SGLT2 inhibitors and atrial fibrillation in type 2 diabetes: a systematic review with meta-analysis of 16 randomized controlled trials

Wen-Jie Li, Xing-Qing Chen, Ling-Ling Xu, Yuan-Qing Li, Bi-Hui Luo, Wen-Jie Li, Xing-Qing Chen, Ling-Ling Xu, Yuan-Qing Li, Bi-Hui Luo

Abstract

Background: Type 2 diabetes is closely related to an increased risk of atrial fibrillation (AF) and atrial flutter (AFL). Whether sodium-glucose cotransporter 2 (SGLT2) inhibitors can attenuate AF/AFL progression remains unclear.

Methods: We searched electronic databases (PubMed, Embase and ClinicalTrials.gov) from their inception to January 2020 for trials evaluating the AF outcomes of SGLT2 inhibitors in patients with type 2 diabetes. The data search and extraction were conducted with a standardized data form and any conflicts were resolved by consensus. Relative risks (RRs) with 95% confidence intervals (CIs) were used for binary variables, and the weighed mean differences (WMDs) with the standard deviation (SDs) were applied for continuous variables.

Results: We included data from 16 identified trials consisting of 38,335 patients with type 2 diabetes. Incorporated data demonstrated that compared to placebo, SGLT2 inhibitors significantly reduced AF/AFL (RR: 0.76; 95% CI 0.65-0.90; p = 0.001) and all-cause mortality (RR: 0.91; 95% CI 0.83-0.99; p = 0.03). AF/AFL reductions were not modified by age, body weight, glycated haemoglobin (HbA1c), or systolic blood pressure (SBP) at baseline (all p-interactions > 0.3). SGLT2 inhibitors also significantly reduced heart failure events (RR: 0.73; 95% CI 0.64-0.84; p < 0.00001), HbA1c (WMD: - 0.62%; 95% CI - 0.89 to - 0.34; p < 0.00001), body weight (WMD: - 2.12 kg; 95% CI - 2.91 to - 1.34; p < 0.00001), SBP (WMD: - 3.34 mmHg; 95% CI - 4.12 to - 2.56; p < 0.00001), and diastolic blood pressure (DBP) (WMD: - 1.11 mmHg; 95% CI - 1.62 to - 0.60; p < 0.0001). Of note, cerebrovascular events and myocardial infarction did not increase in patients taking SGLT2 inhibitors.

Conclusion: SGLT2 inhibitors may confer a specific AF/AFL-reduction benefit in the susceptible type 2 diabetes population, regardless of age, body weight, HbA1c, and systolic blood pressure at baseline. Such an AF/AFL-reduction benefit may be partly attributed to pharmacological effects on reductions in HbA1c, body weight, blood pressure, and the occurrence of heart failure.

Keywords: Atrial fibrillation; Atrial flutter; Meta-analysis; Sodium-glucose cotransporter 2 inhibitors; Type 2 diabetes.

Conflict of interest statement

The authors do not have any possible conflict of interest.

Figures

Fig. 1
Fig. 1
Flow diagram of articles identified, included, and excluded
Fig. 2
Fig. 2
Methodological quality assessment of included randomized controlled trials
Fig. 3
Fig. 3
Forest plot and meta-analysis of atrial fibrillation/atrial flutter events. Weights are from the fixed-effect analysis. The solid line across the square represents the 95% confidence interval (CI)
Fig. 4
Fig. 4
Forest plot and meta-analysis of all-cause mortality. Weights are from the fixed-effect analysis. The solid line across the square represents the 95% confidence interval (CI)
Fig. 5
Fig. 5
Funnel plots illustrating meta-analysis: a heart failure and b atrial fibrillation/atrial flutter

