{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T05:08:55Z","timestamp":1793164135696,"version":"4.5.0"},"reference-count":23,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Jiangsu Hengrui Pharmaceuticals Co., Ltd."}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Med"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Safiglipron is an oral small-molecule glucagon-like peptide-1 (GLP-1) receptor agonist administered without fasting or dietary restrictions. We evaluated its efficacy and safety in OUTSTAND-1, a phase 3, multicenter, randomized, double-blind, placebo-controlled trial at 46 sites in China. We randomized 284 adults with type 2 diabetes managed with diet and exercise alone (mean baseline HbA1c 7.95%, median diabetes duration 1.6\u2009years, 33.1% women) to once-daily safiglipron 30\u2009mg (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200970), 60\u2009mg (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200970), 90\u2009mg (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200972) or placebo (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200972) for 32\u2009weeks, followed by a 20-week active-treatment extension. For the primary endpoint, placebo-adjusted treatment differences in HbA1c change from baseline to week 32 were \u22121.22% (95% CI, \u22121.53 to \u22120.91), \u22121.20% (95% CI, \u22121.52 to \u22120.89) and \u22121.45% (95% CI, \u22121.75 to \u22121.14) for 30\u2009mg, 60\u2009mg and 90\u2009mg, respectively (all\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.0001; treatment policy estimand). Secondary outcomes showed HbA1c\u2009&lt;\u20097.0% in 71.4\u221277.8% versus 25.0%, HbA1c\u2009\u2264\u20096.5% in 58.6\u221268.1% versus 16.7% and placebo-adjusted fasting plasma glucose differences of \u22121.58, \u22121.68 and \u22122.08\u2009mmol\u2009l\n                    <jats:sup>\u2212<\/jats:sup>\n                    <jats:sup>1<\/jats:sup>\n                    , respectively (all\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.0001). Body weight differences were modest (\u22120.65%, \u22122.23% and \u22123.56% versus placebo). Other secondary outcomes generally favored safiglipron for HbA1c\u2009&lt;\u20095.7% attainment, postprandial glycemia, homeostatic model assessment of \u03b2 cell function (HOMA-\u03b2), homeostatic model assessment of insulin resistance (HOMA-IR), disposition index and waist circumference, with less rescue therapy use. Insulin and C-peptide responses varied by dose, and changes in treatment satisfaction were limited. Gastrointestinal adverse events were most common and mostly mild or moderate. Adverse events led to treatment discontinuation in 1.4%, 2.9%, 6.9% and 0% of participants receiving safiglipron 30\u2009mg, 60\u2009mg, 90\u2009mg and placebo, respectively. These findings support once-daily oral safiglipron as an effective treatment option for type 2 diabetes. ClinicalTrials.gov identifier:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/clinicaltrials.gov\/study\/NCT06672172\" ext-link-type=\"uri\">NCT06672172<\/jats:ext-link>\n                    .\n                  <\/jats:p>","DOI":"10.1038\/s41591-026-04651-9","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T09:02:22Z","timestamp":1790672542000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Oral small-molecule GLP-1 receptor agonist safiglipron in early type 2 diabetes: a randomized, double-blind, placebo-controlled trial"],"prefix":"10.1038","author":[{"given":"Miao","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5407-3737","authenticated-orcid":false,"given":"Liang","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengyan","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianghua","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7249-6445","authenticated-orcid":false,"given":"Qifu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuhai","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoyang","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debin","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sihong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yimei","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5411-1441","authenticated-orcid":false,"given":"Guo","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangli","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanlin","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7740-1238","authenticated-orcid":false,"given":"Zi","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5441-7766","authenticated-orcid":false,"given":"Xinhua","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"on 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L.P., Y.X. and Z.Y. declare a patent pending relating to safiglipron. All other authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}