Core Viewpoint - A new oral weight loss drug, Synt-101, developed by Syntis Bio, is emerging as a more accessible alternative to injectable GLP-1 weight loss medications, with a recent funding of $38 million to accelerate its development [4]. Group 1: Company Overview - Syntis Bio, based in Boston, has completed a $33 million Series A funding round, with an additional non-dilutive research grant of up to $5 million [4]. - The company aims to leverage its proprietary "Synt" synthetic tissue lining technology to create a functional coating in the small intestine that lasts approximately 24 hours [4]. Group 2: Product Mechanism and Efficacy - Synt-101 works by temporarily blocking nutrient absorption in the upper small intestine and redirecting nutrients to the lower segment, thereby activating the body's own hormonal responses that regulate satiety and metabolism [4]. - Preclinical data shows that Synt-101 achieved a stable weight loss of about 1% per week in animal models, with a 100% retention of lean body mass [5]. Group 3: Future Developments - The funding will also support the Phase I clinical trials for Synt-101 and initiate human studies for another candidate drug, Synt-202, aimed at treating a rare metabolic disorder in children [7]. - The management believes that ongoing capital and research funding will expedite the implementation of oral treatment solutions in chronic and rare disease areas [7]. Group 4: Industry Context - Industry investors note that the current high-cost and complex drug development models limit patient access to critical treatments, while Syntis Bio's platform could potentially transform drug delivery methods and expand patient options [7].

整理 | GLP1减重宝典内容团队 ▍84周的 中国 研究 结果已经公布 ，替尔泊肽帮助患者减去29.2公斤 替尔泊肽通过激活人体内的GIP和GLP-1受体，减少热量摄入，调节食欲，降低体重和体脂，同时调节脂肪的代谢。 2022年5月，替尔泊肽获得美国FDA的批准，每周注射一次，结合饮食控制和运动，有助于改善成人2型糖尿病患者的血糖控制。此外，其在减 重领域的研究也已展开。 2019年，替尔泊肽的SURMOUNT系列III期临床试验启动，包括4项全球研究、1项中国研究和1项日本研究，共招募了超过5000名肥胖或超重患 者。SURMOUNT-1和SURMOUNT-2研究已经取得了积极的结果。 最近公布的SURMOUNT-3研究（NCT04657016）是一项多中心、随机、双盲、平行、安慰剂对照的研究，旨在评估替尔泊肽与安慰剂在 BMI≥30kg/m²或BMI≥27kg/m²且至少有一种合并症的非2型糖尿病成人患者中的减重效果和安全性。 这项研究纳入了来自美国、巴西和阿根廷的806名患者，他们以1:1的比例随机分配到替尔泊肽（15mg或10mg）和安慰剂组。主要的研究终点是 72周时体重相对于基线的降低百分比，以 ...

Core Viewpoint - The article discusses the potential effects of GLP-1 receptor agonists, commonly used for weight loss, on alcohol consumption and its effects, suggesting that these medications may reduce the sensation of intoxication and drinking desire [5][10]. Summary by Sections What are GLP-1 Drugs? - GLP-1 drugs, such as semaglutide (Ozempic and Wegovy) and tirzepatide (Mounjaro), mimic natural hormones that regulate blood sugar and appetite [7]. Research Findings - A study involving 20 obese adults found that those taking GLP-1 drugs experienced a slower onset of intoxication and reduced feelings of drunkenness compared to those not on the medication. This effect is attributed to delayed gastric emptying, which slows the absorption of alcohol into the bloodstream [8]. - Participants on GLP-1 drugs reported lower drinking desires, and the study indicated that the reduced intoxication was not due to nausea or blood sugar changes, suggesting a unique mechanism of action through the gut [8]. Limitations and Future Research Directions - The study is a small preliminary trial without random assignment, focusing solely on obese patients. More extensive research is needed to determine the effectiveness, long-term effects, and optimal dosages for blood sugar control and alcohol reduction [9]. - Experts caution that the findings do not establish causation and highlight the need for future studies to track overall alcohol intake and drinking desires to assess potential compensatory behaviors [9]. Potential for Addiction Treatment - Emerging data suggest that GLP-1 drugs may play a role in addiction treatment, as GLP-1 receptors influence reward signals related to food, alcohol, and nicotine. If validated in larger studies, these drugs could bridge endocrinology and behavioral health [10].

