本报讯(记者张敏)12月18日，记者从信达生物制药集团(以下简称"信达生物")获悉，信达生物自主开发 的全球首款胰高血糖素(GCG)/胰高血糖素样肽-1(GLP-1)双受体激动剂玛仕度肽注射液(以下简称"玛仕 度肽")，在中国2型糖尿病患者中开展的两项Ⅲ期临床研究(DREAMS-1、DREAMS-2)结果近日在国际知 名学术期刊《自然》(Nature)背靠背以"文章加速预览(Accelerated Article Preview)"形式同步在线发表。 糖尿病与肥胖密切相关，超重会加重胰岛素抵抗，是导致2型糖尿病发生、进展和并发症增加的主要因 素之一。相关并发症可累及血管、眼睛、肾脏、足部等多个器官。与欧美患者相比，我国糖尿病群体普 遍具有更高比例的胰岛素抵抗、脂肪肝和内脏脂肪积聚等代谢特征，常见临床表现为腹型肥胖，但临床 长期缺乏适配中国患者的用药方案。 DREAMS-1第一作者分别为南京大学医学院附属鼓楼医院朱大龙教授和山东第一医科大学附属省立医院 赵家军教授，信达生物制药集团钱镭博士与前述两位共同第一作者为文章共同通讯作者；DREAMS-2第 一作者分别为北京医院郭立新教授和中日友好医院张波教授，中日友好 ...

Core Viewpoint - The application for the high-dose 9mg of Xinermy® (Mastudipeptide injection) for long-term weight control in adults with moderate to severe obesity has been accepted by the National Medical Products Administration (NMPA) in China, providing a new effective and safe treatment option beyond weight loss surgery for this population [1][2]. Group 1: Clinical Study Results - The application is based on the outstanding results of the Phase III clinical study GLORY-2, where the 9mg group showed an average weight reduction of 18.55% at week 60, compared to 3.02% in the placebo group, with 44.0% of participants achieving a weight loss of 20% or more [1][2]. - In participants without type 2 diabetes, the 9mg group achieved an average weight reduction of 20.08% at week 60, while the placebo group had a reduction of 2.81%, with 48.7% of the 9mg group achieving a weight loss of 20% or more [2]. - The study also noted a significant reduction in liver fat content, with an average percentage decrease of 71.9% from baseline, along with improvements in key cardiovascular metabolic indicators such as blood pressure, blood lipids, blood uric acid, and waist circumference [2]. Group 2: Safety and Regulatory Aspects - The safety profile of the 9mg dosage is favorable, with no new safety signals identified [2]. - The company plans to collaborate closely with regulatory authorities to expedite the approval of this important therapy to serve a broad patient population [3]. Group 3: Market Positioning - Xinermy® (Mastudipeptide injection) 9mg is currently the only GLP-1 class drug that can achieve over 20% weight loss in one year through a two-step dosing titration, providing evidence-based medicine for effective weight management in moderate to severe obesity patients [3]. - The development strategy has evolved from targeting a broad overweight/obese population with 2-4-6mg dosages to now focusing on moderate to severe obesity with 3-6-9mg dosages, reflecting deep scientific insights and clear market demand for personalized treatment solutions [3].

Core Viewpoint - The article emphasizes the importance of adequate protein intake while using semaglutide, a GLP-1 receptor agonist, for weight loss and overall health maintenance [2][5]. Group 1: Importance of Protein Intake - Sufficient protein intake is crucial during semaglutide treatment to maintain muscle mass [2][4]. - A balanced diet including protein, vegetables, and whole grains is recommended to enhance fiber intake and reduce side effects like constipation [2][5]. Group 2: Mechanism of GLP-1 Drugs - GLP-1 receptor agonists promote insulin secretion by activating GLP-1 receptors on pancreatic beta cells, which is glucose-dependent [6]. - They inhibit glucagon secretion from pancreatic alpha cells, helping to lower blood sugar levels [6]. - GLP-1 drugs delay gastric emptying, controlling postprandial blood sugar spikes [7]. - They also regulate appetite by acting on the brain's appetite centers, aiding in food intake reduction and weight management [8]. Group 3: Metabolic Effects - Research indicates that GLP-1 drugs not only increase satiety but also directly influence metabolism [10]. - Individuals using GLP-1 analogs exhibit increased metabolic activity, leading to higher energy expenditure and potential weight loss [11][13].

