Mechanisms of Glucagon Receptor Agonism and GLP-1/Glucagon/GIP Receptor Triple Agonism for Treatment of Diabetes and Obesity

Abstract

With an increasing prevalence of diabetes and its complications, there is a need for new therapies to improve glycemic control and weight management. Multireceptor agonists may be a means to address this unmet need. A novel triple agonist peptide at the glucagon receptor, the glucose-dependent insulinotropic polypeptide (GIP) receptor, and the glucagon-like peptide-1 (GLP-1) receptor exhibits balanced glucagon and GLP-1 activity but greater GIP activity. In preclinical research, administration of a triple agonist decreased body weight and enhanced glycemic control. The addition of glucagon receptor-mediated increases in energy expenditure to GIP and GLP-1 receptors-driven calorie restriction promotes body weight loss. In clinical studies, the triple agonist demonstrated an acceptable safety profile, and its pharmacokinetics suggest a once-weekly administration schedule. This discovery, along with the pharmacodynamic findings of robust reductions in body weight and increased glycemic control, indicates a new era of treatment for obesity and type 2 diabetes. This review discusses the metabolic effects of glucagon agonism and the clinical significance of a triple agonist.