Hospital Practice
ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20
Comorbidity of diabetes and obstructive sleep apnea in hospitalized patients Sivakumar Sudhakaran & Salim R. Surani To cite this article: Sivakumar Sudhakaran & Salim R. Surani (2015) Comorbidity of diabetes and obstructive sleep apnea in hospitalized patients, Hospital Practice, 43:2, 79-84, DOI: 10.1080/21548331.2015.1004295 To link to this article: http://dx.doi.org/10.1080/21548331.2015.1004295
Published online: 20 Jan 2015.
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Date: 31 March 2016, At: 00:11
http://informahealthcare.com/hop ISSN: 2154-8331 (print) Hosp Pract, 2015; 43(2): 79–84 DOI: 10.1080/21548331.2015.1004295
REVIEW
Comorbidity of diabetes and obstructive sleep apnea in hospitalized patients Sivakumar Sudhakaran1 & Salim R. Surani 2 1
Texas A&M Health Science Center, TX, USA, and 2Division of Pulmonary, Critical Care and Sleep Medicine, Texas A&M Health Science Center, TX, USA
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Abstract
Keywords:
Obstructive sleep apnea (OSA) and type 2 diabetes are two morbidities commonly encountered in the hospitalized setting. Both diseases will present with an array of complications if not managed in a timely, competent manner. However, a growing body of evidence suggests a link between these two pathologies. It is our hope that through careful review of the literature, we may generate heightened awareness of the OSA/diabetes comorbidity. Through better understanding of these conditions and their interactions, we may insure efficient management in the clinical setting and prevent exacerbation of common complications.
Introduction Obstructive sleep apnea (OSA) is a sleep disorder that is pervasive among overweight and obese adults, a population that comprises at least two-thirds of US citizens today. Prevalence estimates in obese adults from ages 30 to 69 years range from 11% to 46% in women and 33% to 77% in men [1]. OSA is classically seen as repetitive episodes of partial or complete collapse of the upper airway during sleep, resulting in complete cessation (apnea) or reduction (hypopnea) of airflow, leading to hypoxia and arousal during sleep [2]. OSA may present clinically as snoring, excessive daytime sleepiness, witnessed apneas, nocturnal chocking, unrefreshed sleep, morning headaches, sleep maintenance insomnia, and fatigue [3]. OSA is not uncommon in the clinical setting, in fact one study found that previously diagnosed OSA is highly prevalent and undertreated in hospitalized patients. Additionally, the use of computerized alerts by respiratory therapists resulted in significantly more OSA patients receiving appropriate medical care (P < 0.002), which subsequently resulted in significantly fewer patients experiencing hypoxemia (P < 0.006) [4]. Diabetes mellitus, or simply diabetes, is a group of metabolic diseases characterized by hyperglycemia due to defects in insulin production, insulin function, or a combination of both. The chronic hyperglycemia seen in diabetes is associated with several forms of long-term organ damage including the eyes, kidneys, nerves, heart, and blood vessels [5]. Type 2 diabetes, previously referred to as adult-onset diabetes or non-insulindependent diabetes, includes individuals who have insulin
Diabetes, diabetes complications, OSA, OSA and diabetes, OSA complications, History Received 15 September 2014 Accepted 28 October 2014 Published online 20 January 2015
resistance and generally some degree of insulin deficiency. Most patients with type 2 diabetes are obese, excessive weight itself causes some degree of insulin resistance [5]. The prevalence of diabetes in the USA is astounding; currently 29.1 million people (9.3% of the US population) have diabetes [6], with type 2 diabetes accounting for 90% to 95% of these cases [5]. Current standards for the diagnosis of type 2 diabetes can be categorized into one of four ways: (1) hemoglobin A1c (HbA1c) ‡ 6.5%, (2) fasting plasma glucose ‡ 126 mg/dL, (3) 2-hour plasma glucose ‡ 200 mg/dL during an oral glucose tolerance test (OGTT), or (4) random plasma glucose ‡ 200 mg/ dL in a patient with classic symptoms of hyperglycemia [7]. A study found that hyperglycemia was present in 38% of patients admitted to the hospital; of these patients, 26% had a known history of diabetes, whereas 12% had no history of diabetes before the admission [8]. Moreover, patients discharged with a blood glucose level > 250 mg/dL accrued greater cost during hospitalization compared to patients discharged with a blood glucose < 250 mg/dL [9]. In regard to OSA, short-term studies have shown noticeable alterations in metabolic functions including glucose intolerance and insulin resistance due to sleep apnea [10-16]. Conclusions derived from these studies raise questions about the pervasiveness of type 2 diabetes, as well as its interaction with OSA. In this article, we will assess the interplay between OSA and diabetes in hospitalized patients. It is our hope that by analyzing the relationship between OSA and diabetes, we may create a set of simple clinical guidelines that may be helpful for clinicians in everyday hospital practice.
Correspondence: Salim Surani, MD, MPH, MSHM, FACP, FCCP, FAASM, Associate Professor, Division of Pulmonary, Critical Care and Sleep Medicine, Texas A&M Health Science Center, 1177 West Wheeler Ave, Suite 1, Aransas Pass, TX 78336, USA. Tel: +1 361 8857722. Fax: +1 361 850 7563. E-mail: [email protected] 2015 Informa UK Ltd.
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Method A thorough literature search in Medline, Google Scholar, Ovid, and PubMed was done to identify relevant articles pertaining to OSA and diabetes among hospitalized patients. Each article was assessed for relevance regarding OSA and diabetes as well as any related complications in hospitalized patients. Clinical studies in addition to review articles were utilized. Management guidelines were defined by expert opinion of clinical authors as well as current recommendations from the literature.
