Rimonabant

点击“蓝字”关注我们 编者按：肥胖医学协会将肥胖定义为一种严重的、慢性的、进行性的、复发性的、可治疗的多因素神经行为疾病，其中体内脂肪增加促进脂肪组织功能障碍和异常脂肪组织的压迫，导致不良的代谢、生物学和社会心理健康等后果。肥胖患者面临着发病率和死亡率增加的问题，同时在执行日常任务（如爬楼梯）时也受到限制。肥胖与220多种并发症有关，例如2型糖尿病（T2DM）、代谢功能障碍相关脂肪性肝病（MASLD）和慢性肾脏病（CKD），这些并发症也限制了患者的能力，亟需药物治疗[1]。过去多年，减重治疗药物研发历经诸多波折，胰高糖素样肽-1受体激动剂（GLP-1RA）的减重适应证获批为肥胖治疗提供了新变革！本刊邀请解放军总医院第一医学中心臧丽教授对减重药物的研发历史进行回顾，一起来看看！ 臧丽 教授 解放军总医院第一医学中心内分泌科 副主任医师 副教授 硕士生导师 中华医学会糖尿病学分会青年委员会副主任委员 中国医师协会内分泌代谢科分会青年委员会副主任委员 北京医学会糖尿病学分会委员兼工作秘书 解放军医学会内分泌学分会青年委员会秘书长 国际糖尿病杂志青年编委 《Diabetes Care 中文版》青年编委 《Endocrine Reviews 中文版》青年编委 肥胖症的药物治疗有着悠久而曲折的历史，早在19世纪末，西方就已出现用药物治疗肥胖的方法，如甲状腺激素类药物等。在随后100多年，线粒体解偶联剂、肾上腺素能药物等逐渐进入市场。但可惜好景不长，许多有前景的药物因各种问题而被陆续撤回（图1）[2-4]。 图1. 目前FDA批准的减重药物预览 究其根本，安全性是导致减重药物撤市的重要原因。其中，大多数药物（如西布曲明、芬氟拉明、右芬氟拉明、彩虹药丸）与心血管不良影响相关，而部分药物（如利莫那班）可能导致自杀风险增加，部分药物（如甲基苯丙胺）会导致药物依赖和滥用的可能性增加。此外，由于成瘾潜力或出现快速耐受，某些药物仅建议短期使用（芬特明、安非拉酮、盐酸卡汀）[2-4]。 上市减重药物选择有限，研发面临多重挑战 由于技术和社会原因，寻求抗肥胖药物一直极具挑战性。目前，经美国食品药品监督管理局（FDA）批准用于抗肥胖的药物有脂肪酶抑制剂的奥利司他、去甲肾上腺素（NE）激动剂/γ-氨基丁酸（GABA）激动剂和谷氨酸拮抗剂的芬特明/托吡酯组合、阿片受体拮抗剂/多巴胺（DA）和NE再摄取抑制剂的纳曲酮/安非他酮组合、GLP-1RA的利拉鲁肽和司美格鲁肽以及GIP/GLP-1双靶点激动剂的替尔泊肽（图2）[2-4]，而我国批准的药物仅有奥利司他、贝那鲁肽0.2 mg、司美格鲁肽2.4 mg、利拉鲁肽3.0 mg这4种药物[2-4]。 图2. FDA批准的治疗肥胖症的药物及其作用部位 其中，奥利司他作为脂肪酶抑制剂可通过抑制胃肠道和胰腺脂肪酶，从而阻断甘油三酯的水解并减少肠内皮对脂肪酸的吸收。研究发现，其通常会导致与食物一起消耗的大约1/3的脂肪酸不被吸收[2]。XENDOS研究发现，奥利司他组体重减轻为5.8 kg，服用奥利司他后不良反应主要为便秘、腹痛、腹泻、头晕、月经紊乱和皮疹等，长期应用可能导致脂溶性维生素如维生素D、维生素E、维生素K等缺乏[5]。 GLP-1RA占据主导地位，引领减重新变革 实现体重正常化以及适当的耐受能力和安全性的长期药物治疗仍然是一个难以克服的挑战。然而，最近针对包括GLP-1RA在内的先进治疗候选药物的临床试验使大家相信，突破性的、基于药物的肥胖管理有可能实现。2014年，FDA批准利拉鲁肽3 mg用于治疗成人肥胖，成为首个用于体重管理的GLP-1RA[2-4]。今年，FDA批准司美格鲁肽2.4 mg用于初始体重指数（BMI）≥30 kg/m2（肥胖）或≥27 kg/m2至<30 kg/m2（超重）且存在至少1种体重相关合并症，如高血糖、高血压、血脂异常、阻塞性睡眠呼吸暂停或心血管疾病等患者，成为首个用于体重管理的GLP-1RA周制剂。 究其原因，GLP-1RA一方面可延缓胃排空和胃肠蠕动，增加机体饱腹感，降低摄食；同时增加能量消耗，促进内脏白色脂肪向棕色脂肪转化，随着棕色脂肪产热增加，增加能量耗损；另一方面，GLP-1RA可直接刺激阿黑皮素原（POMC）/可卡因苯丙胺调节转录物（CART）阳性神经元，并通过GABA信号间接抑制神经肽Y（NPY）和刺鼠相关肽（AgRP）阳性神经元的神经投射，从而抑制食欲，减少摄食量[2-4]。 STEP系列研究证实了司美格鲁肽2.4 mg每周一次皮下注射与安慰剂相比的疗效和安全性。其结果显示，司美格鲁肽2.4 mg组治疗68周后，显著降低体重达15%~17%（图3）[6-11]。 图3. 司美格鲁肽2.4 mg显著降低体重 司美格鲁肽2.4 mg的安全性也经过了验证，不良事件发生率与安慰剂组相仿，导致停药的不良事件发生率低，通常为轻中度、一过性的胃肠道反应，如恶心、腹泻、呕吐和便秘等，并随治疗时间延长而逐渐减轻或消失[6-11]。纳入STEP 1、2、3和5研究的事后分析发现，68周时，与安慰剂相比，司美格鲁肽2.4 mg治疗不仅不会增加出现抑郁或自杀意念/行为症状的风险，而且可能与抑郁症状的小幅减少相关。 结语 药物研发过程漫长而艰辛，许多药物因各种原因退市，不能成为临床用药。尽管如此，临床肥胖患者需求和巨大市场仍是持续进行抗肥胖药物研发的强大动力。随着GLP-1RA减重适应证的批准上市，肥胖治疗出现了新变革。相信未来随着新兴生物医学工程技术的发展以及个性化多分子药物的开发，肥胖治疗会更安全、更持久、更有效，不仅能更好地减轻体重，还能改善心脏代谢健康，为肥胖症的精准医疗开辟新径。 注：不同剂量的司美格鲁肽注射液用于不同的适应证，本材料所提及的司美格鲁肽（2.4 mg）注射液的适应证均为适用于长期体重管理治疗的GLP-1RA周制剂。其具体适应证为：适用于在控制饮食和增加体力活动的基础上对成人患者的长期体重管理，初始体重指数（BMI）符合以下条件：≥30 kg/m2（肥胖），或≥27 kg/m2至<30 kg/m2（超重）且存在至少1种体重相关合并症，例如高血糖、高血压、血脂异常、阻塞性睡眠呼吸暂停或心血管疾病等。 参考文献 （上下滑动可查看） 1.Craig HC, et al. Obes Pillars. 2024 Aug 8; 12: 100123. 2.Pilitsi E, et al. Metabolism. 2019; 92: 170-192. 3.Müller TD, et al. Nat Rev Drug Discov. 2022; 21(3): 201-223. 4.Onakpoya IJ, et al. BMC Med. 2016; 14(1): 191. 5.Ludvik B, et al.Diabetes Care. 2004; 27(2): 436-440. 6.Wilding JPH, et al. N Engl J Med. 2021; 384(11): 989-1002. 7.Davies M, et al. Lancet. 2021; 397(10278): 971-984. 8.Wadden TA, et al. JAMA. 2021; 325(14): 1403-1413. 9.Rubino D, et al. JAMA. 2021; 325(14): 1414-1425. 10.Garvey WT, et al. Nat Med. 2022; 28(10): 2083-2091. 11.Kadowaki T, et al. Lancet Diabetes Endocrinol. 2022; 10(3): 193-206. 声明：本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。 最新《国际糖尿病》读者专属微信交流群建好了，快快加入吧！扫描左边《国际糖尿病》小助手二维码（微信号：guojitnb），回复“国际糖尿病读者”，ta会尽快拉您入群滴！ （来源：《国际糖尿病》编辑部） 版权声明 版权属《国际糖尿病》所有。欢迎个人转发分享。其他任何媒体、网站未经授权，禁止转载。

SAN ANTONIO — As the GLP-1 class has taken over in recent years, a once-fringe conference has come into the spotlight for the biopharma industry. ObesityWeek, which started in 2013, attracted more than 3,200 attendees over the past four days in San Antonio, according to conference organizers. Viking , Zealand , AstraZeneca and others presented clinical data and researchers showcased posters on animal models of next-generation medicines and delivered real-world analyses of obesity and its many comorbidities. The conference has grown from a basic science confab to one with big pharma booths and crowds of investors and analysts who huddle around data presentations, including a clogged aisle surrounding Viking’s posters on Sunday evening. “Folks here have known that this is a chronic and serious disease for decades and been trying to get that message out,” Nadia Ahmad, an associate VP who runs Eli Lilly’s Phase 3 obesity trials, said in an interview with Endpoints News on the sidelines of the conference. “So, if anything, you see here a sense of affirmation and hope because this is the group that has struggled so hard for decades to get the message out.” Below are some on-the-ground takeaways from the conference. ‘Foodies’ email: Before the conference started, organizers reached out to attendees with the subject line: “Attention Foodies! Where to Eat in San Antonio.” Within steps of the conference venue is the San Antonio Riverwalk, which is home to a lovely path lined with restaurant after restaurant and bar after bar. It’s personal: Structure Therapeutics CEO Raymond Stevens said his sister was on Wegovy for about a year but was just denied continued insurance coverage last week because her weight had come down. “Now they’ll no longer cover it, which is just maddening because it changed her life,” Stevens said. His biotech is working on small molecules to address the accessibility challenges and manufacturing hurdles of the GLP-1 class and other mechanisms, as well, including amylin. Branding differences: Novo Nordisk opted for large Wegovy signage in the exhibit hall and throughout the convention center, whereas Eli Lilly drew attention to its booth with a massive red banner displaying the company’s name. AstraZeneca also had a large square-shaped sign, with the phrase “What science can do” floating above its booth. The UK pharma also had an interactive display. Genetic obesity: Some researchers presented genetic forms of obesity. Congruence Therapeutics outlined its work in MC4R-deficient genetic obesity, which can impact children as little as a few years old, said chief scientific officer Sharath Hegde. The Canadian biotech’s oral small molecule will likely move into the clinic late next year, he said. A CB1 comeback? : Corbus Pharmaceuticals