Shared mechanistic pathways of glucagon signalling: Unlocking its potential for treating obesity, metabolic dysfunction‐associated steatotic liver disease, and other cardio‐kidney‐metabolic conditions

Abstract Glucagon is a pancreatic peptide hormone whose receptor (GCGR) is expressed in the liver, kidney, and, to a lesser extent, various other tissues. Glucagon is well known as the counterpart to insulin in glucose homeostasis. However, recent evidence has revealed other potential roles of glucagon, which include the regulation of amino acid metabolism via a liver–pancreatic alpha cell axis, stimulation of lipolysis and mitochondrial fat oxidation in the liver (and possibly in other tissues), reduction of caloric intake, and an increase in energy expenditure (at least in animal models). These advances in basic science—together with clinical trials that found GCGR antagonists increased body weight, hepatic fat, and serum lipids in people with type 2 diabetes—are driving the development of GCGR‐based agonists for the treatment of obesity, metabolic dysfunction‐associated steatotic liver disease (MASLD), and other cardio‐kidney‐metabolic diseases. Due to the hyperglycaemic effects of glucagon, these unimolecular compounds also incorporate moieties that activate the glucagon‐like peptide‐1 (GLP‐1) receptor, which stimulates insulin secretion to lower blood glucose levels. In early clinical trials, several GCGR‐based multi‐agonists (mazdutide, survodutide [being developed by the sponsor of this review], retatrutide) demonstrated substantial efficacy for eliciting weight loss in people with obesity while improving liver health in those with MASLD. However, the physiological and molecular pathways modulated by chronic pharmacological activation of the GCGR in humans remain to be delineated, as do its potential risks. Thus, there is great interest in the ongoing phase 3 clinical trials of these compounds. As data for their safety and efficacy emerge, glucagon's role in energy regulation and lipid metabolism will become clearer, along with warranting a potential new therapeutic option for obesity and MASLD.