Enfortumab Vedotin and Hyperglycemia
Yes, enfortumab vedotin can cause hyperglycemia, which can be severe and potentially lead to diabetic ketoacidosis in some patients. 1
Evidence for Hyperglycemia with Enfortumab Vedotin
- Hyperglycemia is explicitly listed as a significant adverse effect in the FDA label for PADCEV (enfortumab vedotin), with a specific warning that diabetic ketoacidosis may occur in patients with and without preexisting diabetes mellitus, which may be fatal 1
- In the EV-302/KEYNOTE-39A trial, grade 3 hyperglycemia occurred in 6.1% of patients treated with enfortumab vedotin plus pembrolizumab 2
- The European Association of Urology guidelines (2025) specifically list hyperglycemia as one of the key toxicities of enfortumab vedotin, alongside rash, neuropathy, and ocular disorders 2
- In the EV-201 Cohort 2 trial, hyperglycemia was reported in 16% of patients, with grade 3-4 hyperglycemia occurring in 9% of patients 1
- Laboratory abnormalities from clinical trials show increased glucose (non-fasting) in 33-36% of patients, with grade 3-4 elevations in 9-13% of patients 1
Mechanism and Risk Factors
- While the exact mechanism is not fully elucidated in the evidence provided, case reports suggest that enfortumab vedotin may cause insulin resistance 3, 4
- Patients with pre-existing diabetes may be at higher risk, as demonstrated in case reports where patients with diabetes experienced severe hyperglycemia after enfortumab vedotin administration 4
- However, hyperglycemia and even diabetic ketoacidosis can occur in patients without pre-existing diabetes 5
Severity and Clinical Implications
- Hyperglycemia with enfortumab vedotin can range from mild elevations to severe, potentially fatal diabetic ketoacidosis 1, 5
- Case reports describe instances of severe insulin resistance, diabetic ketoacidosis, and acute kidney injury associated with enfortumab vedotin treatment 3, 4, 5
- One case report described a patient with no prior history of diabetes who developed fatal diabetic ketoacidosis after the second dose of enfortumab vedotin, despite aggressive treatment 5
Management Recommendations
- The FDA label recommends closely monitoring blood glucose levels in patients with, or at risk for, diabetes mellitus or hyperglycemia 1
- Withhold enfortumab vedotin if blood glucose is >250 mg/dL 1
- Patients with uncontrolled diabetes may be ineligible for enfortumab vedotin treatment, according to the European Association of Urology guidelines 2
- For patients who develop hyperglycemia while on enfortumab vedotin, management should follow standard protocols for hyperglycemia, with metformin typically used as first-line therapy for mild cases 6, 7
- For severe hyperglycemia (blood glucose ≥250 mg/dL), insulin therapy may be required 7
Clinical Pearls and Pitfalls
- Pitfall to avoid: Failing to screen for and monitor blood glucose in patients receiving enfortumab vedotin, especially those with risk factors for diabetes 8
- Pitfall to avoid: Underestimating the potential severity of hyperglycemia, which can progress rapidly to diabetic ketoacidosis even in patients without pre-existing diabetes 5
- Clinical pearl: Consider baseline diabetes screening before initiating enfortumab vedotin therapy 5
- Clinical pearl: Educate patients about symptoms of hyperglycemia and the importance of reporting them promptly 8
- Clinical pearl: Have a lower threshold for hospital admission for patients on enfortumab vedotin who develop significant hyperglycemia, as it may progress rapidly 5
Despite the risk of hyperglycemia, enfortumab vedotin (particularly in combination with pembrolizumab) remains a preferred treatment option for eligible patients with advanced urothelial cancer due to its significant survival benefits 2.