Core Viewpoint - The article discusses the use of GLP-1 receptor agonists, particularly semaglutide, for weight management and the implications of pausing medication, emphasizing the importance of gradual dosage reduction to mitigate hunger rebound effects [4][12][14]. Group 1: Medication Effects and Timeline - After subcutaneous injection, semaglutide is absorbed into the bloodstream within 1-2 hours [8] - Peak concentration in the blood occurs within 24-48 hours, where the drug actively binds to GLP-1 receptors [9] - Noticeable effects, such as reduced appetite and improved blood sugar regulation, may begin within 1-2 weeks [10] - Steady-state levels are achieved after 4-5 weeks of weekly injections, leading to more pronounced appetite suppression and accelerated weight loss [11] Group 2: Discontinuation Strategies - It is recommended to start with the lowest dose and gradually increase to minimize side effects [12] - Gradual dose reduction is preferred over abrupt cessation to avoid increased hunger [14] - Monitoring appetite and weight changes is crucial for those planning to stop medication, with a focus on maintaining healthy eating and exercise habits [14] Group 3: Post-Discontinuation Outcomes - A 2021 clinical trial showed that participants lost an average of 10.6% of their weight during 20 weeks of semaglutide treatment, but those switched to a placebo regained an average of 6.9% of their weight [15] - An observational study indicated that 18% of patients regained their lost weight after one year off the medication, while 26% regained more than 25% of their lost weight [15] Group 4: Importance of Continued Medication - The STEP 5 trial demonstrated that continuous use of semaglutide for 2 years resulted in a 15.2% weight loss compared to placebo [18] - In the SELECT trial, patients maintained an average weight loss of about 10% over 4 years, highlighting the chronic nature of obesity and the need for long-term management [18] Group 5: Obesity as a Chronic Disease - Recent studies confirm obesity as a chronic disease, with 76.8% of patients and 94.6% of doctors agreeing on its classification [19] - Obesity is linked to various health issues, including type 2 diabetes and cardiovascular diseases, necessitating its inclusion in chronic disease management [19] Group 6: Weight Loss and Health Improvement - Weight loss of 5% can improve hypertension and blood sugar levels, while a 10-15% reduction significantly lowers risks of cardiovascular diseases and diabetes [21] - Greater weight loss (over 15%) can effectively alleviate type 2 diabetes symptoms and improve overall health outcomes [21]

以下文章来源于肥胖世界ObesityWorld ，作者欢迎订阅 肥胖世界ObesityWorld . 《肥胖世界》Obesity World - 同步传真肥胖及代谢国际新学术进展，为医学减重临床、教研人员搭建一座与国际接轨的桥梁，「每医健」旗下内容平台。 肥胖世界 Obesity World 《肥胖世界》(Obesity World)关注电子杂 志官方账号,用前沿科学理解肥胖 www.obesityworld.cn Obesity World 用 前 沿 科 学 理 解 肥 胖 | nature | | | | | --- | --- | --- | --- | | Explore content ✓ | About the journal ✓ | Publish with us > | Subscribe | | nature > news feature > article | | | | NEWS FEATURE | 11 June 2025 How to keep weight off after obesity drugs Options are emerging for the tens of m ...

