| Background and Purpose Immune checkpoint inhibitors（ICPis）are a new class of anti-tumor drugs that are widely used in clinical practice and have significant effects.However,more and more studies have found that a series of immune-related adverse events were caused by the use of immune checkpoint inhibitors.The purpose of this meta-analysis was to evaluate the risk of endocrine adverse events caused by immune checkpoint inhibitors,including PD-1 inhibitors,PD-L1 inhibitors,and CTLA-4 inhibitors compared with control measures（chemotherapy,placebo,etc.）,and the risk of endocrine adverse events in patients with combination therapy of ICPis compared with monotherapy controls and the same ICPis of different doses.Method By searching the five major databases of Pubmed,Embase,Cochrane Library,Web of science,and CNKI,and using the PICOS principles,all randomized controlled trials（RCTs）on ICPis and endocrine adverse events were retrieved from January 2000 to July 2021.Relevant data were extracted and a meta-analysis was performed.Results 68 RCTs were finally included.Compared with the control groups,patients treated with PD-1 inhibitors appeared to be at higher risks of hypothyroidism [RR 7.13,95%CI（5.79-8.79）],hyperthyroidism [RR 8.54,95%CI（5.83-12.51）],and thyroiditis [RR 4.36,95%CI（2.05-9.26）],hypophysitis or hypopituitarism [RR 3.93,95%CI（1.90-8.11）],diabetes mellitus [RR 2.67,95%CI（1.20-5.94）],primary adrenal insufficiency [RR 2.82,95%CI（1.31-6.08）].Compared with control measures,PD-L1 inhibitors also increased the risk of hypothyroidism [RR 7.00,95%CI（4.81-10.18）] and hyperthyroidism [RR 6.60,95%CI（3.62-12.05）] in tumor patients,while there was no significant difference in the risk of thyroiditis and primary adrenal insufficiency.It was also found that patients treated with CTLA-4 inhibitors were at higher risks of hypothyroidism[RR 5.21,95%CI（2.69-10.11）],hypophysitis and hypopituitarism[RR24.29,95%CI（9.19-64.25）],and primary adrenal insufficiency[RR6.36,95%CI（1.17-34.67）].Compared with ICPis monotherapy,the risks of hypothyroidism [RR 1.76,95%CI（1.44-2.14）],hyperthyroidism [RR 3.81,95%CI（2.55-5.69）],thyroiditis [RR6.78,95%CI（2.53-18.14）],hypophysitis or hypopituitarism [RR 2.99,95%CI（1.89-4.72）],primary adrenal insufficiency [RR 3.55,95%CI（1.95-6.46）],diabetes mellitus [RR 4.99,95%CI（1.10-22.62）] were all increased.Patients with tumors who received high-dose ipilimumab had an increased risk of hypophysitis or hypopituitarism compared with those who received low-dose ipilimumab [RR 2.02,95% CI（1.16-3.52）],while there was no difference in the risk of these endocrine adverse events between high-dose pembrolizumab and low-dose pembrolizumab.Conclusions This meta-analysis showed that patients treated with ICPis were at increased risk of various endocrine adverse effects compared with control measures.Compared with ICPis monotherapy,patients receiving ICPis combination therapy were at increased risks of various endocrine adverse events.Ipilimumab caused a significant dose-response of hypophysitis or hypopituitarism in patients with tumors. |
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