References

    1. Rahman F, Kwan GF, Benjamin EJ. Global epidemiology of atrial fibrillation. Nat Rev Cardiol. 2014;11(11):639–654.
    1. Echouffo-Tcheugui JB, Shrader P, Thomas L, Gersh BJ, Kowey PR, Mahaffey KW, Singer DE, Hylek EM, Go AS, Peterson ED, et al. Care patterns and outcomes in atrial fibrillation patients with and without Diabetes: oRBIT-AF registry. J Am Coll Cardiol. 2017;70(11):1325–1335.
    1. Bell DSH, Goncalves E. Atrial fibrillation and type 2 diabetes: prevalence, etiology, pathophysiology and effect of anti-diabetic therapies. Diabetes Obes Metab. 2019;21(2):210–217.
    1. Wang A, Green JB, Halperin JL, Piccini JP., Sr Atrial fibrillation and diabetes mellitus: JACC review topic of the week. J Am Coll Cardiol. 2019;74(8):1107–1115.
    1. Chan YH, Chang GJ, Lai YJ, Chen WJ, Chang SH, Hung LM, Kuo CT, Yeh YH. Atrial fibrillation and its arrhythmogenesis associated with insulin resistance. Cardiovasc Diabetol. 2019;18(1):125.
    1. Packer M. Disease-treatment interactions in the management of patients with obesity and diabetes who have atrial fibrillation: the potential mediating influence of epicardial adipose tissue. Cardiovasc Diabetol. 2019;18(1):121.
    1. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295–2306.
    1. A study of the effects of canagliflozin (JNJ-28431754) on Renal endpoints in adult participants with type 2 diabetes mellitus (CANVAS-R). .
    1. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Furtado RHM, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019;393(10166):31–39.
    1. Bohm M, Slawik J, Brueckmann M, Mattheus M, George JT, Ofstad AP, Inzucchi SE, Fitchett D, Anker SD, Marx N, et al. Efficacy of empagliflozin on heart failure and renal outcomes in patients with atrial fibrillation: data from the EMPA-REG OUTCOME trial. Eur J Heart Fail. 2020;22(1):126–135.
    1. Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia. 2018;61(10):2108–2117.
    1. Kotecha D, Piccini JP. Atrial fibrillation in heart failure: what should we do? Eur Heart J. 2015;36(46):3250–3257.
    1. Trulock KM, Narayan SM, Piccini JP. Rhythm control in heart failure patients with atrial fibrillation: contemporary challenges including the role of ablation. J Am Coll Cardiol. 2014;64(7):710–721.
    1. Zelniker TA, Braunwald E. Cardiac and renal effects of sodium-glucose co-transporter 2 inhibitors in diabetes: JACC state-of-the-art review. J Am Coll Cardiol. 2018;72(15):1845–1855.
    1. Zelniker TA, Bonaca MP, Furtado RHM, Mosenzon O, Kuder JF, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, 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(15):1227–1234.
    1. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700.
    1. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–560.
    1. Safety and efficacy of the combination of empagliflozin and linagliptin compared to linagliptin alone over 24 weeks in patients with type 2 diabetes. . .
    1. CANVAS—CANagliflozin cardiovascular assessment study. . .
    1. A Phase III Study of BMS-512148 (dapagliflozin) in patients with type 2 diabetes who are not well controlled with diet and exercise. . .
    1. Leiter LA, Cefalu WT, de Bruin TW, Gause-Nilsson I, Sugg J, Parikh SJ. Dapagliflozin added to usual care in individuals with type 2 diabetes mellitus with preexisting cardiovascular disease: a 24-week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension. J Am Geriatr Soc. 2014;62(7):1252–1262.
    1. Wilding JP, Woo V, Soler NG, Pahor A, Sugg J, Rohwedder K, Parikh S. Dapagliflozin 006 Study G: long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann Intern Med. 2012;156(6):405–415.
    1. Wilding JP, Charpentier G, Hollander P, Gonzalez-Galvez G, Mathieu C, Vercruysse F, Usiskin K, Law G, Black S, Canovatchel W, et al. Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial. Int J Clin Pract. 2013;67(12):1267–1282.
    1. Yale JF, Bakris G, Cariou B, Nieto J, David-Neto E, Yue D, Wajs E, Figueroa K, Jiang J, Law G, et al. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease. Diabetes Obes Metab. 2014;16(10):1016–1027.
    1. Rosenstock J, Jelaska A, Zeller C, Kim G, Broedl UC, Woerle HJ. investigators E-RBt: impact of empagliflozin added on to basal insulin in type 2 diabetes inadequately controlled on basal insulin: a 78-week randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2015;17(10):936–948.
    1. Multicenter trial to evaluate the effect of dapagliflozin on the incidence of cardiovascular events (DECLARE-TIMI58). .
    1. Kovacs CS, Seshiah V, Swallow R, Jones R, Rattunde H, Woerle HJ, Broedl UC. investigators E-RPt: empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebo-controlled trial. Diabetes Obes Metab. 2014;16(2):147–158.
