編者按：近年來(lái)，胰高血糖素樣肽-1受體激動(dòng)劑（GLP-1RAs）在糖尿病與肥胖等代謝性疾病的治療中持續(xù)取得突破，正在重塑全球治療范式。隨著多肽類GLP-1RAs的廣泛應(yīng)用與小分子GLP-1RAs的快速崛起，GLP-1療法正由單純“控糖”邁向“綜合代謝管理”。其中，小分子GLP-1RAs憑借口服便利與易于規(guī)?；a(chǎn)等優(yōu)勢(shì)，有望進(jìn)一步提升患者依從性，并推動(dòng)個(gè)體化的代謝疾病管理。長(zhǎng)期以來(lái)，藥明康德依托一體化、端到端CRDMO平臺(tái)，深度參與并賦能全球GLP-1藥物的發(fā)現(xiàn)、開(kāi)發(fā)與生產(chǎn)，助力新一代GLP-1療法加速?gòu)膭?chuàng)新走向臨床應(yīng)用，造福更多患者。

在過(guò)去幾年里，胰高血糖素樣肽-1受體激動(dòng)劑（GLP-1RAs）深刻改變了2型糖尿?。═2DM）和肥胖的治療格局。通過(guò)增強(qiáng)胰島素分泌、抑制胰高血糖素釋放，并幫助減少食欲以促進(jìn)體重管理，這類療法不僅實(shí)現(xiàn)了持續(xù)、穩(wěn)定的血糖控制，也帶來(lái)了顯著且持久的臨床改善。隨著療效的不斷驗(yàn)證，GLP-1RAs在改善代謝與心血管預(yù)后方面發(fā)揮了重要作用，推動(dòng)治療理念從單純“控糖”邁向更全面的代謝疾病綜合管理。

在多肽類GLP-1RAs持續(xù)提升療效的同時(shí)，可口服、易于規(guī)?；a(chǎn)的小分子GLP-1RAs正成為新的突破方向。這類藥物具有化學(xué)性質(zhì)穩(wěn)定、生產(chǎn)工藝成熟等優(yōu)勢(shì)，且無(wú)需額外的滲透增強(qiáng)劑即可口服使用，有望進(jìn)一步提升全球患者的治療可及性與用藥便利性，為更多患者帶來(lái)更優(yōu)的治療體驗(yàn)。

在作用機(jī)制上，小分子GLP-1RAs通過(guò)創(chuàng)新的受體結(jié)合策略，如變構(gòu)調(diào)節(jié)、偏向性激動(dòng)和選擇性激活G蛋白通路等，精準(zhǔn)模擬多肽類似物的療效優(yōu)勢(shì)。借助高分辨率結(jié)構(gòu)數(shù)據(jù)的支持，這類藥物有望實(shí)現(xiàn)更精細(xì)的受體信號(hào)調(diào)控，同時(shí)保持良好的藥代動(dòng)力學(xué)特征和口服生物利用度。

值得一提的是，小分子GLP-1RAs的出現(xiàn)也為聯(lián)合治療開(kāi)辟了新的空間。其口服、與進(jìn)食無(wú)關(guān)的劑型特點(diǎn)，使其能夠與SGLT2抑制劑或二甲雙胍等已獲批口服藥物聯(lián)合，開(kāi)發(fā)為固定劑量的復(fù)方制劑。此類聯(lián)合方案可在血糖管理、體重控制及心代謝保護(hù)方面形成協(xié)同效應(yīng)，實(shí)現(xiàn)多靶點(diǎn)、多通路的疾病調(diào)控，從源頭上降低心血管及腎臟疾病風(fēng)險(xiǎn)。同時(shí)，簡(jiǎn)化的給藥方案有助于提升患者長(zhǎng)期依從性。

目前，臨床進(jìn)展最快的小分子GLP-1RAs之一正處于治療T2DM患者的3期臨床試驗(yàn)階段。已公布的臨床數(shù)據(jù)顯示，該療法在降低糖化血紅蛋白（A1C）水平和體重方面均表現(xiàn)出顯著療效，預(yù)計(jì)將于2026年向全球監(jiān)管機(jī)構(gòu)遞交上市申請(qǐng)。

需要強(qiáng)調(diào)的是，小分子與多肽類GLP-1RAs并非相互替代，而是相輔相成。兩類治療模式的協(xié)同發(fā)展，不僅拓展了患者的治療選擇，也讓臨床醫(yī)生能夠根據(jù)患者特征、生活方式及照護(hù)需求制定更具針對(duì)性的個(gè)體化治療方案，從而進(jìn)一步提升療效與生活質(zhì)量。

藥明康德化學(xué)業(yè)務(wù)平臺(tái)以一體化、端到端的CRDMO模式，自上而下貫穿藥物發(fā)現(xiàn)（R）、開(kāi)發(fā)（D）到商業(yè)化生產(chǎn)（M）全鏈條，業(yè)務(wù)范圍覆蓋從早期研發(fā)到規(guī)?；圃斓拿總€(gè)環(huán)節(jié)，致力于為全球合作伙伴提供快速、靈活、高效、可靠的小分子、寡核苷酸、多肽及各種復(fù)雜偶聯(lián)物新藥研發(fā)一站式解決方案。

