Triple agonist cuts triglyceride levels by 60%

November 08, 2025

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Key takeaways:

• A triple agonist therapy that includes a GLP-1 reduced triglyceride levels by more than 60% for most participants.
• Participants also had a 63% reduction in liver fat.

NEW ORLEANS — An investigational triple agonist that targets fibroblast growth factor 21, glucagon and GLP-1 receptors cut triglyceride levels by more than 60% for patients with severe hypertriglyceridemia over 12 weeks.

Jianping Li

People with severe hypertriglyceridemia, defined as levels greater than 500 mg/dL, are at higher risk for CVD, acute pancreatitis and often develop metabolic dysfunction-associated steatotic liver disease, Jianping Li, MD, PhD, professor and chief of the Institute of Cardiovascular Disease and vice president of Peking University First Hospital, China, said during a late-breaking presentation at the American Heart Association Scientific Sessions.

Data from a previous phase 1b/2a study demonstrated that a long-acting triple agonist targeting the fibroblast growth factor 21 (FGF21), glucagon and GLP-1 receptors enhanced lipid oxidation, decreased hepatic lipogenesis and reduced appetite and food intake, stimulating insulin secretion, Li said.

Study data

For the current phase 2 trial, researchers analyzed data from 79 adults with severe hypertriglyceridemia (500-2,000 mg/dL) prescribed stable lipid-lowering therapies or no therapies, who were randomly assigned 3:1 to weekly subcutaneous DR10624 (Zhejiang Doer Biologics Co.) 12.5 mg, 25 mg and 50 mg (n = 54) or placebo (n = 18) for 12 weeks. The mean age of participants was 46 years, most were men (88.6%) and 25% had type 2 diabetes. Median baseline triglyceride level was 832.5 mg/dL.

The primary endpoint was percent change in triglyceride levels from baseline at week 12. Secondary endpoints included liver fat content, lipid measurements and metabolic markers.

Compared with placebo, participants across all three triple agonist doses had significant reductions in triglyceride levels. At 12 weeks, the median percent change in fasting triglycerides for the pooled dose groups was 68.9% compared with 8% for those assigned placebo.

Researchers also reported 89.5% of those who received any dose of the triple agonist achieved triglyceride levels below 500 mg/dL compared with 25% of participants assigned placebo, whereas 78.5% of those taking DR10624 had a greater than 50% reduction in triglycerides from baseline vs. 5% of those receiving placebo.

“The liver fat content also decreased dramatically,” Li said during a press conference. “In the DR10624 group, the liver fat content decreased by 63.5%, whereas in the placebo group, it decreased by 8.4%.”

DR10624 was well tolerated, Li said. The most common adverse effects were gastrointestinal symptoms and injection-site reactions.

“The number of patients in this trial was small, the duration was short, and the study was only conducted in mainland China,” Li said. “Those are the limitations. Additional clinical studies are needed, which should include more participants from diverse parts of the world, for a longer period, to confirm the findings in this phase 2 trial.”

Favorable data bring questions

Robert S. Rosenson

Robert S. Rosenson, MD, professor of medicine (cardiology) at the Icahn School of Medicine at Mount Sinai and Mount Sinai Fuster Heart Hospital, said the triple agonist demonstrated multiple favorable effects, noting that nearly all participants achieved triglyceride lowering of more than 50%, with up to 87.2% achieving levels below 500 mg/dL. However, any findings are limited by the small cohort size and short study duration, along with a low use of background lipid-lowering therapy (25% to 29.6%).

“Other improvements that we are seeing: the marked reduction in triglyceride-risk lipoproteins, body weight, HbA1c and uric acid,” Rosenson said while discussing the findings. “But because you are using a GLP-1 [receptor] agonist, are there any concerns about pancreatitis, which has been raised with some of the earlier agents? It is a small study, short duration, with no reporting on race and ethnicity, and the placebo group had a lower prevalence of diabetes than the active treatment groups. We look forward to more work with this compound and the very exciting implications.”

Perspective

Back to Top

The FGF21, glucagon and GLP-1 receptor agonists are likely working together to show these benefits, because we know that none of those agonists individually are going to bring triglycerides down to that extent. There is some synergy here that would need to be teased out by conducting another study with two of the three, because we know that none of these alone is going to do the trick. The question is, which agonist is the most active of the three? The safety profile for this triple agonist was also reasonable, at least in a phase 2 trial, so moving on to phase 3 makes sense. An agent like this would be most beneficial for people with type 2 diabetes and high triglycerides.

Christopher M. Kramer, MD

George A. Beller/Lantheus Medical Imaging Distinguished Professor of Cardiovascular Medicine
Chief, Cardiovascular Division
UVA Health
President, American College of Cardiology

Disclosures: Kramer reports receiving consultant fees and research support from Eli Lilly.

Published by:

Sources/Disclosures

Source:

Li J, et al. LBS.01 Groundbreaking trials in cardiometabolic therapeutics. Presented at: American Heart Association Scientific Sessions; Nov. 7-10, 2025; New Orleans.

Disclosures: Li reports no relevant financial disclosures. Rosenson reports receiving research grants from 89Bio, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Eli Lilly, Merck, Novartis, Rona Therapeutics and Shanghai Argo Biopharmaceutical Co.

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