{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T03:03:21Z","timestamp":1793070201357,"version":"4.5.0"},"reference-count":14,"publisher":"American Medical Association (AMA)","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA"],"published-print":{"date-parts":[[2026,8,4]]},"abstract":"\n Importance<\/jats:title>\n The effects of orforglipron, an oral, nonpeptide glucagon-like peptide 1 receptor agonist, added to insulin glargine for treatment of type 2 diabetes have not been described.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To assess efficacy and safety of orforglipron added to titrated insulin glargine in adults with type 2 diabetes and inadequate glycemic control.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n Randomized, double-blind, phase 3 study conducted at 72 sites across the US, Brazil, China, Japan, and Romania between November 10, 2023, and September 15, 2025, in adults with type 2 diabetes taking insulin glargine with or without metformin and\/or sodium-glucose cotransporter 2 inhibitors over 40 weeks.<\/jats:p>\n <\/jats:sec>\n \n Interventions<\/jats:title>\n Participants were randomized (1:1:1:1) to receive once-daily 3-mg (n\u2009=\u2009137), 12-mg (n\u2009=\u2009132), or 36-mg (n\u2009=\u2009136) dosages of orforglipron or placebo (n\u2009=\u2009141), in addition to titrated insulin glargine.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n \n The primary outcome was mean hemoglobin A\n 1c<\/jats:sub>\n (HbA\n 1c<\/jats:sub>\n ) change from baseline to week 40 (for the 12-mg once daily and 36-mg once daily dosages of orforglipron). Key secondary outcomes were mean HbA\n 1c<\/jats:sub>\n change from baseline (for the 3-mg once daily dosage of orforglipron), proportion of participants achieving HbA\n 1c<\/jats:sub>\n targets of lower than 7.0% and 6.5% or lower, and mean body weight change and percentage change from baseline to week 40.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Among 546 randomized participants (median age, 61.0 [IQR, 26-95] years; 52.9% male; median duration of type 2 diabetes, 14.6 [IQR, 0.1-40.7] years; mean HbA\n 1c<\/jats:sub>\n , 8.50% [SD, 0.95%]; mean body mass index, 30.8 [SD, 6.1]), 507 (92.9%) completed the trial. At week 40, the mean changes from baseline in HbA\n 1c<\/jats:sub>\n were \u22121.58%, \u22121.88%, and \u22121.82% with orforglipron, 3 mg, 12 mg, and 36 mg once daily, respectively, vs \u22120.79% with placebo. Each dosage of orforglipron was superior to placebo (estimated treatment differences: 3 mg once daily, \u22120.78% [95% CI, \u22121.02% to \u22120.55%]; 12 mg once daily, \u22121.08% [95% CI, \u22121.33% to \u22120.83%]; 36 mg once daily, \u22121.03% [95% CI, \u22121.28% to \u22120.77%];\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001 for all). All key secondary outcomes demonstrated statistically significant differences in favor of orforglipron compared with placebo. Mean percentage body weight change from baseline was \u22122.6%, \u22124.8%, and \u22125.4% with orforglipron, 3 mg once daily, 12 mg once daily, and 36 mg once daily, respectively, vs 0.2% with placebo. The most frequent adverse events with orforglipron were gastrointestinal (mild to moderate). Orforglipron did not increase the risk of clinically significant hypoglycemia vs placebo.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n In participants with type 2 diabetes inadequately controlled by insulin glargine, addition of oral orforglipron significantly improved glycemic control and body weight, without increasing hypoglycemia risk, compared with placebo.<\/jats:p>\n <\/jats:sec>\n \n Trial Registration<\/jats:title>\n \n ClinicalTrials.gov Identifier:\n NCT06109311<\/jats:ext-link>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jama.2026.9512","type":"journal-article","created":{"date-parts":[[2026,6,7]],"date-time":"2026-06-07T21:30:19Z","timestamp":1780867819000},"page":"389","source":"Crossref","is-referenced-by-count":6,"title":["Orforglipron Added to Titrated Insulin Glargine in Type 2 Diabetes"],"prefix":"10.1001","volume":"336","author":[{"given":"Francesco","family":"Giorgino","sequence":"first","affiliation":[{"name":"Department of Regenerative and Precision Medicine and Ionian Area, Section of Internal Medicine, Endocrinology, Andrology, and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherwin","family":"D\u2019Souza","sequence":"additional","affiliation":[{"name":"St Luke\u2019s Endocrinology, Boise, Idaho"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Ludwig","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company, Indianapolis, Indiana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arihiro","family":"Kiyosue","sequence":"additional","affiliation":[{"name":"Tokyo-Eki Centre-Building Clinic, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilda","family":"Ibriga","sequence":"additional","affiliation":[{"name":"Eli Lilly and Company, Indianapolis, 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