Immune Checkpoint Inhibitor–Induced Diabetes Across National Cancer Institute Trials That Included PD-1 or PD-L1 Agents

Importance Immune-related adverse events (IRAEs) limit the use of cancer immunotherapy. Understanding the risk of severe IRAEs may help improve the use of cancer immunotherapy. Objective To review and assess hyperglycemic events across thousands of patients to characterize immune checkpoint inhibitor (ICI)–induced diabetes (ICI-D) using a large-scale trial conglomerate. Design, Setting, and Participants Adverse event (AE) reports related to diabetes, hyperglycemia, and acidosis were retrieved from the National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) database. Trial data from June 2015 to December 2022 were analyzed. Clinical information was manually retrieved. Overall counts of patients on each trial were retrieved from central NCI data. NCI CTEP trials are hosted in both academic and community medical centers. This analysis includes patients across 158 trials who were treated with varying regimens that included programmed cell death 1 protein (PD-1) or programmed cell death 1 ligand 1 (PD-L1) inhibitors through an NCI CTEP trial for their cancer from June 2015 to December 2022. Data clarifications were requested and then data were analyzed from January 2023 to June 1, 2025. Main Outcomes and Measures Clinical characteristics differentiating ICI-D from other causes of hyperglycemia were enumerated. Cumulative incidence rates of ICI-D were calculated using trial-level data. Logistic regression was used to calculate the odds of developing ICI-D. Results In 13 966 patients across 158 trials, the overall cumulative incidence of ICI-D was low (0.52 per 100 treated patients), but incidence varied by treatment type and was lower if patients were exposed to concurrent chemotherapy (0.65% without chemotherapy vs 0.26% with chemotherapy; odds ratio [OR], 0.38; 95% CI, 0.21-0.71; P = .002) and higher if patients were exposed to combined immunotherapy (0.94% with combination immunotherapy vs 0.37% with PD-1/PD-L1 inhibitor monotherapy; OR, 2.68; 95% CI, 1.69-4.24). Despite these low rates, the health care burden of ICI-D was high, with 90% requiring hospitalization at diagnosis and 43% requiring intensive care. The degree of hyperglycemia can be used to differentiate different etiologies of hyperglycemia, with higher glucose levels being more likely to be due to ICI-D. Conclusions and Relevance Results of this study suggest that ICI-D is a rare but morbid condition that varies based on the combination of ICIs with other agents.