Table 2_Islet function impairment outcomes of immune checkpoint inhibitors in cancer patients: a systematic review and meta-analysis.docx

BackgroundImmune 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.
MethodsFollowing 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).
ResultsA 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.
ConclusionsICPis 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 registrationhttps://www.crd.york.ac.uk/PROSPERO/myprospero, identifier CRD42025639629

背景：免疫检查点抑制剂（Immune checkpoint inhibitors, ICPis）与胰岛功能损害（Islet function impairment, IFI）相关，临床表现为高血糖、糖尿病（Diabetes mellitus, DM）或糖尿病酮症酸中毒（Diabetic ketoacidosis, DKA）。若检测与干预不及时，可能导致不可逆的β细胞损伤及危及生命的并发症。本研究开展系统评价与荟萃分析，旨在评估免疫检查点抑制剂相关胰岛功能损害的发病风险。
方法：遵循PICOS原则，检索PubMed、Embase、Cochrane、中国知网（CNKI）、万方数据、中国生物医学文献数据库（CBM）及维普资讯（VIP）自建库至2024年10月24日的相关文献。纳入对比免疫检查点抑制剂与非免疫检查点抑制剂治疗方案的癌症患者随机对照试验（Randomized Controlled Trial, RCT）。结局指标包括高血糖、糖尿病及糖尿病酮症酸中毒。采用固定效应或随机效应模型合并风险比（Risk Ratio, RR）及95%置信区间（Confidence Interval, CI）。使用Cochrane偏倚风险工具评价研究质量，通过Begg检验评估发表偏倚。本研究方案已在PROSPERO平台注册（注册号：CRD42025639629）。
结果：本研究共纳入31项随机对照试验，涉及15417例患者。结果显示，与非免疫检查点抑制剂治疗组相比，免疫检查点抑制剂治疗显著升高胰岛功能损害的发病风险（RR=1.30，95%CI：1.10~1.53，P=0.002），同时升高3~5级不良反应的发病风险（RR=2.20，95%CI：1.50~3.23，P<0.0001）及1型糖尿病（Type 1 Diabetes Mellitus, T1DM）的发病风险（RR=3.38，95%CI：1.66~6.88，P=0.0008）。亚组分析显示，与非免疫检查点抑制剂组相比，PD-1抑制剂组及帕博利珠单抗（Pembrolizumab）组的胰岛功能损害发病率显著升高（RR=1.57，95%CI：1.22~2.01，P=0.0005；RR=2.38，95%CI：1.43~3.97，P=0.0009）；非小细胞肺癌（Non-Small Cell Lung Cancer, NSCLC）患者接受免疫检查点抑制剂治疗后，胰岛功能损害发病风险显著高于非免疫检查点抑制剂对照组（RR=1.32，95%CI：1.01~1.72，P=0.04）。与各自的非免疫检查点抑制剂对照组相比，免疫检查点抑制剂联合化疗的胰岛功能损害风险点估计值（RR=1.23）低于免疫检查点抑制剂单药治疗组（RR=1.43）；3~5级胰岛功能损害亦呈现相似趋势（RR=1.53 vs 3.39）。未检测到显著发表偏倚。
结论：免疫检查点抑制剂可显著升高胰岛功能损害的发病风险，尤其是1型糖尿病及重度（3~5级）不良事件。PD-1抑制剂及非小细胞肺癌患者属于高风险亚组。本研究强烈推荐开展多学科监测及积极的血糖管理。
系统评价注册信息：https://www.crd.york.ac.uk/PROSPERO/myprospero，注册号CRD42025639629