Investigation of the haemodynamic effects of exenatide in healthy male subjects

Abstract

Aims: In clinical studies of glucagon-like peptide-1 (GLP-1) agonists used in the management of patients with type 2 diabetes, there is often a small accompanying fall in blood pressure. The mechanism underlying this effect is not known, although exenatide, a GLP-1 mimetic, has acute regional vasodilator properties in rats. We have therefore studied the haemodynamic effects of exenatide in healthy male volunteers.

Methods: We compared the effects of a single 10 µg subcutaneous injection of exenatide with placebo in a double-blind, randomized, crossover study. For 2 h after dosing, haemodynamic measurements were made using a Finometer, venous occlusion plethysmography and Doppler ultrasound. The urine sodium : creatinine excretion ratio was determined.

Results: At the end of the study when exenatide was compared with placebo, heart rate had risen by a mean of 8.2 (95% CI 4.2, 12.2, P < 0.01) beats min(-1) , cardiac output by a mean of 1.2 (95% CI 0.42, 20.3, P < 0.05) l min(-1) and total peripheral resistance had fallen by 120 (95% CI -8, -233, P < 0.05) dyn s cm(-5) .There were no differences in blood pressure. The urinary sodium : creatinine ratio was increased by mean 12.4 (95% CI 4.6, 20.2, P < 0.05) mmol mmol(-1) when exenatide was compared with placebo.

Conclusions: Exenatide has significant haemodynamic effects in healthy volunteers. The results of this study are consistent with exenatide having both vasodilator and natriuretic properties. The vascular changes may contribute to the hypotensive effect of exenatide when used chronically in patients with diabetes.