Core Insights - Obesity is a significant global public health issue, with a retrospective study revealing that 69.5% of patients who underwent sleeve gastrectomy (SG) experienced weight regain, with over 40% meeting the medical criteria for "weight regain" [6][7][8] - The study identified the third year post-surgery as a critical period for weight rebound, providing data to help identify high-risk patients and develop preventive strategies [6][8] Summary by Sections Study Overview - A retrospective cohort analysis included 676 patients who underwent SG at Shanghai Jiao Tong University from January 2011 to June 2022, with a median follow-up of 3 years [6][7] - The study aimed to analyze long-term weight changes post-SG and identify factors influencing weight loss [6] Key Findings - The study found that baseline age, initial BMI, male gender, and absence of hypertension were associated with higher percentage of total weight loss (%TWL) post-surgery [7] - The lowest weight for most patients occurred within the first year post-surgery, followed by a significant weight regain in 69.5% of patients, peaking in the third year [7] - Among 540 patients with complete follow-up, the rate of weight regain increased from 21.7% at year 3 to 32.6% at year 5 [7] Weight Change Patterns - Patients who did not experience weight regain were categorized into three groups based on weight change trajectories: significant weight loss, moderate weight loss, and minimal weight loss [7] - The significant weight loss group had higher baseline BMI, waist circumference, fasting insulin, and insulin resistance index (HOMA-IR) compared to the minimal weight loss group [7]

Core Viewpoint - The article focuses on individuals who successfully lose weight through lifestyle changes but experience weight regain, highlighting the challenges of long-term obesity management and effective strategies to prevent weight rebound [7]. Summary by Sections Weight Regain Challenges - A systematic review and meta-analysis indicate that approximately 75% of individuals who lose an average of 14 kg through lifestyle interventions will experience weight regain within about 5 years [7]. - Weight rebound is not limited to those who undergo lifestyle changes; individuals who have weight loss surgery or stop medication also face similar challenges [7]. - There is significant variability in weight regain among individuals, with some maintaining weight loss for years while others revert to their original weight within months [7]. Physiological Mechanisms - A 2022 study found that macrophages in adipose tissue produce elevated levels of lipopolysaccharides and cytokines during obesity, which remain high post-weight loss, indicating a "fat memory" that increases the risk of weight regain [9]. - A 2023 study published in *Nature Metabolism* revealed that obese individuals have a diminished brain response to nutritional stimuli, which may contribute to long-term adaptations that lead to weight rebound after weight loss [9]. Strategies to Reduce Weight Rebound Risk 1. **Dietary Adjustments** - High-protein, low glycemic index (GI), or low glycemic load diets can help reduce the risk of weight rebound. Foods that promote satiety do not lead to significant differences in weight rebound when caloric intake is controlled [11]. - An anti-inflammatory dietary pattern, including olive oil, tomatoes, leafy greens, nuts, fatty fish, and fruits, while minimizing refined carbohydrates, fried foods, sugary drinks, red meat, and margarine, may also lower rebound probabilities [11]. 2. **Increased Physical Activity** - Regular exercise improves leptin sensitivity, enhances sympathetic nervous activity, reduces hunger, increases satiety, promotes fat oxidation, and preserves muscle mass, all of which contribute to maintaining weight loss [12]. - While the effectiveness of different exercise types (aerobic, high-intensity interval, resistance training) is still debated, higher overall activity levels correlate with better weight maintenance outcomes [12]. 3. **Pharmacological and Biomedical Interventions** - In addition to diet and exercise, pharmacological treatments and other biomedical strategies are recommended to prevent weight rebound, such as reducing adipose tissue mass for more stable weight control [13]. 4. **Individualized Management and Ongoing Research** - Weight rebound is influenced by multiple factors, including diet, exercise, medication, and biomedical interventions. Future research should focus on different populations to explore more effective long-term management strategies [14]. - Overall, weight rebound is a common challenge in weight loss journeys, but through scientific dietary practices, regular exercise, appropriate pharmacological interventions, and continuous individualized management, more sustainable weight loss outcomes can be achieved [14].

