Kausik Ray, FMedSci

Dual Agonists and Upstream Obesity Treatment with Kausik Ray, FMedSci

 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 

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.

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 

. “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.”

Ray K. Obesity and Dyslipidemia – Can We Finally Break the Cycle with Dual Agonists. Presented at the 9

 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

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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.

Obicetrapib May Predict and Prevent Cardiovascular Disease, with Kausik Ray, FMedSci

 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, presented recent research on cholesteryl ester transfer protein (CETP) inhibitors and where they could be applied clinically.

Obicetrapib, the latest CETP inhibitor and the first that may advance to clinical practice, has 3 predecessors that were cancelled in production due to insufficient efficacy or poor safety responses. Designed to raise high-density lipoprotein (HDL) and control the increase of lipoprotein (a) (LP(a)) to prevent 

, CETP inhibitors also exhibited the effect of reducing low-density lipoprotein (LDL). This has led to a general shift in perception to identify LP(a) as the core indicator behind cardiovascular risk.

Ray spoke on the difficult history of CETP inhibitors, acknowledging the shortcomings of the potentially life-changing medication in the past.

“There was a whole sort of history with this where the first drug actually tested had an off-target effect of increasing blood pressure,” Ray told 

. “The second of the class, dalcetrapib, didn’t change LDL or APOB and raised HDL modestly; it didn’t have any benefit on outcomes. The third of these showed a modest change in LDL and a large increase in HDL but was probably terminated prematurely.”

Obicetrapib, the most recent CETP inhibitor in the pipeline, is still currently in development; however, recent trials have suggested that it may also be the first to enter clinical practice. Ray also noted the results from the recent BROADWAY study, which investigated patients simultaneously taking a high-intensity statin and obicetrapib.

“It reduced LDL cholesterol by around 33% and APOB by around 24%. So, it’s actually changing all the things that you want it to,” Ray said. “But interestingly, there are a couple of other things as well: lipoprotein (a) went down somewhere between 35 and 48%.”

A later trial on which Ray presented data, called TANDEM, utilized a fixed-dose combination of ezetimibe and obicetrapib. Ray expounded on these results and the optimism that they inspired in investigators.

“The two together gave you 48% lowering of LDL. More patients got to goal on a background of statin therapy; 70% of patients were getting to these really low targets that we now aim for below 55 in our patients,” Ray told 

. “And we also saw LP(a) reductions as well with no safety signal.”

Despite the difficult history surrounding CETP inhibitors, Ray anticipates little to no uncertainty in clinicians utilizing obicetrapib should it be approved for cardiovascular disease prevention.

“I think that this has been approved by the FDA and the European Medicines Agency for LDL lowering based on a whole host of background data from genetics on target reduction,” Ray said. “You’ve got to provide enough safety data, which we have seen. I think that if clinicians know about LDL lowering, they know about the unmet need.”

Additionally, with no other CETP inhibitors in the pipeline or on the horizon, Ray anticipates obicetrapib becoming the first and only CEPT treatment accepted for clinical use in treating cardiovascular disease.

“It’s potentially twice as powerful as bempedoic acid in that regard, so that’s why I think it will be really much more interesting for our physicians and patients,” Ray said.

Ray reports the following disclosures: Amgen, Abbott Laboratories, Astra Zeneca, Esperion, Kowa, Regeneron, Sanofi, and others.

Ray K. CETP Inhibition – Where Might They Fit in Clinical Practice. Presented at the 9

 Annual Heart in Diabetes Conference in Philadelphia, PA, June 6-8, 2025.

Averna M, Cefalù AB. LP(a): The new marker of high cardiovascular risk. Nutr Metab Cardiovasc Dis. 2025;35(3):103845. doi:10.1016/j.numecd.2024.103845

Potentially the first successful CETP inhibitor, obicetrapib has shown positive trial results in reducing the risk of cardiovascular disease when combined with statins.

Kausik Ray, FMedSci

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