Advertisement
Research Article| Volume 198, 110626, April 2023

Association between antidiabetic drugs and the incidence of atrial fibrillation in patients with type 2 diabetes: A nationwide cohort study in South Korea

  • Sunyoung Kim
    Affiliations
    Department of Family Medicine, Kyung Hee University College of Medicine, Kyung Hee University Medical Center, Seoul, Republic of Korea

    Center for Digital Health, Medical Science Research Institute, Kyung Hee University Medical Center, Seoul, Republic of Korea
    Search for articles by this author
  • So Young Park
    Affiliations
    Department of Endocrinology and Metabolism, Kyung Hee University College of Medicine, Kyung Hee University Medical Center, Seoul, Republic of Korea
    Search for articles by this author
  • Bongseong Kim
    Affiliations
    Department of Biostatistics, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
    Search for articles by this author
  • Chanyang Min
    Affiliations
    Center for Digital Health, Medical Science Research Institute, Kyung Hee University Medical Center, Seoul, Republic of Korea
    Search for articles by this author
  • Wonyoung Cho
    Affiliations
    Center for Digital Health, Medical Science Research Institute, Kyung Hee University Medical Center, Seoul, Republic of Korea
    Search for articles by this author
  • Dong Keon Yon
    Affiliations
    Center for Digital Health, Medical Science Research Institute, Kyung Hee University Medical Center, Seoul, Republic of Korea
    Search for articles by this author
  • Joo Young Kim
    Affiliations
    Division of Endocrinology and Metabolism, Department of Internal Medicine, Hanil General Hospital, Seoul, Republic of Korea
    Search for articles by this author
  • Kyung-Do Han
    Affiliations
    Department of Biostatistics, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
    Search for articles by this author
  • Eun-Jung Rhee
    Affiliations
    Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
    Search for articles by this author
  • Won-Young Lee
    Affiliations
    Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
    Search for articles by this author
  • Sang Youl Rhee
    Correspondence
    Corresponding author at: Center for Digital Health, Medical Science Research Institute, Kyung Hee University Medical Center, Seoul, Republic of Korea.
    Affiliations
    Center for Digital Health, Medical Science Research Institute, Kyung Hee University Medical Center, Seoul, Republic of Korea

    Department of Endocrinology and Metabolism, Kyung Hee University College of Medicine, Kyung Hee University Medical Center, Seoul, Republic of Korea
    Search for articles by this author

      Highlights

      • Why did we undertake this study?
      • We aimed to investigate the possibility of a difference in the AF preventive effect of antidiabetic drugs through a national cohort-based real-world data analysis that classifies the entire adult population.
      • What is the specific question(s) we wanted to answer?
      • Which antidiabetic drugs are most effective in preventing AF?
      • What did we find?
      • The combination therapy of MET and TZD is the most effective antidiabetic drug for preventing AF in patients with type 2 diabetes.
      • What are the implications of our findings?
      • Through this study, real world evidence was prepared for the effective results of MET and TZD combination therapy, which is widely used in clinical practice, for AF.

      Abstract

      Background

      Although diabetes is a risk factor for atrial fibrillation (AF), studies on the AF risk according to the antidiabetic drugs are lacking. This study evaluated the effects of antidiabetic drugs on AF incidence in Korean patients with type 2 diabetes.

      Methods

      We included 2,515,468 patients with type 2 diabetes from the Korean National Insurance Service database without a history of AF who underwent health check-ups between 2009 and 2012. Newly diagnosed AF incidence was recorded until December 2018 according to the main antidiabetic drug combinations used in the real world.

      Results

      Of the patients included (mean age, 62 ± 11 years; 60 % men), 89,125 were newly diagnosed with AF. Metformin (MET) alone (hazard ratio [HR] 0.959, 95 % CI 0.935–0.985) and MET combination therapy (HR < 1) significantly decreased the risk of AF compared to the no-medication group. The antidiabetic drugs consistently showing a protective effect against AF incidence were MET (HR 0.977, 95 % CI 0.964–0.99) and thiazolidinedione (TZD; HR 0.926, 95 % CI 0.898–0.956), even after adjusting for various factors. Moreover, this protective effect was more remarkable with MET and TZD combination therapy (HR 0.802, 95 % CI 0.754–0.853) than with other drug combinations. In the subgroup analysis, the preventive effect of MET and TZD treatment against AF remained consistent, regardless of age, sex, duration, and diabetes severity.

