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Aims: In patients with diabetes treated with sunitinib symptomatic hypoglycaemia has been reported. To explore the mechanism of this adverse effect we performed a prospective study to investigate the effect of sunitinib on insulin concentration, insulin clearance and insulin sensitivity., Methods: We studied the early effects of sunitinib on insulin sensitivity and insulin clearance with a hyperinsulinaemic euglycaemic clamp (insulin infusion rate 60 mU m−2 min−1; steady-state 90–120 min) in patients with renal cell carcinoma before and 1 week after the start of sunitinib 50 mg day−1. Insulin sensitivity index (SI) was defined as steady-state glucose disposal divided by the steady-state plasma insulin., Results: Ten patients (one with diabetes, treated with metformin) were included in the study protocol. Steady-state insulin concentrations during the clamp increased after 1 week of sunitinib (from 128.9 ± 9.0 mU l−1 to 170.8 ± 12.8 mU l−1, P < 0.05; 95% CI on difference − 64.3, −19.6). The calculated insulin sensitivity index decreased from 0.22 ± 0.04 before to 0.18 ± 0.02 μmol kg−1 min−1 per mU l−1 insulin (P < 0.05; 95% CI on difference 0.07, 0.08). As the insulin infusion rate was similar for both clamps, the increased steady-state insulin concentration indicates reduced insulin clearance., Conclusion: Sunitinib affects insulin clearance which could possibly lead to overexposure to insulin in patients using insulin or insulin-secretion stimulating agents.

Background: Tyrosine kinase inhibitors targeting angiogenesis have become an important part of the treatment of patients with several types of cancer. One of the most reported side effects of vascular endothelial growth factor receptor (VEGFR)-targeted therapies is hypertension. In this study, we hypothesized that the development of hypertension in patients treated with sunitinib, a multitargeted tyrosine kinase inhibitor, is preceded by reduced endothelium-dependent vasodilation. Moreover, we hypothesized that this endothelial dysfunction is a result of impaired nitric oxide release., Method: In a placebo-controlled experiment, we determined vascular responses in isolated mesenteric arteries of rats (n = 26) after 7 days of sunitinib treatment., Results: Sunitinib reduced endothelium-dependent vasodilation, but not endothelium-independent vasodilation. Moreover, we observed that the difference in endothelium-dependent vasodilation between controls and sunitinib-treated animals disappeared in the presence of N-nitro-L-arginine methyl ester (L-NAME), a nitric oxide antagonist. In patients with metastatic renal cell carcinoma, before and 1 week after start of sunitinib, the endothelium-dependent vasodilator response to intra-arterial acetycholine and the endothelium-independent vasodilator response to intra-arterial sodium nitroprusside was assessed with venous occlusion plethysmography. No changes in forearm blood flow ratios were observed. Mean arterial pressure did significantly increase from 101.9 ± 3.8 to 106.1 ± 2.6 mmHg after 1 week and further to 115.8 (±4.9) mmHg after 2 weeks of treatment., Conclusion: In animals, this study confirms that exposure to high concentrations of sunitinib reduces endothelium-dependent vasodilation by reducing endothelial release of nitric oxide. In humans, however, reduced endothelium-dependent vasodilation does not precede the development of hypertension in patients treated with sunitinib.

Concerns have been raised about the development of heart failure in patients treated for cancer with angiogenesis inhibitors, such as the tyrosine kinase inhibitor sunitinib. Patients with previous coronary artery disease and hypertension have an increased risk of developing heart failure. Therefore, we studied the effect of sunitinib on the contractility of isolated human atrial trabeculae and the effect on recovery after ischemic stimulation. After informed consent, the atrial appendage of patients undergoing cardiac surgery was harvested and isolated trabeculae were placed in an organ bath with a force transducer. During electrical stimulation, contractile force was measured during normal pacing or after simulated ischemia. Of each patient, one trabecula was perfused with control and one with sunitinib. Contractile force (expressed as percentage of baseline force) declined over time to 57 ± 8 and 73 ± 20% after 150 min of stimulation for solvent- and sunitinib-treated trabeculae, respectively (mean ± SE; n = 8; p > 0.1). After simulated ischemia and reperfusion, contractile force was 40 ± 6% in the control compared to 39 ± 6% in the sunitinib-treated trabeculae during the last final 5 min of reperfusion (n = 12; p > 0.1). Sunitinib at low, but clinically relevant, concentrations does not have a direct effect on function of human atrial cardiomyocytes nor does it attenuate the recovery in contractile force of atrial cardiomyocytes after a period of ischemia. A direct and acute toxic effect on cardiomyocytes does not explain the development of heart failure in patients treated with sunitinib.