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Randomized Controlled Trial
. 2025 Mar;27(3):540-551.
doi: 10.1002/ejhf.3478. Epub 2024 Oct 9.

Cardiovascular outcomes with exenatide in type 2 diabetes according to ejection fraction: The EXSCEL trial

João Sérgio Neves  1   2 , Ana Rita Leite  1   2 , Robert J Mentz  3 , Rury R Holman  4 , Faiez Zannad  5 , Javed Butler  6   7 , Milton Packer  8   9 , João Pedro Ferreira  1   5
Affiliations
Free article
Randomized Controlled Trial

Cardiovascular outcomes with exenatide in type 2 diabetes according to ejection fraction: The EXSCEL trial

João Sérgio Neves et al. Eur J Heart Fail. 2025 Mar.
Free article

Abstract

Aims: Glucagon-like peptide-1 receptor agonists reduce major adverse cardiovascular events (MACE) and cardiovascular mortality in people with type 2 diabetes (T2D). However, previous studies suggest the effects on heart failure outcomes vary according to left ventricular ejection fraction (LVEF). We aimed to evaluate the effects of exenatide on cardiovascular events according to LVEF in people with T2D.

Methods and results: Post-hoc analysis of the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial evaluating the effects of once-weekly exenatide (EQW) versus placebo on cardiovascular outcomes according to baseline LVEF (<40% or ≥40%). Outcomes were also evaluated according to New York Heart Association (NYHA) class and obesity. The main outcome was hospitalization for heart failure (HHF). A treatment-by-LVEF interaction was used. In EXSCEL (n = 14 752), 4749 participants had LVEF available at baseline; 455 (10%) with LVEF <40%, 4294 (90%) with LVEF ≥40%. LVEF modified the EQW effect on hHF: hazard ratio (HR) = 1.52 (95% confidence interval [CI] = 0.95-2.43) in participants with LVEF < 40% and HR = 0.74 (95% CI = 0.55-1.01) in those with LVEF ≥ 40% (p-interaction = 0.012). No significant treatment-by-LVEF interactions (p-interaction >0.10) were observed for MACE, cardiovascular death or all-cause mortality. The risk of HHF was also modified by baseline NYHA class (HR 0.91, 95% CI 0.65-1.27 for NYHA class I/II; HR 1.84, 95% CI 0.95-3.59 for NYHA class III/IV; p-interaction = 0.062), mostly driven by the LVEF <40% subgroup. Obesity did not modify the effects of EQW on HHF.

Conclusions: The EQW effect on HHF was influenced by LVEF, with a potentially decreased risk in participants with LVEF ≥40% and increased risk in those with LVEF <40%. The risk of HHF was particularly high in participants with LVEF <40% and NYHA class III/IV. LVEF did not modify the effect of EQW on atherosclerotic outcomes.

Keywords: Ejection fraction; GLP‐1 receptor agonists; Heart failure; Type 2 diabetes.

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References

    1. Sattar N, Lee MMY, Kristensen SL, Branch KRH, Del Prato S, Khurmi NS, et al. Cardiovascular, mortality, and kidney outcomes with GLP‐1 receptor agonists in patients with type 2 diabetes: A systematic review and meta‐analysis of randomised trials. Lancet Diabetes Endocrinol 2021;9:653–662. https://doi.org/10.1016/S2213‐8587(21)00203‐5
    1. Lincoff AM, Brown‐Frandsen K, Colhoun HM, Deanfield J, Emerson SS, Esbjerg S, et al.; SELECT Trial Investigators. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med 2023;389:2221–2232. https://doi.org/10.1056/NEJMoa2307563
    1. Ferreira JP, Saraiva F, Sharma A, Vasques‐Nóvoa F, Angélico‐Gonçalves A, Leite AR, et al. Glucagon‐like peptide 1 receptor agonists in patients with type 2 diabetes with and without chronic heart failure: A meta‐analysis of randomized placebo‐controlled outcome trials. Diabetes Obes Metab 2023;25:1495–1502. https://doi.org/10.1111/dom.14997
    1. Kosiborod MN, Abildstrøm SZ, Borlaug BA, Butler J, Rasmussen S, Davies M, et al.; STEP‐HFpEF Trial Committees and Investigators. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. N Engl J Med 2023;389:1069–1084. https://doi.org/10.1056/NEJMoa2306963
    1. Kosiborod MN, Petrie MC, Borlaug BA, Butler J, Davies MJ, Hovingh GK, et al.; STEP‐HFpEF DM Trial Committees and Investigators. Semaglutide in patients with obesity‐related heart failure and type 2 diabetes. N Engl J Med 2024;390:1394–1407. https://doi.org/10.1056/NEJMoa2313917

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