Semaglutide Shows No Higher Neuropsychiatric Risk

A group of researchers used a propensity-score matched cohort to assess the 12-month neurological and psychiatric outcomes of semaglutide use in patients with type 2 diabetes mellitus (T2DM) (chronic high blood sugar due to insulin resistance or deficiency). Their study was published in the EClinicalMedicine.

Context
A scientific achievement for 2023 is semaglutide, a glucagon-like peptide 1 receptor agonist (GLP1-RA) approved for obesity and type 2 diabetes. With new formulations and uses, healthcare spending on GLP1-RAs is expected to increase. Randomized controlled studies (RCTs) demonstrate the beneficial effects of semaglutide on cardiovascular and metabolic outcomes. Research suggests that there may be neurobiological advantages for problems related to the nervous system, psyche, and substance abuse.

Nevertheless, mood shift reports prompt safety reviews by the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) and the European Medicines Agency (EMA), which raise concerns. To fully understand the effects of semaglutide and GLP1-RAs on general brain health and neuropsychiatric safety in patients with type 2 diabetes, more research is required.

About the study
The Reporting of Studies Conducted using Observational Routinely-collected Health Data (RECORD) principles are followed by this study. Using a large-scale federated database called TriNetX United States (US) Collaborative Network, this study examined anonymised electronic health records (EHRs) from 62 US healthcare organizations, covering over 100 million individuals. Patient information, diagnosis, prescriptions, and treatments are all included on this platform.

Researchers found people with T2DM who were at least 18 years old, diagnosed between December 1, 2017, and May 31, 2021, and who had received their first prescription for semaglutide. For glipizide, empagliflozin, and sitagliptin, comparator cohorts were established. Cohorts were matched in the study according to 179 variables, which included lifestyle, comorbidities, healthcare consumption, medication history, and socioeconomic and demographic characteristics.

Using International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) codes, the study estimated the risk of 22 neurological and psychiatric outcomes within a year following the index event. In order to account for unmeasured confounding, it additionally calculated the chance of 15 negative control outcomes. R and the TriNetX interface were used for propensity-score matching and the ensuing analyses. Multiple testing adjustments were made, and statistical significance was defined at a p-value of less than 0.05.

Four secondary analyses were carried out: an examination of the results at a two-year follow-up, a competing risk analysis including mortality as a component, a subgroup analysis based on age, and a stratification by year of index prescription. The design, data collection, analysis, interpretation, and manuscript writing were all done independently of the study’s funding sources.

Study findings
After applying the inclusion/exclusion criteria, a total of 23,386 patients were included in each cohort for the comparison of semaglutide versus sitagliptin (mean ± SD age: 56.6 ± 12.8 years; 48.6% female); 22,584 patients for the comparison of semaglutide versus empagliflozin (mean ± SD age: 57.6 ± 12.4 years; 48.9% female); and 19,206 patients for the comparison between semaglutide and glipizide (mean ± SD age: 56.3 ± 13.0 years; 49.3% female). Standardized mean differences (SMDs) of less than 0.1 were guaranteed for each comparison and covariate because propensity-score matching was attained.

In comparison to other medications, semaglutide carries a lower risk when the Hazard Ratio (HR) is less than 1, and a higher risk when HR is greater than 1. Semaglutide was related with decreased risks of cognitive deficits compared to sitagliptin (HR 0.72) and glipizide (HR 0.72) but similar to empagliflozin (HR 0.96). However, it was not linked to an elevated risk of any neurological or psychiatric problems.

Semaglutide also reduced the risk of dementia (a cognitive deterioration that impairs memory and thinking) when compared to glipizide (HR 0.63) and sitagliptin (HR 0.52). In addition, glipizide (HR 0.72) and empagliflozin (HR 0.77) demonstrated a considerably higher risk of nicotine dependence than did semaglutide.

Compared to sitagliptin, there are other noteworthy outcomes such as a decreased risk of depression and ischemic stroke (a stroke caused by a blocked blood flow to the brain). For all comparisons, negative control outcomes (NCOs) consistently revealed no difference (HRs for composite NCOs ranging from 0.97 to 1.03, with all p-values more than 0.4). Comparing semaglutide to sitagliptin (95% CI 0.50–0.66, p < 0.0001, HR 0.58), empagliflozin (p 0.035, HR 0.86, 95% CI 0.75–0.99), and glipizide (p < 0.0001, HR 0.55, 95% CI 0.47–0.64), the risk of all-cause death was lower.

These results were validated by secondary analyses. The results of the age subgroup analysis indicated that younger patients had less substance use disorders while older patients had larger relationships with cognitive deficiency and dementia. The substantial correlation between semaglutide and reduced risks of death and other outcomes persisted. Consistent results were obtained when stratification was done by prescription time, covering pre- and post-coronavirus disease 2019 (COVID-19) periods. Similar trends were noted during a two-year follow-up, and glipizide and sitagliptin may also be associated with a decreased risk of psychosis.

With a few exceptions, such as the cognitive deficit between semaglutide and sitagliptin, where the HR decreased over time but stayed below 1, there was no discernible breach of the proportional-hazard assumption.

In conclusion
In summary, compared to other antidiabetic medicines, there was no elevated risk of 22 neurological and mental outcomes throughout a 12-month period in this large-scale trial on semaglutide, a GLP1-RA authorized for T2DM and obesity, with the exception of glipizide’s higher risk of migraines. Semaglutide was linked to potential benefits for cognitive function and nicotine misuse, which is consistent with meta-analyses that point to the benefits of GLP1-RAs for cognitive outcomes. Large sample size and thorough propensity-score matching contribute to the study’s robustness. These results inform regulatory evaluations and public health by supporting semaglutide’s ability to reduce cognitive impairments and substance misuse.

For more information: 12-month neurological and psychiatric outcomes of semaglutide use for type 2 diabetes: a propensity-score matched cohort study, EClinicalMedicine, https://doi.org/10.1016/j.eclinm.2024.102726