撰文丨王聪 编辑丨王多鱼 排版丨水成文 胃肠道中表达的众多 G 蛋白偶联受体 （GPCR） 在激活后作为重要的转导器来调控多种生理功能。其中， TGR5 是一种在肠内分泌 L 细胞中表达的重要的胃肠道 GPCR，它能被肠道 胆汁酸 激活 ， 并促进 GLP- 1 分泌，从而在葡萄糖利用中发挥作用。 然而，TGR5 在体内多组织分布，长期补充外源 TGR5 激动剂会引发 肝胆毒性 ，这大大限制了 TGR5 激 动剂开发。 2025 年 11 月 19 日，中国科学院上海药物 研究 所 甘勇 、 周虎 团队 （ 张雅琪 、 黄蕙 、 汪雅莹 为论 文共同第一作者 ） 在 Science 子刊 Science Translational Medicine 上发表了题为： Intestinal TGR5- targeted Carrier-Drug Conjugate Improves Glycemic Control in Mice and Pigs 为题的研究论文。 该研究提出了一种全新的非吸收 型 载体-药物偶联物 （ CaDC ） 策略，能够在肠 腔侧持续 激活 TGR5 ，实现持续且安全的降血糖，效果超过了 ...

整理 | GLP1减重宝典内容团队 诺和诺德预计将在下月初发布的研究结果可能为GLP-1药物——目前被数百万患者用于治疗糖尿病和减重——是否能减缓阿尔茨海默 病的进展提供最强的指示。 这两项试验，诺和诺德称其为"彩票"，正在测试其糖尿病药物Rybelsus ，该药物与Ozempic和Wegovy含 有相同的活性成分——司美格鲁肽——在数千名轻度阿尔茨海默病患者中，目标是将患者的认知衰退速度至少降低20%。 阿尔茨海默病专家表示，如果试验成功，这将为缓解这种定义为大脑中毒性淀粉样斑块的病症提供一种新的、方便的治疗方法，而全 球约有5000万人受此疾病影响。无论结果如何，研究人员预计将为未来研究提供重要线索，了解像司美格鲁肽这样的药物，以及礼来 的替尔泊肽和Mounjaro，如何在对抗阿尔茨海默病中发挥作用。 点击关注，追踪最新GLP-1资讯 阿尔茨海默病协会首席科学官Maria Carrillo表示，这项研究"有可能具有变革性。"然而，专家们一致认为，GLP-1类药物如何影响大 脑仍不清楚。进入试验的证据大多支持GLP-1类药物用于治疗与糖尿病和肥胖相关的痴呆症患者。2021年启动的阿尔茨海默病研究基 于动物研 ...

整理 | GLP1减重宝典内容团队 11月21日，礼来制药在美股收盘时的市值达到了1万亿美元，创下历史新高，成为全球首家市值突破万亿美元的上市制药公司。而同 日，诺和诺德的市值为2114亿美元，默沙东为2426亿美元，诺华为2442亿美元，强生为4912亿美元，辉瑞为1423亿美元。 过去两年里，礼来的市值一路飙升，凭借明显的领先优势，已经远远超过了强生、艾伯维、诺和诺德等众多全球制药巨头。 | 1066.650 今 开 1041.000 1059.700+ 最高 | | | --- | --- | | +16.410 +1.57% | 最低 1038.000 昨 收 1043.290 | | 成交额 | | | 成交量 | 426.57万股 市盈率(静) 90.50 总股本 9.45亿 | | 换手率 | 0.45% 市盈率(动) 38.55 流通值 9994.02亿 | | 52周最高 1066.650 市净率 1 | 42.11 流通股 9.43亿 | | 52周最低 | 621.500 委 比 77.78% 振 幅 2.75% | | 历史最高 1066.650 量 比 | 1.10 股息TTM 5. ...

