整理 | GLP1减重宝典内容团队 GIP（胃抑制多肽）是一种由肠道K细胞分泌的多肽类激素，与GLP-1（胰高血糖素样肽-1）一起被称为肠促胰素。肠促胰素通过刺激胰岛素分 泌，帮助清除大约80%饮食中吸收的葡萄糖。对于2型糖尿病（T2D）患者来说，肠促胰素的功能几乎完全丧失，因此恢复这一功能对糖尿病治 疗至关重要。近期的研究表明，GIP在肠促胰素中扮演着最重要的角色。口服葡萄糖后，约44%的胰岛素分泌是由GIP刺激产生的，而GLP-1仅 占22%。 替尔泊肽是一种基于GIP序列改造的多肽，是目前研究进展最快的GLP-1/GIP双受体激动剂，也是GIP受体激动剂中的领军药物。通过对GIP进 行C20不饱和脂肪酸侧链修饰，替尔泊肽的半衰期可达到5天，支持每周一次的给药频率。 在受体亲和力方面，替尔泊肽主要偏向于GIP受体 ，其GIP受体的效价与天然GIP相当，而对GLP-1受体的效价比天然GLP-1低约13倍。临床试验表明，替尔泊肽在控制血糖和减轻体重方面优于 GLP-1单一受体激动剂——司美格鲁肽。近期研究发现，降低起始剂量和增加剂量的幅度可以有效减少替尔泊肽的副作用，而胃排空速率对餐 后血糖的影响也被证明是重 ...

Core Viewpoint - The article emphasizes the increasing focus on weight management in China, driven by national health strategies and a growing demand for weight management services across various demographics [5][9][19]. Group 1: National Initiatives and Trends - The National Health Commission highlighted weight management during the recent national congress, indicating a significant governmental focus on this issue [5]. - In 2024, 16 ministries will jointly launch a three-year "Weight Management Year" initiative, reflecting the urgency and importance of addressing weight issues in the population [5]. - The concept of weight management has gained popularity, with hospitals reporting a surge in demand for weight management clinics, particularly among younger individuals and children [5][9]. Group 2: Hospital Services and Patient Demographics - Hospitals like Zhejiang University Second Hospital have established multiple specialized clinics for weight management, including nutrition, pharmacotherapy, and surgical options [9]. - The number of patients visiting weight management clinics has doubled in recent years, with approximately 13,000 visits annually at Zhejiang University Second Hospital [9][10]. - A notable increase in young patients seeking weight management services has been observed, with many presenting additional health issues such as diabetes and high uric acid levels [10][11]. Group 3: Weight Management Approaches - Experts stress that weight management should be viewed as a long-term commitment rather than a quick fix, advocating for sustainable lifestyle changes [7][15]. - A realistic weight loss goal is to lose 4 pounds per month, with an ideal annual target of 10% to 20% of body weight [13]. - Quick weight loss methods often lead to unsustainable practices and rebound weight gain, highlighting the importance of gradual and consistent efforts [14][18]. Group 4: Challenges and Misconceptions - Many patients express unrealistic expectations regarding rapid weight loss, often asking how much weight they can lose in a week [6][12]. - The phenomenon of "weight regain" is common, with many individuals reverting to previous habits after initial success, underscoring the need for ongoing lifestyle management [18]. - The article dispels the myth of "lying down to lose weight," emphasizing that there are no shortcuts to effective weight management [20].

整理 | GLP1减重宝典内容团队 随着全球肥胖症和2型糖尿病（T2DM）发病率持续攀升，开发新型高效的治疗药物成为医学研究的重要方向。GLP-1/GIP双受体激动 剂通过同时激活胰高糖素样肽-1（GLP-1）和葡萄糖依赖性促胰岛素释放多肽（GIP）受体，实现控糖和减重的双重效果，在提高治疗 效率的同时降低剂量相关的不良反应。目前，已有十余种此类药物进入临床阶段，仅有一款正式上市，HRS9531的研发进度在全球位 列第二。 在第85届美国糖尿病协会年会（ADA 2025）上，恒瑞医药自主研发的GLP-1/GIP双受体激动剂HRS9531公布了三项最新研究成果：两 项评估注射剂型在超重或肥胖人群中的疗效与安全性，一项探讨口服制剂在健康人群中的药效、代谢动力学及耐受性。本文对这三项研 究内容进行梳理和总结，展示中国在该领域的最新进展。 研究一：HRS9531注射液在中国超重/肥胖人群中的疗效与安全性（Ⅱ期） 研究目的 本项Ⅱ期临床研究旨在评估HRS9531每周一次皮下注射在未合并糖尿病的中国超重或肥胖成人中的体重管理效果及安全性。 安全性 不 良 事 件 发 生 率 为 HRS9531 组 91.8% ， 安 慰 ...

