DR10624: triple agonist of FGF21, glucagon and GLP-1 receptors significantly reduces triglycerides and liver fat

Phase 2 study evaluates the efficacy and safety of DR10624 in patients with severe hypertriglyceridemia, showing reductions of up to 74.5% in triglyceride levels after 12 weeks of treatment. 

Severe hypertriglyceridemia, defined by serum triglyceride levels above 500 mg/dL, is associated with an increased risk of acute pancreatitis and atherosclerotic cardiovascular disease, posing a therapeutic challenge given the limited efficacy of fibrates and omega-3 fatty acids in achieving substantial lipid reductions. Seeking new strategies, a study presented during AHA 2025 evaluated DR10624, a long-acting triple agonist that simultaneously targets the FGF21, glucagon, and GLP-1 receptors, modulating multiple metabolic pathways involved in lipid and hepatic regulation. 

The phase 2 trial (NCT06555640) was a multicenter, randomized, double-blind, placebo-controlled study including 79 adult patients with severe hypertriglyceridemia and baseline triglyceride levels ranging from 500 mg/dL to 2000 mg/dL. Participants were randomized 3:1 to receive DR10624 at doses of 12.5 mg, 25 mg, or 50 mg, or placebo, administered subcutaneously once weekly for 12 weeks. 

The results demonstrated marked reductions in triglycerides across all DR10624-treated groups compared with placebo: -8.0% with placebo, -74.5% with 12.5 mg, -66.2% with 25 mg, and -68.9% with 50 mg (all p<0.001). Additionally, 89.5% of treated patients achieved triglyceride levels below 500 mg/dL, compared with 25% in the placebo group, and 78.5% reached a ≥50% reduction from baseline. Treatment also led to significant improvements in total cholesterol, HDL-C, non-HDL-C, and triglyceride-rich lipoprotein cholesterol, as well as a 63.5% reduction in liver fat, compared with 8.4% in the placebo group. 

DR10624 was well tolerated, with mostly mild gastrointestinal events and injection site reactions. These findings highlight the potential of DR10624 as an innovative and promising therapy for managing severe hypertriglyceridemia, combining robust lipid and hepatic efficacy with a favorable safety profile. 

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Referências:  

1. Li J, Fang Y, Zhang L, et al. DR10624, a First-In-Class, FGF21 Receptor/Glucagon Receptor/GLP-1 Receptor Triple Agonist, Rapidly and Significantly Reduced Triglycerides, Atherogenic Lipids, and Liver Fat in Patients With Severe Hypertriglyceridemia: Primary Results From a Randomized Phase 2 Trial. Presented at the American Heart Association Scientific Sessions (AHA®) 2025.