每9秒就有1人因此死亡！多款重磅疗法为患者带来新的希望

编者按：糖尿病是全球范围内最常见的代谢疾病之一。根据国际糖尿病联盟（IDF）的报告，2024年每9秒就有1人因糖尿病死亡。近年来，糖尿病的靶向治疗取得多项突破，其中基于胰高血糖素样肽-1（GLP-1）信号通路开发的创新疗法已经成为治疗糖尿病的研发热点之一，目前全球已有近100款GLP-1相关药物或药物组合进入临床开发阶段或上市，其中多肽疗法仍是主流。在GLP-1药物开发热潮到来之前，药明康德旗下的WuXi TIDES早已围绕多肽药物建立了一体化CRDMO平台，提供所有类型的多肽，包括线性、环状和高度修饰的多肽，以及非天然氨基酸、连接子、毒素和多肽偶联药物的合成服务，支持从药物发现、CMC开发到商业化生产的各个阶段，助力合作伙伴更高效地为患者提供新一代GLP-1疗法。在世界糖尿病日到来之际，本文将与读者回顾GLP-1疗法用于治疗糖尿病的发展历程。

解开GLP-1之谜

GLP-1药物的历史可以追溯到上世纪60年代，当时，麻省总医院（MGH）的Joel Habener博士团队发现并克隆了编码胰高血糖素前体的基因，并发表论文显示胰高血糖素是一个包含124个氨基酸的多肽前体的切割产物。然而，这个多肽前体不但包含胰高血糖素，还包含一段与其结构相似的氨基酸序列。这段序列由37个氨基酸组成，后来被命名为胰高血糖素样肽-1。

随后，Daniel Drucker博士加入了Habener博士的实验室，并与同在MGH的Svetlana Mojsov博士合作，对GLP-1的作用机制展开深入研究。他们发现，食物摄入后，肠道释放的GLP-1不但增强胰岛素分泌，还抑制胰高血糖素的释放并减缓胃排空速度。Mojsov博士更确定了GLP-1的第7至第37个氨基酸的序列是其活性成分，合成了这一活性片段并且验证了它的功能。1987年，一项包含7名志愿者的临床研究显示，输注GLP-1能够提高血液胰岛素水平并降低血糖。

与此同时，哥本哈根大学的Jens Juul Holst教授通过研究接受肠道手术的患者，独立证实了GLP-1的存在及其降糖作用。这些科学家因为在发现GLP-1方面的卓越贡献已经获得多个奖项的表彰，包括2024年拉斯克临床医学奖和2025年发布的科学突破奖。

▲Daniel J. Drucker、Joel Habener、Jens Juul Holst、Lotte Bjerre Knudsen和Svetlana Mojsov（从左至右）因为在GLP-1生物学和药物开发方面的贡献而获得生命科学突破奖

虽然GLP-1为降低血糖提供了全新工具，但是将它开发成为药物却面临着巨大的挑战。这是因为GLP-1在体内的半衰期仅有几分钟，极易被二肽基肽酶-4（DPP-4）降解和被肾脏排出。因此，如何提高GLP-1的稳定性成为药物研发人员开发的重要方向。意想不到的是，首款获批GLP-1药物的成功关键，竟是源于一个在蜥蜴毒液中的意外发现……

来自蜥蜴毒液的突破

20世纪80年代，在科学家们研究人类GLP-1的同时，美国国立卫生研究院（NIH）的Jean-Pierre Raufman博士和John Pisano博士也在研究多肽激素。他们的研究方向是从动物毒液中寻找能够刺激胰岛细胞的激素，而效果最好的毒液来自称为希拉毒蜥（Gila monster）的蜥蜴。Raufman博士后来与内分泌学家John Eng博士合作，发现了希拉毒蜥毒液中刺激胰岛细胞的激素，将它们命名为exendin-3和exendin-4。

Eng博士敏锐地觉察到exendin-4可能成为一种治疗糖尿病的新方式，因为它与GLP-1非常类似。人类GLP-1在血液中的半衰期只有几分钟，而exendin-4的半衰期则长达几个小时，因此具备更好的成药潜力。1996年，Eng博士在美国糖尿病协会年会上遇到了Amylin Pharmaceuticals公司的Andrew Young博士。Amylin公司当时正在开发糖尿病疗法，看到exendin-4的研究后，Young博士觉得这是治疗糖尿病的一个新策略，不妨一试。这促成了双方的合作，Eng博士也将exendin-4的开发权益授权给Amylin公司。

