Advertisement

Effects of Sodium/Glucose Cotransporter Inhibitors on Atrial Fibrillation and Stroke: A Meta-Analysis

      Highlights

      • SGLT inhibitors reduced the risk of atrial fibrillation (AF) in our meta-analysis.
      • Risk-reduction in AF remains in diabetics and cardiovascular disease.
      • Risk-reduction in AF is apparent over a longer follow-up duration.
      • Risk-reduction in AF did not extend to patients with heart failure.
      • SGLT inhibitors did not demonstrate an effect on stroke in our meta-analysis.

      Abstract

      Objectives

      Recent clinical trials have shown the potential of sodium glucose cotransporter (SGLT) 2 inhibitors to reduce the risk of atrial fibrillation but not stroke. We conducted a systematic review and meta-analysis to clarify if SGLT2 or combined SGLT1/2 inhibitors affect the risk of atrial fibrillation and stroke in patients regardless of diabetic status.

      Materials and methods

      Four electronic databases were searched on 21st November 2020 for studies evaluating outcomes of stroke and atrial fibrillation with SGLT2 or combined SGLT1/2 inhibitors in both diabetic and non-diabetic patients. Both random and fixed effect, pair-wise meta-analysis models were used to summarize the results of the studies.

      Results

      A total of 13 placebo-controlled, randomized-controlled trials were included. Eight trials comprising 35,702 patients were included in the analysis of atrial fibrillation outcomes and eight trials comprising 47,910 patients were included in the analysis of stroke outcomes. Patients on SGLT inhibitors, particularly SGLT2 inhibitors, had lower odds of atrial fibrillation (Peto odds ratio [95% confidence interval] = 0.76 [0.63–0.92]) compared to placebo. This effect remained significant with a follow-up duration longer than 1 year, in studies utilizing dapagliflozin, patients with type 2 diabetes mellitus, and patients with cardiovascular disease. No difference was observed in the odds of atrial fibrillation in patients with baseline heart failure. No effect was seen on the risk of stroke in patients taking SGLT inhibitors.

      Conclusions

      SGLT2 inhibitors significantly reduced the odds of atrial fibrillation in diabetic patients. However, SGLT inhibitors did not significantly affect the risk of stroke.

      Key Words

      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 Journal of Stroke and Cerebrovascular Diseases
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Saeedi P.
        • Petersohn I.
        • Salpea P.
        • et al.
        Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the international diabetes federation diabetes Atlas, 9th edition.
        Diabetes Res Clin Pract. 2019; 157107843
        • Huxley R.R.
        • Alonso A.
        • Lopez F.L.
        • et al.
        Type 2 diabetes, glucose homeostasis and incident atrial fibrillation: the atherosclerosis risk in communities study.
        Heart. 2012; 98 (British Cardiac Society): 133-138
        • Stroke Risk in Atrial Fibrillation Working G
        Independent predictors of stroke in patients with atrial fibrillation: a systematic review.
        Neurology. 2007; 69: 546-554
        • The Emerging Risk Factors C
        Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies.
        The Lancet. 2010; 375: 2215-2222
        • Fattah H.
        • Vallon V.
        The potential role of SGLT2 inhibitors in the treatment of type 1 diabetes mellitus.
        Drugs. 2018; 78: 717-726
        • Vallon V.
        The mechanisms and therapeutic potential of SGLT2 inhibitors in diabetes mellitus.
        Annu Rev Med. 2015; 66: 255-270
        • Cefalo C.M.A.
        • Cinti F.
        • Moffa S.
        • et al.
        Sotagliflozin, the first dual SGLT inhibitor: current outlook and perspectives.
        Cardiovasc Diabetol. 2019; 18: 20
        • Wiviott S.D.
        • Raz I.
        • Bonaca M.P.
        • et al.
        Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
        N Engl J Med. 2018; 380: 347-357
        • Zelniker T.A.
        • Bonaca M.P.
        • Furtado R.H.M.
        • et al.
        Effect of Dapagliflozin on atrial fibrillation in patients with type 2 diabetes mellitus.
        Circulation. 2020; 141: 1227-1234
        • Fernandes G.C.
        • Fernandes A.
        • Cardoso R.
        • et al.
        Association of SGLT2 inhibitors with arrhythmias and sudden cardiac death in patients with type 2 diabetes or heart failure: a meta-analysis of 34 randomized controlled trials.
        Heart Rhythm. 2021;
        • Okunrintemi V.
        • Mishriky B.M.
        • Powell J.R.
        • et al.
        Sodium-glucose co-transporter-2 inhibitors and atrial fibrillation in the cardiovascular and renal outcome trials.
        Diabetes Obes Metab. 2021; 23: 276-280
        • Guo M.
        • Ding J.
        • Li J.
        • et al.
        SGLT2 inhibitors and risk of stroke in patients with type 2 diabetes: a systematic review and meta-analysis.
        Diabetes Obes Metab. 2018; 20: 1977-1982
        • Page M.J.
        • McKenzie J.E.
        • Bossuyt P.M.
        • et al.
        The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
        BMJ. 2021; 372: n71
        • Higgins J.P.T.
        • Altman D.G.
        • Gøtzsche P.C.
        • et al.
        The cochrane collaboration's tool for assessing risk of bias in randomised trials.
        BMJ. 2011; 343: d5928
      1. Schünemann H, Brożek J, Guyatt G, Oxman A, editors. GRADE handbook for grading quality of evidence and strength of recommendations. Updated October 2013. The GRADE Working Group, 2013.