Core Viewpoint - The article discusses the launch of a three-year "Weight Management Year" initiative by the National Health Commission of China, aimed at promoting healthy lifestyles and addressing the growing obesity issue in the country [4][6]. Group 1: Current Situation of Obesity in China - As of now, there are 230 million people classified as overweight or obese in China, with an overweight rate of 34.3% and an obesity rate of 16.4% among adults aged 18 and above [6][7]. - By 2030, it is predicted that the combined rate of overweight and obesity will rise to 65.3%, indicating a significant public health concern [6]. - In Beijing, the adult overweight and obesity rate has reached 58.4%, with men at a higher rate of 64.3% [7]. Group 2: Health Risks Associated with Obesity - Obesity is linked to various chronic diseases, including hypertension, high cholesterol, type 2 diabetes, and certain cancers, significantly impacting overall health and quality of life [7][8]. - The causes of obesity are multifaceted, with primary obesity being influenced by genetics, lifestyle, and environmental factors [7]. Group 3: Methods to Assess Obesity - The article outlines three common methods for assessing obesity: BMI (Body Mass Index), waist circumference, and body fat percentage [9][10][13]. - In China, a BMI over 24 is considered overweight, while over 28 is classified as obese [9]. - Waist circumference measurements indicate abdominal obesity, which poses higher health risks [11][12]. Group 4: Medical Weight Loss Approach - The article emphasizes a structured medical weight loss approach, which includes five key steps: assessment, daily weight monitoring, personalized diet and exercise plans, progress tracking, and maintaining results [15][16][28]. - Specific dietary strategies mentioned include high-protein diets, energy-restricted diets, and intermittent fasting [21][23][25]. - Regular physical activity is also highlighted as essential for effective weight management [27].

Core Viewpoint - The article discusses the launch of the weight loss drug Semaglutide (brand name: Novo Nordisk) in China and emphasizes the importance of a holistic approach to weight loss that includes dietary changes alongside medication use [1][3]. Group 1: Drug Overview and Usage - Semaglutide was officially launched in China on November 17, leading to an increase in consultations at weight loss and endocrinology clinics [1]. - The use of weight loss medications requires standardized management, as relying solely on drugs is insufficient for effective weight loss [1][3]. Group 2: Nutritional Considerations - Users of Semaglutide should focus on the nutritional density of their food, as rapid weight loss can lead to a decrease in muscle mass [3][4]. - It is crucial for users to ensure adequate intake of high-quality protein, fiber, and hydration, as well as to consider taking multivitamins to address potential nutritional gaps [5][4]. Group 3: Recommended Dietary Practices - A balanced plate should include protein, vegetables, and starches tailored to individual health conditions and preferences [5]. - Specific recommendations include consuming 85-113g of protein, 170g of non-starchy vegetables, and 85g of starch per meal, although many users may struggle to achieve this balance [5]. Group 4: Foods to Avoid - High-fat foods, such as fried items and those cooked in heavy oils, should be avoided as they can cause gastrointestinal discomfort, especially when using Semaglutide [7]. - Foods high in trans fats and saturated fats, such as full-fat dairy and red meats, can exacerbate digestive issues and affect the drug's efficacy [7]. - High-sugar foods and refined carbohydrates should be limited, as they can lead to blood sugar spikes and interfere with the medication's effects [10][9]. - Alcohol consumption should be minimized or avoided due to its potential to aggravate digestive problems and increase the risk of hypoglycemia [11].

Core Viewpoint - Altimmune, Inc. announced positive preliminary results from the IMPACT 2b clinical trial of its candidate drug pemvidutide for the treatment of Metabolic Associated Steatotic Liver Disease (MASH), but the efficacy disappointed investors, leading to a significant drop in stock price [2]. Group 1: Clinical Trial Results - The trial recruited 212 participants diagnosed with MASH at F2/F3 fibrosis stages, with a low dropout rate of only 9% [6]. - In the intention-to-treat (ITT) analysis, 59.1% of the 1.2 mg group and 52.1% of the 1.8 mg group achieved MASH resolution without worsening fibrosis, significantly higher than the 19.1% in the placebo group (both p<0.0001) [10]. - For fibrosis improvement without worsening MASH, the improvement rates were 31.8% and 34.5% for the treatment groups, compared to 25.9% for the placebo, but the differences were not statistically significant [11]. - AI-assisted analysis showed that 30.6% of the 1.8 mg group had a fibrosis reduction of over 60%, significantly better than the 8.2% in the placebo group (p<0.001) [12]. - The treatment groups showed significant improvements in non-invasive fibrosis assessment indicators compared to the placebo [13]. Group 2: Weight Control and Tolerability - The average weight loss for the 1.2 mg and 1.8 mg groups was 5.0% and 6.2%, respectively, compared to only 1.0% in the placebo group (both p<0.001) [14]. - The overall tolerability of the drug was good, with only 0.0% and 1.2% of participants in the treatment groups discontinuing due to adverse reactions, lower than the 2.4% in the placebo group [16]. - No serious adverse events related to the treatment were reported [17]. Group 3: Expert Commentary - The CEO of Altimmune expressed confidence in pemvidutide's potential to change the treatment landscape for MASH, a condition expected to affect over 27 million people in the U.S. by 2030 [9]. - An expert noted that achieving MASH resolution and weight loss within 24 weeks is uncommon among similar drugs, highlighting pemvidutide's superior tolerability and low discontinuation rate [9]. - The results indicate a promising trend for fibrosis improvement, and the company plans to advance to Phase 3 trials following a successful Phase 2 meeting with the FDA in Q4 2025 [9].

