以下文章来源于内分泌早知道 ，作者关注内分泌的 内分泌早知道 . 深度分享内分泌用药经验、病例剖析、指南专业解读并紧跟国内外内分泌领域前沿进展，「每医健」旗下内容平台。 全球约三分之一人群正遭受代谢功能障碍相关性脂肪性肝病（MASLD）的困扰，这个曾用名NAFLD/MAFLD的慢性肝病仍在持续蔓 延。该疾病以肝脏脂肪堆积和代谢异常为典型特征。值得注意的是，MASLD与心血管疾病（CVD）存在显著关联，二者均与肥胖、2 型糖尿病（T2DM）等代谢问题密切相关。在代谢疾病治疗领域，GLP- 1受体激动剂（GLP- 1RA）已成为当之无愧的"明星药物"，其 卓越的血糖调控、体重管理和代谢改善功效已获临床验证。 ▍ 心脏保护新突破！司美格鲁肽减重版降低心血管风险20%，重塑体重管理新理念 SELECT研究作为全球首个验证减重药物心血管获益的大型临床试验，纳入了17,604名超重或肥胖受试者（多数已确诊心血管疾病但未 合并糖尿病），其重磅结果引发行业震动： 在标准治疗基础上，司美格鲁肽减重版较安慰剂显著降低主要不良心血管事件（MACE，含心血管死亡、非致死性心梗及卒中）风险达 20%（HR 0.8 0，95% CI 0 ...

Core Viewpoint - Wave Life Sciences Ltd. presents promising preclinical data for its candidate drug WVE-007, which targets INHBE mRNA to reduce fat mass without compromising muscle quality, potentially lowering the risk of metabolic diseases such as type 2 diabetes and coronary artery disease [1][7]. Group 1: Mechanism and Efficacy - WVE-007 is a GalNAc-modified siRNA that significantly downregulates INHBE mRNA and its product Activin E protein, which inhibits fat breakdown in obesity [2]. - A single administration of WVE-007 results in weight loss comparable to the widely used GLP-1 receptor agonist semaglutide [3]. - The drug effectively reduces visceral fat, decreases adipocyte size, and preserves muscle mass, supporting weight loss through the restoration of adipose tissue function [4]. Group 2: Inflammatory Response - WVE-007 significantly inhibits the recruitment of pro-inflammatory M1 macrophages while maintaining levels of anti-inflammatory M2 macrophages, demonstrating strong anti-inflammatory potential [5]. Group 3: Combination and Maintenance Therapy - When used in conjunction with semaglutide, INHBE-siRNA can double the weight loss effect, indicating a synergistic therapeutic potential [6]. - After discontinuation of semaglutide, INHBE-siRNA significantly slows weight regain, suggesting it could serve as a maintenance or transitional therapy for GLP-1 treatments [7]. Group 4: Genetic Insights and Future Prospects - Individuals carrying INHBE gene loss-of-function variants often exhibit healthier metabolic profiles, including reduced abdominal fat, lower triglyceride levels, and decreased risks of type 2 diabetes and cardiovascular diseases [7]. - The Chief Scientific Officer of Wave emphasizes that if clinical trials confirm these mechanisms, WVE-007 could revolutionize obesity treatment by offering a new pathway that requires only one to two injections per year for healthy weight loss while preserving muscle mass [7].

Core Viewpoint - CureGene's CG-0416 demonstrates significant potential as a dual mechanism candidate drug for treating Metabolic Dysfunction-Associated Steatotic Liver Disease (MASH) and obesity, showing a 58% reduction in liver lipid accumulation, a 66% improvement in weight loss, and a 50% decrease in muscle loss compared to standard therapies [2][4]. Group 1: Breakthroughs in Treatment - CG-0416 overcomes limitations of current GLP-1 receptor agonists by precisely targeting complementary metabolic pathways, enhancing weight control and muscle preservation [3]. - The liver-specific activation of CG-0416 results in a 20-fold higher concentration of active metabolites in the liver compared to peripheral tissues, maximizing safety [4]. - In a 26-week diet-induced obesity mouse model, CG-0416 combined with low-dose semaglutide showed a 66% reduction in fat mass and a muscle fat reduction ratio of 0.18 kg/kg, compared to existing therapies which range from 0.35 to 0.63 kg/kg [4]. Group 2: Clinical Translation Advantages - CG-0416 enhances GLP-1-mediated liver lipid oxidation while activating the IGF-1/Akt/FOXO3a axis to inhibit muscle catabolism, showcasing a dual pathway synergistic effect [4]. - With an oral bioavailability of 92%, CG-0416 is expected to be the first oral therapy used in conjunction with GLP-1 agonists, significantly higher than previously approved THR-β therapies [5]. Group 3: About CG-0416 - CG-0416 is a novel liver-targeted THR-β prodrug under development for treating MASH and obesity-related complications, demonstrating superior metabolic control compared to Resmetirom and VK-2809 in preclinical studies [6]. - As a potential oral adjunct to GLP-1 therapy, CG-0416 combines rapid fat loss with muscle preservation, positioning it as a next-generation metabolic modulator [6]. Group 4: About CureGene - Founded in 2018, CureGene is a biotechnology company based in China with a global focus, specializing in innovative platforms for cardiovascular and antiviral diseases [8]. - The company has successfully transitioned from a research-stage startup to a clinical-stage biotech firm, with a pipeline of drugs showing significant market potential and complete global intellectual property rights [8].