Immune checkpoint inhibitor-related type 1 diabetes incidence, risk, and survival association

Abstract

Aim/introduction: Although immune checkpoint inhibitor-related type 1 diabetes mellitus (ICI-T1DM) is a rare condition, it is of significant concern globally. We aimed to elucidate the precise incidence, risk factors, and impact of ICI-T1DM on survival outcomes.

Materials and methods: The study is a large retrospective cohort study, performed using the DeSC Japanese administrative claims database comprising 11 million patients. The database population is reportedly similar to the entire population of Japan. Patients administered ICI between 2014 and 2022 were enrolled in the study, including 21,121 patients. The risk factors for ICI-T1DM development and their characteristics were evaluated by logistic regression analysis. Development of a new irAE after the day following the first administration of ICI was set as the study outcome.

Results: ICI-T1DM was observed in 102 (0.48%) of the 21,121 patients after ICI initiation. PD-(L)1 and CTLA-4 combination therapy was associated with an increased risk of ICI-T1DM compared with PD-1 monotherapy (odds ratio [OR], 2.36; 95% confidence interval [CI], 1.21-4.58; P = 0.01). Patients with a prior diagnosis of diabetes mellitus (OR, 1.59; 95% CI, 1.03-2.46; P = 0.04) or hypothyroidism (OR, 2.48; 95% CI, 1.39-4.43; P < 0.01) also exhibited an increased risk of ICI-T1DM. The Kaplan-Meier analysis revealed that patients with ICI-T1DM showed higher survival rates than those without (log-lank test, P < 0.01). Multivariable Cox regression analysis demonstrated that ICI-T1DM development was associated with lower mortality (hazard ratio, 0.60; 95% CI, 0.37-0.99; P = 0.04).

Conclusions: Collectively, the results of this study demonstrate the precise incidence and risk factors of ICI-T1DM. The development of ICI-T1DM, like other irAEs, is associated with higher survival rates.

Keywords: Immune checkpoint inhibitors; Survival; Type 1 diabetes mellitus.

Figure 1

Study design. From a total of 21,185 patients receiving ICI in the Japanese administrative claims database, we excluded patients who were diagnosed with type 1 diabetes mellitus prior to ICI administration and those without medical records after the first ICI administration. Eventually, 21,121 patients with ICI administration were included in the analysis.

Figure 2

Forest plot of factors associated with ICI‐T1DM risk (logistic regression analysis). Multivariable analysis was performed using age, sex, ICI type, tumor type, past medical history, steroid administration, prognostic score, and immune‐related adverse events as covariates. Lung cancer was the most common primary disease (54.1% of all study patients) and was therefore used as a reference for the tumor types. Anti‐PD‐(L)1 and anti‐CTLA‐4 combination therapy and a prior diagnosis of diabetes mellitus and hypothyroidism showed a higher risk of ICI‐T1DM. CI, confidence interval; CTLA‐4, cytotoxic T lymphocyte antigen 4; ICI, immune checkpoint inhibitor; ICI‐T1DM, immune checkpoint inhibitor‐related type 1 diabetes mellitus; PD‐1, programmed cell death 1; PD‐L1, programmed cell death ligand 1.

Figure 3

Kaplan–Meier survival curve of patients with or without ICI‐T1DM. Patients with ICI‐T1DM showed superior overall survival compared with those without ICI‐T1DM (P < 0.01, log‐rank test) with 1‐year overall survivals of 89.9 ± 3.4% vs 76.7 ± 0.4%, respectively (P < 0.01; estimated value ± SE, with vs without ICI‐T1DM). ICI‐T1DM, immune checkpoint inhibitor‐related type 1 diabetes mellitus.

Figure 4

Forest plot of factors associated with mortality risk (Cox regression analysis). Cox regression analysis adjusted for the number of ICI doses and duration of ICI administration was performed using age, sex, ICI type, tumor type, past medical history, prognostic score, and immune‐related adverse events as covariates. Lung cancer was the most common primary disease (54.1% of all study patients) and was therefore used as a reference for the tumor types. ICI‐related hypothyroidism and adrenal insufficiency showed a decreased mortality. In addition, the development of ICI‐T1DM showed a decreased mortality. CCI, Charlson Comorbidity Index; CI, confidence interval; ICI, immune checkpoint inhibitor; ICI‐T1DM, immune checkpoint inhibitor‐related type 1 diabetes mellitus.