      Conclusion

      The combination therapy of MET and TZD is the most effective antidiabetic drug for preventing AF in patients with type 2 diabetes.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Diabetes Research and Clinical Practice
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Lippi G.
        • Sanchis-Gomar F.
        • Cervellin G.
        Global epidemiology of atrial fibrillation: an increasing epidemic and public health challenge.
        Int J Stroke. 2021; 16: 217-221
        • Ball J.
        • Carrington M.J.
        • McMurray J.J.V.
        • Stewart S.
        Atrial fibrillation: profile and burden of an evolving epidemic in the 21st century.
        Int J Cardiol. 2013; 167: 1807-1824
        • Mukherjee K.
        • Kamal K.M.
        Impact of atrial fibrillation on inpatient cost for ischemic stroke in the USA.
        Int J Stroke. 2019; 14: 159-166
        • Lau D.H.
        • Nattel S.
        • Kalman J.M.
        • Sanders P.
        Modifiable Risk Factors and Atrial Fibrillation.
        Circulation. 2017; 136: 583-596
        • Dublin S.
        • Glazer N.L.
        • Smith N.L.
        • Psaty B.M.
        • Lumley T.
        • Wiggins K.L.
        • et al.
        Diabetes Mellitus, Glycemic Control, and Risk of Atrial Fibrillation.
        J Gen Intern Med. 2010; 25: 853-858
        • Sun Y.
        • Hu D.
        The link between diabetes and atrial fibrillation: cause or correlation?.
        J Cardiovasc Dis Res. 2010; 1: 10-11
        • Perez M.V.
        • Wang P.J.
        • Larson J.C.
        • Soliman E.Z.
        • Limacher M.
        • Rodriguez B.
        • et al.
        Risk factors for atrial fibrillation and their population burden in postmenopausal women: the Women's Health Initiative Observational Study.
        Heart. 2013; 99: 1173-1178
        • Benjamin E.J.
        • Levy D.
        • Vaziri S.M.
        • D'Agostino R.B.
        • Belanger A.J.
        • Wolf P.A.
        Independent risk factors for atrial fibrillation in a population-based cohort: the Framingham Heart Study.
        JAMA. 1994; 271: 840-844
        • Wang A.
        • Green J.B.
        • Halperin J.L.
        • Piccini J.P.
        Atrial fibrillation and diabetes mellitus: JACC review topic of the week.
        J Am Coll Cardiol. 2019; 74: 1107-1115
        • Bell D.S.
        • Goncalves E.
        Atrial fibrillation and type 2 diabetes: prevalence, etiology, pathophysiology and effect of anti-diabetic therapies.
        Diabetes Obes Metab. 2019; 21: 210-217
        • Goudis C.A.
        • Korantzopoulos P.
        • Ntalas I.V.
        • Kallergis E.M.
        • Liu T.
        • Ketikoglou D.G.
        Diabetes mellitus and atrial fibrillation: pathophysiological mechanisms and potential upstream therapies.
        Int J Cardiol. 2015; 184: 617-622
        • Uthman L.
        • Baartscheer A.
        • Schumacher C.A.
        • Fiolet J.W.
        • Kuschma M.C.
        • Hollmann M.W.
        • et al.
        Direct cardiac actions of sodium glucose cotransporter 2 inhibitors target pathogenic mechanisms underlying heart failure in diabetic patients.
        Front Physiol. 2018; 9: 1575
        • Zelniker T.A.
        • Braunwald E.
        Treatment of heart failure with sodium-glucose cotransporter 2 inhibitors and other anti-diabetic drugs.
        Card Fail Rev. 2019; 5: 27
        • Garber A.J.
        • Handelsman Y.
        • Grunberger G.
        • Einhorn D.
        • Abrahamson M.J.
        • Barzilay J.I.
        • et al.
        Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm – 2020 Executive Summary.
        Endocr Pract. 2020; 26: 107-139
        • Draznin B.
        • Aroda V.R.
        • Bakris G.
        • Benson G.
        • Brown F.M.
        • Freeman R.
        • et al.
        9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2022.
        Diabetes Care. 2022; 45: S125-S143
        • Tseng C.-H.
        Metformin use is associated with a lower incidence of hospitalization for atrial fibrillation in patients with type 2 diabetes mellitus.
        Front Med. 2021; 7: 1031
        • Ostropolets A.
        • Elias P.A.
        • Reyes M.V.
        • Wan E.Y.
        • Pajvani U.B.
        • Hripcsak G.
        • et al.
        Metformin is associated with a lower risk of atrial fibrillation and ventricular arrhythmias compared with sulfonylureas: an observational study.
        Circ Arrhythm Electrophysiol. 2021; 14: e009115
        • Pallisgaard J.L.
        • Lindhardt T.B.
        • Staerk L.
        • Olesen J.B.
        • Torp-Pedersen C.
        • Hansen M.L.
        • et al.
        Thiazolidinediones are associated with a decreased risk of atrial fibrillation compared with other antidiabetic treatment: a nationwide cohort study.
