Comparative Effectiveness of GLP-1 Receptor Agonists on Patients with Diabetic Kidney Disease：a Network Meta-analysis postprint

Abstract: Background　Diabetic nephropathy is one of the microvascular complications of diabetes mellitus，which significantly impacts the quality of life of patients. Owing to abnormal renal function，the application of traditional hypoglycemic medications is severely restricted. At present，GLP-1 receptor agonists not only play a role in lowering blood glucose but also exhibit multiple beneficial effects，including renal protection. Nevertheless，considering the numerous types of GLP-1 receptor agonists available，there is a dearth of relevant clinical evidence-based medical data to assess the relative advantages and disadvantages of the therapeutic effects of different GLP-1 receptor agonists. Objective　To systematically assess the therapeutic effects of various GLP-1 receptor agonists on renal function，proteinuria，and glycemic control in patients with diabetic kidney disease. Methods　A comprehensive literature search was conducted across multiple electronic databases，including PubMed，Embase，the Cochrane Library，China National Knowledge Infrastructure（CNKI），Wanfang Data Knowledge Service Platform，VIP Database，and Sinomed. The search strategy combined both subject headings and free-text terms，with retrieval limited to the period from database inception up to March 16，2025. Randomized controlled trials evaluating the use of various GLP-1 receptor agonists in the treatment of diabetic nephropathy were included. In the experimental groups，patients received GLP-1 receptor agonist therapy，whereas control groups were administered either another GLP-1 receptor agonist or standard conventional treatment. Network meta-analysis and graphical visualization were performed using Stata 16.0 software. The relative efficacy rankings of different GLP-1 receptor agonists across outcome measures were assessed using the surface under the cumulative ranking curve（SUCRA） analysis. Results　A total of 27 studies involving 6 939 patients were included，encompassing seven GLP-1 receptor agonists：exenatide，dulaglutide，semaglutide，liraglutide，polyethylene glycol lovenatide，benaglutide，and apirutide. The results of the network meta-analysis indicated that，the estimated glomerular filtration rate（eGFR） levels of exenatide（WMD=10.21，95%CI=3.09-17.34），polyethylene glycol lovenatide（WMD=9.76，95%CI=1.07-18.46），and liraglutide（WMD=7.13，95%CI=2.79-11.47） were significantly higher than those of conventional standard therapy（all P<0.05）. The serum creatinine（Scr） levels of semaglutide（WMD=-24.03，95%CI=-47.72 to -0.33），exenatide（WMD=-17.55，95%CI=-32.68 to -2.42），and liraglutide（WMD=-10.92，95%CI=-19.05 to -2.80）were significantly lower than those of conventional standard therapy（all P<0.05）. Exenatide was also associated with a lower UACR level compared to traditional standard treatment（WMD=-192.45，95%CI=-353.07 to -31.83；P<0.05）. Regarding UAER reduction，dulaglutide（WMD=-228.51，95%CI=-282.19 to -174.83），exenatide（WMD=-159.67，95%CI=-295.06 to -24.28），liraglutide（WMD=-34.24，95%CI=-47.58 to -20.90），and benaglutide（WMD=-16.68，95%CI=-32.05 to -1.30） showed significantly greater reductions than the control（all P<0.05）. Furthermore，dulaglutide exhibited a significantly lower UAER level than liraglutide（WMD=-194.27，95%CI=-249.58 to -138.96；P<0.05），and both dulaglutide（WMD=-211.83，95%CI=-267.67 to -156.00）and exenatide（WMD=-142.99，95%CI=-279.26 to -6.73）outperformed benaglutide（P<0.05）. Duraglutide（WMD=-2.44，95%CI=-4.05 to -0.83），semaglutide（WMD=-2.00，95%CI=-3.80 to -0.20），and liraglutide （WMD=-0.93，95%CI=-1.64 to -0.22）were associated with significantly lower FPG levels compared to conventional standard therapy（all P<0.05）. Additionally，dulaglutide demonstrated a lower FPG level than apirutide（WMD=-2.34，95%CI=-4.58 to -0.10；P<0.05）. Compared with conventional standard therapy，polyethylene glycol lovenatide（WMD=-1.22，95%CI=-2.09 to -0.35），semaglutide（WMD=-0.81，95%CI=-1.41 to -0.21），and liraglutide（WMD=-0.60，95%CI=-0.87 to -0.34）showed significantly better glycemic control（all P<0.05）. According to SUCRA rankings，exenatide ranked highest in delaying the decline of eGFR and reducing UACR. Semaglutide ranked first in reducing Scr，dulaglutide in reducing UAER and FPG，and pegylated lovenatide in HbA1c reduction. Conclusion　A network meta-analysis was conducted to compare the efficacy of seven GLP-1 receptor agonists，and it was found that dulaglutide may be the best choice in reducing urinary albumin excretion rate and controlling fasting blood glucose. There was no significant difference in the improvement of renal function among different GLP-1 receptor agonists. In the future，more high-quality randomized controlled trials with larger sample sizes and more comprehensivetypes of drugs are needed to verify the results.