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The case of diabetes mellitus and atrial fibrillation: Underlining the importance of non-cardiovascular comorbidities

  • Marco Proietti
    Correspondence
    Corresponding author at: Geriatric Unit, IRCCS Istituti Clinici Scientifici Maugeri, Via Camaldoli 64, Milan 20138, Italy.
    Affiliations
    Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy

    Geriatric Unit, IRCCS Istituti Clinici Scientifici Maugeri, Via Camaldoli 64, Milan 20138, Italy

    Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom
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  • Giulio Francesco Romiti
    Affiliations
    Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom

    Department of Translational and Precision Medicine, Sapienza – University of Rome, Rome, Italy
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  • Stefania Basili
    Affiliations
    Department of Translational and Precision Medicine, Sapienza – University of Rome, Rome, Italy
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      In the currently changing scenario, in which our patients are progressively older and more likely burdened by concomitant chronic long-term conditions [

      World Health Organization Integrated Health Services. Multimorbidity: technical series on safer primary care.; 2016. https://www.who.int/publications/i/item/9789241511650.

      ], diabetes mellitus (DM) play a prominent role in determining the health state of patients worldwide [
      • Lin X.
      • Xu Y.
      • Pan X.
      • et al.
      Global, regional, and national burden and trend of diabetes in 195 countries and territories: an analysis from 1990 to 2025.
      ]. In particular a strict relationship exists between DM and atrial fibrillation (AF), which is one of the most common cardiovascular conditions [
      • Hindricks G.
      • Potpara T.
      • Dagres N.
      • et al.
      2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).
      ]. Indeed, DM is now recognized as one of the most important risk factors leading to the development of AF, with a number of mechanisms involved in determining this relationship [
      • Boriani G.
      • Proietti M.
      Atrial fibrillation prevention: an appraisal of current evidence.
      ,
      • Wang A.
      • Green J.B.
      • Halperin J.L.
      • Piccini J.P.
      Atrial fibrillation and diabetes mellitus: JACC review topic of the week.
      ]. Indeed, through the relationship between glycaemic fluctuations, oxidative stress and inflammation, the presence of DM promotes incident AF, also with a “dose-response” relationship between the severity and duration of disease [
      • Wang A.
      • Green J.B.
      • Halperin J.L.
      • Piccini J.P.
      Atrial fibrillation and diabetes mellitus: JACC review topic of the week.
      ]. Furthermore, data are consistent in reporting that the management of DM is effective in reducing the risk of AF as much as the disease is controlled [
      • Boriani G.
      • Proietti M.
      Atrial fibrillation prevention: an appraisal of current evidence.
      ]. Furthermore, beyond being part of the CHA2DS2-VASc score for the evaluation of the baseline thromboembolic risk [
      • Hindricks G.
      • Potpara T.
      • Dagres N.
      • et al.
      2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS).
      ], the presence of DM increases overall the risk of all the AF-related adverse outcomes [
      • Boriani G.
      • Vitolo M.
      • Diemberger I.
      • et al.
      Optimizing indices of atrial fibrillation susceptibility and burden to evaluate atrial fibrillation severity, risk and outcomes.
      ]. Indeed, in the last years, several studies (Table 1) have shown a largely ranging prevalence of DM among AF cohort (between ∼ 20% and 30%), and substantially agreed on the independent increase of risk for all the major AF-associated clinical outcomes (all-cause death, cardiovascular death, major adverse cardiovascular events) in DM patients [
      • Echouffo-Tcheugui J.B.
      • Shrader P.
      • Thomas L.
      • et al.
      Care patterns and outcomes in atrial fibrillation patients with and without diabetes: ORBIT-AF registry.
      ,
      • Patti G.
      • Lucerna M.
      • Cavallari I.
      • et al.
      Insulin-requiring versus noninsulin-requiring diabetes and thromboembolic risk in patients with atrial fibrillation: PREFER in AF.
      ,
      • Fumagalli S.
      • Said S.A.
      • Laroche C.
      • et al.
      Management and prognosis of atrial fibrillation in diabetic patients: an EORP-AF general pilot registry report.
      ,
      • García-Fernández A.
      • Esteve-Pastor M.A.
      • Roldán-Rabadán I.
      • et al.
      Relationship of adverse events to quality of anticoagulation control in atrial fibrillation patients with diabetes: real-world data from the FANTASIIA registry.
      ,
      • Krittayaphong R.
      • Aroonsiriwattana S.
      • Ngamjanyaporn P.
      • Patmuk T.
      • Kaewkumdee P.
      Outcomes of patients with atrial fibrillation with and without diabetes: a propensity score matching of the COOL-AF registry.
      ].
      Table 1Relationship between diabetes mellitus and outcomes in atrial fibrillation patients.
      Study Year Geographic Location N DM Patients

