Incident Cardiac Events and Sleep Disordered Breathing in Diabetic Patients

Introduction

Diabetes mellitus type 2 (T2DM) is an increasing worldwide epidemic already affecting 25.8 million individuals, representing 8.3% of the U.S. population, and including one in four Americans age 65 years and older.1 The T2DM population has a significantly higher incidence of coronary artery disease (CAD), congestive heart failure (CHF),2,3 atrial fibrillation (AF)4, and shorter lifespan frequently attributed to cardiovascular death.8 The American Diabetes Association (ADA) current guidelines,6 including performing at least annual standardized assessments of the traditional core set of cardiovascular risk factors (glycemic control, overweight/obesity, hypertension, dyslipidemia, and alcohol and tobacco use) in the adult diabetic population, are being increasingly adopted by pediatricians involved in the long-term care of diabetic children and teens.9,10 The American Cardiology Community is a long-standing partner of the ADA in cardiovascular preventive strategies, clinical care, and clinical and experimental research related to cardiac complications in patients with T2DM. While the pathology and mechanisms underlying the association between glucose homeostasis and specific myocardial dysfunction remain to be clarified,2 and cardiac service referrals are no longer recommended for routine screenings of incident cardiac events in asymptomatic diabetics at cardiovascular risk due to a previously demonstrated poor cost/benefit ratio of these interventions,6,11 the benefit of multidisciplinary efforts in recognizing and treating novel cardiovascular risk factors cannot be overstated6-8. Of those, sleep-related conditions are currently gaining increased interest and attention, due to a higher prevalence of sleep disorders (including sleep disordered breathing (SDB), reduced sleeping time, and poor sleep quality) and these conditions' associations with cardiac and cardiovascular risk, and similar patterns of association of the same conditions with glucose intolerance, insulin resistance, and diabetes,6,12,13-16 independent of other common characteristics, such as overweight /obesity17 and depression.

Diabetes, SDB and Incident Cardiac Events

SDB probably represents the most common under-recognized, therefore untreated, chronic sleep disorder worldwide. Previous articles in this series18-21 have already reviewed emerging epidemiological and clinical evidence linking SDB with hypertension, CAD, CHF, AF22-31 and SDB with diabetes and insulin resistance.13 This short review aims to increase the cardiology community's interest in causal association research of the independent role of SDB on new onset cardiac disease in asymptomatic T2DM patients, a topic largely unstudied to date.

The first longitudinal, evidence-based clinical research evaluating the independent role of SDB on the onset of incident CHF, CAD, and AF events in patients with T2DM was published in 2013.32 This study, sponsored and conducted by the Cleveland Clinic Foundation, Heart and Vascular Institute (CCF, HVI), examined 834 consecutive asymptomatic T2DM patients with baseline normal stress echocardiograms and comprehensive baseline evaluations (performed between January 2004 and December 2007 and in accordance with correspondent ADA standard care recommendations), thereby confirming no history of cardiac disease in these patients at the time of recruitment in the study. During a median follow-up of approximately five years, patients with SDB showed nearly three times the rate of AF, as compared with non-SDB patients, and a higher hazard of incident CAD (HR=1.9 [1.1-3.3], p=0.03; adjusted HR=2.2 [1.2-3.9], p=0.01) and HF (HR=2.7 [1.1-7.0], p=0.03; adjusted HR = 3.5 [1.4-9.0], p<0.01) after controlling for age, gender, hypertension, smoking, lipid profile, family history of cardiovascular disease, medical treatments, standard of care-related risk factors, and overweight/obesity. Those findings were supported by previously proposed multiple dysregulations of neuroendocrine and immune system activation pathways, linking SDB with cardiac and cardiovascular risk. These included chronic inflammation, macrophage infiltration, adiponectin reduction, leptin elevation, and mitochondrial dysfunction reported as increasing the insulin resistance and the beta cell dysfunction.18-21 Additional proposed mechanisms included impaired clearance of triglyceride-rich lipoproteins and inactivation of the lipoprotein lipase, endothelial dysfunction, and elevated daytime and nocturnal blood pressure.18-21

This same study also showed no differences or significant higher hazard of incident cardiac events in T2DM women, and explained those findings based on previously shown endothelial dysfunction and more pronounced vasoconstriction in response to both hypoxia and stress,33 larger brachial artery diameters (previously identified as a CAD risk factor),34 and/or flow-mediated diameters in T2DM female patients with SDB when compared to their male counterparts.35

While this study had greater female representation, an adequate sample size, and separation of endpoints, as well as carefully explored the differences between SDB vs. non-SDB diabetics related to traditional CAD risk factors, health care access and quality, and treatment differences for existing co-morbidities, it also had multiple limitations, thereby warranting further research. Due to the observational retrospective nature of the study, including relying on electronic health records, data from a single clinical center, and patients residing only in Ohio, as well as reduced data on behavioral risk factors (e.g. diet and exercise practices), and no data on the specific characteristics of the SDB severity, treatment, and incident cardiac events, the findings of this study should be at least further explored and validated in the general U.S diabetic population.

Conclusion

Further research should address the importance of this topic by providing national inferences of the extent and prevalence of SDB and its associated symptoms in the diabetic U.S. population, as well as validating the predictive role of SDB on the incidence of new cardiac and cardiovascular fatality in the U.S. Additionally, multi-site, prospective clinical trials should be designed and conducted by multidisciplinary teams, including experienced endocrinologists, cardiologists, sleep specialists, and clinical epidemiologists, to generate compelling evidence-based conclusions concerning the utility of integrating SDB screening and long-term treatment and follow-up within the endocrinology and/or cardiology practice.

Finally, gender-specific cost/benefit analyses are warranted to address the effectiveness of SDB-specific clinical interventions on the overall quality of life and/or survivorship in patients with T2DM and SDB, independent of other ongoing efforts to prevent/reduce associated CVD risk factors (e.g., overweight/obesity, hypertension, and hyperlipidemia).


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Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure, Hypertension

Keywords: Cardiovascular Diseases, Coronary Artery Disease, Diabetes Mellitus, Type 2, Dyslipidemias, Heart Failure, Hypertension, Obesity, Overweight


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