对于未来GLP-1类药物市场的表现，摩根大通相关研报则指出，预计2030年全球GLP-1药物市场年销售 额将超过1000亿美元。派格生物的加入，无疑让原本就火热的国内GLP-1赛道更加沸腾。 不过，在近期举办的第十届医药创新与投资论坛上，多位与会专家在提及GLP-1赛道时表示，尽管其市 场前景广阔，但竞争已异常激烈。北京大学人民医院纪立农教授在论坛上直言："从2021年到现在也就 四年的时间，减重药物很快成为红海。" 自"减肥神药"司美格鲁肽火出圈后，GLP-1赛道新入玩家络绎不绝。目前，全球市场由诺和诺德的司美 格鲁肽和礼来的替尔泊肽两大巨头主导，国内药企盯上GLP-1这块蛋糕的同样不在少数，竞争日趋白热 化。 近日，国家药品监督管理局（NMPA）官网公告显示，派格生物研发的GLP-1受体激动剂「维培那肽注 射液」（商品名：派达康 ）正式获得上市批准，适用于改善成人2型糖尿病患者的血糖控制。 这是继华东医药（000963）利拉鲁肽、仁会生物贝那鲁肽、信达生物玛仕度肽、银诺医药依苏帕格鲁肽 等明星药物之后，中国本土企业在GLP-1赛道上的又一重要突破。 派格生物公告中提到，派达康 (PB-119）为本公司开发 ...

Core Viewpoint - The American College of Cardiology (ACC) has officially recognized semaglutide and tirzepatide as preferred medications for obesity treatment, marking a significant shift in the management of obesity and its associated cardiovascular risks [7][10]. Summary by Sections Breakthrough Therapies - Innovative drugs like semaglutide and tirzepatide not only significantly reduce weight but also provide additional cardiovascular protection for high-risk patients, particularly those with type 2 diabetes or existing cardiovascular diseases [10]. Obesity as a Health Threat - Obesity is highlighted as a serious health risk, leading to metabolic disorders, respiratory issues, and various heart diseases. It is recognized as an independent risk factor for cardiovascular diseases [11]. Weight Loss Thresholds - Different weight loss percentages yield varying cardiovascular benefits: a 10%-15% weight loss can reduce general cardiovascular risks, while heart failure patients may need to lose over 15% for significant improvement [12]. Treatment Options - The treatment landscape includes lifestyle interventions, weight loss surgery, and pharmacotherapy. The ACC suggests a reevaluation of the traditional approach of prioritizing lifestyle changes before medication [15]. Third-Generation Weight Loss Drugs - Semaglutide and tirzepatide represent a revolutionary choice in obesity management, with long-term efficacy and safety data supporting their use for weight loss [16]. Weight Loss Effectiveness - Comparative data shows that semaglutide leads to an average weight loss of 14.9%, while tirzepatide achieves an average of 20.9%, making it the most effective option currently available [18][20]. Long-Term Treatment Importance - Long-term treatment is crucial as stopping medication can lead to weight regain. Continuous use combined with lifestyle adjustments is essential for maintaining weight loss [21]. Accessibility and Economic Burden - The main challenges for semaglutide and tirzepatide include limited supply and high costs, which may affect patient access to these therapies [22]. Cardiovascular Benefits Beyond Weight Loss - The NuSH therapy not only aids in weight loss but also reduces the risk of heart attacks and strokes in obese patients without diabetes, and improves outcomes for heart failure patients [23]. Approved Weight Loss Medications in China - The 2024 guidelines in China have approved five medications for adult weight loss, emphasizing a multidisciplinary approach to obesity treatment [24].