Core Viewpoint - The recent research indicates that GLP-1 receptor agonists have potential beyond weight management and metabolic improvement, showing systemic anti-aging effects at the molecular level in aged mice, which could redefine the long-term value and boundaries of GLP-1 drugs [4][5]. Group 1: Research Findings - Long-term, low-dose GLP-1 receptor agonist intervention in aged mice resulted in significant changes in gene expression related to aging, reversal of DNA methylation abnormalities, and a trend towards normalization of metabolic disorders [5]. - The observed anti-aging effects were not solely due to reduced appetite or weight loss, suggesting an independent biological mechanism at play [5]. - The changes were primarily noted in high-energy, aging-prone tissues such as the hypothalamus, cortex, hippocampus, heart, skeletal muscle, adipose tissue, and immune cells, indicating a closer biological state to younger individuals [5][8]. Group 2: Mechanism Insights - The hypothalamus plays a crucial role in mediating the systemic anti-aging effects of GLP-1, indicating a central regulatory axis that influences aging processes throughout the body [8]. - The action trajectory of GLP-1 at the multi-omics level shows similarities to mTOR inhibition, suggesting that GLP-1's health benefits may arise from overlapping underlying pathways, positioning it as a potential platform for health intervention beyond single disease treatment [8]. Group 3: Industry Implications - The indications for GLP-1 drugs are expanding from obesity and diabetes to include cardiovascular, neurodegenerative diseases, and "healthy aging," significantly extending the lifecycle of the patient population [9]. - The valuation logic for companies involved in GLP-1 production may fundamentally change, as these drugs could become central to anti-aging and long-term health management, rather than just weight management tools [9]. - The ongoing research highlights the potential for GLP-1 to influence not just metabolic health but also broader aspects of aging, reshaping the pharmaceutical industry's view on the "intervention potential of aging" [9].

Core Viewpoint - Eli Lilly announced an investment of over $6 billion to build a large pharmaceutical manufacturing facility in Huntsville, Alabama, which will focus on producing new generation synthetic drug active ingredients, including oral small molecule GLP-1 receptor agonist orforglipron, a key product for weight loss and metabolic diseases [6][8]. Group 1: Investment and Economic Impact - The new facility is part of Eli Lilly's plan to establish four major production sites in the U.S., with this being the third project to be launched [6]. - The project is expected to create approximately 450 high-value jobs in engineering, research, operations, and laboratory technology, with an additional 3,000 construction-related jobs during the building phase [6][8]. - For every dollar invested by Eli Lilly in the local economy, it is estimated to generate up to $4 in related economic activity growth [8]. Group 2: Technological Advancements and Strategic Direction - The facility will incorporate digital and automated systems to optimize production processes, enhance operational efficiency, and ensure higher standards of drug safety and quality [8]. - This project reflects Eli Lilly's ongoing commitment to smart manufacturing and localized supply chains, as part of its broader strategy to strengthen domestic production capabilities amid global pharmaceutical supply chain restructuring [8]. Group 3: Broader Expansion Plans - The Alabama project is part of a larger expansion plan, with Eli Lilly also announcing new production facilities in Texas and Virginia, as well as expansions of existing facilities in Puerto Rico [8]. - Further announcements regarding additional U.S. production sites are expected in the coming weeks [8].

Core Viewpoint - Novo Nordisk has submitted a new drug application for CagriSema to the U.S. FDA, marking a significant advancement in the weight loss medication sector, aimed at obese or overweight adults with at least one weight-related comorbidity [6] Group 1: Product Overview - CagriSema combines a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist with cagrilintide, both at a dosage of 2.4 mg, administered via weekly subcutaneous injection [6] - If approved, CagriSema will be the first weight loss therapy to integrate GLP-1 receptor agonists and glucagon-like peptide analogs in a single injection regimen, representing a significant expansion of current treatment options [6] Group 2: Clinical Research Findings - The core evidence for the application is based on two pivotal Phase III clinical studies, REDEFINE 1 and REDEFINE 2 [6] - In REDEFINE 1, CagriSema demonstrated a significant weight loss advantage, with an average weight reduction of 20.4% in the treatment group compared to 3.0% in the control group at week 68, a statistically significant difference [6] - In a scenario where all participants continued treatment, the average weight loss for CagriSema increased to 22.7% at week 68, while the control group saw only a 2.3% reduction [8] - Approximately 92% of patients in the treatment group achieved at least a 5% weight loss, compared to about 30% in the control group, highlighting the potential of the dual mechanism approach in enhancing weight loss and stability [8] Group 3: Market Implications - In a competitive landscape for weight loss medications, Novo Nordisk aims to leverage technological innovation to differentiate itself from competitors [8] - The potential approval of CagriSema could reshape clinical choices in weight loss treatment and significantly impact the market structure of existing GLP-1 medications [8]

