Thiazolidinediones and Risk of Atrial Fibrillation Among Patients with Diabetes and Coronary Disease



      We sought to determine whether insulin-sensitizing therapy (thiazolidinediones or metformin) decreased the risk of developing atrial fibrillation compared with insulin-providing therapy (insulin, sulfonylurea, or a meglitinide). Thiazolidinediones are insulin sensitizers that also decrease the inflammatory response. Because inflammation is a risk factor for atrial fibrillation, we hypothesized that treating diabetes with thiazolidinediones might decrease the risk of developing atrial fibrillation.


      The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial enrolled patients with type 2 diabetes and documented coronary artery disease. All patients were randomized to insulin-sensitizing therapy or insulin-providing therapy.


      A total of 2319 patients entered the study, with 1160 assigned to the insulin-sensitization strategy and 1159 assigned to the insulin-provision strategy. Over a median follow-up of 4.2 years, 90 patients (3.9%) developed new-onset atrial fibrillation. In the intention-to-treat analysis, the incidence of atrial fibrillation was 8.7 per 1000 person-years in patients assigned to insulin sensitization compared with 9.5 in patients assigned to insulin provision with a hazard ratio (HR) of 0.91 (95% confidence interval [CI], 0.60-1.38, P = .66). In a time-varying exposure analysis, the incidence rate per 1000 person-years was 7.2 while exposed to thiazolidinediones and 9.7 while not exposed to thiazolidinediones with an adjusted HR of 0.80 (95% CI, 0.33-1.94, P = .62). In a subset of patients matched on propensity to receive a thiazolidinediones, the HR was 0.75 (95% CI, 0.43-1.30, P = .30).


      We did not find a significant reduction of atrial fibrillation incidence with use of thiazolidinediones.


