OR WAIT null SECS
Dual Agonists and Upstream Obesity Treatment with Kausik Ray, FMedSci
By targeting insulin resistance at its source, dual receptor agonists may have a more efficient method of tackling the growing obesity problem, as well as its cardiovascular effects.
At the 9th Annual Heart in Diabetes Conference in Philadelphia, PA, Kausik Ray, FMedSci, the immediate past president of the European Atherosclerosis Society, director of the Imperial Centre for Cardiovascular Disease Prevention and the Imperial Clinical Trials Unit-Global, and professor of public health and honorary consultant cardiologist at the Imperial College London, discussed the future of dual receptor agonists in treating obesity and its various cardiovascular complications.1
Dual receptor agonists, such as glucagon-like peptide-1 (GLP-1) receptor agonists, have become wildly popular in both the medical and consumer field. With obesity prevalence rapidly increasing in the US, more dual agonist treatments are being developed to target every stage of the disease, from lipid production to glycemia and metabolism regulation. Dual receptor agonists are now being repurposed in an attempt to prevent the causes of obesity rather than the effects.2
Ray discussed the various approaches currently in use to treat everything from abnormal lipid counts to obesity insulin resistance and metabolic syndrome. In the past, clinicians have typically employed a “downstream” method of treatment, targeting triglyceride abnormalities. Ray also acknowledged the diminishing returns that this method provides.
“So, we know, for example, that if you change triglycerides, you lower them by about 25%, and let’s say that doesn’t result in APOV or LDL lowering, then you’re not changing clearance, you’re just remodeling, and that doesn’t reduce cardiovascular outcomes,” Ray told HCPLive. “So, people have moved towards using newer agents, like ANGPTL3.”
These dual receptor agonists, a category that also includes GLP-1 receptor agonists, typically target the APOV pool. As a result, they have an effect on VLDL particles and can influence many of the outcomes of obesity in addition to its symptoms.
“So, we showed, for example, that if you target ANGPTL3 with a drug called solbinsiran, for example, you reduce not only those anthrogenic lipids, but you actually also reduce fatty liver,” Ray said. “I’m mentioning that because we know that fatty liver, MASLD, is associated with obesity and insulin resistance.”
This, Ray suggests, is the alternative “upstream” treatment by which clinicians can take out the underlying cause of these diseases – insulin resistance – and thereby treat the mechanism for obesity and all its related conditions.
“So, what we think that these drugs probably do is improve insulin sensitivity, to reduce the LDL production,” Ray said. “And then also through maybe changing ANGPTL3 and some of these other regulatory proteins in the triglyceride pathway, they probably then help that remodeling to a favorable lipid profile.”
Ray also spoke about upcoming dual agonists in the pipeline and their chances of breaking the cycle between obesity and dyslipidemia. Ray explained that most give a roughly 20% weight loss.
“We saw this trend with the single agonist, but they have less weight loss,” Ray said. “And so, it’s possible that you need a much bigger weight loss to try and break that cycle. And then we have the triple agonist coming down the pipeline, which gives an even bigger opportunity to test this.”
Ultimately, Ray expressed an interest in future trials, possibly combining dual receptor agonists with other medications to expand the impact on lipids.
“I think what I’d be interested in is to see what the effect is of combination therapy with an ANGPTL3 and one of these dual agonists on fatty liver disease, on lipids, for example,” Ray said. “Is it a gain of a doubling, for example? Because if that is the case, we’ve got some really powerful treatments for these people.”
References
Ray K. Obesity and Dyslipidemia – Can We Finally Break the Cycle with Dual Agonists. Presented at the 9th Annual Heart in Diabetes Conference in Philadelphia, PA, June 6-8 2025.
Rodriguez R, Hergarden A, Krishnan S, et al. Biased agonism of GLP-1R and GIPR enhances glucose lowering and weight loss, with dual GLP-1R/GIPR biased agonism yielding greater efficacy. Cell Rep Med. Published online May 30, 2025. doi:10.1016/j.xcrm.2025.102156