    1. Bailey CJ, Gross JL, Hennicken D, Iqbal N, Mansfield TA, List JF. Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled 102-week trial. BMC Med. 2013;11:43.
    1. Mathieu C, Ranetti AE, Li D, Ekholm E, Cook W, Hirshberg B, Chen H, Hansen L, Iqbal N. Randomized, double-blind, phase 3 trial of triple therapy with dapagliflozin add-on to saxagliptin plus metformin in type 2 diabetes. Diabetes Care. 2015;38(11):2009–2017.
    1. Bode B, Stenlof K, Harris S, Sullivan D, Fung A, Usiskin K, Meininger G. Long-term efficacy and safety of canagliflozin over 104 weeks in patients aged 55–80 years with type 2 diabetes. Diabetes Obes Metab. 2015;17(3):294–303.
    1. Barnett AH, Mithal A, Manassie J, Jones R, Rattunde H, Woerle HJ, Broedl UC. investigators E-RRt: efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014;2(5):369–384.
    1. Schotten U, Verheule S, Kirchhof P, Goette A. Pathophysiological mechanisms of atrial fibrillation: a translational appraisal. Physiol Rev. 2011;91(1):265–325.
    1. Rajeev SP, Cuthbertson DJ, Wilding JP. Energy balance and metabolic changes with sodium-glucose co-transporter 2 inhibition. Diabetes Obes Metab. 2016;18(2):125–134.
    1. Abed HS, Samuel CS, Lau DH, Kelly DJ, Royce SG, Alasady M, Mahajan R, Kuklik P, Zhang Y, Brooks AG, et al. Obesity results in progressive atrial structural and electrical remodeling: implications for atrial fibrillation. Heart Rhythm. 2013;10(1):90–100.
    1. Kim YG, Han KD, Choi JI, Boo KY, Kim DY, Oh SK, Lee KN, Shim J, Kim JS, Kim YH. The impact of body weight and diabetes on new-onset atrial fibrillation: a nationwide population based study. Cardiovasc Diabetol. 2019;18(1):128.
    1. Chung MK, Eckhardt LL, Chen LY, Ahmed HM, Gopinathannair R, Joglar JA, Noseworthy PA, Pack QR, Sanders P, Trulock KM et al: Lifestyle and risk factor modification for reduction of atrial fibrillation: a scientific statement from the american heart association. Circulation 2020:CIR0000000000000748.
    1. Gourdie RG, Dimmeler S, Kohl P. Novel therapeutic strategies targeting fibroblasts and fibrosis in heart disease. Nat Rev Drug Discov. 2016;15(9):620–638.
    1. Moss AS, Dimitropoulos G, Connolly DL, Lip GYH. Considerations and treatment options for patients with comorbid atrial fibrillation and diabetes mellitus. Expert Opin Pharmacother. 2017;18(11):1101–1114.
    1. AlKindi F, Al-Omary HL, Hussain Q, Al Hakim M, Chaaban A, Boobes Y. Outcomes of SGLT2 inhibitors use in diabetic renal transplant patients. Transplant Proc. 2020;52(1):175–178.
    1. Cholesterol Treatment Trialists C Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. Lancet. 2019;393(10170):407–415.
    1. Shao Q, Meng L, Lee S, Tse G, Gong M, Zhang Z, Zhao J, Zhao Y, Li G, Liu T. Empagliflozin, a sodium glucose co-transporter-2 inhibitor, alleviates atrial remodeling and improves mitochondrial function in high-fat diet/streptozotocin-induced diabetic rats. Cardiovasc Diabetol. 2019;18(1):165.
    1. Habibi J, Aroor AR, Sowers JR, Jia G, Hayden MR, Garro M, Barron B, Mayoux E, Rector RS, Whaley-Connell A, et al. Sodium glucose transporter 2 (SGLT2) inhibition with empagliflozin improves cardiac diastolic function in a female rodent model of diabetes. Cardiovasc Diabetol. 2017;16(1):9.
    1. Geerlings S, Fonseca V, Castro-Diaz D, List J, Parikh S. Genital and urinary tract infections in diabetes: impact of pharmacologically-induced glucosuria. Diabetes Res Clin Pract. 2014;103(3):373–381.
    1. Liu J, Li L, Li S, Jia P, Deng K, Chen W, Sun X. Effects of SGLT2 inhibitors on UTIs and genital infections in type 2 diabetes mellitus: a systematic review and meta-analysis. Sci Rep. 2017;7(1):2824.
    1. Nyirjesy P, Sobel JD, Fung A, Mayer C, Capuano G, Ways K, Usiskin K. Genital mycotic infections with canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus: a pooled analysis of clinical studies. Curr Med Res Opin. 2014;30(6):1109–1119.
    1. Zinman B, Inzucchi SE, Lachin JM, Wanner C, Fitchett D, Kohler S, Mattheus M, Woerle HJ, Broedl UC, Johansen OE, et al. Empagliflozin and cerebrovascular events in patients with type 2 diabetes mellitus at high cardiovascular risk. Stroke. 2017;48(5):1218–1225.
    1. Low Wang CC, Hess CN, Hiatt WR, Goldfine AB. Clinical update: cardiovascular disease in diabetes mellitus: atherosclerotic cardiovascular disease and heart failure in type 2 diabetes mellitus—mechanisms, management, and clinical considerations. Circulation. 2016;133(24):2459–2502.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren