{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:10:13Z","timestamp":1787314213157,"version":"build-2736575974"},"reference-count":25,"publisher":"BMJ","issue":"5","license":[{"start":{"date-parts":[[2023,5,16]],"date-time":"2023-05-16T00:00:00Z","timestamp":1684195200000},"content-version":"unspecified","delay-in-days":15,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Jiangsu Hansoh Pharmaceutical Group Co., Ltd.","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2023,4,28]]},"published-print":{"date-parts":[[2023,5]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Recent cardiovascular outcomes trials have demonstrated that glucagon-like peptide 1 receptor agonist (GLP-1RA) decreases the incidence of major adverse cardiovascular events (MACEs) in individuals with type 2 diabetes mellitus (T2DM). Polyethylene glycol loxenatide (PEG-Loxe) is a once-weekly GLP-1RA obtained by modifying exendin-4. No clinical trials have been designed to assess the impact of PEG-Loxe on cardiovascular (CV) outcomes in individuals with T2DM. This trial aims to test the hypothesis that compared with placebo, PEG-Loxe treatment does not result in an unacceptable increase in CV risk in individuals with T2DM.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>This study is a multicentre, randomised, double-blind, placebo-controlled trial. Patients with T2DM who fulfilled the inclusion criteria were randomly divided to receive weekly administration of either PEG-Loxe 0.2\u2009mg or placebo (1:1 ratio). The randomisation was stratified according to utilisation of sodium-glucose cotransporter 2 inhibitors, history of CV disease and body mass index. The research period is expected to be 3\u2009years, with a 1-year recruitment period and a 2-year follow-up period. The primary outcome is the occurrence of the first MACE, described as CV death, non-fatal myocardial infarction or non-fatal stroke. The statistical analyses were undertaken on the intent-to-treat patient. The primary outcome was evaluated using a Cox proportional hazards model with treatment and randomisation strata as the covariates.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>The current research has been authorised by the Ethics Committee of Tianjin Medical University Chu Hsien-I Memorial Hospital (approval number: ZXYJNYYhMEC2022-2). Researchers must acquire informed consent from every participant before conducting any protocol-associated procedures. The findings of this study will be published in a peer-reviewed journal.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>ChiCTR2200056410.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2022-069080","type":"journal-article","created":{"date-parts":[[2023,5,16]],"date-time":"2023-05-16T10:02:17Z","timestamp":1684231337000},"page":"e069080","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["Impact of polyethylene glycol loxenatide on cardiovascular outcomes in patients with type 2 diabetes: study protocol for a multicentre, randomised, double-blind, placebo-controlled trial (BALANCE-3)"],"prefix":"10.1136","volume":"13","author":[{"given":"Yun","family":"Xie","sequence":"first","affiliation":[{"name":"NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Kuang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Guangdong Provincial People\u2019s Hospital, Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quanmin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Rocket Army Medical Center of Chinese PLA General Hospital, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5744-5129","authenticated-orcid":false,"given":"Tianpei","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linong","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Peking University People\u2019s Hospital, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2586-1443","authenticated-orcid":false,"given":"Yuanyuan","family":"Kong","sequence":"additional","affiliation":[{"name":"Clinical Epidemiology and EBM Unit, National Clinical Research Center for Digestive Diseases, Capital Medical University Affiliated Beijing Friendship Hospital, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5166-4091","authenticated-orcid":false,"given":"Yale","family":"Duan","sequence":"additional","affiliation":[{"name":"Endocrinology Scientific Group of the Central Medical Department, Jiangsu Hansoh Pharmaceutical Group Co, Shanghai, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liming","family":"Chen","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2023,5,16]]},"reference":[{"key":"2025121513485683000_13.5.e069080.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2021.109119"},{"key":"2025121513485683000_13.5.e069080.2","doi-asserted-by":"crossref","DOI":"10.1186\/s12933-018-0728-6","article-title":"Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007-2017","volume":"17","author":"Einarson","year":"2018","journal-title":"Cardiovasc Diabetol"},{"key":"2025121513485683000_13.5.e069080.3","first-page":"S42","article-title":"Cardiovascular outcomes with once-weekly GLP-1 Ras: clinical and economic implications","volume":"24","author":"Heile","year":"2018","journal-title":"J Manag Care Spec Pharm"},{"key":"2025121513485683000_13.5.e069080.4","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1007\/5584_2020_494","article-title":"GLP-1 receptor agonists and SGLT2 inhibitors for the treatment of type 2 diabetes: new insights and opportunities for cardiovascular protection","volume":"1307","author":"Bertoccini","year":"2021","journal-title":"Adv Exp Med Biol"},{"key":"2025121513485683000_13.5.e069080.5","doi-asserted-by":"publisher","DOI":"10.1177\/0145721715607981"},{"key":"2025121513485683000_13.5.e069080.6","doi-asserted-by":"crossref","first-page":"e2695","DOI":"10.1210\/clinem\/dgaa285","article-title":"Obesity, polycystic ovary