The effect of sodium-glucose link transporter 2 inhibitors on heart failure end points in people with type 2 diabetes mellitus: a systematic review and meta-analysis

Authors

  • Thomas Simon James Crabtree University Hospitals of Derby and Burton NHS Trust; University of Nottingham
  • Robert EJ Ryder Sandwell and West Birmingham Hospitals NHS Trust

DOI:

https://doi.org/10.15277/bjd.2021.307

Keywords:

Diabetes, Type 2, Heart Failure, SGLT-2, CVOT

Abstract

Introduction: Type 2 diabetes is a condition which is frequently associated with macrovascular complications. Sodium-glucose linked transporter-2 inhibitors (SGLT2i) have been demonstrated to improve composite cardiovascular outcomes assessed via a 3-point Major Adverse Cardiovascular Events (MACE). Although they yield some benefit in reducing overall rates of cardiovascular death, stroke and myocardial infarction, it appears that the majority of the beneficial effects of SGLT2i drugs on composite outcomes are mediated by improvements in heart failure outcomes reducing cardiovas cular death. This effect has been noted across multiple different drugs in the SGLT2i class. The aim of this review was to synthesise current evidence from randomised controlled trials (RCTs) comparing SGLT2i with placebo in adults with type 2 diabetes mellitus. The outcomes of interest were hazard ratios compared with placebo for hospitalisation due to heart failure (primary), death due to heart failure (secondary) and incidence rates of heart failure (secondary).

Methods: Searches were performed using recognised terms in MedLine, EMBASE, Pubmed, Cohrane CENTRAL and CINAHL. RCTs comparing SGLT2i with placebo were eligible for inclu- sion, providing they contained results for at least the out- come of interest. Studies were reviewed for inclusion by the two authors and data extraction and bias assessments were performed using a modified Cochrane’s data extraction tool and bias assessment tool. Meta-analysis of hazard ratios (HRs) was performed in RevMan 5.4 using generic inverse variance and a fixed effects model.

Results: 3,212 records were identified of which 13 were even tually included, covering 11 clinical studies. The risk of hospitalisation for heart failure was significantly lower with SGLT2i compared to placebo (HR 0.69; 95% CI 0.64, 0.74). Inter-study heterogeneity was minimal (I2=0%) Only one study contained outcomes for death due to heart failure, but its results were not significant. No current studies report hazard ratios for heart failure diagnoses with SGLT2i use compared with placebo.

Conclusion: SGLT2i drugs reduce the rates of hospitalization  due to heart failure in people with type 2 diabetes. This may help mediate the improvements seen in composite cardiovas cular outcomes. More evidence is needed to support their use in reducing mortality due to heart failure and incidence rates of new heart failure in this high-risk cohort.

References

References

Sarwar N, Gao P, Kondapally SR, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta- analysis of 102 prospective studies. Lancet 2010;375(9733):2215–22. https://doi.org/10.1016/S0140-6736(10)60484-9

Nichols GA, Gullion CM, Koro CE, Ephross SA, Brown JB. The incidence of congestive heart failure in type 2 diabetes. Diabetes Care 2004; 27(8):1879–84. https://doi.org/10.2337/diacare.27.8.1879

Thrainsdottir IS, Aspelund T, Thorgeirsson G, et al. The association be- tween glucose abnormalities and heart failure in the population-based Reykjavik study. Diabetes Care 2005;28(3):612–16. https://doi.org/ 10.2337/diacare.28.3.612

Taylor CJ, Ordóñez-Mena JM, Roalfe AK, et al. Trends in survival after a diagnosis of heart failure in the United Kingdom 2000–2017: population based cohort study. BMJ 2019;364:l223. https://doi.org/10.1136/ bmj.l223

MacDonald MR, Petrie MC, Varyani F, et al. Impact of diabetes on out- comes in patients with low and preserved ejection fraction heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme. Eur Heart J 2008; 29(11):1377–85. https://doi.org/10.1093/eurheartj/ehn153

McAllister DA, Read SH, Kerssens J, et al. Incidence of hospitalization for heart failure and case-fatality among 3.25 million people with and with- out diabetes mellitus. Circulation 2018;138(24):2774–86. https://doi.org/ 10.1161/CIRCULATIONAHA.118.034986

Wallach JD, Wang K, Zhang AD, et al. Updating insights into rosiglita- zone and cardiovascular risk through shared data: individual patient and summary level meta-analyses. BMJ 2020;368:l7078. https://doi.org/ 10.1136/bmj.l7078

Bae JC. Diabetes drugs and cardiovascular safety. Endocrinol Metab (Seoul)

;31(2):239–44. https://doi.org/10.3803/EnM.2016.31.2.239

Low Wang CC, Everett BM, Burman KD, Wilson PWF. Cardiovascular safety trials for all new diabetes mellitus drugs? Circulation 2019;139(14):1741-https://doi.org/10.1161/CIRCULATIONAHA.118.038771

Zinman B, Inzucchi SE, Lachin JM, et al. Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOME™). Cardiovasc Di- abetol 2014;13(1):102. https://doi.org/10.1186/1475-2840-13-102

Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular out- comes, and mortality in type 2 diabetes. N Engl J Med 2015; 373(22):2117–28. https://doi.org/10.1056/NEJMoa1504720