Core Insights - The article discusses the challenges and new perspectives in the treatment of resistant hypertension, particularly focusing on the potential of GLP-1/GIP receptor agonists in managing blood pressure in patients who do not respond to traditional medications [6][7][12]. Group 1: Resistant Hypertension - Resistant hypertension is defined as a condition where patients cannot achieve effective blood pressure control despite using five or more antihypertensive medications at maximum doses [6]. - This condition significantly increases the risk of cardiovascular and renal complications, highlighting the need for more effective treatment options [6]. Group 2: Case Study - A case study of a 71-year-old female patient illustrates the potential of GLP-1/GIP receptor agonists. Despite being on eight antihypertensive medications, her blood pressure remained uncontrolled until she began treatment with liraglutide in 2013, which reduced her systolic blood pressure from 206 mmHg to 160 mmHg over six years [8][10]. - The treatment was later switched to dulaglutide and then to terzepatide, resulting in further blood pressure reduction to 135 mmHg, demonstrating the effectiveness of these agents in resistant hypertension [9][10]. Group 3: Mechanism of Action - GLP-1/GIP receptors are widely distributed in the hypothalamus, carotid body, vascular endothelium, and kidneys. Animal studies suggest that these receptor agonists may lower blood pressure by inhibiting sympathetic nervous system activity, improving endothelial dysfunction, and/or reducing vascular remodeling [12]. - The findings from the case study indicate that GLP-1/GIP receptor agonists may have broader applications in blood pressure control, especially for patients with resistant hypertension, and emphasize the need for further exploration of their mechanisms [12].

Core Insights - The article discusses the efficacy of Semaglutide for weight management in both diabetic and non-diabetic patients, highlighting a significant difference in weight loss outcomes between the two groups [4][5][7]. Summary by Sections Efficacy in Non-Diabetic Patients - Non-diabetic patients using Semaglutide experience an average weight loss of 10.3% to 17.4%, while diabetic patients achieve an average weight loss of only 6.2% [5][9]. - In clinical trials, 86.4% to 88.7% of non-diabetic participants lost at least 5% of their body weight when treated with Semaglutide compared to placebo [9]. Efficacy in Diabetic Patients - The STEP 2 trial, which involved overweight or obese adults with type 2 diabetes, showed that Semaglutide resulted in an average weight loss of 6.2% compared to placebo, with 68.8% of participants losing at least 5% of their body weight [10]. Explanations for Efficacy Differences - The article suggests several potential reasons for the superior efficacy of Semaglutide in non-diabetic patients, including the impact of concomitant medications that promote weight gain in diabetic patients, such as sulfonylureas and insulin [11][13]. - Fear of hypoglycemia in diabetic patients may lead to increased food intake, negatively affecting weight loss outcomes [13]. - Differences in energy expenditure and the longer duration of obesity in diabetic patients may also contribute to the observed disparities in weight loss efficacy [14]. Clinical Trial Overview - The STEP series of clinical trials, which began in June 2018, included approximately 25,000 participants and demonstrated the long-term efficacy and safety of Semaglutide for weight management [7].

Core Insights - The article discusses the growing interest of Western pharmaceutical companies in China's biopharmaceutical market, highlighting both opportunities and challenges in collaboration with local firms [4][11]. Group 1: Cultural Differences - One of the main challenges in collaborating with Chinese companies is the cultural differences, particularly in communication and decision-making processes [7][8]. - In China, decision-making is often hierarchical, with authority resting with founders or chairpersons rather than operational CEOs, necessitating careful identification of decision-makers by foreign firms [7][19]. - Building trust through informal interactions over 6 to 12 months is crucial, as relationships (guanxi) play a significant role in Chinese business culture [7][19]. Group 2: Decision Dynamics and Collaboration Models - The rapid development of China's biopharmaceutical industry has led to a shift from merely importing Western assets to a more globalized collaboration model, with Chinese firms increasingly focusing on independent R&D [9][11]. - Foreign companies need to understand the importance of "headline numbers" in negotiations, which often reflect high upfront payments or market promotion figures, and adjust contract structures accordingly [9][11]. Group 3: Risk Management and Data Transparency - Data transparency remains a challenge, as the quality of data provided by Chinese biopharmaceutical companies may not always meet FDA or EU standards, necessitating thorough due diligence [10][15]. - Collaborating with local experts can help foreign firms ensure data accuracy and mitigate risks associated with data discrepancies [10][15]. Group 4: Future Outlook - Despite challenges, foreign companies maintain confidence in the Chinese biopharmaceutical market due to its rapid growth, large market demand, and supportive government policies [11][24]. - Partnerships with Chinese firms are essential for cost savings of 40%-70%, and future collaboration models will likely become more diverse, including joint ventures and new business units [11][24].

