Glucagon agonism in the treatment of metabolic diseases including type 2 diabetes mellitus and obesity

Abstract Type 2 diabetes mellitus (T2DM) is associated with obesity and, therefore, it is important to target both overweight and hyperglycaemia. Glucagon plays important roles in glucose, amino acid and fat metabolism and may also regulate appetite and energy expenditure. These physiological properties are currently being exploited therapeutically in several compounds, most often in combination with glucagon‐like peptide‐1 (GLP‐1) agonism in the form of dual agonists. With this combination, increases in hepatic glucose production and hyperglycaemia, which would be counterproductive, are largely avoided. In multiple randomized trials, the co‐agonists have been demonstrated to lead to significant weight loss and, in participants with T2DM, even improved glycated haemoglobin (HbA1c) levels. In addition, significant reductions in hepatic fat content have been observed. Here, we review and discuss the studies so far available. Twenty‐six randomized trials of seven different GLP‐1 receptor (GLP‐1R)/glucagon receptor (GCGR) co‐agonists were identified and reviewed. GLP‐1R/GCGR co‐agonists generally provided significant weight loss, reductions in hepatic fat content, improved lipid profiles, insulin secretion and sensitivity, and in some cases, improved HbA1c levels. A higher incidence of adverse effects was present with GLP‐1R/GCGR co‐agonist treatment than with GLP‐1 agonist monotherapy or placebo. Possible additional risks associated with glucagon agonism are also discussed. A delicate balance between GLP‐1 and glucagon agonism seems to be of particular importance. Further studies exploring the optimal ratio of GLP‐1 and glucagon receptor activation and dosage and titration regimens are needed to ensure a sufficient safety profile while providing clinical benefits.