Atrial Fibrillation and Diabetes Mellitus
2019; Lippincott Williams & Wilkins; Volume: 12; Issue: 5 Linguagem: Inglês
10.1161/circep.119.007351
ISSN1941-3149
AutoresFrancis Ugowe, Larry R. Jackson, Kevin L. Thomas,
Tópico(s)Parkinson's Disease Mechanisms and Treatments
ResumoHomeCirculation: Arrhythmia and ElectrophysiologyVol. 12, No. 5Atrial Fibrillation and Diabetes Mellitus Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBAtrial Fibrillation and Diabetes MellitusCan We Modify Stroke Risk Through Glycemic Control? Francis E. Ugowe, MD, Larry R. Jackson II, MD and Kevin L. Thomas, MD Francis E. UgoweFrancis E. Ugowe Duke University Medical Center (F.E.U., L.R.J., K.L.T.), Duke University, Medical Center, Durham, NC. , Larry R. Jackson IILarry R. Jackson II Duke University Medical Center (F.E.U., L.R.J., K.L.T.), Duke University, Medical Center, Durham, NC. Duke Clinical Research Institute, (L.R.J., K.L.T.), Duke University, Medical Center, Durham, NC. and Kevin L. ThomasKevin L. Thomas Kevin L. Thomas, MD, Duke Clinical Research Institute, 200 Morris St, Durham, NC 27705. Email E-mail Address: [email protected] Duke University Medical Center (F.E.U., L.R.J., K.L.T.), Duke University, Medical Center, Durham, NC. Duke Clinical Research Institute, (L.R.J., K.L.T.), Duke University, Medical Center, Durham, NC. Originally published18 Apr 2019https://doi.org/10.1161/CIRCEP.119.007351Circulation: Arrhythmia and Electrophysiology. 2019;12:e007351This article is a commentary on the followingGlycemic Status and Thromboembolic Risk in Patients With Atrial Fibrillation and Type 2 Diabetes MellitusSee Article by Fangel et alAtrial fibrillation (AF) is the most common sustained arrhythmia worldwide and represents a major health burden affecting an estimated 33 million individuals and climbing.1 The development of AF is multifactorial in etiology with age, sex, genetics, race, and comorbid conditions such as smoking, obesity, and diabetes mellitus playing a role.2 Diabetes mellitus affects ≈285 million lives globally; this number is projected to increase to 439 million people by 2030.3 Studies have demonstrated that patients with diabetes mellitus possess a 40% higher risk for developing AF relative to patients without diabetes mellitus and overall risk increases about 3% per year of diabetes mellitus.4Moreover, the insulin resistance of diabetes mellitus also conveys increased thromboembolic risk through various means including induced hypercoagulability, endothelial dysfunction, and impaired fibrinolysis.5 Diabetes mellitus and AF are believed to share related mechanistic pathways for thrombosis.6 Findings from the Emerging Risk Factors Collaboration demonstrated that the adjusted hazard ratios for risk of stroke in patients with diabetes mellitus were 2.27 (95% CI, 1.95–2.65) for ischemic strokes and 1.56 (95% CI, 1.19–2.05) for hemorrhagic strokes.7 The risk of stroke and systemic arterial embolism (SSE) in diabetes mellitus coupled with the risk of thromboembolism in AF is a unique risk profile, one that has rightfully been the focus of several recent studies.In this issue of Circulation: Arrhythmia and Electrophysiology, Fangel et al8 investigate the effect of glycemic state on the risk of thromboembolism in patients with incident AF and comorbid type 2 diabetes mellitus. Using data from several Danish registries from May 1, 2005, to December 31, 2015, investigators identified 5386 patients with type 2 diabetes mellitus and incident AF and divided these patients into groups based on their HbA1c (hemoglobin A1c)—HbA1c ≤48 mmol/mol (6.5%), HbA1c of 49 to 58 mmol/mol (6.6%–7.5%), and HbA1c >58 mmol/mol (7.5%)—and duration of diabetes mellitus ≥10 or 58 mmol/mol, respectively.8 After adjusting for confounding factors including