syndrome, and infertility: a new avenue for GLP-1 receptor agonists","volume":"105","author":"Cena","year":"2020","journal-title":"J Clin Endocrinol Metab"},{"key":"2025121513485683000_13.5.e069080.7","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)31149-3"},{"key":"2025121513485683000_13.5.e069080.8","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1603827"},{"key":"2025121513485683000_13.5.e069080.9","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1607141"},{"key":"2025121513485683000_13.5.e069080.10","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1056\/NEJMoa2108269","article-title":"Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes","volume":"385","author":"Gerstein","year":"2021","journal-title":"N Engl J Med"},{"key":"2025121513485683000_13.5.e069080.11","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1111\/1753-0407.12397","article-title":"Polyethylene glycol loxenatide injections added to metformin effectively improve glycemic control and exhibit favorable safety in type 2 diabetic patients","volume":"9","author":"Chen","year":"2017","journal-title":"J Diabetes"},{"key":"2025121513485683000_13.5.e069080.12","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1002\/jcph.386","article-title":"Pharmacokinetics and pharmacodynamics of a polyethylene glycol (PEG) -conjugated GLP-receptor agonist once Weekly in Chinese patients with type 2 diabetes","volume":"55","author":"Yang","year":"2015","journal-title":"J Clin Pharmacol"},{"key":"2025121513485683000_13.5.e069080.13","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1111\/dom.14198","article-title":"Efficacy and safety of polyethylene glycol loxenatide monotherapy in type 2 diabetes patients: a multicentre, randomized, double-blind, placebo-controlled phase 3A clinical trial","volume":"23","author":"Shuai","year":"2021","journal-title":"Diabetes Obes Metab"},{"key":"2025121513485683000_13.5.e069080.14","doi-asserted-by":"crossref","first-page":"2375","DOI":"10.1111\/dom.14163","article-title":"Efficacy and safety of polyethylene glycol loxenatide as add-on to metformin in patients with type 2 diabetes: a multicentre, randomized, double-blind, placebo-controlled, phase 3B trial","volume":"22","author":"Gao","year":"2020","journal-title":"Diabetes Obes Metab"},{"key":"2025121513485683000_13.5.e069080.15","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1111\/dom.13553","article-title":"Cardiovascular safety of oral semaglutide in patients with type 2 diabetes: rationale, design and patient baseline characteristics for the pioneer 6 trial","volume":"21","author":"Bain","year":"2019","journal-title":"Diabetes Obes Metab"},{"key":"2025121513485683000_13.5.e069080.16","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1509225"},{"key":"2025121513485683000_13.5.e069080.17","doi-asserted-by":"crossref","DOI":"10.1056\/NEJMoa1612917","article-title":"Once-Weekly exenatide and cardiovascular outcomes in type 2 diabetes","volume":"377","author":"Holman","year":"2017","journal-title":"N Engl J Med"},{"key":"2025121513485683000_13.5.e069080.18","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1901118"},{"key":"2025121513485683000_13.5.e069080.19","doi-asserted-by":"crossref","first-page":"e30","DOI":"10.2337\/dc21-1839","article-title":"GLP-1 receptor agonists for cardiovascular protection: a matter of time","volume":"45","author":"Caruso","year":"2022","journal-title":"Diabetes Care"},{"key":"2025121513485683000_13.5.e069080.20","doi-asserted-by":"crossref","first-page":"893971","DOI":"10.3389\/fendo.2022.893971","article-title":"Exposure-response analysis of cardiovascular outcome trials with incretin-based therapies","volume":"13","author":"Pan","year":"2022","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2025121513485683000_13.5.e069080.21","doi-asserted-by":"crossref","first-page":"879294","DOI":"10.3389\/fmolb.2022.879294","article-title":"Polyethylene glycol loxenatide injection (GLP-1) protects vascular endothelial cell function in middle-aged and elderly patients with type 2 diabetes by regulating gut microbiota","volume":"9","author":"Chen","year":"2022","journal-title":"Front Mol Biosci"},{"key":"2025121513485683000_13.5.e069080.22","first-page":"1378","article-title":"Understanding the merits and drawbacks of noninferiority trials in cardiovascular medicine","volume":"37","author":"Kaul","year":"2021","journal-title":"Can J Cardiol"},{"key":"2025121513485683000_13.5.e069080.23","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1007\/s13300-020-00981-0","article-title":"The role of tirzepatide, dual GIP and GLP-1 receptor agonist, in the management of type 2 diabetes: the surpass clinical trials","volume":"12","author":"Min","year":"2021","journal-title":"Diabetes Ther"},{"key":"2025121513485683000_13.5.e069080.24","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1504720"},{"key":"2025121513485683000_13.5.e069080.25","unstructured":"Center for Drug Evaluation and Research, Food and Drug Administration, U.S. Department of Health and Human Services . Guidance for industry. type 2 diabetes mellitus: evaluating the safety of new drugs for improving glycemic control. Available: https:\/\/www.fda.gov\/media\/135936\/download [Accessed 22 Mar 2023]."}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2022-069080","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T21:49:04Z","timestamp":1765835344000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2022-069080"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5]]},"references-count":25,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,5,16]]},"published-print":{"date-parts":[[2023,5]]}},"alternative-id":["10.1136\/bmjopen-2022-069080"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2022-069080","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5]]}}}