Glucagon-based therapy for people with diabetes and obesity: What is the sweet spot?

• Published in: Peptides (New York, N.Y. : 1980) N.Y. : 1980), 2024-06, Vol.176, p.171219-171219, Article 171219
• Main Authors: McGlone, Emma Rose, Tan, Tricia M.-M.
• Format: Article
• Language: English
• Subjects: Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Glucagon; Glucagon - metabolism; Glucagon-like peptide-1; Glucagon-Like Peptide-1 Receptor - agonists; Glucagon-Like Peptide-1 Receptor - metabolism; Glucose-dependent insulinotropic polypeptide; Humans; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Metabolic dysfunction-associated steatotic liver disease (MASLD); Obesity; Obesity - drug therapy; Obesity - metabolism; Receptors, Glucagon - agonists; Receptors, Glucagon - metabolism; Type 2 diabetes
• ISSN: 0196-9781; 1873-5169
• DOI: 10.1016/j.peptides.2024.171219

People with obesity and type 2 diabetes have a high prevalence of metabolic-associated steatotic liver disease, hyperlipidemia and cardiovascular disease. Glucagon increases hepatic glucose production; it also decreases hepatic fat accumulation, improves lipidemia and increases energy expenditure. Pharmaceutical strategies to antagonize the glucagon receptor improve glycemic outcomes in people with diabetes and obesity, but they increase hepatic steatosis and worsen dyslipidemia. Co-agonism of the glucagon and glucagon-like peptide-1 (GLP-1) receptors has emerged as a promising strategy to improve glycemia in people with diabetes and obesity. Addition of glucagon receptor agonism enhances weight loss, reduces liver fat and ameliorates dyslipidemia. Prior to clinical use, however, further studies are needed to investigate the safety and efficacy of glucagon and GLP-1 receptor co-agonists in people with diabetes and obesity and related conditions, with specific concerns regarding a higher prevalence of gastrointestinal side effects, loss of muscle mass and increases in heart rate. Furthermore, co-agonists with differing ratios of glucagon:GLP-1 receptor activity vary in their clinical effect; the optimum balance is yet to be identified. •Glucagon antagonists worsen hepatic steatosis and hyperlipidemia in people with diabetes and obesity.•Glucagon/GLP-1 receptor co-agonism improves weight loss, hepatic steatosis and hyperlipidemia, without worsening glycemia.•Glucagon/GLP-1 receptor co-agonists have a high rate of gastrointestinal adverse effects.