Immune checkpoint inhibitors and metabolic events: results from a European safety analysis

Background: Immune checkpoint inhibitors (ICIs) include programmed death-1 receptor (PD1) inhibitors, programmed death-ligand 1 (PDL1) inhibitors, and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitors. The use of ICIs has been associated with multiple endocrine immune-related adverse events. This study aims to describe Individual Case Safety Reports (ICSRs) of metabolic events reported in the European database (Eudravigilance, EV) and to compare the reporting frequency of metabolic effects between ICIs. Methods: A retrospective, European, pharmacovigilance study was conducted to evaluate ICSRs reporting metabolic events with ICIs between 2018 and 2022. Findings: A total of 6,220 ICSRs reporting an ICI as a suspected drug and at least one metabolic event were identified. The most reported ICI was pembrolizumab (N = 2,466; 39.6%), followed by nivolumab (N = 1,823; 29·3%). The most reported glycemic alteration was type 1 diabetes mellitus (N = 1,001; 13·2%), followed by diabetic ketoacidosis (N = 563, 7·4%). The use of anti-PD1 was associated with a higher reporting of type 1 diabetes mellitus than anti-CTLA4 (ROR, 4·85; 95%CI, 1·56 − 15·09) and anti-PDL1 (ROR, 1·74; 95%CI, 1·41 − 2·13), while no difference was found between anti-PDL1 and anti-CTLA4 (Fig. 4A). Moreover, anti-PD1 was associated with a higher reporting of type 2 diabetes than anti-PDL1 (ROR, 2·06; 95%CI, 1·03–4·10). In addition, the reporting probability of type 1 diabetes mellitus was higher with age ≥ 65 years than < 65 years (ROR, 15·74; 95%CI, 10·44 − 23·73), while no significant difference was found for type 2 diabetes mellitus. Interpretation: In conclusion, the use of anti-PD1 has been associated with higher reporting of both type 1 and type 2 diabetes. Larger longitudinal studies are needed to interpret these reports and to advance hypotheses of pathogenetic mechanisms of this association.