▲艾塞那肽的分子结构（图片来源：PubChem）

Amylin人工合成了exendin-4的类似物艾塞那肽（exenatide），随后的临床试验显示，这种新药不但显著降低血糖水平，而且相比胰岛素，更能减少患者发生低血糖的风险。这些在真实世界中取得的结果赢得了大药企的青睐。2002年，礼来（Eli Lilly and Company）与Amylin达成3.25亿美元合作，共同开发艾塞那肽。它在2005年4月28日获FDA批准（商品名Byetta）用于治疗2型糖尿病。

Byetta的获批是GLP-1药物开发历史上的重要里程碑，然而这款药物也存在进一步优化的空间：患者通常每天需要注射两次，使用不够便利。同时，由于它与人类GLP-1之间的差异较大，部分患者会产生免疫反应，产生的抗体进而降低药物疗效。因此，研发人员也在探索其它方法来提高GLP-1药物的稳定性。

更高效、持久、便捷的GLP-1药物

在艾塞那肽开发的同时，诺和诺德（Novo Nordisk）的科学家们也在积极探索优化人类GLP-1稳定性的策略。最初的探索并不顺利——经过了一年多的尝试，GLP-1多肽链的主干半衰期只从2分钟提高到了5分钟。最终，Lotte Bjerre Knudsen女士率领的团队使用脂肪酸侧链对GLP-1进行修饰，促进了GLP-1与血液中白蛋白（albumin）的可逆结合。这种创新策略不仅保护GLP-1免于被DPP-4降解，还延缓了GLP-1在肾脏中的排出。这一系列改造带来了利拉鲁肽（liraglutide），它在2010年获得FDA批准（商品名Victoza），是一款每日注射一次的GLP-1受体激动剂，其在血浆中的半衰期达到13个小时。

其它延长GLP-1受体激动剂半衰期的策略包括将药物封装在可以被生物降解的缓释微球中（每周一次的艾塞那肽），该疗法在2012年获FDA批准，商品名为Bydureon。将GLP-1多肽与抗体Fc片段融合生成的度拉鲁肽（dulaglutide），和与白蛋白融合构建的阿必鲁肽（albiglutide）均在2014年获批治疗糖尿病，商品名分别为Trulicity和Tanzeum。

在利拉鲁肽基础上，Knudsen女士的团队进一步优化了脂肪酸侧链的设计，并且将GLP-1多肽中第8位的丙氨酸替换成α-氨基异丁酸。这一系列改良形成了司美格鲁肽（semaglutide），在保持GLP-1与受体结合亲和力的同时，更有效抵抗了DPP-4的降解，将半衰期延长至165个小时。它在2017年获得FDA批准治疗2型糖尿病（商品名Ozempic），患者只需每周接受一次注射。

▲长效GLP-1受体激动剂结构比较（图片来源：参考资料[4]）

注射型司美格鲁肽获批不到两年后，口服司美格鲁肽（商品名Rybelsus）也成功获得FDA的批准上市治疗2型糖尿病。Rybelsus创新地将司美格鲁肽与一种名为SNAC的小分子吸收增强剂结合，使药物更有效地在胃部被吸收，同时避免被胃中的肽酶降解。这一突破性口服GLP-1药物，极大地提高了患者的用药便捷性。

2022年，礼来公司的替尔泊肽（tirzepatide，商品名Mounjaro）获FDA批准治疗2型糖尿病，它是一款葡萄糖依赖性促胰岛素多肽（GIP）和GLP-1受体双重激动剂，旨在通过同时激活两条肠促胰岛素通路改善血糖控制。

GLP-1药物的发展方向

在治疗2型糖尿病之外，近10年来GLP-1药物还多次获批扩展适应症，在治疗肥胖症、阻塞性睡眠障碍、代谢功能障碍相关性脂肪性肝炎等疾病方面也表现出显著疗效。研究人员还在临床试验中探索GLP-1药物治疗神经退行性疾病、慢性肾病、高血压、银屑病关节炎等多种疾病的疗效。

研究人员也在探索进一步提高GLP-1药物疗效、安全性和便捷性的手段。其中一个重要研发方向是将GLP-1受体激动剂与靶向其它代谢相关通路的药物联合构成组合疗法，或在同一分子中靶向GLP-1受体和其它信号通路。已经获批的替尔泊肽就是一个范例。目前的在研疗法在靶向GLP-1信号通路之外，还可同时靶向胰高血糖素受体（GCGR）、肠淀素受体、葡萄糖依赖性促胰岛素多肽受体或降钙素受体等不同受体介导的信号通路。