heart failure, hypertension, age, and history of prior stroke, researchers observed a higher risk of thromboembolism in patients with HbA1c of 49 to 58 mmol/mol (HR, 1.49; 95% CI, 1.09–2.05) and HbA1c >58 mmol/mol (HR, 1.59; 95% CI, 1.13–2.23) compared with patients with HbA1c <48 mmol/mol.8 In their secondary analyses, similar findings were observed when the cohort was stratified by age, sex, and prior thromboembolism status. Investigators found that the associations were similar when diabetes mellitus was present for 58 mmol/mol.8 Interestingly, when the duration of diabetes mellitus was ≥10 years, higher HbA1c values were not associated with higher rates of thromboembolism, and the association of increased stroke risk with glycemic state attenuated at the highest levels of HbA1c.8Several recent cohort studies have sought to better understand the intersection between AF, diabetes mellitus, and thromboembolic risk. In May 2015, Saliba et al9 demonstrated in their cohort of 37 358 patients with comorbid AF and diabetes mellitus that elevated glycated hemoglobin levels were associated with an increased risk of stroke and when added to CHA2DS2-VASc scoring helped to improve the predictive accuracy of the model. Overad et al10 from their work concluded the duration of diabetes mellitus was the primary provocateur for the increased risk of SSE. This finding was further supported using data from the ATRIA study (Anticoagulation and Risk Factors in Atrial Fibrillation) when Ashburner et al11 observed that duration of diabetes mellitus ≥3 years relative to 9.0%) and intermediate (HbA1c, 7.0%–8.9%) glycemic control were not significantly associated with an increased rate of ischemic stroke compared with patients with HbA1c <7.0%. In early 2017, investigators from PREFER in AF (European Prevention of Thromboembolic Events–European Registry in Atrial Fibrillation) found that the risk of SSE was the highest in individuals with diabetes mellitus treated with insulin compared with those not on insulin treatment (5.2% versus 1.8%; HR, 2.96; 95% CI, 1.49–5.87) and those without a diagnosis of diabetes mellitus (5.2% versus 1.9%; HR, 2.89; 95% CI, 1.67–5.02).12 Finally, a study of the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation observed that AF and comorbid diabetes mellitus was related to a higher risk of death and hospitalizations but no increase in thromboembolic or bleeding events.13Fangel et al8 should be congratulated for their work, which represents another chapter in our quest to understand the role of glycemic control on the risk of stroke in patients with AF and diabetes mellitus. The authors methodically approach the question with a robust cohort of patients, salient outcomes of interest, and attempt to control for variables that have confounded previous analyses. However, there are a few limitations that merit attention. First, in the present analysis, the determination of glycemic status/control was based on a single HbA1c value that resulted from a time span either 2 years before or 4 weeks after the diagnosis of AF. Glycated hemoglobin theoretically functions as a snapshot of a patient's glycemic control over the preceding 3 months and fluctuates with changes to medications or nonadherence to therapy over time. The investigators did not account for potential changes in HbA1c during follow-up; thus, the HbA1c measurement could have been ≤2 years old at the time of AF diagnosis and ≤7 years old at the time of SSE. In the current study, the mean amount of time since the last HbA1c measurement was ≈9 months.8 Unless the majority of patients' HbA1c values remained stable during the study duration, it is problematic to make inferences regarding the effect of glycemic status/control on SSE risk with one static value. One