Core Viewpoint - The article emphasizes the urgent need for weight management due to the global obesity crisis, which is linked to various metabolic diseases and health issues. It advocates for a dual approach to weight management: self-discipline through lifestyle changes and external interventions such as medication or surgery [6][10]. Summary by Sections Obesity as a Public Health Crisis - The National Health Commission has issued a warning about the critical state of public health due to obesity, which is a major contributor to diseases like type 2 diabetes and cardiovascular issues [6]. Weight Management Approaches - Effective weight management requires both self-discipline (through exercise, diet, and sleep) and external aids (such as medications and surgical options) [6]. GLP-1 Receptor Agonists - Medications like Semaglutide and Liraglutide, which are GLP-1 receptor agonists, have been approved for weight loss. These drugs mimic the natural peptide GLP-1 in the body, aiding in appetite control and energy balance [7]. Discovery of BRINP2-Related Peptide (BRP) - A new peptide, BRP, has been identified by a Stanford University team using AI tools. This peptide shows significant potential in reducing food intake and improving blood sugar levels, comparable to GLP-1 receptor agonists, without causing anxiety or behavioral changes [8][14]. Mechanism of Action - BRP operates independently from known appetite-related peptides and activates specific neuronal pathways in the hypothalamus to regulate appetite. It enhances fat oxidation and reduces overall food intake without adverse effects [14][16]. Experimental Results - In mouse studies, BRP significantly reduced food intake and body weight, improving glucose tolerance and insulin sensitivity. The effects were similar to those of Liraglutide, indicating its potential as a weight loss treatment [14][16]. Future Directions - The discovery of BRP opens new avenues for obesity treatment, although further research is needed to understand its mechanisms and long-term safety before clinical application [18].

Core Viewpoint - The article discusses the advancements and efficacy of Tirzepatide, a dual GLP-1/GIP receptor agonist, in treating obesity and type 2 diabetes, highlighting its superior weight loss results compared to traditional GLP-1 receptor agonists like Semaglutide [7][10][12]. Group 1: Mechanism and Efficacy - GIP plays a crucial role in insulin secretion, accounting for approximately 44% of insulin release after oral glucose intake, while GLP-1 contributes only 22% [5]. - Tirzepatide, modified from GIP, has a half-life of 5 days, allowing for weekly administration, and shows better efficacy in blood sugar control and weight loss compared to GLP-1 receptor agonists [7][8]. - Clinical trials indicate that Tirzepatide significantly reduces body weight in patients with obesity or prediabetes, with weight loss percentages of 15.4% (5mg), 19.9% (10mg), and 22.9% (15mg) compared to a mere 2.1% in the placebo group [10]. Group 2: Clinical Trials and Results - The SURMOUNT-2 study demonstrated that higher doses of Tirzepatide led to an average weight loss of 15.7% (15.6kg) in type 2 diabetes patients over 72 weeks, with 81.6% of patients in the 10mg group losing over 5% of their body weight [12]. - The SURMOUNT-3 trial showed a weight reduction of up to 26.6% after 12 weeks of lifestyle intervention and 72 weeks of Tirzepatide treatment [14]. - In the SURMOUNT-5 trial, patients treated with Tirzepatide lost an average of 22.8kg, outperforming the active control group by 47% in weight loss [14]. Group 3: Safety and Side Effects - Approximately 80% of Tirzepatide users reported at least one side effect, primarily gastrointestinal issues such as nausea and diarrhea, similar to those experienced with Semaglutide [15]. - The incidence of nausea was reported at 33% for the highest dose of Tirzepatide, compared to 44% for Semaglutide, indicating a potentially lower side effect profile for Tirzepatide [15][17]. - GIP's role in appetite suppression may help mitigate some of the adverse effects associated with GLP-1 receptor activation, enhancing patient compliance and treatment efficacy [19].