12-month neurological and psychiatric outcomes of semaglutide use for type 2 diabetes: a propensity-score matched cohort study.
Level 3 - non-randomized controlled study
Non-randomized controlled cohort study using propensity-score matching
PubMed 39764175 · doi:10.1016/j.eclinm.2024.102726
What was done
This retrospective cohort study used electronic health records from the TriNetX US Collaborative Network covering over 100 million patients. Patients with type 2 diabetes prescribed semaglutide between December 1, 2017, and May 31, 2021, were 1:1 propensity-score matched with comparator cohorts receiving sitagliptin (23,386 pairs), empagliflozin (22,584 pairs), or glipizide (19,206 pairs). Using Cox proportional hazards regression, the researchers assessed the 12-month risks of 22 neurological and psychiatric outcomes (including cognitive deficit, dementia, encephalitis, stroke, depression, psychosis, suicidality, and substance misuse). Negative control outcomes were evaluated to detect unmeasured confounding. The study was exploratory and did not have a pre-registered protocol.
What was found
Semaglutide was not associated with an increased risk for any of the 22 neurological or psychiatric outcomes. After multiple-testing correction, semaglutide was associated with significantly reduced risks for: - Cognitive deficit versus sitagliptin (HR 0.72, 95% CI 0.64–0.80) and glipizide (HR 0.72, 95% CI 0.63–0.81). - Dementia versus sitagliptin (HR 0.52, 95% CI 0.40–0.68). - Nicotine misuse versus glipizide (HR 0.72, 95% CI 0.61–0.85) and empagliflozin (HR 0.77, 95% CI 0.65–0.90), while the reduction versus sitagliptin (HR 0.82, 95% CI 0.70–0.95) did not remain statistically significant after multiple-comparison adjustment. Empagliflozin showed the fewest differences from semaglutide. Negative control outcomes showed no differences between matched cohorts.
Why it matters
These findings provide real-world safety reassurance against concerns of adverse psychiatric events like suicidality or depression with semaglutide. Observed reductions in cognitive deficits and substance misuse support further investigation of GLP-1 receptor agonists in prospective clinical trials for neurological conditions.
Limits
The study is observational and retrospective, relying on electronic health record diagnostic codes that may be vulnerable to misclassification and residual confounding. The study lacked a pre-registered protocol or pre-specified statistical analysis plan. Follow-up was limited to 12 months, which is brief for evaluating slow-progressing neurodegenerative diseases, and findings in patients with diabetes may not generalize to individuals prescribed semaglutide solely for weight management.
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