      2. Review Manager (RevMan) [Computer program]. Version 5.4, The Cochrane Collaboration, 2020.

        • Higgins J.P.T.
        • Thomas J.
        • Chandler J.
        Cochrane handbook for systematic reviews of interventions.
        2nd ed. The Cochrane Collaboration, 2019
        • de Boer R.A.
        • Núñez J.
        • Kozlovski P.
        • et al.
        Effects of the dual sodium–glucose linked transporter inhibitor, licogliflozin vs placebo or empagliflozin in patients with type 2 diabetes and heart failure.
        Br J Clin Pharmacol. 2020; 86: 1346-1356
        • Cannon C.P.
        • Pratley R.
        • Dagogo-Jack S.
        • et al.
        Cardiovascular outcomes with Ertugliflozin in type 2 diabetes.
        N Engl J Med. 2020; 383: 1425-1435
        • Bradburn M.J.
        • Deeks J.J.
        • Berlin J.A.
        • et al.
        Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events.
        Stat Med. 2007; 26: 53-77
        • Cummings P.
        The relative merits of risk ratios and odds ratios.
        Arch Pediatr Adolesc Med. 2009; 163: 438-445
        • Cefalu W.T.
        • Leiter L.A.
        • de Bruin T.W.A.
        • et al.
        Dapagliflozin's effects on glycemia and cardiovascular risk factors in high-risk patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension.
        Diabetes Care. 2015; 38: 1218-1227
        • McMurray J.J.V.
        • Solomon S.D.
        • Inzucchi S.E.
        • et al.
        Dapagliflozin in patients with heart failure and reduced ejection fraction.
        N Engl J Med. 2019; 381: 1995-2008
        • Verma S.
        • Mazer C.D.
        • Yan A.T.
        • et al.
        Effect of Empagliflozin on left ventricular mass in patients with type 2 diabetes mellitus and coronary artery disease.
        Circulation. 2019; 140: 1693-1702
        • Heerspink H.J.L.
        • Stefánsson B.V.
        • Correa-Rotter R.
        • et al.
        Dapagliflozin in patients with chronic kidney disease.
        N Engl J Med. 2020; 383: 1436-1446
        • Lee M.M.Y.
        • Brooksbank K.J.M.
        • Wetherall K.
        • et al.
        Effect of Empagliflozin on left ventricular volumes in patients with type 2 diabetes, or prediabetes, and heart failure with reduced ejection fraction (SUGAR-DM-HF).
        Circulation. 2021; 143: 516-525
        • Neal B.
        • Perkovic V.
        • Mahaffey K.W.
        • et al.
        Canagliflozin and cardiovascular and renal events in type 2 diabetes.
        N Engl J Med. 2017; 377: 644-657
        • Zinman B.
        • Wanner C.
        • Lachin J.M.
        • et al.
        Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
        N Engl J Med. 2015; 373: 2117-2128
        • Garg S.K.
        • Henry R.R.
        • Banks P.
        • et al.
        Effects of Sotagliflozin Added to insulin in patients with type 1 diabetes.
        N Engl J Med. 2017; 377: 2337-2348
        • Packer M.
        • Anker S.D.
        • Butler J.
        • et al.
        Effect of Empagliflozin on the clinical stability of patients with heart failure and a reduced ejection fraction.
        Circulation. 2021; 143: 326-336
        • Shimizu W.
        • Kubota Y.
        • Hoshika Y.
        • et al.
        Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: the EMBODY trial.
        Cardiovasc Diabetol. 2020; 19: 148
        • Colilla S.