Cannon CP, Perkovic V, Agarwal R, et al. Canagliflozin reduces cardiovas- cular and renal events in patients with type 2 diabetes and chronic kidney disease regardless of baseline HbA1c, including those with HbA1c <7%: results from the CREDENCE trial. Circulation 2019;141(5):407–10. https://doi.org/10.1161/CIRCULATIONAHA.119.044359

Bhatt DL, Verma S, Braunwald E. The DAPA-HF trial: a momentous victory in the war against heart failure. Cell Metab 2019;30(5):847–9. https://doi.org/10.1016/j.cmet.2019.10.008

Anker SD, Butler J, Filippatos G, et al. Effect of empagliflozin on cardiovas- cular and renal outcomes in patients with heart failure by baseline diabetes status: results from the EMPEROR-Reduced trial. Circulation 2021; 143(4)337–49. https://doi.org/10.1161/CIRCULATIONAHA.120.051824

Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383(15):1413– 24. https://doi.org/10.1056/NEJMoa2022190

McGuire DK, Shih WJ, Cosentino F, et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 dia- betes: a meta-analysis. JAMA Cardiol 2021;6(2):148–58. https://doi.org/ 10.1001/jamacardio.2020.4511

Hupfeld C, Mudaliar S. Navigating the “MACE” in cardiovascular out- comes trials and decoding the relevance of atherosclerotic cardiovascular disease benefits versus heart failure benefits. Diabetes Obes Metab 2019;21(8):1780–9. https://doi.org/10.1111/dom.13740

Kohsaka S, Lam CSP, Kim DJ, et al. Risk of cardiovascular events and death associated with initiation of SGLT2 inhibitors compared with DPP- 4 inhibitors: an analysis from the CVD-REAL 2 multinational cohort study. Lancet Diabetes Endocrinol 2020;8(7):606–15. https://doi.org/10.1016/ S2213-8587(20)30130-3

Ryder, RE, MA Abdul-Ghani,RA DeFronzo. Diabetes medications with cardiovascular protection: the likelihood of benefit from combination therapy increases further following new evidence during 2020. Br J Diabetes 2020;20(2):84-88. https://doi.org/10.15277/bjd.2020.276

Packer M, Anker SD, Butler J, Filippatos G, Zannad F. Effects of sodium- glucose cotransporter 2 inhibitors for the treatment of patients with heart failure: proposal of a novel mechanism of action. JAMA Cardiol 2017;2(9):1025–9. https://doi.org/10.1001/jamacardio.2017.2275

Lopaschuk GD, Verma S. Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors: a state-of-the-art review. JACC Basic Transl Sci 2020;5(6):632–44. https://doi.org/10.1016/j.jacbts.2020.02.004

Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred re- porting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009;339:b2535. https://doi.org/10.1136/bmj.b2535

Higgins JPT, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (eds). Cochrane Handbook for Systematic Reviews of Interventions version 6.1. 2020. www.training.cochrane.org/handbook

Higgins JPT, Altman DG, Gøtsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928. https://doi.org/10.1136/bmj.d5928

Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377(7):644–57. https://doi.org/10.1056/NEJMoa1611925

Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380(24):2295– 306. https://doi.org/10.1056/NEJMoa1811744

Wheeler DC, Stefánsson BV, Jongs N, et al. Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol 2021;9(1):22–31. https://doi.org/10.1016/S2213-8587(20)30369-7

McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019; 381(21):1995–2008. https://doi.org/10.1056/NEJMoa1911303

Petrie MC, Verma S, Docherty KF, et al. Effect of dapagliflozin on wors- ening heart failure and cardiovascular death in patients with heart failure with and without diabetes. JAMA 2020;323(14):1353–68. https://doi.org/10.1001/jama.2020.1906

Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular out- comes in type 2 diabetes. N Engl J Med 2019;380(4):347–57. https://doi.org/10.1056/NEJMoa1812389

Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med 2021;384(2):117–28. https://doi.org/10.1056/NEJMoa2030183

Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med 2020;383(15):1425– 35. https://doi.org/10.1056/NEJMoa2004967

Anker SD, Butler J, Filippatos G et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med 2021. https://doi.org/ 10.1056/NEJMoa2107038

Bhatt DL, Szarek M, Pitt B, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med 2020;384(2):129-139. https://doi.org/10.1056/NEJMoa2030186.

Singh M, Kumar A. Risks associated with SGLT2 inhibitors: an overview. Curr Drug Saf 2018;13(2):84–91. https://doi.org/10.2174/ 1574886313666180226103408

Kristensen SL, Rørth R, Jhund PS, et al. Cardiovascular, mortality, and kid- ney outcomes with GLP-1 receptor agonists in patients with type 2 dia- betes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol 2019;7(10):776–85. https://doi.org/ 10.1016/S2213-8587(19)30249-9

Eurich DT, Weir DL, Majumdar SR, et al. Comparative safety and effec- tiveness of metformin in patients with diabetes mellitus and heart failure: systematic review of observational studies involving 34,000 patients. Circ Heart Fail 2013;6(3):395–402. https://doi.org/10.1161/CIRCHEARTFAIL- URE.112.000162

Davies MJ, D'Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Dia- betes (EASD). Diabetes Care 2018;41(12):2669–701. https://doi.org/ 10.2337/dci18-0033

Dandona P, Mathieu C, Phillip M, et al. Efficacy and safety of da- pagliflozin in patients with inadequately controlled type 1 diabetes: the DEPICT-1 52-Week Study. Diabetes Care 2018;41(12):2552–9. https://doi.org/10.2337/dc18-1087

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2021-09-13

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