ImportanceImmune checkpoint inhibitors (ICIs) have revolutionized cancer care; however, accompanying immune-related adverse events (irAEs) confer substantial morbidity and occasional mortality. Life-threatening irAEs may require permanent cessation of ICI, even in patients with positive tumor response. Therefore, it is imperative to comprehensively define the spectrum of irAEs to aid individualized decision-making around the initiation of ICI therapy.ObjectiveTo define incidence, risk factors, and clinical spectrum of an irreversible and life-threatening irAE: ICI-induced diabetes.Design, Setting, and ParticipantsThis cohort study, conducted at an academic integrated health care system examined 14 328 adult patients treated with ICIs, including 64 patients who developed ICI-induced diabetes, from July 2010 to January 2022. The data were analyzed from 2022 to 2023. Cases of ICI-induced diabetes were manually confirmed; detailed clinical phenotyping was performed at diagnosis and 1-year follow-up. For 862 patients, genotyping data were available, and polygenic risk for type 1 diabetes was determined.Main Outcomes and MeasuresFor ICI-induced diabetes cases and controls, demographic characteristics, comorbidities, tumor category, and ICI category were compared. Among ICI-induced diabetes cases, markers of glycemic physiology were examined at diagnosis and 1-year follow-up. For patients with available genotyping, a published type 1 diabetes polygenic score (T1D GRS2) was calculated.ResultsOf 14 328 participants, 6571 (45.9%) were women, and the median (range) age was 66 (8-106) years. The prevalence of ICI-induced diabetes among ICI-treated patients was 0.45% (64 of 14 328), with an incidence of 124.8 per 100 000 person-years. Preexisting type 2 diabetes (odds ratio [OR], 5.91; 95% CI, 3.34-10.45) and treatment with combination ICI (OR, 2.57; 95% CI, 1.44-4.59) were significant clinical risk factors of ICI-induced diabetes. T1D GRS2 was associated with ICI-induced diabetes risk, with an OR of 4.4 (95% CI, 1.8-10.5) for patients in the top decile of T1D GRS2, demonstrating a genetic association between spontaneous autoimmunity and irAEs. Patients with ICI-induced diabetes were in 3 distinct phenotypic categories based on autoantibodies and residual pancreatic function, with varying severity of initial presentation.Conclusions and RelevanceThe results of this analysis of 14 328 ICI-treated patients followed up from ICI initiation determined the incidence, risk factors and clinical spectrum of ICI-induced diabetes. Widespread implementation of this approach across organ-specific irAEs may enhance diagnosis and management of these conditions, and this becomes especially pertinent as ICI treatment rapidly expands to treat a wide spectrum of cancers and is used at earlier stages of treatment.

中文翻译：

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免疫检查点抑制剂诱导的糖尿病的鉴定


重要性免疫检查点抑制剂 （ICI） 彻底改变了癌症护理;然而，伴随的免疫相关不良事件 （irAEs） 会导致大量的发病率和偶尔的死亡率。危及生命的 irAE 可能需要永久停止 ICI，即使在肿瘤反应阳性的患者中也是如此。因此，必须全面定义 irAE 的范围，以帮助围绕 ICI 治疗的开始做出个体化决策。目的定义不可逆且危及生命的 irAE 的发病率、危险因素和临床谱：ICI 诱发的糖尿病。设计、设置和参与者这项队列研究在学术综合医疗保健系统进行，检查了 2010 年 7 月至 2022 年 1 月期间接受 ICI 治疗的 14 328 名成年患者，其中包括 64 名患上 ICI 诱发糖尿病的患者。对 2022 年至 2023 年的数据进行了分析。人工确认 ICI 诱发的糖尿病病例;在诊断和 1 年随访时进行详细的临床表型分析。对于 862 例患者，有基因分型数据，并确定了 1 型糖尿病的多基因风险。主要结局和指标对于 ICI 诱导的糖尿病病例和对照，比较人口学特征、合并症、肿瘤类别和 ICI 类别。在 ICI 诱导的糖尿病病例中，在诊断和 1 年随访时检查血糖生理标志物。对于具有可用基因分型的患者，计算已发表的 1 型糖尿病多基因评分 （T1D GRS2）。结果在 14 328 名参与者中，6571 名 （45.9%） 为女性，中位 （范围） 年龄为 66 （8-106） 岁。在 ICI 治疗患者中，ICI 诱发的糖尿病患病率为 0.45%（14 328 人中的 64 人），发病率为 124.8/100 000 人年。先前存在的 2 型糖尿病（比值比 [OR]，5.91;95% CI，3.34-10.45）和联合 ICI 治疗 （OR，2.57;95% CI，1.44-4.59） 是 ICI 诱导糖尿病的重要临床危险因素。T1D GRS2 与 ICI 诱导的糖尿病风险相关，T1D GRS2 前十分位数患者的 OR 为 4.4 （95% CI，1.8-10.5），表明自发性自身免疫与 irAEs 之间存在遗传关联。ICI 诱导的糖尿病患者根据自身抗体和残余胰腺功能分为 3 种不同的表型类别，初始表现的严重程度不同。结论和相关性对 14 328 例 ICI 治疗患者进行 ICI 开始随访的分析结果确定了 ICI 诱导的糖尿病的发病率、危险因素和临床表现。在器官特异性 irAE 中广泛实施这种方法可能会加强对这些疾病的诊断和管理，随着 ICI 治疗迅速扩展到治疗广泛的癌症并用于治疗的早期阶段，这一点变得尤为重要。