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We evaluated its efficacy and safety versus dapagliflozin in OUTSTAND-2, a phase 3, multicenter, randomized, double-blind, double-dummy, active-comparator-controlled trial conducted at 98 sites in China. We randomized 810 adults (mean hemoglobin A1C (HbA1c) 8.60%, median diabetes duration 5.0\u2009years, 35.7% women) to safiglipron 30\u2009mg (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009202), safiglipron 60\u2009mg (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009203), safiglipron 90\u2009mg (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009203) or dapagliflozin 10\u2009mg (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009202) for 32\u2009weeks, followed by a 20-week active-treatment extension. For the primary endpoint, treatment differences versus dapagliflozin in change from baseline in HbA1c at week 32 under the primary non-inferiority estimand were \u22120.30% (95% confidence interval (CI): \u22120.51 to \u22120.09), \u22120.22% (\u22120.44 to \u22120.01) and \u22120.40% (\u22120.62 to \u22120.19) for safiglipron 30\u2009mg, 60\u2009mg and 90\u2009mg, respectively, establishing non-inferiority for all three doses (all\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.0001; non-inferiority margin 0.4%). Under the treatment policy estimand, 90\u2009mg met the prespecified statistical criterion for superiority (difference \u22120.25%; 95% CI: \u22120.45 to \u22120.05; one-sided\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.0067), whereas 60\u2009mg did not (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.0789), after which fixed-sequence testing stopped. HbA1c target attainment rates with safiglipron versus dapagliflozin were 54.9\u221263.5% versus 36.5% for HbA1c &lt;7.0% and 38.9\u221248.6% versus 16.1% for HbA1c \u22646.5%. Mean body weight changes were \u22122.35%, \u22123.55%, \u22124.17% and \u22123.60% for safiglipron 30\u2009mg, safiglipron 60\u2009mg, safiglipron 90\u2009mg and dapagliflozin, respectively. Fasting plasma glucose, seven-point self-monitored blood glucose profiles, waist circumference, HOMA-\u03b2, HOMA-IR and changes in treatment satisfaction showed varying degrees of improvement from baseline with both safiglipron and dapagliflozin. Rescue therapy was used by 0.5\u22121.5% versus 0% of participants, respectively. Gastrointestinal adverse events were more frequent with safiglipron and mostly mild or moderate; adverse events led to treatment discontinuation in 4.0%, 4.0%, 3.9% and 1.5% of participants, respectively. Safiglipron provides an effective oral treatment option for adults with type 2 diabetes inadequately controlled with metformin. ClinicalTrials.gov identifier:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/clinicaltrials.gov\/study\/NCT06589765\" ext-link-type=\"uri\">NCT06589765<\/jats:ext-link>\n                    .\n                  <\/jats:p>","DOI":"10.1038\/s41591-026-04713-y","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T09:02:00Z","timestamp":1791190920000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Oral small-molecule GLP-1RA safiglipron versus dapagliflozin in type 2 diabetes: a randomized, double-blind, active-comparator-controlled phase 3 trial"],"prefix":"10.1038","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6863-1798","authenticated-orcid":false,"given":"Lixin","family":"Guo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongni","family":"Yu","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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5407-3737","authenticated-orcid":false,"given":"Liang","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debin","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoyang","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangxiu","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingyan","family":"Zhong","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"}]},{"name":"on behalf of the OUTSTAND-2 Investigator Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixin","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debin","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoyang","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangxiu","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,5]]},"reference":[{"key":"4713_CR1","unstructured":"IDF Diabetes Atlas 11th edn (eds Magliano, D. 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L.P., Y.X. and Z.Y. declare a patent pending relating to safiglipron. The other authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}