 5 to 7 times higher compared to that of Caucasians [7]; however, there have been no population-based large studies focusing on OSA and its comorbidities within the Asian ethnicity.
Moreover, OSA is a chronic, age-dependent disease that affects the patients throughout their lives, persisting into old age [8]; consequently, OSA increases susceptibility to comorbidities as the duration of illness prolongs. Furthermore, the prevalence and comorbidity rate of OSA vary according to gender. The prevalence of sleep-disordered breathing in Korea is estimated as 27% in men and 16% in women [9]. Women generally have a shorter and less collapsible pharynx, resulting in less pronounced snoring and daytime sleepiness, which contribute to lower detection and treatment rates. These features contribute to a higher comorbidity rate of OSA in women compared to men [10].
Therefore, deeper and broader understanding of comorbidities disposed by OSA and the difference according to sex and age is critical for managing both OSA and medical condition. However, data for Asian population group have been scarce, limiting the ability to predict the comorbidities and clinical courses of OSA patients in Korea.
This study aimed to explore the comorbidity of OSA compared with general population using the nationwide healthcare system data in Korea. This study holds significance because it is the first, large-scale, nationwide study conducted in Asian population. We also performed subgroup analyses according to age and sex to further evaluate the impact of demographics on the risk of comorbidity in Asian OSA patients.
METHODS
Data collection
This was a nationwide, population-based, retrospective study using the National Health Insurance (NHI) claims database in Korea (from 2010 to 2019). The NHI system is one of the largest national insurance services covering more than 98% of the Korean population as it is mandated by law. The database contains claims information on all diseases, providing reliable estimates of prevalence and comorbid diagnosis of certain diseases.
In the NHI database, diagnoses are recorded according to the International Classification of Diseases, 10th revision (ICD-10) (Table 1). Patients were included only if at least 3 documented physician contacts were present under the diagnosis of OSA as the principal diagnosis. Demographic information such as age and sex were obtained from the information provided in the first visit of the diagnosis.
ICD-10 codes for comorbidities
Medical comorbidities
Medical comorbidities highly associated with OSA were extracted using the ICD-10 revision diagnosis code; ischemic heart disease, stroke, heart failure, hypertension, dyslipidemia, diabetes, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), liver cirrhosis, asthma, gastroesophageal reflux disease (GERD). Patients were defined to have a certain comorbidity if it was recorded as a primary diagnosis on at least three clinical visits.
Control group
To represent the general population, patients who were recorded to have undergone appendectomy between 2010 and 2019 were included as the control group; however, patients who had a concomitant diagnosis of OSA were excluded.
Statistical analysis
The baseline characteristics of patients in the OSA and the control group were compared using an independent t-test for continuous variables and the chi-squared test for categorical variables. The Cox proportional hazard ratio (HR) model was used to estimate the effect of OSA on the incidence of medical disorders. Both crude HR and adjusted HR along with 95% confidence intervals (CI) are reported. Subgroup analyses disaggregated by sex and age were also conducted. All statistical analyses were performed using SAS Enterprise Guide version 7.1 (SAS Institute, Cary, NC, USA). This study was approved by the Institutional Review Boards of St. Vincent’s Hospital (VC11QISE0225, Suwon, Korea).
RESULTS
Baseline characteristics
The demographic characteristics of the study population are summarized in Table 2. In total, 103,785 patients with OSA were identified. Among patients who underwent appendectomy, 207,570 age- and sex-matched patients without OSA were included in the control group. The mean age in the OSA group and the control group were 58.36±14.12 years and 57.25±20.31 years, respectively. Male patients accounted for 83.06% and the most common age was 40–59 years in both the OSA and the control groups. There was a notable difference between the OSA group and the control group in terms of insurance coverage. Classification based on insurance type revealed that 3.11% of OSA patients were recipients of medical aid, while this percentage was higher in the control group (5.01%).
Demographic characteristics of the study population
Medical comorbidities in OSA
Table 3 presents the crude HR and adjusted HR (corrected for age, sex, and socioeconomic status) for medical comorbidities in the OSA group. The prevalence of ischemic heart disease was highest even after adjusting for hypertension, dyslipidemia, and diabetes (adjusted HR, 2.109; 95% CI, 2.088–2.130). The adjusted HR for stroke (1.462; 95% CI, 1.442–1.482) was also higher after further adjusting for hypertension, dyslipidemia, and diabetes mellitus. Heart failure demonstrated a slightly higher adjusted HR (1.188; 95% CI, 1.160–1.218) compared to the control group.
The adjusted HRs for hypertension (1.757; 95% CI, 1.745–1.770), dyslipidemia (1.587; 95% CI, 1.566–1.608), and diabetes (1.561; 95% CI, 1.546–1.575) were also higher in the OSA group compared with the control group.
Additionally, patients with OSA had a significantly higher risk of CKD (adjusted HR, 1.518; 95% CI, 1.483–1.554) and GERD (adjusted HR, 1.445; 95% CI, 1.434–1.455).
However, patients with OSA had a significantly lower risk of COPD (adjusted HR, 0.824; 95% CI, 0.804–0.844). Moreover, liver cirrhosis and asthma were not significantly associated with OSA.