多家公司正在推进口服GLP-1药物开发，以进一步提升患者用药便捷性。这一研发方向上的一个策略是开发注射型GLP-1药物的口服剂型，诺和诺德的Rybelsus代表着这一策略的重要突破。而另一个策略是开发GLP-1受体的口服小分子激动剂，目前多款小分子GLP-1受体激动剂已经在临床试验中表现出积极的疗效。提高患者用药便捷性的另一个方向是开发长效GLP-1药物，减少患者需要接受注射的次数。目前多款长效GLP-1药物在临床试验中只需每月一次或更低频率的注射就能够维持疗效。

▲处于临床开发阶段的新一代GLP-1药物（图片来源：参考资料[1]）

药明康德很高兴能够为多款GLP-1药物赋能。在今年9月举办的药明康德投资者开放日活动上公布的数据显示，全球有近百款GLP-1受体激动剂处于临床试验阶段或已上市，其中23款由药明康德化学业务平台支持，包括11款多肽类候选药物和11款小分子候选药物。展望未来，药明康德将继续秉持“让天下没有难做的药，难治的病”的愿景，依托全球研发基地与生产网络，凭借独特的一体化、端到端CRDMO模式，持续推动新一代GLP-1药物的开发进程，造福全球患者。

在世界糖尿病日到来之际，我们再一次认识到，糖尿病治疗不只是控制血糖，更关乎生活质量、长期并发症风险与公共健康负担的系统性改善。GLP-1疗法的演变，是生物医学创新如何在疾病层面产生持续影响的一个缩影。期待随着全球研发的进展，GLP-1药物及其它疗法的持续推进，人类更接近“让糖尿病可以被更好管理和延缓，甚至逆转”的长期目标。

CRDMO: Advancing Diabetes Care, The Scientific Journey and Future of GLP-1 Therapeutics

Diabetes is one of the most common metabolic diseases worldwide. According to the International Diabetes Federation (IDF), every nine seconds in 2024, someone dies as a result of this disease. In recent years, targeted therapies for diabetes have made significant progress, particularly those developed based on the glucagon-like peptide-1 (GLP-1) signaling pathway, which has become a central focus of therapeutic research. About 100 GLP-1–related drugs or drug combinations are currently in clinical development or have been approved worldwide, with peptide-based therapies continuing to represent the major therapeutic modality.

WuXi TIDES, an integral part of WuXi AppTec, has built an integrated CRDMO platform focused on peptides. The platform offers high-throughput library synthesis and custom peptide synthesis, supporting a wide range of peptides, including linear, cyclic, and highly modified peptides, unnatural amino acids (UAAs), linkers, toxins and peptide conjugates. WuXi TIDES simplifies peptide drug development by providing discovery, CMC development, and the entire manufacturing supply chain under one roof. WuXi TIDES enables partners to accelerate the development and delivery of next-generation GLP-1 therapies to patients. In recognition of World Diabetes Day, this article reviews the scientific and clinical progress of GLP-1 therapies in diabetes treatment.

Unraveling the GLP-1 Mystery

The origins of GLP-1 research date back to the 1960s, when Dr. Joel Habener’s team at Massachusetts General Hospital (MGH) discovered and cloned the gene encoding proglucagon.They demonstrated that glucagon is derived from a 124–amino acid polypeptide precursor, which also contains an additional 37–amino acid sequence. This sequence was later identified as glucagon-like peptide-1 (GLP-1).

Dr. Daniel Drucker joined Dr. Habener’s laboratory and, together with Dr. Svetlana Mojsov at MGH, carried out seminal work that elucidated GLP-1’s mechanism of action. They found that GLP-1 released from the intestine after food intake enhances insulin secretion, suppresses glucagon release, and slows gastric emptying. Dr. Mojsov further pinpointed that the 7–37 amino acid fragment constitutes the biologically active form of GLP-1, synthesized the peptide and confirmed its activity experimentally.

Clinical evidence soon followed. In 1987, a study involving seven volunteers demonstrated that GLP-1 infusion increased circulating insulin levels while lowering blood glucose. Around the same time, Professor Jens Juul Holst at the University of Copenhagen independently confirmed the existence and glucose-lowering effects of GLP-1 through observations in patients who had undergone intestinal surgery. For their foundational contributions to GLP-1 biology and drug development, these scientists were recognized with major awards, including the 2024 Lasker Clinical Medical Research Award and the 2025 Breakthrough Prize in Life Sciences.

