New weight-loss drugs are having a revolutionary effect on metabolism. Now, Duke University School of Medicine researchers are charged with understanding why. Pharmaceutical companies Eli Lilly and Denmark-based Novo Nordisk created the latest weight-loss medications by combining GLP-1 drugs with hormones naturally produced in the gut.
The drugs have produced game-changing results in treating type 2 diabetes and obesity, both of which are strongly linked to cardiovascular disease, metabolic disorders, and numerous other chronic diseases. The new medications have generated enormous public interest for their potential to confer wider-ranging health benefits, but scientists caution that these claims are as yet unsupported by solid clinical trial data.
Researchers in the Duke Molecular Physiology Institute (DMPI) are collaborating with the pharmaceutical companies to uncover how these powerful drug combinations work. As federal research funding remains uncertain, DMPI scientists say sponsored research agreements make up some of the gaps.
“These drugs are very potent for inducing weight loss, and with that comes a lower risk of diabetes,” said Christopher Newgard, PhD, W. David and Sarah W. Stedman Distinguished Professor of Nutrition in the School of Medicine and director of the DMPI.
The DMPI is dedicated to understanding the molecular makeup of obesity and type 2 diabetes and the cardiovascular disease that often accompanies them, and to developing early-detection strategies and new treatments.
The institute is well known for its expertise in metabolomics, studying the small molecules that are made when the body breaks down food, drugs, and chemicals, to learn how metabolism works in cells, tissues, and organisms.
First-generation GLP-1 drugs, like Ozempic, mimic GLP-1, an incretin hormone in the gut that regulates blood sugar, slows digestion, and signals fullness to the brain. Second-generation GLP-1 drugs contain an added hormone, gastrointestinal inhibitory peptide (GIP), which further enhances the body’s ability to manage blood sugar and shed weight.
For the third, emerging generation, scientists added glucagon, another hormone, to the medication. “As you add GIP to GLP-1, and add glucagon together, weight loss [increases] with each addition,” Newgard said. “Each time you add another molecule, you get better efficacy. GLP-1 plus GIP is more effective than GLP-1 alone at inducing weight loss. But we need to help drug companies understand what you do to metabolism as you add each of these warheads to the drugs.”
Newgard and Guofang Zhang, PhD, associate professor in the Duke Department of Medicine, are leading the development of metabolic analysis methods for the collaboration.
David D'Alessio, MD, Lindquist Presidential Distinguished Chair in the Duke Department of Medicine, and Jonathan Campbell, PhD, associate professor in the Duke Department of Medicine, are focusing on how the incretin hormones work with their receptors.
DMPI scientists are partnering with Heather Whitson, MD, Duke Distinguished Professor of Neuroscience and director of the Duke Center for the Study of Aging and Human Development, to research how GLP-1 medications affect aging.
For all their remarkable effectiveness, the current GLP-1 drugs have some limitations.
“There are some opportunities to improve on the current drugs,” Campbell said. “One, they’re injectables, so we’re looking for either needle-free delivery options or less frequent dosing. And another is the variable response we see. Not everybody responds in exactly the same way to these drugs.”
Most patients taking GLP-1 drugs lose an average of 10-15% of their body weight in a year. A small percentage of patients lose significantly more. A larger group loses little or no weight. Side effects, mostly mild to moderate gastrointestinal complaints that often subside over time, are common. For various reasons, estimates are that up to half of all patients who start taking GLP-1 drugs stop taking them within a year.
“The GLP-1 receptor has turned out to be a fantastic drug target for diabetes and obesity,” D’Alessio said. “The positive effects have not been maximized yet, and the side effects can likely be reduced with newer formulations. Combination of GLP-1 active compounds built with additional receptor stimulation are likely to be the more efficacious drugs that we need.”
This story first appeared in the Spring 2026 print edition of Magnify Magazine