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Prevalence of OSA in patients with diabetes and vice versa The highest estimate regarding prevalence of OSA in type 2 diabetes was 86% and was reported in a Sleep AHEAD (action for health in diabetes) study [17]. However, the average estimate of OSA in type 2 diabetic patients is ~ 71%, determined by the data provided from five different studies that encompassed ~ 1200 type 2 diabetic patients [15,17-21]. The prevalence estimates in these studies may have differed due to a variety of factors including different diagnostic methodologies for sleep apnea, scoring criteria, or study populations [22]. A recent retrospective analysis totaling more than 16,000 diabetic patients in one of 27 primary care ambulatory practices revealed that only 18% of the study population (23% of obese patients) had an OSA diagnosis [23]. These numbers differ vastly from the 71% averaged from the previously mentioned studies, suggesting that millions of diabetic patients may currently be suffering from undiagnosed OSA. A recently published study conducted in Nigeria analogously found that a substantial proportion of patients with type 2 diabetes might have OSA, with the key predictor being neck circumference after controlling for obesity [24]. Conversely, there have been a number of studies that have evaluated the prevalence of type 2 diabetes in OSA patients [13,25-30]. Most of these studies used polysomnography to determine OSA and adjusted for shared risk factors, including age, sex, body mass index (BMI), neck, and waist circumference [18]. To assess diabetes the majority of studies used validated diabetes definitions based on OGTTs or 2-hour post-challenge glucose levels [28,29,31,32], whereas a few studies relied on self-reported diabetes [33]. As a whole, the cross-sectional analyses from these studies illustrated a significantly higher prevalence of diabetes in patients with OSA as compared to those without OSA. The prevalence estimates from these studies ranged from 15% to 30%, depending on the study population as well as the specific techniques employed to diagnose type 2 diabetes and OSA [13,25-27,29]. A number of other studies revealed a similar link between type 2 diabetes in OSA patients. One study in Sweden found that after various adjustments (length of treatment, BMI, age, hypertension, etc.) severity of oxygen desaturation in OSA could serve as a predictor for developing diabetes [33]. Additionally, a separate study found that nocturnal intermittent hypoxia was associated with an increased risk of developing type 2 diabetes [34]. Some studies even found a correlation between the degree of severity of OSA and increased frequency of diabetes [26,29].
Hosp Pract, 2015; 43(2):79–84
Currently, a select number of studies found in the literature have aimed to find an independent link between OSA and type 2 diabetes. A historical cohort study recently published controlled for nearly all OSA-related variables including sex, age, BMI, smoking status, comorbidities, as well as income, and found that among patients with OSA, initial OSA severity predicted subsequent risk of incident diabetes [35]. Additionally, an Australian population-based cohort study looked at OSA as an independent risk factor for diabetes. The study found that moderate-to-severe sleep apnea was a significant risk factor for incident diabetes. However, it should be noted that confidence intervals for the analysis were wide; thus, studies with greater power will be required to verify the relationship between sleep apnea and the incidence of diabetes in community-based populations [36]. Overall, the literature strongly suggests that independent of various risk factors, including age, race, gender, baseline fasting glucose, and BMI, sleep apnea is significantly associated with the risk of type 2 diabetes [28]. Evidence from clinic- or hospital-based studies suggests a link between OSA and glucose metabolism Clinic-based studies examining the relationship between OSA and glucose metabolism generally use laboratory polysomnography to determine the degree of OSA [37]. In a clinic-based study containing 595 men suspected of OSA, cross-sectional data from polysomnography and 2-hour OGTTs revealed that type 2 diabetes was present in 30.1% of OSA patients versus 13.9% in nonapneic snorers. As the severity of OSA increased, fasting as well as post-load blood glucose levels increased, whereas insulin sensitivity decreased, independent of age or BMI [13]. Similar findings were found in two more different case–control studies. In one study, 19 of 24 patients (79%) with OSA had abnormal glucose, compared to only 2 of 9 patients without OSA. Additionally, 25% of these patients had previously undiagnosed type 2 diabetes [38]. In the other study, visceral adiposity (assessed by abdominal computed tomography) was controlled for, and test results again showed that OSA was associated with elevated fasting glucose levels [39]. Finally, a recent study of hospitalized patients in Beijing revealed a high prevalence (66.7%) of OSA in a sample of patients with type 2 diabetes [40]. It is worth mentioning that a select number of studies failed to find an independent link between OSA and metabolic abnormalities [41,42]. However, the majority of clinic-based studies consistently described an independent association between OSA and abnormal glucose metabolism [37]. These minor inconsistencies may be attributed to how body fat distribution was determined, or varying diabetic plasma glucose screening levels between studies. Screening for OSA/diabetes comorbidity and complications A recently published study found after controlling for multiple confounders that initial OSA severity and its physiological consequences predicted subsequent risk for incident diabetes [35]. Furthermore, a separate study found increased
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DOI: 10.1080/21548331.2015.1004295
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risk factors associated with OSA in hospitalized type 2 diabetic patients [40]. These studies illustrate that common diabetic and OSA complications may be exacerbated due to a cumulative OSA/diabetes comorbidity. OSA is associated with a number of complications including daytime somnolence [43], hypertension [44,45], stroke [46], coronary artery disease [47], arrhythmias [48], heart failure [49], and type 2 diabetes [13]. Diabetic complications include stroke, hypertension, dyslipidemia, heart disease, nephropathy, retinopathy, and neuropathy [7]. These comorbidities and complications can cause significant challenges for physicians and may lead to an increased length of stay for hospitalized patients. Screening for type 2 diabetes includes a fasting (defined as no caloric intake for at least 8 hours) plasma glucose level > 126 mg/dL [7]. There have been a number of screening tools designed for sleep-related breathing disorders including the Berlin and STOP-BANG questionnaires. The Berlin questionnaire was first validated in primary care against portable unattended sleep studies. A ‘high risk’ Berlin score predicted a respiratory disturbance index of > 5 with sensitivity of 0.86, specificity of 0.77, positive predictive value of 0.89, and likelihood ratio of 3.79 [50]. Similarly, STOP-BANG is an OSA screening test developed for use in preoperative surgical clinics; it is part questionnaire (STOP) and part demographic or physical measures (BANG) [51]. For identifying severe OSA, a STOP-BANG score of 4 has a sensitivity of 88%; to confirm OSA a score of 6 is more specific [52]. Based on current evidence, physicians should be advised to carefully screen and assess the risk of OSA in type 2 diabetic patients and, conversely, evaluate glucose tolerance in patients with known OSA to avoid compounding the aforelisted complications [37].