Core Viewpoint - GLP-1 class drugs are becoming a significant treatment direction in the fields of glycemic control and weight loss, with Orforglipron emerging as a promising oral non-peptide small molecule GLP-1 receptor agonist that offers convenience and efficacy [1][3][13] Summary by Sections Introduction to GLP-1 Drugs - Current GLP-1 therapies primarily use peptide structures requiring subcutaneous injection, which is inconvenient for patients [1] Orforglipron Overview - Orforglipron is a non-peptide small molecule GLP-1 receptor agonist with high oral bioavailability, allowing for administration without dietary or drinking restrictions [3] - It was recognized in 2023 as a notable small molecule in the "Hunter of Drugs" annual list due to its technological path, scientific value, clinical prospects, and innovation [3] Clinical Trial Results - The ACHIEVE-1 trial, a phase 3 study, included 559 adults with early-stage type 2 diabetes, assessing three doses of Orforglipron (3 mg, 12 mg, 36 mg) over 40 weeks [4] - The trial demonstrated significant improvements in HbA1c levels, with 68% to 73% of patients achieving treatment goals (HbA1c < 7.0%) [3][5] Efficacy Results - At week 40, all Orforglipron treatment groups showed significantly better glycemic control compared to the placebo group (P<0.001) [5] - HbA1c reductions were as follows: 3 mg group -1.24%, 12 mg group -1.47%, 36 mg group -1.48%, while the placebo group saw a reduction of only -0.41% [5] Blood Sugar Control Performance - Orforglipron groups showed superior results in achieving various HbA1c targets compared to the placebo group [6] - Notably, 17%-24% of Orforglipron patients reached HbA1c ≤ 5.7%, compared to only 4% in the placebo group [6] Weight Loss and Metabolic Improvement - Orforglipron demonstrated dose-dependent weight loss: 3 mg group -4.5% (4.2 kg), 12 mg group -5.8% (5.2 kg), 36 mg group -7.6% (7.2 kg) [8] - In comparison, the placebo group lost only 1.7% (1.5 kg) [8] - The proportion of patients achieving weight loss ≥5% was 43%-61% in the Orforglipron groups versus 17% in the placebo group [9] Lipid Regulation - Orforglipron also showed positive effects on lipid levels, particularly in the 36 mg group, with significant reductions in triglycerides and non-HDL cholesterol [11] Safety Observations - The most common adverse effects were mild to moderate gastrointestinal discomfort, primarily during dose escalation, with no serious hypoglycemic events reported [12] Conclusion and Outlook - Orforglipron presents a promising option for type 2 diabetes patients who struggle to achieve glycemic control through lifestyle changes alone, offering a convenient oral administration method that enhances blood sugar management, weight control, and metabolic parameters [13]

