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Lenvatinib, an oral multi-kinases inhibitor, -associated hypertension: Potential role of vascular endothelial
Daisuke Sueta1, Koichi Suyama2, Aiko Sueta3
1Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Background And Aims:
Lenvatinib (Lenvima®), an oral multi-kinase inhibitor, is effective in the treatment of differentiated thyroid carcinomas (DTCs). A severe adverse effect of lenvatinib is hypertension, thus limiting its use as an anti-cancer treatment. Although the pathogenesis of hypertension is generally assumed to involve microvascular bed reduction and an increase in peripheral vascular resistance due to a decrease in nitrogen oxide (NOx) production after vascular endothelial growth factor (VEGF) inhibition, the effects of hypertension on vascular endothelial function in actual patients remain unclear. Here, we examined how lenvatinib affects vascular endothelial function.
Methods:
Ten consecutive DTC patients who did not take any cardiovascular agents were orally administered 24 mg of lenvatinib once daily. Using an EndoPAT2000® system, we used reactive hyperemia-peripheral arterial tonometry (RH-PAT) and evaluated vascular endothelial function on the basis of the RH-PAT index (RHI). We expressed the results as %RHI, which indicates the change compared with pretreatment levels. Additionally, we measured serum NOx and plasma VEGF concentrations pre- and post-treatment.
Results:
All of the patients treated with lenvatinib exhibited significant hypertension; the %RHI levels were significantly decreased the day after treatment with lenvatinib. Furthermore, serum NOx and plasma VEGF concentrations were significantly decreased and increased, respectively, compared with pretreatment levels. These results indicate that hypertension induced by lenvatinib may be caused by a decrease in nitric oxide production, as a result of VEGF inhibition and impaired vascular endothelial function.
Conclusions:
We provide the first demonstration that lenvatinib causes hypertension via vascular endothelial dysfunction in human subjects.
Insights
Lenvatinib treatment for differentiated thyroid cancer causes hypertension by impairing vascular endothelial function and reducing nitric oxide production, linked to vascular endothelial growth factor inhibition.
Area of Science:
- Oncology
- Cardiovascular Research
- Pharmacology
Background:
- Lenvatinib is an effective oral multi-kinase inhibitor for differentiated thyroid carcinomas (DTCs).
- Hypertension is a severe adverse effect limiting lenvatinib's use.
- The precise mechanism of lenvatinib-induced hypertension on vascular endothelial function in patients is unclear.
Purpose of the Study:
- To investigate the impact of lenvatinib on vascular endothelial function in DTC patients.
- To elucidate the relationship between lenvatinib, hypertension, and endothelial function.
Main Methods:
- Ten DTC patients received 24 mg daily oral lenvatinib without cardiovascular agents.
- Vascular endothelial function was assessed using reactive hyperemia-peripheral arterial tonometry (RH-PAT) and the RH-PAT index (%RHI).
- Serum nitric oxide (NOx) and plasma vascular endothelial growth factor (VEGF) levels were measured pre- and post-treatment.
Main Results:
- All patients developed significant hypertension.
- A significant decrease in %RHI was observed the day after lenvatinib treatment.
- Serum NOx levels decreased, while plasma VEGF levels increased post-treatment.
Conclusions:
- Lenvatinib induces hypertension through vascular endothelial dysfunction in human subjects.
- The findings suggest that VEGF inhibition by lenvatinib leads to decreased nitric oxide production, contributing to hypertension.