{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T12:54:45Z","timestamp":1793105685241,"version":"4.5.0"},"reference-count":41,"publisher":"American Medical Association (AMA)","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"\n Importance<\/jats:title>\n Few of the available therapies for type 2 diabetes (T2D) comprehensively address disease burden beyond glycemic control. Examining whether berberine ursodeoxycholate (HTD1801), a first-in-class gut-liver anti-inflammatory metabolic modulator, has the potential to treat the core aspects of metabolic disease is important.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To assess the safety and efficacy of HTD1801 in patients with T2D that is inadequately controlled with diet and exercise.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n \n This phase 2 double-blind, placebo-controlled, 12-week randomized clinical trial, conducted in China between March 2022 and January 2023, included patients with T2D who underwent 8 or more weeks of diet and exercise, had a hemoglobin A\n 1c<\/jats:sub>\n (HbA\n 1c<\/jats:sub>\n ) level of 7.0% to 10.5%, and had a fasting plasma glucose (FPG) level less than 250.5 mg\/dL.\n <\/jats:p>\n <\/jats:sec>\n \n Interventions<\/jats:title>\n Patients were randomized 1:1:1 to placebo (n\u2009=\u200938), HTD1801 500 mg twice daily (n\u2009=\u200937), and HTD1801 1000 mg twice daily (n\u2009=\u200938).<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n \n The primary end point was the HbA\n 1c<\/jats:sub>\n level change from baseline to week 12. Secondary end points included glycemic, hepatic, and cardiometabolic parameters. The primary end point was analyzed using a mixed-effects model for repeated measures, with the HbA\n 1c<\/jats:sub>\n level change from baseline as the dependent variable. Treatment group, measurement time point, and interaction between treatment group and measurement time point were independent variables.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n The study included 113 patients with T2D (mean [SD] age, 54.3 [10.6] years; 72 male [63.7%]) who were randomized. Among these patients, the mean (SD) HbA\n 1c<\/jats:sub>\n level was 8.2% (0.8%); body mass index, 25.5 (3.7), calculated as weight in kilograms divided by height in meters squared; and FPG level, 160.7 (38.3) mg\/dL. Baseline disease severity was balanced across treatment groups. The primary end point was achieved with significant dose-dependent reductions in the HbA\n 1c<\/jats:sub>\n level in both HTD1801 groups compared with the placebo group. The least-squares mean difference in the HbA\n 1c<\/jats:sub>\n level at week 12 was \u22120.4% (95% CI, \u22120.79% to \u22120.03%;\n P<\/jats:italic>\n \u2009=\u2009.04) for the 500-mg group and \u22120.7% (95% CI, \u22121.10% to \u22120.35%;\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001) for the 1000-mg group compared with the placebo group. HbA\n 1c<\/jats:sub>\n level reductions were paralleled with mean (SD) improvements in the FPG level in both the 500-mg group (\u221213.0 [38.2] mg\/dL) and the 1000-mg group (\u221218.4 [21.8] mg\/dL) groups. Reductions were observed in lipids and markers of liver injury in the 1000-mg group. HTD1801 was safe and well tolerated, with 110 patients (97.3%) completing the study. Treatment-emergent adverse events, generally mild, occurred in 59 patients (52.2%) overall. One patient (in the 500-mg group) experienced a serious adverse event of retinal hemorrhage, which was unlikely related to treatment. No patients discontinued due to an adverse event.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n \n In this placebo-controlled randomized clinical trial, treatment with HTD1801 resulted in significant reductions in the HbA\n 1c<\/jats:sub>\n level and improvements in key cardiometabolic and liver parameters. HTD1801 was safe and well tolerated. These findings are being confirmed in ongoing phase 3 studies. The effects demonstrated by HTD1801 support an oral treatment option for T2D and its comorbidities.\n <\/jats:p>\n <\/jats:sec>\n \n Trial Registration<\/jats:title>\n \n ClinicalTrials.gov Identifier:\n NCT06411275<\/jats:ext-link>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2024.62185","type":"journal-article","created":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T11:03:06Z","timestamp":1740999786000},"page":"e2462185","source":"Crossref","is-referenced-by-count":35,"title":["Berberine Ursodeoxycholate for the Treatment of Type 2 Diabetes"],"prefix":"10.1001","volume":"8","author":[{"given":"Linong","family":"Ji","sequence":"first","affiliation":[{"name":"Department of Endocrinology, Peking University People\u2019s Hospital, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Nanjing First Hospital, Nanjing, Jiangsu, 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