Semaglutide linked to lower neuropsychiatric event risk vs other diabetes drugs in observational study

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medRxiv Published April 24, 2026 Medically reviewed April 30, 2026 Study authors: murugadoss, k.; Venkatakrishnan, A.; Soundararajan, V. DOI ↗ By Dr. Amelia Tan, PhD · Internal Medicine & Chronic Disease

Key Takeaway

Consider these observational associations as hypothesis-generating only; do not infer causation.

This observational cohort study used a large federated US data platform to analyze 63,215 patients with baseline neuropsychiatric conditions before initiating semaglutide or comparators (metformin, SGLT2 inhibitors, DPP-4 inhibitors). The pre-landmark period was the 2 years from treatment initiation, and the post-landmark period was the following 2 years. The primary outcome was not reported; secondary outcomes included incident neuropsychiatric diagnostic codes across multiple categories.

Compared with metformin, SGLT2 inhibitors, and DPP-4 inhibitors, semaglutide treatment was associated with broadly lower risk of neuropsychiatric events. Within semaglutide users, higher attained dose during the pre-landmark period was associated with significantly lower incidence during the post-landmark period for substance-related disorders (P<0.001), mood disorders (P<0.001), anxiety- and stress-related disorders (P<0.001), CNS atrophies (P<0.001), neuromuscular disorders (P=0.013), eating/sleep/behavioral disorders (P=0.022), and personality/impulse-control disorders (P=0.028). Incidence of dementia or CNS degenerative diseases was similar between high-dose and low-dose semaglutide cohorts (P=0.15). Cognitive symptoms and speech/language symptoms were more closely linked to pre-landmark weight-loss magnitude than to maximum attained dose (P<0.001 and P<0.003, respectively).

Safety and tolerability were not reported. Effect sizes and absolute numbers were not reported. Key limitations include the observational design, use of propensity-matched comparator analyses, and potential data constraints within the federated platform. The study motivates prospective clinical studies and mechanistic analyses to clarify the impact of GLP-1 receptor agonists on human neuropsychiatric pathways and disease processes. Associations reported are not evidence of causation.

Study Details

Study typeCohort

Sample sizen = 63,215

EvidenceLevel 3

PublishedApr 2026

View Original Abstract ↓

GLP-1 receptor agonists have reshaped obesity therapeutics, but their impact on neuropsychiatric outcomes remains poorly characterized. From 29 million patients in a large federated data platform across the USA, including 489,785 semaglutide treated patients, we conducted an observational study integrating longitudinal neuropsychiatric outcomes. From this population, we assembled a cohort of 63,215 patients with baseline neuropsychiatric conditions before treatment initiation and evaluated 24 incident neuropsychiatric outcomes. In propensity-matched comparator analyses, during the 2 year time-period from treatment initiation, semaglutide was associated with broadly lower neuropsychiatric event risk than metformin, SGLT2 inhibitors, and DPP-4 inhibitors. Within the semaglutide-treated cohort, higher attained dose during the first two years after the first prescription ("pre-landmark period") was associated with significantly lower incidence during the following two years ("post-landmark period") of diagnostic codes associated with substance-related disorders (P<0.001), mood disorders (P<0.001), anxiety- and stress-related disorders (P<0.001), CNS atrophies (P<0.001), neuromuscular disorders (P=0.013), eating/sleep/behavioral disorders (P=0.022), and personality/impulse-control disorders (P=0.028). Consistent with previous clinical trials, the post-landmark incidence of dementia or CNS degenerative diseases was similar between the high-dose and low-dose semaglutide cohorts (P=0.15). For most neuropsychiatric diagnoses, post-landmark incidence was strongly associated with the maximum attained semaglutide dose during the pre-landmark period, but incident cognitive symptoms and speech/language symptoms were more closely linked to the pre-landmark weight-loss magnitude (p<0.001 and p<0.003, respectively). Bulk and single-cell transcriptomic analyses demonstrated GLP1R expression in CNS tissues (hypothalamus, caudate, putamen, nucleus accumbens, cerebellum) and peripheral nerves. Age-associated heterogeneity in GLP1R expression was evident in several of these compartments including the caudate nucleus, suggesting dynamic changes in the availability of the neurobiological substrate for semaglutide response. Together, these data support a model in which semaglutide confers a sustained, dose-dependent, weight loss-independent benefit across multiple neuropsychiatric conditions via direct CNS target engagement. This observational study motivates prospective clinical studies and mechanistic analyses to clarify the impact of GLP-1 receptor agonists on human neuropsychiatric pathways and disease processes.