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].

Core Viewpoint - The article discusses the initiation of the TRIUMPH-7 Phase III clinical trial by Eli Lilly, which aims to evaluate the efficacy and safety of Retatrutide in patients with obesity or overweight and chronic low back pain, marking the first global Phase III study of GLP1R/GIPR/GCGR triple agonists for pain treatment [2][3]. Group 1 - TRIUMPH-7 is a randomized, double-blind, placebo-controlled international multicenter study expected to start in June 2025 and complete by September 2027 [3]. - The trial plans to enroll 586 participants who will be randomly assigned to receive either weekly injections of Retatrutide or a placebo for 80 weeks [3]. - Primary endpoints include the change in pain intensity from baseline and the percentage change in weight from baseline, while secondary endpoints cover the number of patients achieving pain relief and weight loss targets [3]. Group 2 - Retatrutide is classified as a GLP1R/GIPR/GCGR triple agonist and is currently the fastest advancing candidate in this field, undergoing Phase III trials for multiple indications including obesity, type 2 diabetes, secondary prevention of cardiovascular events, and obstructive sleep apnea [3].

整理 | GLP1减重宝典内容团队 6 月 24 日，信达生物宣布，其 GCG/GLP-1 双受体激动剂玛仕度肽（研发代号 IBI362）在中国 2 型糖尿病患者中的 III 期临床研究 （DREAMS-1）主要结果已在 2025 年美国糖尿病协会（ADA）科学年会以口头报告形式（306-OR）正式发布。信达生物制药集团钱镭博士作 为报告人，对研究核心数据进行了汇报。相关详细研究结果将随后发表于权威学术期刊。 玛仕度肽在降糖方面表现出显著疗效。24 周时，玛仕度肽 4 mg 和 6 mg 组 HbA1c 分别下降 1.57% 和 2.15%，显著优于安慰剂组的 0.14%。 在达标率方面，玛仕度肽组 HbA1c <7.0% 的比例分别为 68.6% 和 87.4%，而安慰剂组仅为 10.7%；HbA1c ≤6.5% 的达标率分别为 55.6% 和 81.5%，安慰剂组仅为 4.4%。 减重方面，玛仕度肽同样展现出明确优势。24 周时，4 mg 和 6 mg 组体重较基线下降幅度分别为 5.61% 和 7.81%，显著高于安慰剂组的 1.26%。体重下降 ≥5% 的患者占比分别为 50.9% 和 69.0%，而 ...

Core Viewpoint - Semaglutide, developed by Novo Nordisk, has significantly impacted the weight loss market with over $7.8 billion in global sales in Q1 this year, approved for treating type 2 diabetes and obesity [2] - Tirzepatide, developed by Eli Lilly, is rapidly gaining ground, showing superior weight loss results compared to Semaglutide in recent studies [4][5] Group 1: Clinical Trial Results - In the SURMOUNT-5 trial, Tirzepatide led to an average weight loss of 20.2% (approximately 22.8 kg) over 72 weeks, with 31.6% of participants losing 25% or more of their body weight [5] - The REDEFINE 1 trial showed that the combination of Cagrilintide and Semaglutide (CagriSema) resulted in an average weight loss of 20.4% (approximately 26.6 kg) over 68 weeks, outperforming both Semaglutide and Cagrilintide alone [8] - In the REDEFINE 2 trial, CagriSema achieved an average weight loss of 13.7% in type 2 diabetes patients, significantly higher than the 3.4% in the placebo group [10][13] Group 2: Safety and Side Effects - CagriSema treatment was associated with a higher incidence of gastrointestinal adverse events (79.6%) compared to the placebo group (39.9%), though most symptoms were mild to moderate [8][13] - In the REDEFINE 2 trial, 72.5% of CagriSema participants reported gastrointestinal side effects, again higher than the 34.4% in the placebo group [13] Group 3: Market Outlook - The combination of Semaglutide and Cagrilintide shows potential to become a significant player in the obesity treatment market, alongside Semaglutide and Tirzepatide [14] - The results from recent clinical trials suggest that CagriSema may redefine the competitive landscape of weight loss medications, particularly in both diabetic and non-diabetic populations [14]