and post-CPAP therapy. Using a subcutaneous glucose sensor, interstitial glucose levels were measured 288 times a day in 25 diabetic patients. The authors also noted a significant decrease in HbA1c level in all 17 patients who had a baseline HbA1c of > 7%. Moreover, the study found that 1-hour postprandial interstitial glucose levels were considerably reduced after roughly 3 months of CPAP therapy. In fact, reduction in HbA1c levels correlated notably with the number of days of CPAP therapy in patients who complied with treatment for > 4 hours/night [56]. A separate retrospective study found a comparable clinically significant drop of HbA1c levels in 38 diabetic patients after roughly 3 to 4 months of CPAP therapy [57]. According to various preliminary studies, CPAP therapy has shown improvement in insulin sensitivity [58] and glucose homeostasis [58] in sleep apnea patients. Although there is growing evidence that CPAP use has a beneficial impact on OSA patients with diabetes, a select number of studies have failed to find improvements in glucose metabolism [59-61], insulin resistance [62], or HbA1c levels [62]. These conflicting results may be due to a variety of factors including varying sample size, duration of CPAP therapy, or degree of adherence to treatment. Nevertheless, there is a substantial amount of evidence to suggest that CPAP treatment has a beneficial effect on glucose metabolism, insulin resistance, and HbA1c level. Additionally, CPAP therapy has shown benefits such as improved daytime alertness, reduced fatigue, reduced cardiovascular risks, improved blood pressure, enhanced left ventricular function [63], and better overall quality of life outcomes [64]. However, large-scale studies controlling for variables such as duration and adherence of CPAP use must be executed to fully assess the metabolic effects of CPAP therapy.
Continuous positive airway pressure treatment of OSA and it effects on glucose metabolism and the diabetic state
Potential mechanisms linking OSA to insulin resistance, glucose intolerance, and other common diabetic presentations
There have been a number of studies that have examined how continuous positive airway pressure (CPAP) treatment for OSA has affected glucose metabolism. Current studies suggest that abnormalities in glucose metabolism may be corrected by CPAP therapy to a moderate degree. These studies have assessed a wide spectrum of variables concerning CPAP therapy and diabetes. By using the hyperinsulinemiceuglycemic clamp, widely considered the most accurate technique for measurement of insulin sensitivity, one study found that diabetic patients using CPAP treatment saw improvement in insulin sensitivity in as little as 2 days. Interestingly, this rapid improvement in insulin sensitivity with CPAP use was found to be marginal in patients with a BMI of ‡ 30 kg/m2 [53]. A German study found that insulin sensitivity improved in nine obese type 2 diabetics over 3 months of CPAP therapy but also failed to find any significant improvement after 2 days of treatment [54]. Similarly, a separate study found improvement in insulin sensitivity in 10 obese diabetic patients after 4 months of CPAP use [55]. These studies indicate that CPAP treatment can still improve insulin sensitivity in obese diabetic patients; however, a longer time course of treatment may be required. Another study looked at the response of HbA1c levels in diabetic patients 3 months prior
The two classic features of OSA are intermittent hypoxia and sleep fragmentation, both of which may alter normal physiological processes and adversely affect glucose control. Continuous or sustained hypoxia and sleep loss may affect glucose metabolism through a number of mechanisms ranging from changes in inflammatory pathways to activation of the sympathetic nervous system or hypothalamic-pituitary axis [65]. In fact, one study found that in healthy humans, 20-minute exposure to intermittent voluntary hypoxic apnea resulted in sustained elevation of muscle sympathetic nerve activity and that hypoxia was the primary agent of this pronounced response [66]. Furthermore, a study involving 14 healthy men compared insulin use in vivo during normal oxygen saturation versus 30 minutes of acute hypoxia at an oxygen saturation of 75%. The authors found that sustained hypoxia resulted in glucose intolerance with associated increases in heart rate and plasma epinephrine levels [67]. The cyclic pattern of hypoxia/reoxygenation seen in OSA patients is similar to that of ischemia/reperfusion in organ tissue, and analogously results in an increased production of reactive oxygen species. The oxidative stress caused by reactive oxygen species alters a host of metabolic processes
S. Sudhakaran & S. R. Surani Patient present with [83] (1) Frequent urination (2) Feeling thirsty constantly (3) Feeling hungry – even when eating (4) Extreme fatigue (5) Blurry vision (6) Cuts/bruises that are sloe to heal (7) Tingling, pain, or numbness in the hands/feet Conduct routine diabetic tests Test results [84] (1) Hemoglobin Alc (Alc) ≥ 6.5% (2) Fasting plasma glucose ≥ 126 mg/dL (3) 2-hour plasma glucose ≥ 200 mg/dL during an oral glucose tolerance test (OGTT) (4) Random plasma glucose ≥ 200 mg/dL in a patient with classic symptoms of hyperglycemia
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All values fall below
tes
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Be a w com are of orbi O dity SA/Dia if be
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One or more value falls above