approach to avoid misclassification bias would have been to perform an analysis with HbA1c as a time varying exposure; however, the database may not have afforded that pursuit. Second, determining incident AF by an International Classification of Diseases, Tenth Revision, code is inherently flawed, particularly in a non-AF registry with no previous mention of validation of the diagnosis by ECG, Holter monitor, loop recorder, or other proven modality. Although the authors reference a study by Schmidt et al,14 in which records from the Danish National Patient Registry were analyzed and found to have a high validity for AF diagnosis, the question remains, whether we are capturing the true burden of incident disease. Third, no information was provided on the quality of anticoagulation in warfarin-treated patients or medication adherence/persistence of other anticoagulants and consequently may have resulted in residual confounding. Notably, despite a mean CHA2DS2-VASc score of 4.0, only 61% of individuals in this cohort were treated with oral anticoagulation highlighting the broad underutilization of anticoagulation.The above limitations notwithstanding, the clinical implications of the findings from the current analysis must not be overlooked. It appears that an association exists between SSE and comorbid AF and diabetes mellitus, with higher glucose levels in the first 10 years of diabetes mellitus signaling a higher risk of thromboembolism. The study by Fangel et al8 suggests that earlier and tighter control of HbA1c will help mitigate this increased risk. However, when put into the context of previous data in the field,9–13 it is apparent that further investigation is warranted to better understand the pathophysiology driving stroke risk. It is physiologically plausible that relative insulin deficiency and resistance is the underlying link and perhaps HbA1c,8,9 duration of disease,10,11 and insulin use12 (as a proxy measure for insulin resistance) are all interconnected.This article notwithstanding, many questions remain: is the increased risk of stroke among individuals with poorly controlled diabetes mellitus and AF due to increased thromboembolic events or progression of atherosclerotic cerebrovascular disease? Additionally, what explains the lack of association of increased stroke risk at the highest levels of A1C and hyperglycemia? Finally, if in fact poor glycemic control increases the risk of stroke in patients with AF and diabetes mellitus, is the method of glucose lowering (pharmacotherapy versus exercise) mediate that risk to varying extents? As once remarked by Aesop, the legendary Greek storyteller, "Every truth has two sides; it is as well to look at both, before we commit ourselves to either."DisclosuresDr Thomas reports being a consultant for Janssen, Pfizer, and Bristol-Myers Squibb. The other authors report no conflicts.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Kevin L. Thomas, MD, Duke Clinical Research Institute, 200 Morris St, Durham, NC 27705. Email kevin.[email protected]duke.eduReferences1. Rahman F, Kwan GF, Benjamin EJ. Global epidemiology of atrial fibrillation.Nat Publ Gr. 2014; 11:639–654.Google Scholar2. Staerk L, Sherer JA, Ko D, Benjamin EJ, Helm RH. Atrial fibrillation: epidemiology, pathophysiology, and clinical outcomes.Circ Res. 2017; 120:1501–1517. doi: 10.1161/CIRCRESAHA.117.309732LinkGoogle Scholar3. Chen R, Ovbiagele B, Feng W. Diabetes and stroke: epidemiology, pathophysiology, pharmaceuticals and outcomes.Am J Med Sci. 2016; 351:380–386. doi: 10.1016/j.amjms.2016.01.011CrossrefMedlineGoogle Scholar4. Dublin S, Glazer NL, Smith NL, Psaty BM, Lumley T, Wiggins KL, Page RL, Heckbert SR. Diabetes mellitus, glycemic control, and risk of atrial fibrillation.J Gen Intern Med. 2010; 25:853–858. doi: 10.1007/s11606-010-1340-yCrossrefMedlineGoogle Scholar5. Meijers JCM, Holleman F, Hermanides J, Lemkes BA, Devries JH, Hoekstra JBL. Hyperglycemia: a prothrombotic factor?J Thromb Haemost. 