Anti-obesity medications and cognitive disorder risk: a discrepancy between RCTs and real-world evidence

To investigate the association between anti-obesity medication (AOM) use and the risk of cognitive disorder in individuals with overweight and obesity.

We systematically searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science and Clinicaltrials.gov from inception to August 2025 for randomized controlled trials (RCTs) and observational studies of AOMs. Relative risks were calculated using a random-effect model.

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's disease (OR = 0.43, 95% CI 0.19 to 0.97, P = 0.04) than non-users.

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.