Continue monitoring patient, if found to be in prediabetic state suggest [83] (1) Losing 7% of their body weight (2) Exercising moderately (such as brisk walking) 30 minutes a day, five days a week
Patient present with [3] (1) Snoring (2) Excessive daytime sleepiness (3) Witnessed apneas (4) Nocturnal choking (5) Unrefreshed sleep (6) Morning headaches (7) Sleep maintenance insomnia (8) Fatigue Recommend sleep study using either polysomnography or home portable monitoring
Test results [85] (1) AHI has been used to grade the degree of seveity of OSA. AHI of 5–14 is regarded as mild, 15–30 as moderate, and greater than 30 as severe OSA 2) AHI ≥ 5, but ≤ 14 events per hour with: a. Symptoms of excessive daytime sleepiness, impaired cognition or mood disorders b. Comorbid cardiovascular disease such as hypertension, congestive heart failure or history of CVA If one or more of the If none of the listed listed criterion is seen criterion are met
Patient meets criteria for type 2 diabetes [83,84] (1) Follow standard therapeutic guidelines (2) Encourage healthy eating and exercies Patient meets criteria for OSA [3,86] Be aware of OSA/diabetes comorbidity if (1) Consider use of CPAP or oral appliances (2) If CPAP therapy is indicated, CPAP titration polysomnography must be completed to determine the appropiate therapeutic pressure before CPAP use. Alternatively, for select patients Auto-PAP allows unrattended in-home titration by adjusting pressure to the minimum required (3) Encourage lifestyle intervention aimed at weight reduction with a healthy diet and physical activity
Continue monitoring patient for OSA [86] Encourage lifestyle intervention aimed at weight reduction with a healthy diet and physical activity
Figure 1. Guidelines for management of OSA and diabetes. Abbreviations: OSA = Obstructive sleep apnea; OGTT = Oral glucose tolerance test.
including increased lipid peroxidation, decreased nitric oxide bioavailability, and upregulation of transcriptional factors (hypoxia-inducible factor 1, nuclear factor-kB, etc.) [68,69]. Additionally, in animal models, oxidative damage has been described as a mechanism for insulin resistance spurring a diabetic onset [70,71]. Overall, a positive relationship between hypoxemia and glycemia supports the need to assess correction of sleep apnea and its associated hypoxemia as a management strategy for glycemic control [72]. There is strong evidence that sleep fragmentation or shortened sleep times may cause the development of type 2 diabetes [73-77]. Study results have consistently shown an increased risk of developing diabetes in non-diabetic subjects who reported shortened sleep durations or difficulties initiating or maintaining sleep [37]. Under well-controlled conditions, laboratory studies have found that restricting sleep quality or duration negatively affects glucose metabolism [78], HbA1c [79], and insulin sensitivity [80]. The mechanisms behind these changes are still somewhat unclear; however, various studies have noted interesting physiological responses attributed to sleep fragmentation. Separate studies have shown that fragmented sleep causes increased plasma catecholamine levels [81] and metabolic rate [82], when compared to normal sleep. Consequently, sleep fragmentation in OSA patients may cause elevated sympathetic nervous activity, causing an increase in catecholamine release and metabolic rate resulting in fluctuations of glucose
metabolism [37]. Future research is required to fully comprehend the pathophysiological links between sleep fragmentation, hypoxia, and deleterious glycemic control.
Therapeutic guidelines for managing diabetes and OSA in the clinical setting A substantial portion of type 2 diabetic patients suffer from OSA, and conversely diabetes was found to be more prevalent in OSA patients than in non-OSA patients. Recognition and simultaneous management of type 2 diabetes and OSA is critical to prevent escalation of either condition. Included in Figure 1 is a diagram designed to guide therapeutic management in the clinical setting. Standard screening values for both type 2 diabetes and OSA tests are outlined in Figure 1, as well as interventional lifestyle changes that may prevent advancement of these deleterious conditions. Most importantly, if a patient meets any of the criteria for either type 2 diabetes or OSA, physicians should have an elevated suspicion for a diabetic/OSA comorbidity.
Conclusion After reviewing the literature, it is clear that there is an increased prevalence of diabetes in OSA as well as the
DOI: 10.1080/21548331.2015.1004295
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converse. Furthermore, specific case-controlled clinic-based studies showed an independent link between glucose metabolism and OSA. Although the full effect of CPAP therapy on glucose metabolism has yet to be elucidated, the majority of preliminary studies have shown positive effects on glucose metabolism, insulin resistance, and HbA1c. The full physiological pathway underlying the link between OSA and diabetes has yet to be confirmed; however, a number of possible mechanisms are currently being reviewed. It is essential that physicians be aware of this common diabetic/OSA comorbidity in hospitalized patients to prevent exacerbation of any underlying pathologies. Ultimately, screening for OSA and diabetes in the hospitalized setting will identify patients at elevated risk for further assessment and treatment, and recognizing and aiding these patients is critical to improving patient care.
Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents, received or pending, or royalties.
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ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20
Comorbidity of diabetes and obstructive sleep apnea in hospitalized patients Sivakumar Sudhakaran & Salim R. Surani To cite this article: Sivakumar Sudhakaran & Salim R. Surani (2015) Comorbidity of diabetes and obstructive sleep apnea in hospitalized patients, Hospital Practice, 43:2, 79-84, DOI: 10.1080/21548331.2015.1004295 To link to this article: http://dx.doi.org/10.1080/21548331.2015.1004295
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http://informahealthcare.com/hop ISSN: 2154-8331 (print) Hosp Pract, 2015; 43(2): 79–84 DOI: 10.1080/21548331.2015.1004295
REVIEW
Comorbidity of diabetes and obstructive sleep apnea in hospitalized patients Sivakumar Sudhakaran1 & Salim R. Surani 2 1
Texas A&M Health Science Center, TX, USA, and 2Division of Pulmonary, Critical Care and Sleep Medicine, Texas A&M Health Science Center, TX, USA
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Abstract
Keywords:
Obstructive sleep apnea (OSA) and type 2 diabetes are two morbidities commonly encountered in the hospitalized setting. Both diseases will present with an array of complications if not managed in a timely, competent manner. However, a growing body of evidence suggests a link between these two pathologies. It is our hope that through careful review of the literature, we may generate heightened awareness of the OSA/diabetes comorbidity. Through better understanding of these conditions and their interactions, we may insure efficient management in the clinical setting and prevent exacerbation of common complications.
Introduction Obstructive sleep apnea (OSA) is a sleep disorder that is pervasive among overweight and obese adults, a population that comprises at least two-thirds of US citizens today. Prevalence estimates in obese adults from ages 30 to 69 years range from 11% to 46% in women and 33% to 77% in men [1]. OSA is classically seen as repetitive episodes of partial or complete collapse of the upper airway during sleep, resulting in complete cessation (apnea) or reduction (hypopnea) of airflow, leading to hypoxia and arousal during sleep [2]. OSA may present clinically as snoring, excessive daytime sleepiness, witnessed apneas, nocturnal chocking, unrefreshed sleep, morning headaches, sleep maintenance insomnia, and fatigue [3]. OSA is not uncommon in the clinical setting, in fact one study found that previously diagnosed OSA is highly prevalent and undertreated in hospitalized patients. Additionally, the use of computerized alerts by respiratory therapists resulted in significantly more OSA patients receiving appropriate medical care (P < 0.002), which subsequently resulted in significantly fewer patients experiencing hypoxemia (P < 0.006) [4]. Diabetes mellitus, or simply diabetes, is a group of metabolic diseases characterized by hyperglycemia due to defects in insulin production, insulin function, or a combination of both. The chronic hyperglycemia seen in diabetes is associated with several forms of long-term organ damage including the eyes, kidneys, nerves, heart, and blood vessels [5]. Type 2 diabetes, previously referred to as adult-onset diabetes or non-insulindependent diabetes, includes individuals who have insulin
Diabetes, diabetes complications, OSA, OSA and diabetes, OSA complications, History Received 15 September 2014 Accepted 28 October 2014 Published online 20 January 2015
resistance and generally some degree of insulin deficiency. Most patients with type 2 diabetes are obese, excessive weight itself causes some degree of insulin resistance [5]. The prevalence of diabetes in the USA is astounding; currently 29.1 million people (9.3% of the US population) have diabetes [6], with type 2 diabetes accounting for 90% to 95% of these cases [5]. Current standards for the diagnosis of type 2 diabetes can be categorized into one of four ways: (1) hemoglobin A1c (HbA1c) ‡ 6.5%, (2) fasting plasma glucose ‡ 126 mg/dL, (3) 2-hour plasma glucose ‡ 200 mg/dL during an oral glucose tolerance test (OGTT), or (4) random plasma glucose ‡ 200 mg/ dL in a patient with classic symptoms of hyperglycemia [7]. A study found that hyperglycemia was present in 38% of patients admitted to the hospital; of these patients, 26% had a known history of diabetes, whereas 12% had no history of diabetes before the admission [8]. Moreover, patients discharged with a blood glucose level > 250 mg/dL accrued greater cost during hospitalization compared to patients discharged with a blood glucose < 250 mg/dL [9]. In regard to OSA, short-term studies have shown noticeable alterations in metabolic functions including glucose intolerance and insulin resistance due to sleep apnea [10-16]. Conclusions derived from these studies raise questions about the pervasiveness of type 2 diabetes, as well as its interaction with OSA. In this article, we will assess the interplay between OSA and diabetes in hospitalized patients. It is our hope that by analyzing the relationship between OSA and diabetes, we may create a set of simple clinical guidelines that may be helpful for clinicians in everyday hospital practice.
Correspondence: Salim Surani, MD, MPH, MSHM, FACP, FCCP, FAASM, Associate Professor, Division of Pulmonary, Critical Care and Sleep Medicine, Texas A&M Health Science Center, 1177 West Wheeler Ave, Suite 1, Aransas Pass, TX 78336, USA. Tel: +1 361 8857722. Fax: +1 361 850 7563. E-mail: [email protected] 2015 Informa UK Ltd.
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Method A thorough literature search in Medline, Google Scholar, Ovid, and PubMed was done to identify relevant articles pertaining to OSA and diabetes among hospitalized patients. Each article was assessed for relevance regarding OSA and diabetes as well as any related complications in hospitalized patients. Clinical studies in addition to review articles were utilized. Management guidelines were defined by expert opinion of clinical authors as well as current recommendations from the literature.