A Breakthrough from Lizard Venom

Although GLP-1 introduced an entirely new therapeutic mechanism, transforming it directly into a drug proved challenging due to its extremely short half-life of only a few minutes, resulting in rapid degradation by DPP-4 and clearance by the kidneys. The search for more stable analogs took an unexpected turn in the 1980s, when Dr. Jean-Pierre Raufman and Dr. John Pisano at the U.S. National Institutes of Health (NIH) began studying peptide hormones from animal venom. They observed that venom from the Gila monster strongly stimulated pancreatic islet cells. Working with endocrinologist Dr. John Eng, they identified two peptides, exendin-3 and exendin-4.

Dr. Eng realized that exendin-4’s strong structural similarity to GLP-1, combined with its significantly longer half-life of several hours, made it a highly promising therapeutic candidate. In 1996, he met Dr. Andrew Young of Amylin Pharmaceuticals at the American Diabetes Association Annual Meeting, which led Amylin to license exendin-4 and develop its synthetic analog, exenatide. Clinical trials showed that exenatide effectively reduced blood glucose while also lowering the risk of hypoglycemia compared with insulin. Eli Lilly and Company entered a $325 million partnership with Amylin in 2002, andon April 28, 2005, exenatide (brand name Byetta) was approved by the FDA for the treatment of type 2 diabetes.

Although Byetta marked a major milestone, its twice-daily injection schedule and potential immunogenicity prompted continued efforts to develop longer-acting and more convenient GLP-1 therapies.

Toward Longer-Acting and More Convenient GLP-1 Therapies

At Novo Nordisk, researchers sought to enhance GLP-1 stability using structural modification strategies. After extensive work, they introduced a fatty acid side chain enabling reversible binding to serum albumin, thereby protecting the molecule from enzymatic degradation and slowing renal clearance. This innovation led to liraglutide (Victoza), which was approved in 2010. Its extended half-life enabled once-daily dosing.

Additional approaches soon followed. A biodegradable microsphere formulation of exenatide, enabling once-weekly administration, was approved in 2012 as Bydureon. Dulaglutide (Trulicity), which fuses GLP-1 to an Fc antibody fragment, and albiglutide (Tanzeum), which fuses GLP-1 to albumin, were both approved in 2014.

Building on liraglutide, researchers optimized the lipid side chain and substituted the amino acid at position 8 with α-aminoisobutyric acid to create semaglutide (Ozempic). With a half-life of approximately 165 hours, semaglutide enabled once-weekly dosing and was approved in 2017. Two years later, oral semaglutide (Rybelsus) was approved, using the absorption enhancer SNAC to promote gastric uptake. In 2022, Eli Lilly’s tirzepatide (Mounjaro), a dual GIP/GLP-1 receptor agonist, was approved for type 2 diabetes.

Future Directions in GLP-1 Therapeutics

Beyond type 2 diabetes, GLP-1 therapies have demonstrated efficacy in obesity, obstructive sleep apnea, and metabolic dysfunction–associated steatohepatitis (MASH), with ongoing clinical trials exploring potential applications in neurodegenerative disease, chronic kidney disease, hypertension, and psoriatic arthritis. Research directions now include developing multi-receptor agonists that integrate GLP-1 signaling with pathways such as GIP and glucagon receptor signaling, advancing orally bioavailable GLP-1 receptor agonists, and designing long-acting formulations requiring administration only monthly or even less frequently.

According to data shared at WuXi AppTec’s Investor Day in September, nearly 100 GLP-1 receptor agonists are currently in clinical development or already on the market globally, with 23 supported by WuXi AppTec’s chemistry platform, including 11 peptide candidates and 11 small-molecule candidates. Looking ahead, WuXi AppTec will continue to support the advancement of next-generation GLP-1 therapies through its unique integrated, end-to-end CRDMO platform, helping bring innovative therapeutic options to patients worldwide.

参考资料：

[1] Drucker (2025). GLP-1-based therapies for diabetes, obesity and beyond. Nature Reviews Drug Discovery, https://doi.org/10.1038/s41573-025-01183-8

[2] Diabetes global report 2000 — 2050. Retrieved October 29, 2025, from https://diabetesatlas.org/data-by-location/global/

[3] Zheng et al., (2024). Glucagon-like peptide-1 receptor: mechanisms and advances in therapy. Signal Transduction and Targeted Therapy, https://doi.org/10.1038/s41392-024-01931-z

[4] Andersen et al., (2018). Glucagon-like peptide 1 in health and disease. Nature Reviews Endocrinology, https://doi.org/10.1038/s41574-018-0016-2

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