Core Viewpoint - The approval of XinErMei® (a dual receptor agonist for glucagon and GLP-1) by the National Medical Products Administration (NMPA) marks a significant advancement in obesity treatment, aiming to address the urgent issue of overweight and obesity in China [2][5][6]. Group 1: Product Overview - XinErMei® is the world's first GCG/GLP-1 dual receptor agonist for weight management, which not only suppresses appetite but also promotes fat burning and reduces visceral fat [5][11]. - Clinical studies indicate that patients using XinErMei® can achieve a weight loss of up to 21%, with liver fat content reduced by over 80%, waist circumference decreased by 11 cm, and neck circumference by 3 cm [5][12]. Group 2: Market Context - China faces a severe obesity crisis, with approximately 500 million adults classified as overweight or obese, the highest globally [8][9]. - The World Obesity Federation estimated that the economic loss due to overweight and obesity in China could reach $283.3 billion in 2020 [8]. Group 3: Clinical Evidence - The approval of XinErMei® is based on the results of the GLORY-1 Phase III clinical trial, which demonstrated significant weight loss compared to placebo, with mean percentage changes from baseline at week 48 being -12.0% and -14.8% for the 4 mg and 6 mg doses, respectively [11][12]. - The trial also showed that 73.5% and 82.8% of participants in the 4 mg and 6 mg groups, respectively, achieved a weight loss of at least 5% from baseline [11]. Group 4: Regulatory and Clinical Guidelines - The National Health Commission has included "weight management" in the "Healthy China 2030" initiative, emphasizing the need for effective weight management strategies [6][9]. - Recent clinical guidelines recommend the early initiation of pharmacological treatment for patients who do not achieve weight loss goals through lifestyle interventions alone [9][10]. Group 5: Future Implications - XinErMei® is expected to reshape the clinical treatment landscape for obesity in China, providing a new therapeutic option that addresses both weight loss and metabolic health [6][14]. - The innovative delivery system of XinErMei® enhances convenience and safety, making it a promising choice for patients [14].

Core Viewpoint - The article discusses the approval and potential impact of the dual receptor agonist Mazdutide (信尔美®), developed by Innovent Biologics and Eli Lilly, for weight management in overweight and obese adults in China. This drug is the first of its kind globally, targeting both GLP-1 and GCGR receptors to enhance weight loss and metabolic health [2][4][12]. Group 1: Drug Approval and Mechanism - Mazdutide has received approval from the National Medical Products Administration in China for long-term weight control in adults with obesity or overweight [2]. - Unlike traditional single-target GLP-1 receptor agonists, Mazdutide activates both GLP-1 and glucagon (GCG) receptors, combining appetite suppression and energy expenditure to improve metabolic health [4][9]. - The drug's dual mechanism allows it to effectively reduce body weight while also improving liver lipid metabolism, showcasing its potential in managing metabolic diseases [4][18]. Group 2: Clinical Efficacy and Safety - Multiple clinical studies have confirmed the efficacy and safety of Mazdutide, with significant weight loss and improvement in metabolic markers observed [5][21]. - The GLORY-1 Phase III clinical trial, led by a Chinese research team, demonstrated that Mazdutide significantly reduced weight and improved various metabolic indicators in overweight or obese populations [6][12]. - At 48 weeks, participants receiving Mazdutide showed an average weight reduction of -12.0% and -14.8% for the 4mg and 6mg doses, respectively, compared to a -0.5% reduction in the placebo group [20]. Group 3: Impact on Liver Health - Mazdutide has shown promising results in reducing liver fat content, which is crucial for addressing metabolic dysfunction-related fatty liver disease (MASH) [21][22]. - In participants with baseline liver fat content ≥10%, the drug resulted in a reduction of liver fat by -65.85% and -80.24% for the 4mg and 6mg doses, respectively, compared to -5.27% in the placebo group [22]. - The drug's ability to lower liver fat and improve metabolic health positions it as a potential treatment for MASH, which currently lacks effective therapies [21][22]. Group 4: Broader Implications and Future Research - The introduction of Mazdutide is expected to reshape the clinical treatment landscape for obesity and metabolic diseases in China, aligning with national health initiatives aimed at managing overweight and obesity [17][25]. - The drug's innovative delivery system enhances user convenience and safety, addressing common concerns associated with injectable medications [25]. - Ongoing and planned clinical studies will further explore Mazdutide's efficacy in various populations, including adolescents and patients with heart failure [29].

Core Viewpoint - AstraZeneca's AZD6234 and AZD9550 injections have been approved for clinical trials in China, aimed at long-term weight management for overweight or obese adults with at least one obesity-related comorbidity [2][4]. Group 1: Clinical Trial Details - AZD6234 is a long-acting insulin analog currently undergoing Phase II monotherapy studies for obesity in China and the US, while also being tested in combination with AZD9550 in various countries [4]. - AZD9550 is a dual receptor agonist targeting GLP-1R and GCGR, with indications covering metabolic dysfunction-related fatty liver disease, type 2 diabetes, and obesity, and is also in clinical research [4]. - The ASCEND study is a global, multi-center, randomized, double-blind, placebo-controlled Phase IIb clinical trial, evaluating the efficacy, safety, and tolerability of the combination therapy or monotherapy in overweight/obese adults with obesity-related complications, aiming to enroll 360 participants [4]. Group 2: Product Pipeline - AstraZeneca has three innovative products in its obesity treatment pipeline: AZD5004, AZD6234, and AZD9550, with AZD5004 currently in Phase II monotherapy clinical trials for diabetes and obesity [4].