Core Insights - The article discusses groundbreaking research published in Nature that reveals the complex biological mechanisms behind obesity and weight loss, challenging traditional views of fat as merely an energy storage tissue [6][7]. Group 1: Obesity Mechanisms - Fat tissue is described as a complex "micro-society" composed of various cell types that communicate to maintain metabolic balance, rather than just a storage depot for energy [7]. - The study identifies five catastrophic changes in fat tissue during obesity: 1. An "inflammatory storm" occurs with a significant increase in immune cells, particularly lipid-associated macrophages (LAMs), leading to chronic inflammation [8]. 2. The metabolic system of fat cells becomes overloaded and dysfunctional, resulting in the accumulation of toxic byproducts [9]. 3. Cells within fat tissue exhibit signs of aging, activating senescence-associated secretory phenotype (SASP) and exacerbating inflammation and metabolic disorders [9]. 4. The microenvironment of fat tissue is altered, leading to abnormal communication between stressed fat cells and immune cells, which amplifies inflammation [9]. 5. The vascular network within fat tissue deteriorates, causing dysfunction and contributing to hypoxia and inflammation [10]. Group 2: Weight Loss and Recovery - The research highlights that weight loss leads to a remarkable transformation in fat tissue, characterized by: 1. A "metabolic super-reboot," where fat cells regain and enhance their metabolic flexibility, improving insulin sensitivity [10]. 2. A significant reduction in inflammatory immune cells, restoring immune balance in fat tissue [10]. 3. The elimination of senescent cells, which may provide new insights into anti-aging therapies [10]. 4. Restoration of normal vascular function, improving blood supply and alleviating hypoxic conditions [10]. Group 3: Implications for Obesity Treatment - The study reveals concerning findings about "obesity memory," where certain immune cells retain a "memory" of the obese state, potentially leading to rapid weight regain after weight loss [11][12]. - This suggests that successful weight loss may require interventions targeting the mechanisms of inflammation memory to achieve long-term weight management [13]. - The research indicates a shift in obesity treatment strategies from simple weight loss to more complex approaches focused on "tissue reprogramming," offering hope for billions affected by obesity [14].

Core Viewpoint - The article discusses a groundbreaking study by Professor Katrin Svensson's team at Stanford University, which developed an AI system called "Peptide Predictor" that discovered 2,683 previously unknown bioactive peptides, potentially revolutionizing obesity treatment [6][8]. Group 1: AI and Drug Discovery - The AI model significantly enhances drug discovery by accurately predicting which prohormone fragments may have therapeutic potential, moving from a trial-and-error approach to a more precise method [8]. - The discovery of the BRP (BRINP2-related peptide) highlights the potential of AI in identifying effective obesity treatments, showcasing its ability to select promising candidates from a vast pool [10]. Group 2: BRP's Mechanism and Benefits - BRP demonstrated remarkable appetite suppression in animal studies, showing effects comparable to popular GLP-1 drugs, indicating its strong anti-appetite activity [10]. - The peptide also optimizes metabolic regulation, enhancing fat oxidation while maintaining stable oxygen consumption and carbon dioxide production, suggesting it primarily regulates appetite rather than basal metabolic rate [12][14]. - BRP's unique mechanism of action, which activates specific neurons in the hypothalamus, avoids common side effects associated with GLP-1 drugs, such as nausea and gastrointestinal discomfort [14]. Group 3: Future Prospects - The research team has initiated preclinical safety assessments for BRP and plans to conduct the first human trials in 2026, with hopes of bringing the drug to market by 2030 [17]. - The goal is to develop a safe and effective weight loss medication that respects the body's natural metabolic balance, representing a new direction in obesity drug development [17].