Tirzepatide cardiovascular benefits and adverse events assessment: a Bayesian network meta-analysis

Abstract

Objective To comprehensively assess the cardiovascular benefits and adverse events of tirzepatide (including different control groups, different dosages and different patients). Method A systematic search was conducted on PubMed, Web of Science,The Cochrane Library and ClinicalTrials.gov. Randomized controlled trials (RCTs) of at least 26 weeks that compared tirzepatide (TZP) at doses of 5mg, 10mg, and 15 mg once weekly with another antihyperglycemic drug or placebo in adults with obesity or type 2 dabetes mellitus(T2DM) were included. Data Synthesis was performed using R 4.2.2 and Stata 18.0 software. Each outcome was presented as a relative risk (RR) with a 95% confidence interval (CI). The results were also displayed using network plots, the surface under the cumulative ranking curve value (SUCRA), league table and forest plot. Results A total of 14 RCTs with 14654 participants with T2DM or obesity were included inthis study. Generally, compared to placebo, insulin and glucagon-like peptide-1 receptor agonists (GLP-1RAs), TZP did not increase the risk of four-component major adverse cardiovascular events (MACE-4) (RR [95% CI], 0.54[0.25 to 1.06], 0.85 [0.45 to 1.81], 1.00 [0.34 to 2.92], respectively) and significantly increased total adverse events(TAEs)(RR[95% CI], 1.09[1.01,1.19], 1.22 [1.11,1.35], 1.03 [0.91,1.16], respectively). Compared to placebo, TZP 5mg, TZP 10mg and TZP 15mg all reduced the incidence of MACE-4 (RR [95% CI], 0.47 [0.23 to 1.12], 0.46 [0.15 to 1.48], 0.38 [0.17 to 0.84], respectively) and increased the risk of TAEs (RR[95% CI] 1.04[0.96,1.13], 1.07[0.99,1.16], 1.10[1.02,1.19], respectively). Compared to GLP-1 RAs, TZP 5 mg, TZP 10 mg, and TZP 15 mg all increased the risk of TAEs(RR [95% CI], 1.01[0.91,1.11], 1.04[0.94,1.14], 1.07[0.97,1.17], respectively) and TZP 15mg reduced the risk of MACE-4 (0.82 [0.31 to 2.22]). Compared to obesity, patients with T2DM experienced greater benefits of MACE-4 (RR[95% CI], 0.44[0.04 to 2.65])and lower risk of TAEs (RR [95% CI], 0.95 [0.77 to 1.24]). Additionlay, TZP reduced all-cause death (ACD) and serious adverse events(SAEs) but increased the risk of DAEs. And these benefits were not superior to those of GLP-1RAs, while the risk of adverse events leading to discontinuation of study treatment (DAEs) was higher than that of GLP-1RAs. TZP 15mg was more effective in reducing ACD and SAEs, but also increased the risk of discontinuation. among patients who use TZP, T2DM patients had greater benefits in ACD and less risk of SAEs and DAEs compared to obeity patients. Conclusions TZP is not inferior to GLP-1 RAs in reducing cardiovascular events. The effect is greater with TZP 15mg, but there are also more adverse events. Additionally, the use of TZP in T2DM patients may have a greater effect and fewer adverse events than in obesity patients.