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Prevalence of OSA in patients with diabetes and vice versa The highest estimate regarding prevalence of OSA in type 2 diabetes was 86% and was reported in a Sleep AHEAD (action for health in diabetes) study [17]. However, the average estimate of OSA in type 2 diabetic patients is ~ 71%, determined by the data provided from five different studies that encompassed ~ 1200 type 2 diabetic patients [15,17-21]. The prevalence estimates in these studies may have differed due to a variety of factors including different diagnostic methodologies for sleep apnea, scoring criteria, or study populations [22]. A recent retrospective analysis totaling more than 16,000 diabetic patients in one of 27 primary care ambulatory practices revealed that only 18% of the study population (23% of obese patients) had an OSA diagnosis [23]. These numbers differ vastly from the 71% averaged from the previously mentioned studies, suggesting that millions of diabetic patients may currently be suffering from undiagnosed OSA. A recently published study conducted in Nigeria analogously found that a substantial proportion of patients with type 2 diabetes might have OSA, with the key predictor being neck circumference after controlling for obesity [24]. Conversely, there have been a number of studies that have evaluated the prevalence of type 2 diabetes in OSA patients [13,25-30]. Most of these studies used polysomnography to determine OSA and adjusted for shared risk factors, including age, sex, body mass index (BMI), neck, and waist circumference [18]. To assess diabetes the majority of studies used validated diabetes definitions based on OGTTs or 2-hour post-challenge glucose levels [28,29,31,32], whereas a few studies relied on self-reported diabetes [33]. As a whole, the cross-sectional analyses from these studies illustrated a significantly higher prevalence of diabetes in patients with OSA as compared to those without OSA. The prevalence estimates from these studies ranged from 15% to 30%, depending on the study population as well as the specific techniques employed to diagnose type 2 diabetes and OSA [13,25-27,29]. A number of other studies revealed a similar link between type 2 diabetes in OSA patients. One study in Sweden found that after various adjustments (length of treatment, BMI, age, hypertension, etc.) severity of oxygen desaturation in OSA could serve as a predictor for developing diabetes [33]. Additionally, a separate study found that nocturnal intermittent hypoxia was associated with an increased risk of developing type 2 diabetes [34]. Some studies even found a correlation between the degree of severity of OSA and increased frequency of diabetes [26,29].
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Currently, a select number of studies found in the literature have aimed to find an independent link between OSA and type 2 diabetes. A historical cohort study recently published controlled for nearly all OSA-related variables including sex, age, BMI, smoking status, comorbidities, as well as income, and found that among patients with OSA, initial OSA severity predicted subsequent risk of incident diabetes [35]. Additionally, an Australian population-based cohort study looked at OSA as an independent risk factor for diabetes. The study found that moderate-to-severe sleep apnea was a significant risk factor for incident diabetes. However, it should be noted that confidence intervals for the analysis were wide; thus, studies with greater power will be required to verify the relationship between sleep apnea and the incidence of diabetes in community-based populations [36]. Overall, the literature strongly suggests that independent of various risk factors, including age, race, gender, baseline fasting glucose, and BMI, sleep apnea is significantly associated with the risk of type 2 diabetes [28]. Evidence from clinic- or hospital-based studies suggests a link between OSA and glucose metabolism Clinic-based studies examining the relationship between OSA and glucose metabolism generally use laboratory polysomnography to determine the degree of OSA [37]. In a clinic-based study containing 595 men suspected of OSA, cross-sectional data from polysomnography and 2-hour OGTTs revealed that type 2 diabetes was present in 30.1% of OSA patients versus 13.9% in nonapneic snorers. As the severity of OSA increased, fasting as well as post-load blood glucose levels increased, whereas insulin sensitivity decreased, independent of age or BMI [13]. Similar findings were found in two more different case–control studies. In one study, 19 of 24 patients (79%) with OSA had abnormal glucose, compared to only 2 of 9 patients without OSA. Additionally, 25% of these patients had previously undiagnosed type 2 diabetes [38]. In the other study, visceral adiposity (assessed by abdominal computed tomography) was controlled for, and test results again showed that OSA was associated with elevated fasting glucose levels [39]. Finally, a recent study of hospitalized patients in Beijing revealed a high prevalence (66.7%) of OSA in a sample of patients with type 2 diabetes [40]. It is worth mentioning that a select number of studies failed to find an independent link between OSA and metabolic abnormalities [41,42]. However, the majority of clinic-based studies consistently described an independent association between OSA and abnormal glucose metabolism [37]. These minor inconsistencies may be attributed to how body fat distribution was determined, or varying diabetic plasma glucose screening levels between studies. Screening for OSA/diabetes comorbidity and complications A recently published study found after controlling for multiple confounders that initial OSA severity and its physiological consequences predicted subsequent risk for incident diabetes [35]. Furthermore, a separate study found increased
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risk factors associated with OSA in hospitalized type 2 diabetic patients [40]. These studies illustrate that common diabetic and OSA complications may be exacerbated due to a cumulative OSA/diabetes comorbidity. OSA is associated with a number of complications including daytime somnolence [43], hypertension [44,45], stroke [46], coronary artery disease [47], arrhythmias [48], heart failure [49], and type 2 diabetes [13]. Diabetic complications include stroke, hypertension, dyslipidemia, heart disease, nephropathy, retinopathy, and neuropathy [7]. These comorbidities and complications can cause significant challenges for physicians and may lead to an increased length of stay for hospitalized patients. Screening for type 2 diabetes includes a fasting (defined as no caloric intake for at least 8 hours) plasma glucose level > 126 mg/dL [7]. There have been a number of screening tools designed for sleep-related breathing disorders including the Berlin and STOP-BANG questionnaires. The Berlin questionnaire was first validated in primary care against portable unattended sleep studies. A ‘high risk’ Berlin score predicted a respiratory disturbance index of > 5 with sensitivity of 0.86, specificity of 0.77, positive predictive value of 0.89, and likelihood ratio of 3.79 [50]. Similarly, STOP-BANG is an OSA screening test developed for use in preoperative surgical clinics; it is part questionnaire (STOP) and part demographic or physical measures (BANG) [51]. For identifying severe OSA, a STOP-BANG score of 4 has a sensitivity of 88%; to confirm OSA a score of 6 is more specific [52]. Based on current evidence, physicians should be advised to carefully screen and assess the risk of OSA in type 2 diabetic patients and, conversely, evaluate glucose tolerance in patients with known OSA to avoid compounding the aforelisted complications [37].
