GLP-1 physiology informs the pharmacotherapy of obesity

Abstract

Background: Glucagon-like peptide-1 receptor agonists (GLP1RA) augment glucose-dependent insulin release and reduce glucagon secretion and gastric emptying, enabling their successful development for the treatment of type 2 diabetes (T2D). These agents also inhibit food intake and reduce body weight, fostering investigation of GLP1RA for the treatment of obesity.

Scope of review: Here I discuss the physiology of Glucagon-like peptide-1 (GLP-1) action in the control of food intake in animals and humans, highlighting the importance of gut vs. brain-derived GLP-1 for the control of feeding and body weight. The widespread distribution and function of multiple GLP-1 receptor (GLP1R) populations in the central and autonomic nervous system are outlined, and the importance of pathways controlling energy expenditure in preclinical studies vs. reduction of food intake in both animals and humans is highlighted. The relative contributions of vagal afferent pathways vs. GLP1R+ populations in the central nervous system for the physiological reduction of food intake and the anorectic response to GLP1RA are compared and reviewed. Key data enabling the development of two GLP1RA for obesity therapy (liraglutide 3 mg daily and semaglutide 2.4 mg once weekly) are discussed. Finally, emerging data potentially supporting the combination of GLP-1 with additional peptide epitopes in unimolecular multi-agonists, as well as in fixed-dose combination therapies, are highlighted.

Major conclusions: The actions of GLP-1 to reduce food intake and body weight are highly conserved in obese animals and humans, in both adolescents and adults. The well-defined mechanisms of GLP-1 action through a single G protein-coupled receptor, together with the extensive safety database of GLP1RA in people with T2D, provide reassurance surrounding the long-term use of these agents in people with obesity and multiple co-morbidities. GLP1RA may also be effective in conditions associated with obesity, such as cardiovascular disease and non-alcoholic steatohepatitis (NASH). Progressive improvements in the efficacy of GLP1RA suggest that GLP-1-based therapies may soon rival bariatric surgery as viable options for the treatment of obesity and its complications.

Keywords: Brain; Diabetes; G protein-coupled receptor; Hunger; Obesity; Weight loss.

Figure 1

Representative targets for GLP-1 action and sites of GLP1R expression within the nervous system, and consequences of GLP-1 therapy in people with obesity.

Figure 2

Summary of categorical weight loss with liraglutide in the SCALE trials. ∗p < 0.001. Data are observed proportions (except SCALE Diabetes, which is estimated proportions) with the last observation carried forward (LOCF) at end of the trial. N = number contributing to the analysis. Data are from [[75], [76], [77], [78], [79]]. ^†, individuals with prediabetes at trial entry; ^‡, low-calorie diet (total energy intake 1200–1400 kcal/day). OR= Odds Ratio.

Figure 3

Weight loss in the STEP trials with semaglutide. Data represent the trial product estimand, assuming the medication has been taken as assigned. ∗Statistically significant vs placebo. BW, body weight; IBT, intensive behavioral therapy. Data are from [[84], [85], [86], [87]].