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Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To investigate the association between anti-obesity medication (AOM) use and the risk of cognitive disorder in individuals with overweight and obesity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We systematically searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science and\n                      <jats:ext-link>Clinicaltrials.gov<\/jats:ext-link>\n                      from inception to August 2025 for randomized controlled trials (RCTs) and observational studies of AOMs. Relative risks were calculated using a random-effect model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our analysis included 4 RCTs (n = 35,924; 17,963 AOM users, 17,961 placebo recipients) and 2 retrospective cohort studies (n = 2,303,492; 1,151,746 GLP-1RA users, 1,151,746 non-users). In RCTs, the use of AOMs was not associated with a lower risk of cognitive disorder (RR = 0.94, 95% CI 0.39 to 2.25, P = 0.88) or dementia (RR = 1.02, 95% CI 0.41 to 2.54, P = 0.97) versus placebo. Every 5-kg weight reduction mediated by AOMs was not associated with a decreased risk of cognitive disorder (RR = 0.95, 95% CI 0.44 to 2.05, P = 0.82) compared with placebo. Meta-regression further confirmed that neither absolute weight loss nor weight reduction difference between AOM and placebo groups was associated with a reduced risk of cognitive disorder. However, retrospective cohort studies showed that GLP-1RA users had lower risks of cognitive disorder (OR = 0.44, 95% CI 0.21 to 0.91, P = 0.03) and Alzheimer\u2019s disease (OR = 0.43, 95% CI 0.19 to 0.97, P = 0.04) than non-users.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>While short-term RCTs did not observe a substantial cognitive benefit of AOMs, real-world evidence indicated that GLP-1RAs may offer potential protection against cognitive disorders. These divergent findings highlight the need for long-term prospective trials with dedicated cognitive endpoints.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1859388","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T05:38:12Z","timestamp":1782797892000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Anti-obesity medications and cognitive disorder risk: a discrepancy between RCTs and real-world evidence"],"prefix":"10.3389","volume":"17","author":[{"given":"Chengwen","family":"Li","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolism, Peking University People\u2019s Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chu","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Peking University People\u2019s Hospital","place":["Beijing, China"]},{"name":"Peking University Diabetes Center","place":["Beijing, China"]},{"name":"Beijing Key Laboratory of Innovative Drug and Device Translation in Endocrine and Metabolic Diseases","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zonglin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Peking University People\u2019s Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Peking University People\u2019s Hospital","place":["Beijing, China"]},{"name":"Peking University Diabetes Center","place":["Beijing, China"]},{"name":"Beijing Key Laboratory of Innovative Drug and Device Translation in Endocrine and Metabolic Diseases","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjia","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Peking University People\u2019s Hospital","place":["Beijing, China"]},{"name":"Peking University Diabetes Center","place":["Beijing, China"]},{"name":"Beijing Key Laboratory of Innovative Drug and Device Translation in Endocrine and Metabolic Diseases","place":["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","place":["Beijing, China"]},{"name":"Peking University Diabetes Center","place":["Beijing, China"]},{"name":"Beijing Key Laboratory of Innovative Drug and Device Translation in Endocrine and Metabolic Diseases","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoling","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Peking University People\u2019s Hospital","place":["Beijing, China"]},{"name":"Peking University Diabetes Center","place":["Beijing, China"]},{"name":"Beijing Key Laboratory of Innovative Drug and Device Translation in Endocrine and Metabolic Diseases","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"502","DOI":"10.3390\/biomedicines13020502","article-title":"Obesity: a global health challenge demanding urgent action","volume":"13","author":"Abad-Jim\u00e9nez","year":"2025","journal-title":"Biomedicines"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1533317519899546","DOI":"10.1177\/1533317519899546","article-title":"Antidiabetic drugs for the risk of alzheimer disease in patients with type 2 DM using FAERS","volume":"35","author":"Akimoto","year":"2020","journal-title":"Am. 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