        Eur Heart J-Cardiovasc Pharmacother. 2017; 3: 140-146
        • Woo A.
        • Lee S.W.
        • Koh H.Y.
        • Kim M.A.
        • Han M.Y.
        • Yon D.K.
        Incidence of cancer after asthma development: 2 independent population-based cohort studies.
        J Allergy Clin Immunol. 2021; 147: 135-143
        • Nam G.E.
        • Kim Y.-H.
        • Han K.
        • Jung J.-H.
        • Rhee E.-J.
        • Lee W.-Y.
        • et al.
        Obesity fact sheet in Korea, 2020: prevalence of obesity by obesity class from 2009 to 2018.
        JOMES. 2021; 30: 141-148
        • Rhee S.Y.
        • Han K.-D.
        • Kwon H.
        • Park S.-E.
        • Park Y.-G.
        • Kim Y.-H.
        • et al.
        Association between glycemic status and the risk of Parkinson disease: a nationwide population-based study.
        Diabetes Care. 2020; 43: 2169-2175
        • Lee S.W.
        Regression analysis for continuous independent variables in medical research: statistical standard and guideline of Life Cycle Committee.
        Life Cycle. 2022; 2: e3
        • Rizzo M.R.
        • Sasso F.C.
        • Marfella R.
        • Siniscalchi M.
        • Paolisso P.
        • Carbonara O.
        • et al.
        Autonomic dysfunction is associated with brief episodes of atrial fibrillation in type 2 diabetes.
        J Diabetes Complications. 2015; 29: 88-92
        • Bettoni M.
        • Zimmermann M.
        Autonomic tone variations before the onset of paroxysmal atrial fibrillation.
        Circulation. 2002; 105: 2753-2759
        • Vinik A.I.
        • Maser R.E.
        • Mitchell B.D.
        • Freeman R.
        Diabetic Autonomic Neuropathy.
        Diabetes Care. 2003; 26: 1553-1579
        • Chang S.-H.
        • Wu L.-S.
        • Chiou M.-J.
        • Liu J.-R.
        • Yu K.-H.
        • Kuo C.-F.
        • et al.
        Association of metformin with lower atrial fibrillation risk among patients with type 2 diabetes mellitus: a population-based dynamic cohort and in vitro studies.
        Cardiovasc Diabetol. 2014; 13: 1-8
        • Zhang Z.
        • Zhang X.
        • Korantzopoulos P.
        • Letsas K.P.
        • Tse G.
        • Gong M.
        • et al.
        Thiazolidinedione use and atrial fibrillation in diabetic patients: a meta-analysis.
        BMC Cardiovasc Disord. 2017; 17: 96
        • Zelniker T.A.
        • Bonaca M.P.
        • Furtado R.H.
        • Mosenzon O.
        • Kuder J.F.
        • Murphy S.A.
        • et al.
        Effect of dapagliflozin on atrial fibrillation in patients with type 2 diabetes mellitus: insights from the DECLARE-TIMI 58 trial.
        Circulation. 2020; 141: 1227-1234
        • Lee T.-W.
        • Lee T.-I.
        • Lin Y.-K.
        • Chen Y.-C.
        • Kao Y.-H.
        • Chen Y.-J.
        Effect of antidiabetic drugs on the risk of atrial fibrillation: mechanistic insights from clinical evidence and translational studies.
        Cell Mol Life Sci. 2021; 78: 923-934
        • Liu T.
        • Li G.
        Thiazolidinediones as novel upstream therapy for atrial fibrillation in diabetic patients: a review of current evidence.
        Int J Cardiol. 2012; 156: 215-216
        • Gu J.
        • Liu X.
        • Wang Q.-x.
        • Guo M.
        • Liu F.
        • Song Z.-p.
        • et al.
        Beneficial effects of pioglitazone on atrial structural and electrical remodeling in vitro cellular models.
        J Mol Cell Cardiol. 2013; 65: 1-8
        • Kume O.
        • Takahashi N.
        • Wakisaka O.
        • Nagano-Torigoe Y.
        • Teshima Y.
        • Nakagawa M.
        • et al.
        Pioglitazone attenuates inflammatory atrial fibrosis and vulnerability to atrial fibrillation induced by pressure overload in rats.
        Heart Rhythm. 2011; 8: 278-285
        • Fauchier L.
        • Fauchier G.
        • Bisson A.
        • Bodin A.
        • Herbert J.
        • Angoulvant D.
        • et al.
        Antidiabetic drugs use and new-onset atrial fibrillation in patients with diabetes mellitus.
        Eur Heart J. 2021; 42ehab724.0457
        • Shi W.
        • Zhang W.
        • Zhang D.
        • Ren G.
        • Wang P.
        • Gao L.
        • et al.
        Comparison of the effect of glucose-lowering agents on the risk of atrial fibrillation: a network meta-analysis.
        Heart Rhythm. 2021; 18: 1090-1096
        • Hur K.Y.
        • Moon M.K.
        • Park J.S.
        • Kim S.-K.
        • Lee S.-H.
        • Yun J.-S.
        • et al.
        2021 Clinical practice guidelines for diabetes mellitus of the Korean Diabetes Association.
        Diabetes Metab J. 2021; 45: 461-481