      N (%)
      Results
      ORBIT-AF
      • Echouffo-Tcheugui J.B.
      • Shrader P.
      • Thomas L.
      • et al.
      Care patterns and outcomes in atrial fibrillation patients with and without diabetes: ORBIT-AF registry.
      2017 US 9749 2874 (29.5) DM increases the risk of all the outcomes examined, as all-cause death (aHR 1.63, 95% CI 1.04–2.56 in patients <70 years and aHR 1.25, 95% CI 1.09–1.44 in patients ≥70 years) and CV death (aHR 2.20, 95% CI 1.22–3.98 in patients <70 years and aHR 1.24, 95% CI 1.02–1.51 in patients ≥70 years)
      PREFER-AF
      • Patti G.
      • Lucerna M.
      • Cavallari I.
      • et al.
      Insulin-requiring versus noninsulin-requiring diabetes and thromboembolic risk in patients with atrial fibrillation: PREFER in AF.
      2017 Europe 5717 1288 (22.5) Insulin-requiring DM increases the risk of IS/SE both compared to non-insulin-requiring DM and no-diabetes
      EORP-AF Pilot
      • Fumagalli S.
      • Said S.A.
      • Laroche C.
      • et al.
      Management and prognosis of atrial fibrillation in diabetic patients: an EORP-AF general pilot registry report.
      2018 Europe 3101 638 (20.6) DM independently increases the risk of all-cause death in full multivariate analysis (aHR 1.86, 95% CI 1.31–2.62)
      FANTASIIA
      • García-Fernández A.
      • Esteve-Pastor M.A.
      • Roldán-Rabadán I.
      • et al.
      Relationship of adverse events to quality of anticoagulation control in atrial fibrillation patients with diabetes: real-world data from the FANTASIIA registry.
      2020 Spain 1956 574 (29.3) DM increases risk of MACEs (aHR 2.03, 95% CI 1.47–2.80), CV death (aHR 2.40, 95% CI 1.62–3.56), all-cause death (aHR 1.58, 95% CI 1.20–2.07)
      COOL-AF
      • Krittayaphong R.
      • Aroonsiriwattana S.
      • Ngamjanyaporn P.
      • Patmuk T.
      • Kaewkumdee P.
      Outcomes of patients with atrial fibrillation with and without diabetes: a propensity score matching of the COOL-AF registry.
      2021 Thailand 3402 923 (27.1) Presence of DM Increases Risk of Outcomes in PM Analysis: IS/TIA aHR 1.67, 95% CI 1.02–2.73; MB aHR 1.65, 95% CI 1.13–2.40; HF aHR 1.87, 95% CI 1.34–2.59
      Legend: aHR= adjusted Hazard Ratio; CI= Confidence Interval; CV= Cardiovascular; DM= Diabetes Mellitus; HF= Heart Failure; IS= Ischemic Stroke; MACE= Major Adverse Cardiovascular Events; MB= Major Bleeding; PM= Propensity Matched; SE= Systemic Embolism; TIA= Transient Ischemic Attack.
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