Clinical safety of a triple gut hormone co-agonist: The future of obesity therapy?

Obesity and diabetes type 2 represent a major health threat of our society – more than one billion people worldwide suffer from these diseases. Effective therapies are urgently needed. Polyagonists are designed to combine the beneficial effects of several independent hormones into a single molecule of enhanced efficacy and sustained action. These synthetic “master molecules” act simultaneously through multiple specific receptors in the brain and the periphery, and thereby enhance metabolic outcome beyond what is possible with targeting any single receptor type alone. Triple agonists for example, activate the signaling pathways of the hormones GIP, GLP-1 and glucagon. Results show, similar to pretty much all currently reported polyagonist trials: Appetite can be powerfully curbed, the release of insulin strongly promoted and fat burning much increased – making gut hormone polyagonists game changers for the treatment of obesity and diabetes type 2.

The currently best studied unimolecular co-agonists are the GIP/GLP-1 dual agonists, which were discovered by Matthias Tschöp in close collaboration with the peptide chemist Richard DiMarchi. A first version of this drug class has recently been approved as a drug in the US: This GIP/GLP-1 dual agonist is called Tirzepatide (Mounjaro®) and is produced by Eli Lilly in Indianapolis, USA. Tirzepatide decreases body weight at an average of 22%, a much greater weight loss than previousy possible with any safe drug treatment. Whether the clinical success of GLP-1/GIP dual-agonism can yet again be surpassed by the drug class of GLP-1/GIP/Glucagon tri-agonism, another discovery of Tschöp and DiMarchi, remains to be demonstrated.

In the current issues of The Lancet, Urva and colleagues report clinical trial data from a phase 1b study of a novel GIP/GLP-1/glucagon tri-agonist. In their comment, Müller and Tschöp summarize the results of the publication: The tri-agonist was well tolerated, with the preservation of comparable safety but enhanced efficacy relative to GLP-1 monotherapy. While a direct comparison with Tirzepatide was not included in the study design, the results nevertheless show that a triple combination of glucagon, GLP-1 and GIP can be used to further decrease body weight and glycemic improvement. Whether a tri-agonist can really double the beneficial effects of Tirzepatide, as indicated by preclinical models, remains to be shown in further studies.