Memorandum
An article recently published in Nature Medicine outlined the development of a new GLP-1/GIP/glucagon receptor triagonist (that’s a triple agonist) that successfully reduced body weight and complications of diabetes in rodent models of obesity. The research team, led by Dr. Matthias Tschoep (Helmholtz Diabetes Center, Neuherberg, Germany) and the very well known and highly regarded Dr. Richard DiMarchi (Indiana University, Bloomington, IN), engineered the novel peptide after finding that simultaneous administration of a GLP-1/GIP coagonist with a glucagon receptor (GCGR) agonist led to superior weight loss and glycemic improvements compared to existing single and dual agonists. Consistent with those results, the triagonist delivered metabolic benefits (body weight loss, improved glucose tolerance, and decreased food intake) that were superior to those of the respective dual agonists in mouse models of obesity and type 2 diabetes. Chronic treatment (11 weeks) with the triagonist in obese rats safely lowered body weight without the risk of hypoglycemia; importantly, the GCGR agonist component did not exacerbate hyperglycemia in diabetic mice, even at high doses. The authors characterized the peptide’s efficacy as a result of synergistic GLP-1 action to reduce caloric intake and improve glucose control, GIP action to enhance the incretin effect and buffer against hyperglycemia, and glucagon action to increase energy expenditure. They also highlighted the triagonist’s ability to induce comparable weight and metabolic effects to the dual agonists at substantially lower doses. Excitingly, the article notes that the metabolic improvements produced by the triagonist rival those elicited by bariatric surgery in rodent studies – that turned our heads! If translatable to humans (a major if, of course), this would be a very significant breakthrough. Although much more research is needed to determine whether this compound would be a viable therapeutic option in humans, we believe these findings, also featured in a recent JAMA article, represent a compelling new approach for the treatment of type 2 diabetes and obesity.