2010; 8:1663–1669.CrossrefMedlineGoogle Scholar6. Watson T, Shantsila E, Lip GY. 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Overvad TF, Skjøth F, Lip GY, Lane DA, Albertsen IE, Rasmussen LH, Larsen TB. Duration of diabetes mellitus and risk of thromboembolism and bleeding in atrial fibrillation: nationwide cohort study.Stroke. 2015; 46:2168–2174. doi: 10.1161/STROKEAHA.115.009371LinkGoogle Scholar11. Ashburner JM, Go AS, Chang Y, Fang MC, Fredman L, Applebaum KM, Singer DE. Effect of diabetes and glycemic control on ischemic stroke risk in AF patients.J Am Coll Cardiol. 2016; 67:239–247.CrossrefMedlineGoogle Scholar12. Patti G, Lucerna M, Cavallari I, Ricottini E, Renda G, Pecen L, Romeo F, Le Heuzey JY, Zamorano JL, Kirchhof P, De Caterina R. Insulin-requiring versus noninsulin-requiring diabetes and thromboembolic risk in patients with atrial fibrillation: PREFER in AF.J Am Coll Cardiol. 2017; 69:409–419. doi: 10.1016/j.jacc.2016.10.069CrossrefMedlineGoogle Scholar13. Echouffo-Tcheugui JB, Shrader P, Thomas L, Gersh BJ, Kowey PR, Mahaffey KW, Singer DE, Hylek EM, Go AS, Peterson ED, Piccini JP, Fonarow GC. Care patterns and outcomes in atrial fibrillation patients with and without diabetes: ORBIT-AF Registry.J Am Coll Cardiol. 2017; 70:1325–1335.CrossrefMedlineGoogle Scholar14. Schmidt EB, Lundbye-Christensen S, Rix TA, Overvad K, Joensen AM, Riahi S. Validity of the diagnoses atrial fibrillation and atrial flutter in a Danish patient registry.Scand Cardiovasc J. 2012; 46:149–153.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Zhang C, Shen L, Pan M, Zheng Y, Gu Z and Lin H (2021) Perceptions and knowledge gaps on CHA 2 DS 2 -VASc score components: a joint survey of Chinese clinicians and clinical pharmacists , Postgraduate Medicine, 10.1080/00325481.2021.1996815, 134:1, (64-77), Online publication date: 2-Jan-2022. Handelsman Y, Bunch T, Rodbard H, Steinberg B, Thind M, Bigot G, Konigsberg L, Wieloch M and Kowey P (2022) Impact of dronedarone on patients with atrial fibrillation and diabetes: A sub-analysis of the ATHENA and EURIDIS/ADONIS studies, Journal of Diabetes and its Complications, 10.1016/j.jdiacomp.2022.108227, 36:7, (108227), Online publication date: 1-Jul-2022. Bilak J, Gulsin G and McCann G (2021) Cardiovascular and systemic determinants of exercise capacity in people with type 2 diabetes mellitus, Therapeutic Advances in Endocrinology and Metabolism, 10.1177/2042018820980235, 12, (204201882098023), Online publication date: 1-Jan-2021. Hua Y, Sun J, Su Y, Qu Q, Wang H, Sun W and Kong X (2020) The Safety and Efficacy of Rivaroxaban Compared with Warfarin in Patients with Atrial Fibrillation and Diabetes: A Systematic Review and Meta-analysis, American Journal of Cardiovascular Drugs, 10.1007/s40256-020-00407-z, 21:1, (51-61), Online publication date: 1-Jan-2021. Preda A, Liberale L and Montecucco F (2021) Imaging techniques for the assessment of adverse cardiac remodeling in metabolic syndrome, Heart Failure Reviews, 10.1007/s10741-021-10195-6 Related articlesGlycemic Status and Thromboembolic Risk in Patients With Atrial Fibrillation and Type 2 Diabetes MellitusMia Vicki Fangel, et al. Circulation: Arrhythmia and Electrophysiology. 2019;12 May 2019Vol 12, Issue 5 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCEP.119.007351PMID: 30995870 Originally publishedApril 18, 2019 Keywordsstrokeatrial fibrillationEditorialshumanscerebrovascular disordersPDF download Advertisement SubjectsAtrial FibrillationIschemic StrokeRisk Factors
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