Core Insights - The article discusses the dual role of Neuropeptide Y (NPY) in regulating appetite and energy expenditure, revealing its complex functions in both the brain and peripheral fat tissues [7][12][16]. Group 1: NPY's Role in Appetite Regulation - NPY is known to stimulate appetite in the brain, but its absence does not significantly affect daily food intake in mice [11]. - Mutations in the NPY gene are associated with higher Body Mass Index (BMI) in humans, indicating a link between NPY and obesity that is not solely dependent on food consumption [11][17]. Group 2: NPY's Role in Energy Expenditure - In peripheral fat tissues, NPY helps maintain the thermogenic capacity of brown adipose tissue (BAT) and promotes energy expenditure [7][12]. - Research shows that knocking out NPY in the sympathetic nerves of mice leads to a reduction in brown fat, decreased thermogenic ability, and increased susceptibility to weight gain, even without changes in food intake or exercise [14][16]. Group 3: Mechanisms of Action - Approximately 40% of sympathetic neurons in white adipose tissue express NPY, which is involved in regulating blood vessel stability and the differentiation of thermogenic fat cells [14]. - NPY promotes the proliferation of perivascular cells, which are crucial for the development of blood vessels and can generate thermogenic fat cells [14][16].

Core Viewpoint - The article emphasizes the importance of adequate protein intake and a balanced diet for individuals using semaglutide, a GLP-1 receptor agonist, for weight loss and diabetes management [2][4][5]. Group 1: Importance of Protein and Diet - Adequate protein intake is crucial when using semaglutide to maintain muscle mass during weight loss [2]. - A balanced diet that includes high fiber foods, such as vegetables and whole grains, is recommended to reduce side effects like constipation and to enhance satiety [2][4]. - The use of multivitamins may help address nutritional deficiencies that arise from reduced food intake during weight loss [4]. Group 2: Mechanism of GLP-1 Drugs - GLP-1 receptor agonists, like semaglutide, mimic the action of the natural hormone GLP-1, which plays a significant role in blood sugar regulation [6]. - These drugs promote insulin secretion from pancreatic beta cells in a glucose-dependent manner, helping to lower postprandial blood sugar levels [6]. - They inhibit glucagon secretion from alpha cells, which typically raises blood sugar levels, thus contributing to lower blood sugar [6]. - GLP-1 receptor agonists delay gastric emptying, reducing the rate at which food enters the small intestine, which aids in controlling post-meal blood sugar spikes [7]. - They also act on the brain's appetite regulation centers to suppress appetite, assisting in weight management [8]. - Long-term use may improve or protect pancreatic beta cell function, which is particularly important for type 2 diabetes patients [9]. Group 3: Impact on Metabolism - A study indicated that semaglutide not only increases satiety but also directly affects metabolism, leading to increased energy expenditure [10]. - The basal metabolic rate (BMR), which accounts for approximately 70% of daily energy expenditure, may be enhanced in individuals using GLP-1 analogs, making it easier to lose weight [11]. - Increased metabolic activity in users of GLP-1 drugs suggests that these medications play a significant role in weight loss by promoting higher energy consumption [11][13].

肥胖世界ObesityWorld . 《肥胖世界》Obesity World - 同步传真肥胖及代谢国际新学术进展，为医学减重临床、教研人员搭建一座与国际接轨的桥梁，「每医健」旗下内容平台。 以下文章来源于肥胖世界ObesityWorld ，作者欢迎订阅 《 临 床 内 分 泌 与 代 谢 杂 志 》 （ The Journal of Clinical Endocrinology & Metabolism ） 近 日 刊 登 了 一 篇 题 为 "Effectiveness of the Dual GIP/GLP1-Agonist Tirzepatide in 2 Cases of Alström Syndrome, a Rare Obesity Syndrome"的病例报告。研究团队首次报道了双重葡萄糖依赖 性促胰岛素多肽（GIP）/胰高糖素样肽-1（GLP-1）受体激动剂替尔泊肽，在两例罕见遗传性肥胖综合征——Alström综合征患者中展现出十 分抢眼的治疗表现。这也是首次在此类人群中系统评估该类药物的应用，为临床管理带来了全新的思路与方向。 患者B（20岁）：起始BMI为46.3kg/m²，伴有明显脂肪 ...