Core Viewpoint - Obesity has become a global public health issue, with over 890 million adults classified as obese, accounting for 13% of the total population. The rise in obesity is linked to lifestyle changes and has increased the risk of chronic diseases such as cardiovascular issues. Traditional weight loss strategies of "eat less, move more" are often insufficient, leading to a growing interest in pharmacological interventions like the popular weight loss drug semaglutide, which suppresses appetite [7][12]. Group 1 - The World Health Organization reports that the number of obese adults has surpassed 890 million globally, representing 13% of the total population [7]. - The increase in obesity rates over the past 40 years has been significant in many countries, including China, leading to higher risks of related chronic diseases [7]. - A new study published in the journal "Cell" has identified a group of previously unknown neurons in the mouse brain that regulate satiety by releasing cholecystokinin (CCK), signaling the body to stop eating [7][8]. Group 2 - These newly discovered neurons are located in the brainstem, suggesting that similar mechanisms may exist in the human brain [8]. - Unlike traditional satiety neurons that only sense whether the gastrointestinal tract is filled, these neurons track food information throughout the digestive process and integrate various hormonal signals to determine when to stop eating [8][10]. - Researchers used optogenetics to control these neurons in mice, demonstrating that activating them led to slower eating and reduced food intake [10]. Group 3 - The study also found that GLP-1 receptor agonists, the active ingredient in popular weight loss drugs, can activate these neurons, while appetite-stimulating hormones decrease their activity [12]. - This research provides new insights into the mechanisms of satiety and could lead to the development of more effective methods for appetite control, potentially reducing the risk of obesity [12].

整理 | GLP1减重宝典内容团队 美国加州生物技术公司ProLynx近日完成7000万美元A轮融资，目标直指一个核心痛点：让减重药物"打得更少、效果更久"。公司希望 通过独特的化学技术，将现有GLP-1类药物的给药周期，从每周一次，延长至每月甚至每季度一次，从而重塑减重治疗的依从性与商业 模式。 ProLynx成立于2010年，由两位化学家联合创立。一位是加州大学旧金山分校教授Daniel Santi，曾多次参与生物科技公司孵化；另一 位是拥有20多年产业经验的Gary Ashley。公司长期处于低调研发状态，直到本轮融资才首次系统性对外披露其技术路线与产品布局。 ProLynx的核心技术并不局限于减重领域，而是一种可广泛适用于小分子、肽类以及抗体药物的"半衰期延长平台"。其基本思路是构建 一种三段式分子结构：药物本体通过可调控释放的化学连接子，连接到微球状水凝胶载体上，从而在体内实现缓慢、可控释放。 Boulton指出，许多患者在注射后的前几天会出现明显不适，而到一周后期，食欲抑制效果又开始减弱。"如果能把这种波动拉平，让药 效更稳定、给药频率更低，将显著改善治疗体验，也能让更多患者长期坚持用药。" 正是 ...

