DR10624, a Novel Triple Agonist Targeting FGF21R, GCGR, and GLP-1R, Demonstrates Superior Anti-Atherosclerotic Effects in Preclinical Models

Atherosclerosis serves as the primary pathological basis of cardiovascular diseases, yet there remains a lack of therapeutic interventions capable of multi-pathway intervention with significant efficacy. As a novel triple agonist, DR10624 has previously demonstrated pronounced lipid-lowering and hepatic fat-reducing effects in clinical studies. This study further investigated the therapeutic effects and underlying mechanisms of DR10624 in an atherosclerosis model. An atherosclerosis model was established using high-fat diet-fed apolipoprotein E knockout (ApoE KO) mice. The mice were treated with DR10624 via subcutaneous injection, with semaglutide—a GLP-1 receptor (GLP-1R) mono-agonist proven to confer cardiovascular benefits—serving as the positive control. The results demonstrated that DR10624 significantly reduced body weight, serum total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) levels in mice, while improving cardiovascular risk-associated parameters such as non-high-density lipoprotein cholesterol (non-HDL-C).

In terms of vascular pathology, DR10624 treatment significantly reduced aortic lipid deposition and abnormal collagen accumulation within plaques, while concurrently improving hepatic lipid metabolism. Aortic transcriptomic sequencing analysis revealed that, as a multi-target agonist, DR10624 broadly modulates multiple pathways associated with atherosclerosis pathogenesis, including inflammatory signaling, cholesterol metabolism, and extracellular matrix remodeling, demonstrating more comprehensive regulatory effects and broader pathway coverage compared to semaglutide. This provides scientific rationale for the comprehensive benefits DR10624 may offer in atherosclerosis treatment, extending beyond conventional lipid-lowering and weight-reduction effects.

Research findings demonstrate that DR10624 not only modulates lipid profiles, reduces body weight, and improves hepatic lipid metabolism, but also acts directly on the vascular wall to significantly reduce plaque burden and enhance plaque stability. Its consistent and superior efficacy across multiple key endpoints compared to semaglutide underscores the clinical translational potential of DR10624 as a comprehensive therapeutic strategy for atherosclerosis.