and post-CPAP therapy. Using a subcutaneous glucose sensor, interstitial glucose levels were measured 288 times a day in 25 diabetic patients. The authors also noted a significant decrease in HbA1c level in all 17 patients who had a baseline HbA1c of > 7%. Moreover, the study found that 1-hour postprandial interstitial glucose levels were considerably reduced after roughly 3 months of CPAP therapy. In fact, reduction in HbA1c levels correlated notably with the number of days of CPAP therapy in patients who complied with treatment for > 4 hours/night [56]. A separate retrospective study found a comparable clinically significant drop of HbA1c levels in 38 diabetic patients after roughly 3 to 4 months of CPAP therapy [57]. According to various preliminary studies, CPAP therapy has shown improvement in insulin sensitivity [58] and glucose homeostasis [58] in sleep apnea patients. Although there is growing evidence that CPAP use has a beneficial impact on OSA patients with diabetes, a select number of studies have failed to find improvements in glucose metabolism [59-61], insulin resistance [62], or HbA1c levels [62]. These conflicting results may be due to a variety of factors including varying sample size, duration of CPAP therapy, or degree of adherence to treatment. Nevertheless, there is a substantial amount of evidence to suggest that CPAP treatment has a beneficial effect on glucose metabolism, insulin resistance, and HbA1c level. Additionally, CPAP therapy has shown benefits such as improved daytime alertness, reduced fatigue, reduced cardiovascular risks, improved blood pressure, enhanced left ventricular function [63], and better overall quality of life outcomes [64]. However, large-scale studies controlling for variables such as duration and adherence of CPAP use must be executed to fully assess the metabolic effects of CPAP therapy.
Continuous positive airway pressure treatment of OSA and it effects on glucose metabolism and the diabetic state
Potential mechanisms linking OSA to insulin resistance, glucose intolerance, and other common diabetic presentations
There have been a number of studies that have examined how continuous positive airway pressure (CPAP) treatment for OSA has affected glucose metabolism. Current studies suggest that abnormalities in glucose metabolism may be corrected by CPAP therapy to a moderate degree. These studies have assessed a wide spectrum of variables concerning CPAP therapy and diabetes. By using the hyperinsulinemiceuglycemic clamp, widely considered the most accurate technique for measurement of insulin sensitivity, one study found that diabetic patients using CPAP treatment saw improvement in insulin sensitivity in as little as 2 days. Interestingly, this rapid improvement in insulin sensitivity with CPAP use was found to be marginal in patients with a BMI of ‡ 30 kg/m2 [53]. A German study found that insulin sensitivity improved in nine obese type 2 diabetics over 3 months of CPAP therapy but also failed to find any significant improvement after 2 days of treatment [54]. Similarly, a separate study found improvement in insulin sensitivity in 10 obese diabetic patients after 4 months of CPAP use [55]. These studies indicate that CPAP treatment can still improve insulin sensitivity in obese diabetic patients; however, a longer time course of treatment may be required. Another study looked at the response of HbA1c levels in diabetic patients 3 months prior
The two classic features of OSA are intermittent hypoxia and sleep fragmentation, both of which may alter normal physiological processes and adversely affect glucose control. Continuous or sustained hypoxia and sleep loss may affect glucose metabolism through a number of mechanisms ranging from changes in inflammatory pathways to activation of the sympathetic nervous system or hypothalamic-pituitary axis [65]. In fact, one study found that in healthy humans, 20-minute exposure to intermittent voluntary hypoxic apnea resulted in sustained elevation of muscle sympathetic nerve activity and that hypoxia was the primary agent of this pronounced response [66]. Furthermore, a study involving 14 healthy men compared insulin use in vivo during normal oxygen saturation versus 30 minutes of acute hypoxia at an oxygen saturation of 75%. The authors found that sustained hypoxia resulted in glucose intolerance with associated increases in heart rate and plasma epinephrine levels [67]. The cyclic pattern of hypoxia/reoxygenation seen in OSA patients is similar to that of ischemia/reperfusion in organ tissue, and analogously results in an increased production of reactive oxygen species. The oxidative stress caused by reactive oxygen species alters a host of metabolic processes
S. Sudhakaran & S. R. Surani Patient present with [83] (1) Frequent urination (2) Feeling thirsty constantly (3) Feeling hungry – even when eating (4) Extreme fatigue (5) Blurry vision (6) Cuts/bruises that are sloe to heal (7) Tingling, pain, or numbness in the hands/feet Conduct routine diabetic tests Test results [84] (1) Hemoglobin Alc (Alc) ≥ 6.5% (2) Fasting plasma glucose ≥ 126 mg/dL (3) 2-hour plasma glucose ≥ 200 mg/dL during an oral glucose tolerance test (OGTT) (4) Random plasma glucose ≥ 200 mg/dL in a patient with classic symptoms of hyperglycemia
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All values fall below
tes
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Be a w com are of orbi O dity SA/Dia if be
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One or more value falls above