Core Viewpoint - Zealand Pharma is seeking partners for innovative weight loss treatments that target the brain directly, emphasizing the central nervous system's role in metabolic regulation and immune response [4][6]. Group 1: Strategic Collaborations - Zealand is exploring collaborations to develop therapies that can cross the blood-brain barrier, with a focus on "shuttle technology" to safely deliver drugs to the brain [4][6]. - The company has engaged in discussions with Roche and other institutions regarding brain-targeted research, acknowledging the high difficulty of these projects but recognizing their potential to fundamentally change metabolic disease treatment [6]. - Zealand has entered a partnership with OTR Therapeutics, paying a $20 million upfront fee, potentially reaching $30 million, to leverage OTR's oral small molecule platform for new metabolic disease therapies [8]. Group 2: Product Pipeline and Development - Zealand's pipeline includes the promising drug petrelintide, which is expected to show an average weight loss of 8.6% over 16 weeks in its Phase II trial, with results anticipated in mid-2026 [9]. - The company is also advancing the dual agonist survodutide in Phase III trials for obesity and MASH, alongside other candidates targeting short bowel syndrome and congenital hyperinsulinism [9]. - Zealand's strategy includes a roadmap titled "Metabolic Frontier 2030," aiming to launch five products by 2030, indicating a long-term vision for growth in the metabolic disease sector [9]. Group 3: Market Position and Future Outlook - Zealand is aware of the competitive landscape in oral weight loss medications, particularly with Novo Nordisk's oral semaglutide awaiting regulatory approval, and is cautious about committing to outcomes without believing in their potential [8]. - The company has a robust research capability and financial reserves, allowing it to navigate uncertainties in the market while continuing to innovate [9]. - Zealand's future innovations may include improving insulin sensitivity unrelated to weight and directly modulating brain receptors, showcasing a commitment to long-term health impacts [10].

Core Insights - Tirzepatide has been shown to reduce the risk of developing diabetes by 94% in prediabetic patients compared to those taking a placebo [3][5] - A study comparing Tirzepatide and Semaglutide indicates that Tirzepatide may be more effective for weight loss in overweight or obese adults [6][14] Group 1: Tirzepatide Efficacy - In a study tracking over 1,000 overweight or obese prediabetic individuals, those taking Tirzepatide lost nearly 20% of their body weight compared to placebo [5] - The drug targets GLP-1 and GIP hormones, helping to regulate blood sugar levels and appetite [5] - Approximately 81.8% of participants on Tirzepatide lost at least 5% of their body weight, compared to 66.5% on Semaglutide, with a risk ratio of 1.76 [11][13] Group 2: Comparative Study Results - The study included 18,386 participants, with an average follow-up of 165 days, and found similar gastrointestinal adverse event risks between both drug groups [8] - Weight loss percentages at different intervals showed Tirzepatide outperforming Semaglutide: 5.9% vs. 3.6% at 3 months, 10.1% vs. 5.8% at 6 months, and 15.3% vs. 8.3% at 12 months [13] - The findings contribute valuable data for understanding the effectiveness of these weight loss medications and may influence future clinical guidelines [14]

Core Viewpoint - Eli Lilly's next-generation weight loss drug retatrutide has shown the strongest weight loss results to date in its latest Phase III trial, significantly alleviating knee osteoarthritis pain and opening a promising start for upcoming research sequences [4][6]. Group 1: Weight Loss Efficacy - In the highest dose group of the trial, participants achieved an average weight loss of 23.7% over 68 weeks, with those adhering to treatment losing an average of 28.7% [4]. - The trial results indicate that retatrutide's weight loss effects are comparable to those of weight loss surgery, particularly targeting patients with a BMI of 35 or above, with 84% of participants classified as severely obese [6]. Group 2: Pain Relief and Safety - The study found that retatrutide reduced knee osteoarthritis pain by an average of 62.6%, with over 12.5% of patients reporting complete pain relief by the end of treatment [7]. - Approximately 18% of patients in the highest dose group discontinued treatment due to adverse reactions, compared to 4% in the placebo group, with the discontinuation rate closely linked to initial BMI [7]. Group 3: Competitive Landscape - Retatrutide, known as a "Triple G" drug, simultaneously mimics GLP-1, GIP, and glucagon, providing stronger appetite suppression and satisfaction compared to competitors like Novo Nordisk's semaglutide, which only targets GLP-1 [8]. - In response to retatrutide's promising data, Novo Nordisk has invested up to $2 billion to acquire global rights to an early-stage triple hormone candidate from a Chinese pharmaceutical company, aiming to catch up with retatrutide's development timeline [8]. Group 4: Future Outlook - Eli Lilly anticipates releasing results from seven additional Phase III trials by the end of 2026, which may yield even higher efficacy data specifically designed for weight loss [7]. - The global market for obesity and diabetes medications is expected to exceed $100 billion by the 2030s, indicating significant growth potential in this sector [6].