Core Viewpoint - Amgen's experimental obesity treatment drug MariTide requires starting treatment at low doses to minimize side effects such as vomiting, leading to a nearly 6% drop in the company's stock price following the announcement of new trial results [2][5]. Group 1: Trial Results and Drug Efficacy - The ongoing 72-week Phase III trial will assign overweight or obese participants to one of three dosing regimens, starting with lower initial doses and gradually increasing over eight weeks [2]. - In a Phase II trial, MariTide helped patients lose up to 20% of their weight, with effective results observed for both monthly and bi-monthly dosing [5]. - The drug combines antibodies and two peptides targeting receptors activated by GLP-1, which suppresses appetite and regulates blood sugar, while also blocking GIP, a hormone involved in digestive functions [5]. Group 2: Side Effects and Comparisons - Nearly 90% of participants who started at the highest dose reported vomiting, while only 22% of those who gradually reached the target dose experienced the same issue [3]. - Amgen reported no new safety concerns in the trial, with side effects consistent with other GLP-1 class drugs. In comparison, Novo Nordisk's Wegovy had a vomiting rate of 24%, and Eli Lilly's Zepbound had a rate of 13% [6]. Group 3: Future Plans and Additional Benefits - Amgen plans to initiate more Phase III clinical trials this year to evaluate MariTide's effects on patients with complex health conditions, such as cardiovascular diseases and obstructive sleep apnea [7]. - The drug has shown potential to lower blood sugar levels by up to 2.2 percentage points in type 2 diabetes patients and is associated with improvements in key cardiovascular metabolic indicators, including waist circumference, blood pressure, inflammatory markers, and cholesterol levels [7].

Core Viewpoint - The article highlights the promising results of RAY1225, a novel GLP-1/GIP dual receptor agonist developed by Zhongsheng Pharmaceutical, showcasing its efficacy and safety in treating overweight, obesity, and type 2 diabetes during the ADA conference [2][5]. Group 1: Clinical Results - RAY1225 demonstrated significant weight loss effects, with an average reduction exceeding 10% in all dosage groups by week 10, and over 15% in the 9mg group by week 24 [2]. - Approximately 95.1% of participants achieved a weight loss of 5% or more by week 24, indicating strong efficacy [2]. - The gastrointestinal side effects associated with RAY1225 were mostly mild, with lower incidence rates of diarrhea, nausea, and vomiting compared to Tirzepatide [3]. Group 2: Administration and Compliance - RAY1225 is administered bi-weekly, which is more convenient than the weekly injection schedule of Tirzepatide, potentially improving patient adherence to the treatment [4]. Group 3: Ongoing Research - The Phase III clinical trial (REBUILDING-2) for RAY1225 has commenced, featuring a multi-center, randomized, double-blind, placebo-controlled design, with ethical approval obtained from relevant institutions [5].

Core Viewpoint - Zealand Pharma A/S announced positive preliminary results for its GLP-1/GLP-2 dual receptor agonist dapiglutide in a Phase I b multi-dose escalation trial, showing significant weight loss without lifestyle interventions [1][4]. Group 1: Trial Results - In the dapiglutide treatment group, participants experienced an average weight loss of 11.6% over 28 weeks, compared to only 0.2% in the placebo group [1][4]. - The trial included 30 participants, predominantly male (approximately 93%), with a median age of 44.5 years and a median starting body mass index (BMI) of 28.8 kg/m² [4][5]. - The trial demonstrated good tolerability at the highest dose of 26 mg, with no severe or serious treatment-related adverse events reported [4][5]. Group 2: Adverse Events - Most adverse reactions were mild gastrointestinal symptoms, such as nausea and vomiting, with two participants withdrawing due to adverse reactions, one related to gastrointestinal discomfort [4][5]. - Injection site reactions were minimal and all were mild, consistent with the profile of similar incretin drugs in other trials [4][5]. Group 3: Drug Mechanism and Future Directions - Dapiglutide is designed to address obesity-related comorbidities driven by chronic low-grade inflammation, combining GLP-1 mediated weight control and GLP-2's improvement of gut barrier function [7]. - Zealand Pharma is advancing a range of differentiated GLP-1 related therapies, including the insulin analog petrelintide, as potential foundational treatments in the weight loss field [4][7]. Group 4: Study Design - The Phase I b trial was a single-center, randomized, double-blind, placebo-controlled study, enrolling participants with a BMI between 27.0 and 39.9 kg/m² [5][6]. - The first part of the trial included 54 participants across three dosage groups, with results indicating an additional weight loss of 8.3% in the dapiglutide group compared to placebo over 13 weeks [5].