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Keywords:

  • blood pressure;
  • exenatide;
  • glucagon-like peptide-1;
  • haemodynamic;
  • natriuresis;
  • urinary sodium : creatinine ratio

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Large clinical trials show that chronic use of GLP-1 agonists cause a fall in blood pressure independent of weight loss. Animal studies have shown acute haemodynamic and vasodilator effects of these drugs. The exact mechanism of the blood pressure drop and acute cardiovascular effects has not been studied in humans.

WHAT THIS STUDY ADDS

• This study shows that exenatide also has acute haemodynamic effects in humans. This study demonstrates direct vascular effects and potentially direct cardiac effects. This will enable future studies to look at GLP-1 agonists as aids in the treatment of cardiovascular disease in type 2 diabetes.

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.