Series: Cardiovascular outcome trials for diabetes drugs Canagliflozin and the CANVAS Program, dapagliflozin and DECLARE-TIMI 58, ertugliflozin and VERTIS CV
DOI:
https://doi.org/10.15277/bjd.2021.320Keywords:
diabetes, cardiovascular outcome trial, canagliflozin, dapagliflozin, ertugliflozinAbstract
EMPA-REG OUTCOME was a landmark trial with the sodium-glucose co-transporter-2 (SGLT2) inhibitor empagliflozin, which demonstrated significant reductions in major adverse cardiovascular events (MACE, a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke) driven by reductions in cardiovascular deaths and accompanied by an early reduction in hospitalisation for heart failure. This was followed by cardiovascular outcome trials with canagliflozin, dapagliflozin and ertugliflozin. The CANVAS Program was an integrated analysis of the CANVAS and CANVAS-R trials with canagliflozin. It demonstrated a significant reduction in MACE, but not in any of the components, and there was an unexpected increase in amputations and fractures with canagliflozin. The DECLARE-TIMI 58 trial with dapagliflozin had two co-primary endpoints. A composite endpoint of cardiovascular death or hospitalisation for heart failure was significantly reduced, but there was no significant difference in MACE comparing dapagliflozin with placebo. Analysis of patients with a prior myocardial infarction, however, demonstrated significant reductions in MACE. The VERTIS CV trial with ertugliflozin was disappointing as there was no difference in MACE comparing ertugliflozin and placebo. In all four trials a reduction in hospitalisation for heart failure was observed in patients with type 2 diabetes, regardless of whether they had existing atherosclerotic cardiovascular disease or increased cardiovascular risk. Pre-specified renal outcomes were reduced with empagliflozin, canagliflozin and dapagliflozin, and these drugs are now commonly used in the management of people with type 2 diabetes. It is hard to envisage an ongoing role for ertugliflozin in routine clinical management as the evidence for its cardiovascular benefit is not convincing.
References
Zinman B, Wanner C, Lachin JM, et al, for the EMPA-REG OUTCOME investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–28. https://doi.org/10.1056/NEJMoa1504720
Neal B, Perkovic V, Mahaffey KW, et al, for the CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644–57. https://doi.org/10.1056/NEJMoa1611925
Wiviott SD, Bonaca MP, Mosenzon O, et al, for the DECLARE-TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347–57. https://doi.org/10.1056/NEJMoa1812389
Cannon CP, Pratley R, Dagogo-Jack S, et al, for the VERTIS CV Investigators. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med 2020;383:1425–35. https://doi.org/10.1056/NEJMoa2004967
Fisher M. Empagliflozin and EPA-REG OUTCOME. Br J Diabetes 2020;20: 138–41. https://doi.org/10.15277/bjd.2020.254
Neal B, Perkovic V, de Zeeuw D, et al. Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)—a randomized placebo-controlled trial. Am Heart J 2013;166:217–23. https://doi.org/10.1016/j.ahj.2013.05.007
Neal B, Perkovic V, Mathews DR, et al. Rationale, design and baseline characteristics of the CANagliflozin cardioVascular Assessment Study–Renal (CANVAS-R): a randomized, placebo-controlled trial. Diabetes Obes Metab 2017;19:387–93. https://doi.org/10.1111/dom.12829
Neal B, Perkovic V, Mathews DR, et al. Optimizing the analysis strategy for the CANVAS Program: a prespecified plan for the integrated analyses of the CANVAS and CANVAS-R trials. Diabetes Obes Metab 2017;19:926–35. https://doi.org/10.1111/dom.12924
Mathews DR, Li Q, Perkovic V, et al. Effects of canagliflozin on amputation risk in type 2 diabetes: the CANVAS Program. Diabetologia 2019;62:926–38. https://doi.org/10.1007/s00125-019-4839-8
Zhou Z, Jardine M, Perkovic V, et al. Canagliflozin and fracture risk in individuals with type 2 diabetes: results from the CANVAS Program. Diabetologia 2019;62:1854–67. https://doi.org/10.1007/s00125-019-4955-5
