Increased Risk of Hyperglycemia in Advanced Urothelial Cancer Patients Treated with Enfortumab Vedotin: A Systematic Review and Meta-Analysis

Background: Enfortumab vedotin, an anti-nectin-4 antibody-drug conjugate, is a key treatment for advanced urothelial cancer. However, hyperglycemia, a major adverse event, varies in incidence and can progress to diabetic ketoacidosis. We conducted a systematic review and meta-analysis to quantify the risk of hyperglycemia with enfortumab vedotin. Material and methods: We searched studies published through September 30, 2024. Eligible clinical trials evaluated enfortumab vedotin as a monotherapy or combined with pembrolizumab. Pooled incidence and relative risk of hyperglycemia were calculated using random- or fixed-effects models. Results: Seven studies with 2,138 patients were included in our analysis. The summary incidence of all-grade hyperglycemia was 10.3% (95% CI: 8.6–12.2%), and high-grade hyperglycemia occurred in 5.7% (95% CI: 4.5–7.1%) of patients. No significant difference was observed between monotherapy and combination therapy (p = 0.16). Enfortumab vedotin significantly increased the risk of all-grade (RR = 16.97, 95% CI: 6.22–48.25, p < 0.001) and high-grade hyperglycemia (RR = 34.78, 95% CI: 4.77–253.43, p < 0.001). Conclusion: Enfortumab vedotin is associated with a significantly increased risk of all-grade and high-grade hyperglycemia in urothelial cancer. Its combination with pembrolizumab does not appear to elevate this risk further. Routine glucose monitoring and early intervention should be implemented, particularly in high-risk patients.