Glucagon-like peptide-1 agonism — GLP-1, common in obesity medicines — is not essential to weight management, according to preclinical research led by Richard DiMarchi and Matthias Tschöp, with funding from their startup company Bluewater Biosciences .
This research represents a potential alternative obesity treatment, as it could make peptide-containing medicines more tolerable and easier to employ for a large pool of patients by eliminating unfavorable gastrointestinal side effects.
In a report published in Molecular Metabolism in April 2026, DiMarchi of Indiana University Bloomington, and Tschöp, of Ludwig Maximilian University of Munich, said that while GLP-1 activity remains an effective approach to managing obesity, adverse gastrointestinal effects keep many patients from initiating and maintaining treatment. Their research shows that in leading-edge triple agonist peptides containing GLP-1, glucagon and gastrointestinal peptide (GIP) agonism the GLP-1 can be eliminated without destroying weight-loss efficacy.
DiMarchi and Tschöp's pioneering work on the study of GLP-1 hormones contributed to the foundation for popular weight-management drugs sold under name brands like Zepbound and Wegovy. They discovered that the weight-loss effects from therapeutics containing the GLP-1 hormone activity could be enhanced by including two other hormone activities: glucagon and GIP.
"The mindset right now is that the GLP-1 hormone itself is the secret sauce to weight loss," DiMarchi said. "What we've found in rodents and monkeys is that the combination of glucagon and GIP activity alone are sufficient to achieve comparable weight loss, without the lengthy dosage adjustment and adverse GI side effects. It provides a path to develop obesity therapy that is patient-centric rather than drug-centric."
The discovery originates from their collaborative work with first author Diego Perez-Tilve, associate professor of pharmacology, physiology and neurobiology at the University of Cincinnati, and Andy Vick, pharmacologist at Bluewater Biosciences. This work is embedded in the broader context of research on the treatment of diseases associated with obesity, such as diabetes, liver fibrosis and osteoarthritis.
They discovered that adding hormones to leading-edge metabolic peptides could "supercharge" their activity enough that in subsequent studies, they observed that GLP-1 activity was not essential.
They evaluated the new mechanism through three independent approaches and came to the same conclusion.
"We removed the GLP-1 to see what the other hormone activities could do and discovered that we still maintained the weight-loss benefits," DiMarchi said. "GLP-1 is such a potent appetite suppressant, it was camouflaging what the other hormones were able to achieve in its absence."
The findings are the most recent in a series of important contributions for DiMarchi, the Linda and Jack Gill Chair in Biomolecular Science in the IU College of Arts and Sciences. He attributes his success to maintaining a receptivity to observations from rodent testing and the collaborative support of his chemical and biological colleagues.
"This latest invention demonstrates that if you're on your way to interrogate one hypothesis, but maintain an open mind, you might discover something unexpected and more valuable," DiMarchi said. "And that ironically replicates how GLP-1 evolved from a diabetes drug to an obesity drug."
The next phase of research will be assessing the new mechanism and drug candidates in obese patients.
"If patients can tolerate GLP-1s, they should continue to use them; they're safe and effective," DiMarchi said. "But for those patients who can't tolerate GLP-1 drugs, there's reason for optimism."