整理 | GLP1减重宝典内容团队 礼来同时表示，已就这款GLP-1口服药orforglipron向美国食品药品监督管理局提交上市申请。FDA此前已授予该药物优先审评资格， 这意味着审批周期有望从常规流程压缩至数月。受消息影响，美股盘前礼来股价整体保持平稳，市场反应相对克制。 此次试验的核心意义，在于解决当前减重治疗中的一个现实难题：大量患者在停用每周注射型减肥药后，体重往往出现明显反弹。尽管 口服药在整体减重幅度上不及注射剂，但最新数据表明，它或可作为一种"过渡性方案"，帮助患者在告别针剂的同时，尽量守住已经取 得的减重成果。 美国制药巨头礼来最新披露的一项后期临床试验结果，为火热的GLP-1减重市场带来了新的想象空间。数据显示，部分肥胖患者在停止 使用注射类减肥药、转而服用礼来研发的每日一次口服减肥药后，仍能在较长时间内维持大部分减重成果。这一结果被视为口服减肥药 在"维持治疗"场景中的关键突破。 版权声明：所有「GLP1减重宝典」的原创文章，转载须联系授权，并在文首/文末注明来源、作者、微信ID，否则减重宝典将向其追究法律责 任。部分文章推送时未能与原作者或公众号平台取得联系。若涉及版权问题，敬请原作者 ...

Core Viewpoint - The article discusses the urgent need for new mechanisms in obesity treatment, highlighting the development of a novel siRNA candidate drug, SGB-7342, by Shengyin Biotech, which targets INHBE for obesity treatment [4][11]. Group 1: Obesity as a Public Health Challenge - Obesity is a chronic metabolic disease characterized by abnormal or excessive fat accumulation, significantly increasing the risk of cardiovascular diseases, type 2 diabetes, and various cancers [5]. - The global population of obese individuals has surpassed 1 billion and is expected to reach approximately 1.37 billion by 2035; in China, there are about 180 million adult obesity patients [6]. Group 2: Current Treatment Limitations - Current mainstream obesity treatments primarily involve GLP-1 receptor agonists, which suppress appetite through the central nervous system but have drawbacks such as gastrointestinal side effects, muscle loss risk, and weight regain after discontinuation [7]. Group 3: RNAi Therapy as a New Approach - RNAi therapy offers a differentiated treatment strategy that does not rely on central appetite regulation, aiming to regulate fat metabolism at the source by targeting key genes involved in fat breakdown and storage [8]. - This approach is expected to selectively reduce fat while preserving muscle mass and improving overall metabolic health, potentially lowering the risk of adverse effects associated with traditional therapies [8]. Group 4: INHBE as a Novel Metabolic Target - The INHBE gene, primarily expressed in the liver, encodes the secreted protein Activin E, which regulates fat breakdown and energy storage by binding to the ALK7 receptor in adipose tissue [9]. - Genetic studies indicate that individuals with INHBE loss-of-function mutations exhibit favorable metabolic traits, providing a biological basis for targeting INHBE in drug development [9]. Group 5: SGB-7342 Candidate Drug - SGB-7342 is a siRNA candidate drug targeting INHBE for obesity treatment, utilizing Shengyin Biotech's proprietary GalNAc conjugation delivery technology for precise liver targeting [10]. - The mechanism involves silencing INHBE mRNA in the liver to lower Activin E protein levels, promoting fat breakdown without inducing muscle loss, thereby improving metabolic disorders and insulin resistance [10]. - Preclinical studies show that SGB-7342 leads to significant weight loss and improved body composition while maintaining muscle mass, demonstrating good safety and tolerability [10]. Group 6: Future Outlook - Obesity is recognized as a complex systemic metabolic disease rather than merely a weight issue, with significant unmet clinical needs in the global obesity treatment landscape [11]. - RNAi therapy, with its novel mechanism directly targeting metabolic pathways, is expected to offer differentiated advantages in selective fat reduction, muscle protection, and long-lasting treatment [11].