        • Crow A.
        • Petkun W.
        • et al.
        Estimates of current and future incidence and prevalence of atrial fibrillation in the U.S. adult population.
        Am J Cardiol. 2013; 112: 1142-1147
        • The GBD 2016 Lifetime Risk of Stroke Collaborators
        Global, Regional, and Country-Specific Lifetime Risks of Stroke, 1990 and 2016.
        N Engl J Med. 2018; 379: 2429-2437
        • 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 task force for the diagnosis and management of atrial fibrillation of the European society of cardiology (ESC) developed with the special contribution of the European heart rhythm association (EHRA) of the ESC.
        Eur Heart J. 2020; 42: 373-498
        • Ludwig L.
        • Darmon P.
        • Guerci B.
        Computing and interpreting the number needed to treat for cardiovascular outcomes trials.
        Cardiovasc Diabetol. 2020; 19: 65
        • Cosentino F.
        • Grant P.J.
        • Aboyans V.
        • et al.
        2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the task force for diabetes, pre-diabetes, and cardiovascular diseases of the European society of cardiology (ESC) and the European association for the study of diabetes (EASD).
        Eur Heart J. 2019; 41: 255-323
        • McDonagh T.A.
        • Metra M.
        • Adamo M.
        • et al.
        2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the task force for the diagnosis and treatment of acute and chronic heart failure of the European society of cardiology (ESC) with the special contribution of the heart failure association (HFA) of the ESC.
        Eur Heart J. 2021;
        • Savarese G.
        • Lund L.H.
        Global public health burden of heart failure.
        Card Fail Rev. 2017; 3: 7-11
        • Kornej J.
        • Börschel C.S.
        • Benjamin E.J.
        • et al.
        Epidemiology of atrial fibrillation in the 21st century: novel methods and new insights.
        Circ Res. 2020; 127: 4-20
        • Santhanakrishnan R.
        • Wang N.
        • Larson M.G.
        • et al.
        Atrial fibrillation begets heart failure and vice versa.
        Circulation. 2016; 133: 484-492
        • Ziff O.J.
        • Carter P.R.
        • McGowan J.
        • et al.
        The interplay between atrial fibrillation and heart failure on long-term mortality and length of stay: insights from the, United Kingdom ACALM registry.
        Int J Cardiol. 2018; 252: 117-121
        • Kang S.
        • Verma S.
        • Hassanabad A.F.
        • et al.
        Direct effects of Empagliflozin on extracellular matrix remodelling in human cardiac myofibroblasts: novel translational clues to explain EMPA-REG OUTCOME results.
        Can J Cardiol. 2020; 36: 543-553
        • Sohns C.
        • Marrouche N.F.
        Atrial fibrillation and cardiac fibrosis.
        Eur Heart J. 2019; 41: 1123-1131
        • Nishinarita R.
        • Niwano S.
        • Niwano H.
        • et al.
        Canagliflozin suppresses atrial remodeling in a canine atrial fibrillation model.
        J Am Heart Assoc. 2021; 10 (e017483)e017483
        • Page R.L.
        • Wilkinson W.E.
        • Clair W.K.
        • et al.
        Asymptomatic arrhythmias in patients with symptomatic paroxysmal atrial fibrillation and paroxysmal supraventricular tachycardia.
        Circulation. 1994; 89: 224-227

      Linked Article