Tirzepatide ushered in the era of dual agonists in type 2 diabetes and obesity management. Many novel agents, including dual and triple agonists and antagonists targeting different entero-pancreatic pathways, are now poised to further transform the therapeutic landscape of type 2 diabetes and obesity.

The symposium, Next Generation Therapies for Type 2 Diabetes and Obesity, on Sunday, June 22, from 4:30–6:00 p.m., in Room 184 A-D of the McCormick Place Convention Center, will explore emerging therapies targeting one or more of the hormones glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon, and amylin. On-demand access to recorded presentations will be available to registered participants following the conclusion of the 85^th Scientific Sessions, from June 25–August 25.

“GLP-1 receptor agonists have transformed the care that we provide to patients with type 2 diabetes and/or obesity, owing to their ability to significantly improve not only glycemic management and weight loss, but also confer cardiovascular and renal benefits,” said Dimitris Papamargaritis, MCRP, PhD, Associate Professor and Honorary Consultant in Diabetes and Endocrinology at the Leicester Diabetes Center at Leicester University, United Kingdom. “However, a limitation of GLP-1 receptor mono-agonists is that even the most effective of them result in around 15% weight loss. This falls short of the weight loss achievable with bariatric surgery. Also, not all patients respond equally to treatment with GLP-1 receptor agonists.”

That is why  there is an interest in developing agents that target multiple hormonal pathways with complementary actions (dual and triple agonists). The most advanced of these multi-targeted agents are the dual agonists that target both GLP-1 and GIP receptors, e.g., tirzepatide, explained Dr.  Papamargaritis.

“We are trying to find treatments that offer benefits beyond those provided by GLP-1 receptor agonists, aiming to mimic the weight loss achievable with bariatric surgery, maintain or improve the glycemic management seen with GLP-1 receptor agonists, and enhance additional outcomes, such as body composition and liver fat profiles,” he said. “While bariatric surgery is a highly effective intervention for obesity, it is not scalable to the population level.”

During the symposium, Dr. Papamargaritis will discuss advances in dual GLP-1/glucagon receptor agonists, which have been targets of interest in the diabetes space for many years. Glucagon antagonists, while reducing blood glucose, can also increase liver enzymes and promote liver fat deposition. On the other hand, unlike glucagon antagonists, glucagon agonists appear to “melt” liver fat, he explained.

Dr. Papamargaritis will also highlight clinical data for mazdutide, with phase 3 clinical trial data from Chinese patients with type 2 diabetes and/or obesity, and for pemvidutide, for which he said there is some “reassuring data” from phase 2 studies regarding the impact on body composition. Pemvidutide did not result in disproportional fat mass to muscle mass reduction, a concern that has been raised with glucagon agonists due to amino-acid suppression.

Glucagon agonists may benefit people with metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), Dr. Papamargaritis noted.

Phase 3 studies of dual GLP-1/glucagon agonists as treatments for obesity and in type 2 diabetes are anticipated to be completed over the next one to two years. In addition to efficacy findings for these agents and their potential approval, Dr. Papamargaritis said there needs to be more information gathered on their long-term safety to understand better their position in treatment guidelines for obesity and type 2 diabetes management.

The symposium will also include presentations on amylin receptor agonists, by Thomas A. Lutz, DVM, PhD, Professor and Deputy Director of the Institute of Veterinary Physiology at the University of Zurich, Switzerland; GIP agonism versus antagonism, by David D’Alessio, MD, Professor and Chief of the Division of Endocrinology and Metabolism at Duke University Medical Center; and glucagon antagonists, by Sofie Hædersdal, MD, PhD, Clinician-Scientist at the Steno Diabetes Center Copenhagen, Denmark.

“Having a range of therapies targeting different pathways offers us the opportunity to move obesity and type 2 diabetes care into more personalized medicine,” Dr. Papamargaritis said.