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Clinical Outcomes with GLP-1 Receptor Agonists in Patients with Heart Failure: A Systematic Review and Meta-analysis of Randomized Controlled Trials

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Abstract

Background

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, there remains uncertainty about the efficiency of GLP-1 RAs in patients with heart failure (HF).

Methods

Randomized placebo-controlled trials (RCTs) that reported the effect of GLP-1 RAs on prognosis in patients with HF were identified by searching databases. The primary outcome was defined as MACE. Trail Sequential Analysis (TSA) was used to evaluate the reality and authenticity.

Results

Nine RCTs involving 8920 patients with HF were included. GLP-1 RAs significantly reduced the risk of MACE compared with placebo (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.77–0.98) in HF coexisting with T2DM. The benefit was not observed in all-cause death (HR 0.99, 95% CI 0.84–1.15), hospitalization for heart failure (HR 1.04, 95% CI 0.89–1.22), cardiovascular death (HR 0.95, 95% CI 0.79–1.16), myocardial infarction (HR 0.88, 95% CI 0.71–1.08), stroke (HR 1.03, 95% CI 0.75–1.43) and death or hospitalization for HF (HR 1.07, 95% CI 0.78–1.46). GLP-1 RAs did not improve the change in LVEF (mean difference [MD]): − 0.86, p = 0.12, left-ventricular end-diastolic volume (LVEDV) (MD: 3.54, p = 0.11), left-ventricular end-systolic volume (LVESV) (MD: 2.78, p = 0.07) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) (MD: − 140.36, p = 0.08).

However, GLP-1 RAs significantly increased the change in the 6-min walk test (MWT) distance (MD: 19.74, p = 0.002). In the subgroup analyses, human GLP-1 RAs, but not nonhuman GLP-1 RAs, reduced the risk of MACE in patients with HF (p interaction = 0.11). Grading of Recommendations Assessment, Development and Evaluation (GRADE) showed moderate certainty for MACE, all-cause death and hospitalization for HF. Trail Sequential Analysis revealed that there may be a high possibility of false positive results for MACE.

Conclusion

Compared with placebo, GLP-1 RAs may reduce the risk of MACE in patients with HF coexisting with T2DM, with a more significant efficiency of human GLP-1 RAs. More RCTs are needed to assess the cardiovascular benefits of GLP-1 RAs in HF, regardless of T2DM.

Registration

The protocol for this meta-analysis is registered on PROSPERO [CRD42022357886].

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Author information

Author notes

  1. Huilei Zhao and Yang Liu and contributed equally.

Authors and Affiliations

  1. Department of Anesthesiology, The Third Hospital of Nanchang, Nanchang, Jiangxi, China

    Huilei Zhao

  2. Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China

    Yang Liu & Jing Zhang

  3. Department of Cardiology, Seventh People’s Hospital of Zhengzhou, Zhengzhou, China

    Menglu Liu & Yujie Zhao

  4. Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China

    Yi Xu, Qin Ling & Peng Yu

  5. Department of Gastroenterology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Weichun Lin

  6. Department of Sports Rehabilitation, Shenyang Sport University, Shenyang, Liaoning, China

    Zhiwei Yan

  7. Provincial University Key Laboratory of Sport and Health Science, School of Physical Education and Sport Sciences, Fujian Normal University, Fuzhou, China

    Zhiwei Yan

  8. Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China

    Jianyong Ma

  9. Department of Rehabilitation, Liaoning Province Jinqiu Hospital, Shenyang, Liaoning, China

    Weiguang Li

  10. Department of Cardiology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China

    Xiao Liu & Jingfeng Wang

  11. Guangdong Provincial Key Laboratory of Arrhythmia and Electrophysiology, Sun Yat-Sen University, Guangzhou, Guangdong, China

    Xiao Liu & Jingfeng Wang

  12. Guangzhou Key Laboratory of Molecular Mechanism and Translation in Major Cardiovascular Disease, Guangzhou, Guangdong, China

    Xiao Liu & Jingfeng Wang

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  1. Huilei Zhao
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Corresponding authors

Correspondence to Peng Yu or Xiao Liu.

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Funding 

This work was supported by the Natural Science Foundation of Jiangxi Province (No. 20212BAB216051 to J.Z., No. 20212BAB216047 to P.Y.); the Jiangxi Province Thousands of Plans (No. jxsq2023201105 to P.Y.); and the Hengrui Diabetes Metabolism Research Fund (No. Z-2017-26-2202-4 to P.Y.); and the National Natural Science Foundation of China (nos. 82160371 to J.Z. and nos. 82100869 to P.Y., nos. 82100347 to X.L. no. 21866019), National High Technology Research and Development Program of Guangzhou (nos. 20180304001 and nos. 2019GZR110406004 to J.F-W), Natural Science Foundation of Guangdong Province (nos. 2022A1515010582 and nos. 202201011395 to X.L. and Science and Technology Projects in Guangzhou (nos. 202102010007 to J.F-W), China Postdoctoral Science Foundation (Nos. 2021M703724).

Conflict of interest

Huilei Zhao, Yang Liu, Menglu Liu, Yi Xu, Qin Ling, Weichun Lin, Jing Zhang, Zhiwei Yan, Jianyong Ma, Weiguang Li, Yujie Zhao, Jingfeng Wang, Peng Yu, Xiao Liu declared that they had no potential conflicts of interest.

Authors’ contributions

X-L and Z-H contributed to the study concept and design and revised the draft. Y-L, X-L and P-Y performed the search strategy and contributed to database research, acquisition of data and statistical analyses. All the authors participated in data analysis and reviewed and approved the final manuscript.

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All data generated or analyzed during this study are included in this published article (and its supplementary information files).

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Additional information

Jingfeng Wang: Senior author.

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Zhao, H., Liu, Y., Liu, M. et al. Clinical Outcomes with GLP-1 Receptor Agonists in Patients with Heart Failure: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Drugs 83, 1293–1307 (2023). https://doi.org/10.1007/s40265-023-01932-2

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