and Skye Bioscience presented preclinical data on their CB1 programs two months after Novo toplined its Phase 2 data. The field is relatively scarce, Corbus CEO Yuval Cohen said, as “this was a class that was deemed untouchable, in effect, following rimonabant’s downfall in 2007.” The obesity drug was pulled in Europe after concerns of mental health side effects. Corbus’ asset will enter the clinic early next year and is less brain-penetrant than rimonabant and Novo’s monlunabant, Cohen said. Main lecture hall named after a historical mayor: The 2,319-seat Lila Cockrell Theatre — where researchers presented long-term data on Lilly’s Zepbound and Novo Nordisk’s Wegovy, among other keynote talks at the conference — is named after the first female mayor of San Antonio. At the time, in the mid-70s, Cockrell was one of the only female mayors of a major city. So many clinical trials: With a long list of obesity medicines now in the clinic, could it become harder to find ideal or “sophisticated and skilled” clinical trial sites? “Is it close to saturation? I don’t think so,” said Philip Just Larsen, CEO of preclinical startup SixPeaks Bio. “But at least in oncology, we’ve seen that access to the right trial sites, the right patients in certain academic centers, did turn out to comprise a real bottleneck. I don’t see it the same way for weight management trials and obesity drugs, but it could be that you would have to resort to trial sites that are not top of the league.” Each patient is different: Many conference speakers and attendees noted obesity is a heterogeneous disease and that patients will respond differently to drugs. “Just as there are 200 medications for diabetes or hypertension, I think that’s where we’re going in terms of obesity treatment, and we will get there, but what we really need to do is the research to understand the different types of obesity,” said Ania Jastreboff, director of the Yale Obesity Research Center, during a presentation on Zepbound SURMOUNT-1 results. Have a TikToker moment: A TikTok-style ring light gave an optimal glow for attendees to take selfies in front of an Obesity Society backdrop. Partnering: Biotechs must stand out if they want to find a pharma partner at this stage in the obesity drug R&D revolution. It’s “not an area you go half-hearted,” said Regor CEO Xiayang Qiu. The biotech has raised about $130 million to date, he said and just sold a cancer drug candidate to Roche. Regor will start a Phase 2b in the coming months for its once-daily, oral small molecule GLP-1 agonist RGT-075, he said. The company hasn’t presented Phase 2a data yet. Some MASH talk: The fatty liver disease has become a bigger focus in recent quarters with Madrigal Pharmaceuticals’ landmark FDA approval and Novo’s Wegovy readout last week. Eccogene, the company that sold an oral GLP-1 to AstraZeneca last year, plans to enter Phase 2 in MASH around the middle of 2025, CEO Jingye Zhou told Endpoints. ‘Bark park’: Of course, there had to be dogs. The friendly animals could be seen on the main exhibit floor. Attendees even had the chance to adopt them.