A Novel Antihypertensive Effect of Exenatide, a GLP-1 Agonist

Exenatide, the first glucagon-like peptide-1 (GLP-1) receptor agonist to be licensed for clinical use, improves glycemia but also induces weight loss secondary to its action on the satiety and hunger mechanisms in the hypothalamus. In addition, in a retrospective study, it was observed that the administration of exenatide to obese type 2 diabetics had resulted in not only an improvement in glycemia and weight loss but also reductions in systolic blood pressure, plasma C-reactive protein (CRP), and triglyceride concentrations.1 The study by Okerson et al. in this issue, presents pooled data from 2,171 patients with type 2 diabetes from six trials investigating the effects of exenatide treatment on glycemia.2 The studies were not directed primarily to investigate an effect on blood pressure. However, it is clear from the data available from these studies that there was a consistent reduction in systolic blood pressure (2–3mmHg) following exenatide treatment when compared with either placebo or insulin treatment. The reductions in systolic BP were greater if the patients had systolic hypertension and were the greatest if the systolic blood pressure was >150mmHg (4.6–8.2mmHg). There was, however, no change in diastolic blood pressure. These patients thus had a significant reduction in pulse pressure: it was reduced by 3mm in those who had a pulse pressure of >40mmHg. A separate analysis of the African-American population included in these studies revealed similar results. Furthermore, the fall in systolic blood pressure could not be explained by weight loss and appeared to be independent of it. Since one major factor which increases systolic pressure is arterial stiffness, a study of the effect of exenatide on arterial pulse wave velocity is warranted. These beneficial effects of exenatide and other GLP-1 analogues have now been confirmed in several studies including those with liraglutide.3 All studies show a significant reduction in systolic blood pressure, CRP, and triglycerides. In view of their additional effect on weight loss, these agents may become the ideal treatment for the metabolic syndrome in future in patients with and without diabetes. In this context, it is of interest that liraglutide at a dose of 3mg daily (greater than the doses required for diabetic control) has now been shown to induce weight loss greater than that induced by orlistat.3 In addition to the actions stated above, GLP-1 infusion has been shown to be cardioprotective in patients with acute myocardial infarction. The mechanism underlying this action is not entirely clear. Its potential anti-inflammatory action may contribute to this. In addition, it may exert an antiapoptotic effect like insulin.4 In experimental models, these agents have been shown to exert beneficial cardiovascular effects as well.4 GLP-1 is a vasodilator, induces c-GMP and c-AMP release and protects cardiac myocytes from injury following ischemia-reperfusion.5 Clearly, there is far more to these drugs than meets the eye at this moment. They bring tremendous excitement to the field of diabetes, obesity, metabolic syndrome, and thus cardiovascular disease. The authors declared no conflict of interest.