At the beginning of his recent Vanderbilt Discovery Lecture on glucagon-like peptide-1 (GLP-1) receptor agonists, Daniel Drucker, MD, joked that the title for his presentation could be “What I still don’t understand about how GLP-1 works.”
Drucker is a pioneering scientist whose research contributed to the development of the blockbuster GLP-1 medicines used to treat diabetes and obesity. His presentation on “GLP-1 Medicines: Where and How Do They Work?” was also the Irwin Eskind, MD, Lecture in Biomedical Science.
Drucker is professor of Medicine in the Division of Endocrinology at the University of Toronto and holds the Banting and Best Diabetes Centre-Novodisk Chair in Incretin Biology. He is also a senior scientist at the Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital in Toronto.
“The good news is that these are very effective, and we keep getting better and better medications,” Drucker said. “The bad news is that the companies responsible for semaglutide and tirzepatide have been unable to meet the global demand and have priced these medications in a way that they’re not affordable, which is a big challenge.”
Drucker and his team study the molecular biology and physiology of the GLP-1 and GLP-2 molecules that regulate glucose metabolism, insulin secretion and energy balance. GLP-1 receptor agonists, including exenatide, liraglutide, tirzepatide and semaglutide, mimic the action of GLP-1 and have been approved by the Food and Drug Administration to treat Type 2 diabetes and obesity.
Groundbreaking clinical trials published in late 2023 and 2024 show that semaglutide, approved in 2019 for treating diabetes and in 2021 for weight management, also reduces rates of heart disease and kidney disease, and reduces tissue and systemic inflammation. GLP-1 medications are also now being studied in individuals with metabolic liver disease, peripheral artery disease and neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease.
“What we try to do in the lab is ask how all these things work — all of these non-glucose, non-body weight-regulating actions of GLP-1, and I still don’t know,” Drucker said. “What we’ve tried to do is based in part on the human data. In humans, these drugs work really well to reduce myocardial infarction, stroke, kidney disease, metabolic disease, osteoarthritis, death, etc. And it turns out much of this is not strictly weight loss dependent.”
In the SELECT cardiovascular outcomes trial published in November 2023, semaglutide was associated with a 20% risk reduction in major adverse cardiovascular events in patients 45 years of age or older compared with placebo.
In May, results of the FLOW trial showed that participants with Type 2 diabetes and chronic kidney disease who received semaglutide had a 24% lower risk of having a major kidney disease event than those receiving a placebo.
“The KDIGO (Kidney Disease: Improving Global Outcomes) guidelines are currently being revised, and I’m not privy to those discussions, but I would think that it’s quite likely that this will become one of the major pillars of standard of care for the prevention of chronic kidney disease,” Drucker said.
Initial results of the Phase 3 ESSENCE trial looking at the effect of semaglutide on liver disease were released at the November 2024 American Association for the Study of Liver Diseases meeting. At week 72, semaglutide was more effective than placebo at resolving steatohepatitis (a type of fatty liver disease) without worsening liver fibrosis (62.9% vs. 34.1%). It also improved liver fibrosis without worsening steatohepatitis (37.0% vs. 22.5%). In animal studies, these types of benefits were noted, independent of weight loss.
Outcomes from the Phase 3 SURMOUNT-1 study show adults with prediabetes and obesity or overweight who received tirzepatide had a 94% reduction in the risk of progression to Type 2 diabetes. Participants receiving tirzepatide also achieved a 22.5% average decrease in weight.
Collectively, studies have shown that benefits of GLP-1 medications, beyond weight loss and glucose control, are seen across diverse populations — older and younger men and women and individuals of various ethnicities — Drucker said. The exact mechanisms of how these benefits happen remain largely unknown, but there are several large studies underway to evaluate theories.
Looking forward, several new GLP-1 medicines are being developed and will likely be released in combination with another medicine, Drucker said. He is hopeful that these drugs can be targeted for specific diseases and disorders.
He stressed that many questions about GLP-1 medications remain, and there is a need for more research, such as identifying genotypes that are better matches for specific GLP-1 drugs, and reporting outcomes data in children. Drucker encouraged scientists in the audience to roll up their sleeves to help find the answers.
“There are really fantastic research opportunities going forward to tease out these mechanisms,” said Drucker, who began studying GLP-1 40 years ago. “It’s taken a long time, but it feels like we’re just starting the most exciting chapters in terms of new, more effective molecules, new delivery systems and potentially new indications to improve human health.”
Drucker’s Discovery Lecture was sponsored by the Vanderbilt Diabetes Center. To view this lecture and archived videos of previous lectures, visit https://www.vumc.org/discovery-lecture-series/upcoming-lectures.