Perkovic V, Jardine MJ, Neal B, et al, for the CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295–306. https://doi.org/10.1056/NEJMoa1811744
Wiviott SD, Raz I, Bonaca MP, et al. The design and rationale for the Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 Trial. Am Heart J 2018;200:83–9. https://doi.org/10.1016/j.ahj.2018.01.012
Raz I, Mosenzon O, Bonaca MP, et al. DECLARE-TIMI 58: Participants’ baseline characteristics. Diabetes Obes Metab 2018;20:1102–10. https://doi.org/10.1111/dom.13217
Furtado RHM, Bonaca MP, Raz I, et al. Dapagliflozin and cardiovascular outcomes in patients with type 2 diabetes mellitus and previous myocardial infarction: subanalysis from the DECLARE-TIMI 58 Trial. Circulation 2019;139: 2516–27. https://doi.org/10.1161/CIRCULATIONAHA.119.039996
Cannon CP, McGuire DK, Pratley R, et al. Design and baseline characteristics of the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes trial (VERTIS-CV). Am Heart J 2018;206:11–23. https://doi.org/10.1016/j.ahj.2018.08.016
McGuire DK, Shih WJ, Cosentino F, et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes. A meta-analysis. JAMA Cardiol 2021;6:148–58. https://doi.org/10.1001/jamacardio.2020.4511
Cherney DZI, Charbonnel B, Cosentino F, et al. Effects of ertugliflozin on kidney composite outcomes, renal function and albuminuria in patients with type 2 diabetes mellitus: an analysis from the randomised VERTIS CV trial. Diabetologia 2021;64:1256–67. https://doi.org/10.1007/s00125-021-05407-5
McMurray JJV, Solomon SD, Inzucchi SE, et al, for the DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995–2008. https://doi.org/10.1056/NEJMoa1911303
Packer M, Anker SD, Butler J, et al, for the EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413–24. https://doi.org/10.1056/NEJMoa2022190
Anker SD, Butler J, Filipatos G, et al, for the EMPEROR-Preserved Trial Investigators. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med 2021;385:1451–61. https://doi.org/10.1056/NEJMoa2107038
Solomon SD, de Boer RA, DeMets D, et al. Dapagliflozin in heart failure with preserved and mildly reduced ejection fraction: rationale and design of the DELIVER trial. Eur J Heart Fail 2021;23:1217–25. https://doi.org/10.1002/ejhf.2249
Heerspink HJ, Stefansson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383:1436–46. https://doi.org/10.1056/NEJMoa2024816
Herrington WG, Preiss D, Haynes R, et al. The potential for improving cardio-renal outcomes by sodium-glucose co-transporter-2 inhibition in people with chronic kidney disease: a rationale for the EMPA-KIDNEY study. Clin Kidney J 2018;11:749–61. https://doi.org/10.1093/ckj/sfy090
Cowie MR, Fisher M. SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. Nat Rev Cardiol 2020;17:761–72. https://doi.org/10.1038/s41569-020-0406-8
Perkovic V, de Zeeuw D, Mahaffey KW, et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials. Lancet Diabetes Endocrinol 2018;6:691–704. https://doi.org/10.1016/S2213-8587(18)30141-4
Radholm K, Figtree G, Perkovic V, et al. Canagliflozin and heart failure in type 2 diabetes mellitus: results from the CANVAS Program. Circulation 2018;138:458–68. https://doi.org/10.1161/CIRCULATIONAHA.118.034222
Kato ET, Silverman MG, Mosenzon O, et al. Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus. Circulation 2019;139:2528–36. https://doi.org/10.1161/CIRCULATIONAHA.119.040130
Mosenzon O, Wiviott SD, Cahn A, et al. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial. Lancet Diabetes Endocrinol 2019;7:606–17. https://doi.org/10.1016/S2213-8587(19)30180-9
Cahn A, Raz I, Bonaca M, et al. Safety of dapagliflozin in a broad population of patients with type 2 diabetes: analyses from the DECLARE-TIMI 58 study. Diabetes Obes Metab 2020;22:1357–68. https://doi.org/10.1111/dom.14041
Cosentino F, Cannon CP, Cherney DZI, et al. Efficacy of ertugliflozin on heart failure–related events in patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease results of the VERTIS CV trial. Circulation 2020;142:2205–15. https://doi.org/10.1161/CIRCULATIONAHA. 120.050255
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