Comparison of the efficacy and safety of 10 glucagon-like peptide-1 receptor agonists as add-on to metformin in patients with type 2 diabetes: a systematic review

Front Endocrinol (Lausanne). 2023 Aug 28:14:1244432. doi: 10.3389/fendo.2023.1244432. eCollection 2023.

Abstract

Purpose: This study aimed to perform a network meta-analysis to objectively evaluate the efficacy and safety of 10 Glucagon-like peptide-1 receptor agonists (GLP-1RAs) in combination with metformin that is approved for use worldwide in patients with type 2 diabetes and to provide evidence-based support and reference for the selection of clinical treatment.

Methods: Three databases (PubMed, Embase, and Cochrane Library) were searched from their respective inception until September 30, 2022. Only randomized controlled trials comparing the efficacy and safety of GLP-1RAs for treating type 2 diabetes (T2D) were included. The 10 GLP-1RAs are exenatide (including exenatide twice daily and once weekly), liraglutide, lixisenatide, dulaglutide, PEX168, semaglutide (subcutaneous and oral semaglutide), tirzepatide and albiglutide.

Results: 34 RCTs with 10 GLP-1RAs and 12993 patients were included in the Network Meta-Analysis (NMA). According to the NMA, tirzepatide 15 mg, semaglutide 1.0 mg, PEX168-200μg, oral semaglutide 14 and dulaglutide 1.5 mg reduced HbA1c by -2.23%, -1.57%, -1.12%, -1.10%, -1.09% and body weight by -11.33 kg, -5.99 kg, +0.40 kg, -3.95 kg, -1.87 kg, respectively. There was no significant difference in the rate of adverse events for tirzepatide 15 mg, oral-semaglutide 14 mg, and semaglutide 1.0 mg. PEX168-200μg, tirzepatide 15mg, and oral semaglutide 14mg had Surface Under the Cumulative Ranking (SUCRA) values greater than placebo, and only tirzepatide 15mg and oral semaglutide 14mg were significantly different from placebo in the rate of serious adverse events. All GLP-1RA did not lead to increased incidence of hypoglycemia. Albiglutide 30mg and semaglutide 1.0mg significantly differed from placebo in Adverse Event (AE) withdrawal. Finally, the sensitivity analysis and publication bias analysis results indicate that the study results are reliable.

Conclusion: This study's results showed that GLP-1RAs were effective in lowering HbA1c and reducing body weight without increased incidence of hypoglycemic reactions. In addition, this study may provide reference and evidence-based medical evidence for clinicians to select GLP-1RAs in patients with T2D and high body mass index (BMI). Based on the NMA results, tirzepatide 15mg and semaglutide 1.0mg may be preferred.

Keywords: efficacy; glucagon-like peptide-1 receptor agonists; randomized controlled trials; safety; systematic review; type 2 diabetes.

Publication types

  • Comparative Study
  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Body Weight
  • Diabetes Mellitus, Type 2* / drug therapy
  • Exenatide
  • Glucagon-Like Peptide-1 Receptor
  • Glycated Hemoglobin
  • Humans
  • Metformin* / therapeutic use

Substances

  • Exenatide
  • Glucagon-Like Peptide-1 Receptor
  • Glycated Hemoglobin
  • Metformin
  • polyethylene glycol loxenatide

Grants and funding

This study was supported by the National Key Specialty Construction Project (Clinical Pharmacy) and the High-level Clinical Key Specialty of Guangdong Province, and funded by the Central Finance Subsidy Fund for the Improvement of Medical Services and Guarantee Capacity, code Z155080000004; Guangzhou Minsheng Science and Technology Research Program Project, code 201803010096.