Glucagon-like peptide-1 receptor agonism and end-organ protection

Identification of exendin-4 (a glucagon-like peptide-1 receptor agonist, GLP-1RA) in Gila monster venom may be regarded as one of the most serendipitous discoveries of recent times.GLP-1RAs are now an established therapeutic approach in type 2 diabetes (T2D), body weight management, and cardiovascular (CV) risk protection.Furthermore, there is a growing platform of evidence that GLP-1RA has extended benefit in renal, hepatic, respiratory, and neurological diseases.One can speculate on the biological advantage of exendin-4 to the Gila monster, but for humankind GLP-1RAs are peptides with significant potential to improve disease-related outcomes.We report on the latest evidence and mechanisms for GLP-1RA-mediated end-organ protection that uniquely highlight its future development potential across multiple disease areas. Glucagon-like peptide-1 (GLP-1) physiology and drug developmentGLP-1, a peptide consisting of 30 amino acids in humans, was first recognised to reduce plasma glucose levels following a mealthe 'incretin effect'.GLP-1 potentiates glucosedependent insulin secretion, suppresses glucagon secretion, and delays gastric emptying to limit fasting and postprandial glucose excursions (Figure 1).Additional physiological actions of GLP-1 via parasympathetic nerves and central effects on hypothalamic nuclei and other brain regions have been shown to promote satiety, reduce appetite, and modulate food preference, thereby contributing to body weight reduction 1.These centrally mediated effects of GLP-1 on food intake may be complemented by delayed gastric emptying and gut relaxation, which have been suggested to promote satiety and prevent overeating 2, although these effects have not been consistently reported in all studies 3.Together, these physiological actions of GLP-1 formed the rationale for developing GLP-1RAs for the treatment of T2D 4 and subsequent exploration of higher dose ranges established their utility in body weight management 5.Induction of negative energy balance with body weight reduction may partly contribute to blood pressure (BP) and lipid lowering which are also observed with GLP-1RA therapy 6,7.Interestingly, short and long-acting injectable peptide GLP-1RAs (Table 1) differ with respect to their pharmacokinetic and pharmacodynamic profiles.GLP-1RAs with a short half-life exhibit a more dominant effect on gastric emptying and postprandial glucose reduction, whereas agents with longer halflives exert greater insulinotropic and glucagonostatic effects, leading to more prominent reduction of fasting glucose 4, overall improvement in glycaemic control 8, and in some cases more favourable tolerability 4,8,9.Gastrointestinal adverse events including nausea and vomiting are commonly observed with GLP-1RA therapy.Although there are limitations for symptom assessment in trials 10, meta-analyses have demonstrated that nausea