Continue monitoring patient, if found to be in prediabetic state suggest [83] (1) Losing 7% of their body weight (2) Exercising moderately (such as brisk walking) 30 minutes a day, five days a week
Patient present with [3] (1) Snoring (2) Excessive daytime sleepiness (3) Witnessed apneas (4) Nocturnal choking (5) Unrefreshed sleep (6) Morning headaches (7) Sleep maintenance insomnia (8) Fatigue Recommend sleep study using either polysomnography or home portable monitoring
Test results [85] (1) AHI has been used to grade the degree of seveity of OSA. AHI of 5–14 is regarded as mild, 15–30 as moderate, and greater than 30 as severe OSA 2) AHI ≥ 5, but ≤ 14 events per hour with: a. Symptoms of excessive daytime sleepiness, impaired cognition or mood disorders b. Comorbid cardiovascular disease such as hypertension, congestive heart failure or history of CVA If one or more of the If none of the listed listed criterion is seen criterion are met
Patient meets criteria for type 2 diabetes [83,84] (1) Follow standard therapeutic guidelines (2) Encourage healthy eating and exercies Patient meets criteria for OSA [3,86] Be aware of OSA/diabetes comorbidity if (1) Consider use of CPAP or oral appliances (2) If CPAP therapy is indicated, CPAP titration polysomnography must be completed to determine the appropiate therapeutic pressure before CPAP use. Alternatively, for select patients Auto-PAP allows unrattended in-home titration by adjusting pressure to the minimum required (3) Encourage lifestyle intervention aimed at weight reduction with a healthy diet and physical activity
Continue monitoring patient for OSA [86] Encourage lifestyle intervention aimed at weight reduction with a healthy diet and physical activity
Figure 1. Guidelines for management of OSA and diabetes. Abbreviations: OSA = Obstructive sleep apnea; OGTT = Oral glucose tolerance test.
including increased lipid peroxidation, decreased nitric oxide bioavailability, and upregulation of transcriptional factors (hypoxia-inducible factor 1, nuclear factor-kB, etc.) [68,69]. Additionally, in animal models, oxidative damage has been described as a mechanism for insulin resistance spurring a diabetic onset [70,71]. Overall, a positive relationship between hypoxemia and glycemia supports the need to assess correction of sleep apnea and its associated hypoxemia as a management strategy for glycemic control [72]. There is strong evidence that sleep fragmentation or shortened sleep times may cause the development of type 2 diabetes [73-77]. Study results have consistently shown an increased risk of developing diabetes in non-diabetic subjects who reported shortened sleep durations or difficulties initiating or maintaining sleep [37]. Under well-controlled conditions, laboratory studies have found that restricting sleep quality or duration negatively affects glucose metabolism [78], HbA1c [79], and insulin sensitivity [80]. The mechanisms behind these changes are still somewhat unclear; however, various studies have noted interesting physiological responses attributed to sleep fragmentation. Separate studies have shown that fragmented sleep causes increased plasma catecholamine levels [81] and metabolic rate [82], when compared to normal sleep. Consequently, sleep fragmentation in OSA patients may cause elevated sympathetic nervous activity, causing an increase in catecholamine release and metabolic rate resulting in fluctuations of glucose
metabolism [37]. Future research is required to fully comprehend the pathophysiological links between sleep fragmentation, hypoxia, and deleterious glycemic control.
Therapeutic guidelines for managing diabetes and OSA in the clinical setting A substantial portion of type 2 diabetic patients suffer from OSA, and conversely diabetes was found to be more prevalent in OSA patients than in non-OSA patients. Recognition and simultaneous management of type 2 diabetes and OSA is critical to prevent escalation of either condition. Included in Figure 1 is a diagram designed to guide therapeutic management in the clinical setting. Standard screening values for both type 2 diabetes and OSA tests are outlined in Figure 1, as well as interventional lifestyle changes that may prevent advancement of these deleterious conditions. Most importantly, if a patient meets any of the criteria for either type 2 diabetes or OSA, physicians should have an elevated suspicion for a diabetic/OSA comorbidity.
Conclusion After reviewing the literature, it is clear that there is an increased prevalence of diabetes in OSA as well as the
DOI: 10.1080/21548331.2015.1004295
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converse. Furthermore, specific case-controlled clinic-based studies showed an independent link between glucose metabolism and OSA. Although the full effect of CPAP therapy on glucose metabolism has yet to be elucidated, the majority of preliminary studies have shown positive effects on glucose metabolism, insulin resistance, and HbA1c. The full physiological pathway underlying the link between OSA and diabetes has yet to be confirmed; however, a number of possible mechanisms are currently being reviewed. It is essential that physicians be aware of this common diabetic/OSA comorbidity in hospitalized patients to prevent exacerbation of any underlying pathologies. Ultimately, screening for OSA and diabetes in the hospitalized setting will identify patients at elevated risk for further assessment and treatment, and recognizing and aiding these patients is critical to improving patient care.
Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents, received or pending, or royalties.
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