Subgroup analysis
When stratified by sex, the risk of increased medical comorbidities in OSA patients showed a slight variation. OSA was associated with an increased risk of hypertension, dyslipidemia, diabetes, ischemic heart disease, stroke, heart failure, CKD, and GERD in both sexes (Table 4). However, OSA was associated with an increased risk of COPD in female (adjusted HR, 1.854; 95% CI, 1.512–2.274), but a decreased risk of COPD in male (adjusted HR, 0.767; 95% CI, 0.694–0.848). A similar pattern was observed with respect to the risk of asthma in OSA patients (adjusted HR, 1.349; 95% CI, 1.278–1.424 in female and adjusted HR, 0.544; 95% CI, 0.525–0.565 in male). The risk of liver cirrhosis was significantly higher only in female with OSA (adjusted HR, 2.064; 95% CI, 1.550–2.748).
Subgroup analysis by sex group
Subgroup analysis by age revealed that OSA was a risk factor for dyslipidemia, diabetes, and GERD in all age groups (Table 5). The increased risk of hypertension and ischemic heart disease in OSA patients was significant in all age groups, except for the 20–39 age group. The risk of stroke and heart failure in OSA patients was higher in the 40–59 and 60–79 years age groups.
Subgroup analysis by age group
DISCUSSION
To the best of our knowledge, this is the first study to examine the risk of medical comorbidities in patients with OSA using a large nationally representative Korean database. A total of 103,785 patients with OSA were enrolled in this study, and 207,570 age- and sex-matched patients who underwent appendectomy were included as the control group.
Our results showed that Korean patients with OSA have a higher risk of ischemic heart disease and stroke, even after adjusting for hypertension, dyslipidemia, and diabetes. The OSA group also showed a higher risk of metabolic diseases, such as diabetes and dyslipidemia, compared to the control group. Furthermore, this study observed an increased risk of chronic diseases such as COPD, GERD, and CKD in Korean patients with OSA.
When stratified by sex, the trend showed some differences between males and females. Female OSA patients exhibited a higher risk of liver cirrhosis, COPD, and asthma, whereas male OSA patients demonstrated a decreased risk of COPD and asthma. When stratified by age, an increasing trend was observed in the HRs for stroke, ischemic heart disease, heart failure, and hypertension according to the age, with the peak observed in the 40–59 age group.
Cardio-cerebrovascular disease
In this study, OSA was identified as a risk factor for ischemic heart disease and stroke even after adjusting for diabetes, hypertension, and dyslipidemia. Notably, the adjusted HR was highest for ischemic heart disease. Additionally, patients with OSA also showed a higher risk of heart failure.
Several clinical studies, including a nationwide study based on the US health claims database, have consistently identified a close relationship between OSA and cardiovascular diseases, such as congestive heart failure, stroke, arrhythmia, and ischemic heart disease [11]. Our results align with the previous studies, indicating a significantly increased risk of cardiovascular diseases in Korean patients with OSA.
A nationwide database study in Denmark (2000–2012) also showed an increased risk of heart failure in patients with OSA [12]. The increased risk of heart failure in Danish patients with sleep apnea was observed across all age groups, which is similar to the pattern observed in Korean patients with OSA. An important finding was that application of continuous positive airway pressure (CPAP) significantly reduced the risk of heart failure in patients aged ≥60 years.
Additionally, Peker et al. [13] revealed that patients with coronary disease who had comorbid OSA showed a higher mortality rate (38% vs. 9%; p=0.018). Subsequently, a study conducted in France investigated patients diagnosed with both OSA and coronary artery disease [14]. Patients who received treatment for OSA were found to have a significantly lower risk of cardiovascular death, acute coronary syndrome, hospitalization due to heart failure, and coronary revascularization rate (HR, 0.24; 95% CI, 0.09–0.62) compared to the untreated group.
These studies suggest that treating OSA may help prevent the onset, progression, and exacerbation of cardiovascular disease in OSA patients. Considering the high risk of cardiovascular diseases in Korean patients with OSA, treatment of OSA seems crucial to prevent cardiac events and decrease mortality rates.
Metabolic syndrome-related disease
In this study, Korean patients with OSA had a higher risk of metabolic syndrome-related diseases, which is consistent with the previous studies including a US nationwide cohort study.
Hypoxia caused by airway obstruction triggers a systemic inflammatory reaction. Repeated hypoxic damage in adipose tissue triggers chronic inflammation, increasing the level of inflammatory cytokines, such as tumor necrosis factor α and interleukin-6 [15]. Systematic inflammatory reaction induces vascular endothelial damage, which in turn causes insulin resistance and glucose intolerance, leading to the onset of metabolic diseases [16].
Other chronic diseases
In this study, the HR for CKD in OSA patients was higher than that in the general population in Korea. This is similar to the results of a large-scale cohort study in the US, where 1.66% of OSA patients were found to have comorbid CKD [11].
