Possible mechanisms of action of glucagon-like peptide-1 receptor agonists on blood pressure beyond body weight.

Glucagon-like petide-1 (GLP-1) potentiates insulin and suppresses glucagon secretion from the pancreas in response to the ingestion of nutrients. Due to a short plasma half-life of native GLP-1, several synthesized GLP-1 receptor agonists (RAs) were developed for type 2 diabetes mellitus (DM) treatment. In clinical trials, GLP-1 RAs were shown to significantly lower blood pressure (BP) in addition to HbA1c and body weight (BW), indicating the possibility as anti-hypertensive medication of type 2 DM individuals. Although the hypotensive effect of GLP-1 RAs seems to be manifested by BW losing, other mechanisms not related to BW might be implied by the mediation meta-analysis, which suggests an existence of BW-independent hypotensive effect of GLP-1 RA, along with the clinical evidence of weak or no correlations, and difference in time course between BP lowering and BW reducing effects. Both human and animal studies reported inconsistent BP response to acute administration but showed hypotensive effect of chronic administration of GLP-1/ GLP-1 RAs. As for the mechanisms of hypotensive effect beyond BW, augmentation of natriuresis by inhibiting sodium hydrogen exchanger at proximal tubule, ameliorating angiotensin II activity, and enhancing vasodilation can be postulated. Since GLP-1 RAs improve both morning surge and nocturnal hypertension, they are expected as promising remedies for morning hypertension. GLP-1 RAs exert three properties, that are glucose, BW and BP lowering actions, all of which are expected to exert potent and coordinated effects for conquering noncommunicable diseases, including type 2 DM and hypertension.