在2025年9月舉辦的藥明康德投資者開(kāi)放日活動(dòng)上公布的數(shù)據(jù)顯示，全球有近百款GLP-1RAs處于臨床試驗(yàn)階段或已上市，其中23款由藥明康德化學(xué)業(yè)務(wù)平臺(tái)支持。展望未來(lái)，藥明康德將繼續(xù)秉持“讓天下沒(méi)有難做的藥，難治的病”的愿景，依托全球研發(fā)基地與生產(chǎn)網(wǎng)絡(luò)，憑借獨(dú)特的一體化、端到端CRDMO模式，持續(xù)推動(dòng)新一代GLP-1藥物的開(kāi)發(fā)進(jìn)程，造福全球患者。

Small-Molecule GLP-1 Receptor Agonists: Expanding the Horizon of Metabolic Disease Treatment

In recent years, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have achieved continuous breakthroughs in the treatment of diabetes and obesity, reshaping the global therapeutic paradigm. With the widespread adoption of peptide-based GLP-1RAs and the rapid emergence of small-molecule GLP-1RAs, GLP-1 therapies are evolving from a focus on “glycemic control” toward comprehensive metabolic management. Among them, small-molecule GLP-1RAs—offering the advantages of oral convenience and scalable manufacturing—hold great promise in enhancing patient adherence and advancing personalized management of metabolic diseases. Leveraging its fully integrated, end-to-end CRDMO platform, WuXi AppTec has long been deeply involved in and empowering the global discovery, development, and manufacturing of GLP-1 therapies. WuXi AppTec continues to help accelerate the innovation and clinical translation of next-generation GLP-1 therapeutics, bringing transformative treatments to patients around the world.

Over the past few years, GLP-1RAs have transformed care for type 2 diabetes mellitus (T2DM) and obesity. By enhancing glucose-stimulated insulin secretion, suppressing glucagon, and curbing appetite to support weight loss, these therapies deliver sustained glycemic control and meaningful clinical benefits. Their success has reset clinical expectations, improving metabolic and cardiovascular outcomes and ushering in a new era that addresses not only blood glucose but also the broader drivers of metabolic disease.

While peptide-based GLP-1RAs continue to elevate patient outcomes, the emergence of orally available, small-molecule GLP-1RAs opens a complementary frontier.These agents are chemically stable, readily manufactured at scale, and suitable for oral dosing without permeation enhancers, which expands accessibility and convenience for patients worldwide.

Mechanistically, small-molecule GLP-1RAs recapitulate the beneficial signaling of peptide analogs through novel receptor-engagement strategies, including allosteric modulation, biased agonism, and selective activation of G-protein–mediated pathways. Supported by high-resolution structural insights, these approaches enable precise control of receptor signaling while maintaining favorable pharmacokinetics and oral bioavailability.

The emergence of small-molecule GLP-1RAs is opening new possibilities for combination therapy.Their oral, food-independent formulation enables convenient co-administration with approved oral agents such as SGLT2 inhibitors or metformin to create fixed-dose combination regimens.These combinations may deliver synergistic benefits in glucose control, weight management, and cardiometabolic protection, while offering multi-target, multi-pathway modulation to help reduce cardiovascular and renal risks at their source. At the same time, a simplified dosing regimen can further improve long-term treatment adherence among patients.

Currently, one of the most advanced oral small-molecule GLP-1RAs is in Phase 3 clinical trials for patients with type 2 diabetes (T2DM). Published clinical data have demonstrated significant reductions in both A1C and body weight. The therapy is expected to be submitted for regulatory approval worldwide in 2026.

Importantly, small-molecule and peptide-based GLP-1RAs should not be viewed as competing alternatives but as complementary therapeutic options.Together, they expand the spectrum of treatment possibilities, enabling physicians to tailor personalized regimens based on patients’ characteristics, lifestyles, and care needs—ultimately improving clinical outcomes and enhancing quality of life.

WuXi AppTec’s Chemistry platform adopts an integrated, end-to-end CRDMO model that seamlessly connects drug discovery (R), development (D), and commercial manufacturing (M). Covering every stage from early discovery to large-scale production, the platform is committed to providing global partners with fast, flexible, efficient, and reliable one-stop small-molecule, oligonucleotides, peptides, and complicated conjugates drug development solutions.

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.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.

參考資料：

[1] Oral Small-Molecule GLP-1 Receptor Agonists: Mechanistic Insights and Emerging Therapeutic Strategies. Retrieved October 20, 2025 from https://www.mdpi.com/2218-0532/93/2/26

[2] Lilly's oral GLP-1, orforglipron, superior to oral semaglutide in head-to-head trial. Retrieved October 20, 2025 from https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-superior-oral-semaglutide-head

[3] WuXi Chemistry: A Global Leading CRDMO Platform. Retrieved November 3, 2025 from https://officialsite-static.wuxiapptec.com/upload/WXAT_2025_Investor_Day_Wu_Xi_Chemistry_CRDMO_bfb07e912d.pdf

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