COPD, on the other hand, exhibited significantly lower HR in patients with OSA. The results contradict the findings of a population-based study in the United States, where the odds ratio for chronic pulmonary disease was significantly higher in patients with OSA [11]. A cohort study conducted in 2022 revealed that 77% of COPD patients in Korea had the non-chronic bronchitis type COPD [17]. Higher prevalence of non-chronic bronchitis type COPD, along with the lower average body mass index (BMI) in Asian ethnicity could explain the lower HR for COPD in Korean patients with OSA [18].
The HR for GERD, on the other hand, appeared to be high in Korean populations with OSA, aligning with the US studies.
Subgroup analysis
In a subgroup analysis by sex, the HR for liver cirrhosis in male OSA patients was not significantly different compared to the general population, similar to the unstratified analysis. However, in female OSA patients, the HR for liver cirrhosis was significantly higher than that in the matched control population.
Chronic intermittent hypoxia in patients with OSA seems to increase the risk of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NASH) by inducing oxidative stress in the liver [19]. Yang et al. [20] reported that in females diagnosed with NASH, the post-menopausal reduction in estrogen level leads to liver fibrosis at a level similar to that seen in male NASH patients. Considering the age of the subjects in this study (approximately 70% of patients over the age of 40 years), it is tempting to speculate that OSA may accelerate the progression to liver cirrhosis in post-menopausal women.
Furthermore, the HRs for COPD and asthma compared to the matched control population were significantly higher in females. This finding raises questions regarding the relationship between chronic pulmonary disease and OSA. Yet, these results are somewhat consistent with the findings of the US study—our study had a sex ratio of 5:1, while the US NHI study had a 1:1 sex ratio—which indicated a high comorbidity rate of chronic pulmonary disease.
Bahammam et al. [21] reported that in female OSA patients, the rapid eye movement (REM)-predominant OSA type is associated with a higher incidence of asthma. Females, with a generally smaller pharyngeal size than males, are prone to pharyngeal wall collapse during REM sleep due to atonia [22]. Similarly, there is a potential increase in comorbid COPD in female OSA patients due to heightened sensitivity to REM sleep. Further study utilizing additional data such as polysomnography and BMI in female OSA patients is warranted.
When stratified by age, the HRs for ischemic heart disease, stroke, hypertension, and CKD increased with age in the OSA group. Considering that the average age at onset of OSA is 36 years [23], we can infer that as the morbidity period of OSA lengthens, the vascular burden is also increased. The lack of significant differences in the HRs for CKD and stroke in OSA patients aged ≥80 years compared to the general population could potentially be biased due to a higher mortality rate [24].
Limitations
Some limitations of this study should be considered while interpreting the results. First, this study is based solely on insurance benefit-based patient information. The gold standard for the diagnosis of OSA is polysomnography. However, in Korea, polysomnography was not covered by insurance until September 2018. Therefore, there may have been more cases of OSA that were not covered by NHI due to the high cost of polysomnography, which may have introduced an element of selection bias. Second, a study found that the consistency of medical records with residential diseases of claims data was approximately 70%. It is difficult to completely exclude the influence of physician subjectivity related to diagnoses and prescriptions. Third, The ICD-10 diagnosis does not distinguish OSA severity. Indeed, the severity of OSA is a potential confounding factor that may influence the incidence of related comorbidities. Finally, our data lack information about BMI and smoking status, which can influence both OSA and the occurrence of comorbid disease. There may be other confounding factors that were not addressed in this study.
Conclusion
This is the first nation-wide population-based study conducted in Korea to demonstrate that patients with OSA are at a significantly higher risk of cardio-cerebrovascular diseases. In addition, the risk of ischemic heart disease and stroke was found to increase according to the patients’ age. Korean female with OSA were found to be at a higher risk of liver cirrhosis, COPD, and asthma compared with the general population group.
Our findings underline the significance of early detection and appropriate management of OSA to prevent the progression of cardiovascular diseases and other related metabolic and chronic diseases in individuals with OSA. A further study on the effect of the treatment of OSA on comorbidity and mortality among the Asian population is warranted.
Notes
Availability of Data and Material
The datasets generated or analyzed during the study are available from the corresponding author on reasonable request.
Conflicts of Interest
Yoo Hyun Um, a contributing editor of the Psychiatry Investigation, was not involved in the editorial evaluation or decision to publish this article. All remaining authors have declared no conflicts of interest.
Author Contributions
Conceptualization: all authors. Data curation: Minbi Lee, Jihye Oh. Formal analysis: Minbi Lee, Jihye Oh, Yoo Hyun Um. Investigation: all authors. Methodology: Young-Chan Kim, Tae-Won Kim, Ho Jun Seo, Jong-Hyun Jeong, Seung Chul Hong. Project administration: Minbi Lee, Jihye Oh, Yoo Hyun Um, Young-Chan Kim. Supervision: Jong-Hyun Jeong, Seung Chul Hong. Validation: Yoo Hyun Um, Young-Chan Kim, Tae-Won Kim, Ho Jun Seo, Jong-Hyun Jeong, Seung Chul Hong. Writing—original draft: Minbi Lee. Writing—review & editing: all authors.
Funding Statement
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Acknowledgements
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