A meta-analysis of the risk of adverse cardiovascular events in patients with cancer treated with inhibitors of the PI3K/AKT/mTOR signaling pathway

Background: With the increasing of PI3K/AKT/mTOR (PAM) inhibitors in cancer therapy, there is a growing need to understand the incidence of cardiovascular events (CVAEs) associated with PAM inhibitors. Methods: A systematic search of all randomized clinical trials (RCTs) containing at least one PAM group in electronic databases such as PubMed, ClinicalTrials.gov registry, Embase, Medline, Cochrane Library, and major conferences was performed to extract available CVAEs. The cut-off date was January 31, 2024. Study heterogeneity was assessed using the I ² statistic. The risk of CVAEs associated with PAM inhibitors was calculated using Peto OR. Main outcomes and measures: The primary outcome was the incidence (95% CI) of PAM inhibitors cardiovascular adverse events in the total population and subgroups. The secondary outcome was the pooled risk of different CVAEs associated with PAM inhibitor exposure in the RCTs. Results: 33 unique RCTs (n=12,351) were included. The incidence of PAM inhibitors CVAEs of any grade in the intervention group was 48.2%, yielding a combined OR of 2.52 (95% CI, 1.82 - 3.49). The incidence of severe adverse cardiovascular events (≥ grade 3) in the intervention group was estimated at 7.1%, yielding a combined Peto OR of 1.41 (95% CI,1.04 - 1.93). PAM inhibitors were associated with an increased risk of 5 CVAEs including peripheral edema, lymphoedema, hypercholesterolemia, hypertriglyceridaemia and hyperlipidemia, with higher risks for hypercholesterolemia (Peto OR:3.27,95% CI:2.61-4.11, P<0.01; I ² = 55.5%，P=0.06) and hyperlipidemia (Peto OR:3.53. 95%CI:1.70-7.32, P<0.01; I ² = 19.3%，P=0.29). Conclusion: This study identified an overall incidence of PAM inhibitors CVAEs and the increased risks associated with PAM inhibitor for five specific CVAEs, not confined to hypercholesterolemia and peripheral edema.