Abstract
BACKGROUND: Immune checkpoint inhibitors (ICPis) are associated with islet function impairment (IFI), manifesting as hyperglycemia, diabetes mellitus (DM), or diabetic ketoacidosis (DKA). Delayed detection and management may lead to irreversible β-cell damage and life-threatening complications. We conducted a systematic review and meta-analysis to assess the risk of IFI associated with ICPis. METHODS: Following PICOS principles, we searched PubMed, Embase, Cochrane, CNKI, Wanfang, CBM, and VIP databases from inception to October 24, 2024. We included randomized controlled trials (RCTs) comparing ICPis versus non-ICPis regimens in cancer patients. Outcomes included hyperglycemia, DM, and DKA. Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using fixed- or random-effects models. Quality was assessed with the Cochrane Risk of Bias tool, and publication bias was evaluated by Begg's test. The protocol was registered with PROSPERO (CRD42025639629). RESULTS: A total of 31 RCT studies with 15,417 patients were included in this study. Results showed that ICPis treatment significantly increased the risk of associated IFI (RR = 1.30, 95%CI: 1.10-1.53, P = 0.002), the risk of grade 3-5 (RR = 2.20, 95%CI: 1.50-3.23, P < 0.0001) and type 1 diabetes (T1DM) (RR = 3.38, 95%CI: 1.66-6.88, P = 0.0008) compared to those treated with non-ICPis; Subgroup analysis showed that, compared with non-ICPis, the PD-1 inhibitor and Pembrolizumab groups significantly increased the incidence of developing IFI (RR = 1.57, 95%CI: 1.22-2.01, P = 0.0005; RR = 2.38, 95%CI: 1.43-3.97, P = 0.0009); Patients with NSCLC receiving ICPis had a significantly higher risk of developing IFI compared with non-ICPis (RR = 1.32, 95%CI: 1.01-1.72, P = 0.04). Compared to their respective non-ICPis controls, the point estimate for IFI risk was lower with ICPis plus chemotherapy (RR = 1.23) than with ICPis monotherapy (RR = 1.43); a similar pattern was observed for grade 3-5 IFI (RR = 1.53 vs. 3.39). No publication bias was detected. CONCLUSIONS: ICPis significantly increase the risk of IFI, particularly T1DM and severe (grade 3-5) events. PD-1 inhibitors and patients with NSCLC represent high-risk subgroups. We strongly recommend multidisciplinary monitoring and proactive blood glucose management. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/myprospero, identifier CRD42025639629.