      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 to The American Journal of Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Huxley R.R.
        • Filion K.B.
        • Konety S.
        • Alonso A.
        Meta-analysis of cohort and case-control studies of type 2 diabetes mellitus and risk of atrial fibrillation.
        Am J Cardiol. 2011; 108: 56-62
        • Perez M.V.
        • Wang P.J.
        • Larson J.C.
        • 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
        • Pallisgaard J.L.
        • Lindhardt T.B.
        • Olesen J.B.
        • Hansen M.L.
        • Carlson N.
        • Gislason G.H.
        Management and prognosis of atrial fibrillation in the diabetic patient.
        Expert Rev Cardiovasc Ther. 2015; 13: 643-651
        • Pallisgaard J.L.
        • Schjerning A.M.
        • Lindhardt T.B.
        • et al.
        Risk of atrial fibrillation in diabetes mellitus: a nationwide cohort study.
        Eur J Prev Cardiol. 2016; 23: 621-627
        • Aviles R.J.
        • Martin D.O.
        • Apperson-Hansen C.
        • et al.
        Inflammation as a risk factor for atrial fibrillation.
        Circulation. 2003; 108: 3006-3010
        • Ahlehoff O.
        • Gislason G.H.
        • Jørgensen C.H.
        • et al.
        Psoriasis and risk of atrial fibrillation and ischaemic stroke: a Danish Nationwide Cohort Study.
        Eur Heart J. 2012; 33: 2054-2064
        • Kristensen S.L.
        • Lindhardsen J.
        • Ahlehoff O.
        • et al.
        Increased risk of atrial fibrillation and stroke during active stages of inflammatory bowel disease: a nationwide study.
        Europace. 2014; 16: 477-484
        • Chung M.K.
        • Martin D.O.
        • Sprecher D.
        • et al.
        C-reactive protein elevation in patients with atrial arrhythmias: inflammatory mechanisms and persistence of atrial fibrillation.
        Circulation. 2001; 104: 2886-2891
        • Engelmann M.D.M.
        • Svendsen J.H.
        Inflammation in the genesis and perpetuation of atrial fibrillation.
        Eur Heart J. 2005; 26: 2083-2092
        • Picchi A.
        • Capobianco S.
        • Qiu T.
        • et al.
        Coronary microvascular dysfunction in diabetes mellitus: a review.
        World J Cardiol. 2010; 2: 377-390
        • Zhang Q.
        • Liu T.
        • Ng C.Y.
        • Li G.
        Diabetes mellitus and atrial remodeling: mechanisms and potential upstream therapies.
        Cardiovasc Ther. 2014; 32: 233-241
        • 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
        • Kadappu K.K.
        • Boyd A.
        • Eshoo S.
        • et al.
        Changes in left atrial volume in diabetes mellitus: more than diastolic dysfunction?.
        Eur Heart J Cardiovasc Imaging. 2012; 13: 1016-1023
        • Henry W.L.
        • Morganroth J.
        • Pearlman A.S.
        • et al.
        Relation between echocardiographically determined left atrial size and atrial fibrillation.
        Circulation. 1976; 53: 273-279
        • Lee Y.-S.
        • Hyun D.W.
        • Jung B.C.
        • et al.
        Left atrial volume index as a predictor for occurrence of atrial fibrillation after ablation of typical atrial flutter.
        J Cardiol. 2010; 56: 348-353
        • Otake H.
        • Suzuki H.
        • Honda T.
        • Maruyama Y.
        Influences of autonomic nervous system on atrial arrhythmogenic substrates and the incidence of atrial fibrillation in diabetic heart.
        Int Heart J. 2009; 50: 627-641
        • Cariou B.
        • Charbonnel B.
        • Staels B.
        Thiazolidinediones and PPARγ agonists: time for a reassessment.
        Trends Endocrinol Metab. 2012; 23: 205-215
        • Straus D.S.
        • Glass C.K.
        Anti-inflammatory actions of PPAR ligands: new insights on cellular and molecular mechanisms.
        Trends Immunol. 2007; 28: 551-558
        • Kahn S.E.
        • Haffner S.M.
        • Heise M.A.
        • et al.
        Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy.
        N Engl J Med. 2006; 355: 2427-2443
        • Ermakov S.
        • Azarbal F.
        • Stefanick M.L.
        • et al.
        The associations of leptin, adiponectin and resistin with incident atrial fibrillation in women.
        Heart. 2016; 102: 1354-1362
      1. FDA Approved Drug Products.
        (Available at:)
        • International Diabetes Federation Guideline Development Group
        Global guideline for type 2 diabetes.
        Diabetes Res Clin Pract. 2014; 104: 1-52
        • Gu J.
        • Liu X.
        • Wang X.
        • et al.
        Beneficial effect of pioglitazone on the outcome of catheter ablation in patients with paroxysmal atrial fibrillation and type 2 diabetes mellitus.
        Europace. 2011; 13: 1256-1261
        • Anglade M.W.
        • Kluger J.
        • White C.M.
        • Aberle J.
        • Coleman C.I.
        Thiazolidinedione use and post-operative atrial fibrillation: a US nested case-control study.
        Curr Med Res Opin. 2007; 23: 2849-2855
        • Chao T.-F.
        • Leu H.-B.
        • Huang C.-C.
        • et al.
        Thiazolidinediones can prevent new onset atrial fibrillation in patients with non-insulin dependent diabetes.
        Int J Cardiol. 2012; 156: 199-202
        • Liu T.
        • Korantzopoulos P.
        • Li G.
        • Li J.
        The potential role of thiazolidinediones in atrial fibrillation.
        Int J Cardiol. 2008; 128: 129-130
        • Brooks M.M.
        • Frye R.L.
        • Genuth S.
        • et al.
        Hypotheses, design, and methods for the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial.
        Am J Cardiol. 2006; 97: 9G-19G
        • Hlatky M.A.
        • Boothroyd D.B.
        • Melsop K.A.
        • et al.
        Economic outcomes of treatment strategies for type 2 diabetes mellitus and coronary artery disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial.
        Circulation. 2009; 120: 2550-2558
        • Bach R.G.
        • Brooks M.M.
        • Lombardero M.
        • et al.
        Response to letter regarding article, “rosiglitazone and outcomes for patients with diabetes mellitus and coronary artery disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D). Trial”.
        Circulation. 2014; 129: e460-e461
        • Pallisgaard J.L.
        • Lindhardt T.B.
        • Staerk 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. 2016;
        • Dormandy J.A.
        • Charbonnel B.
        • Eckland D.J.A.
        • et al.
        Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial.
        Lancet. 2005; 366: 1279-1289