Semaglutide: No increased risk of neurological or psychiatric outcomes versus other antidiabetic medications, study finds

Semaglutide is not linked to an increased 12-month risk of adverse neuropsychiatric outcomes when compared to other antidiabetic medications," the researchers wrote in eClinicalMedicine. In contrast, semaglutide exhibited a potential benefit on cognition and nicotine misuse.

Although semaglutide is approved for type 2 diabetes mellitus (T2DM) and is explored as a potential treatment for brain disorders, concerns about adverse neuropsychiatric events have surfaced. Consequently, further data is needed to evaluate the effects of semaglutide on brain health. The study provides robust estimates of the risk of psychiatric and neurological outcomes following semaglutide use compared to three other antidiabetic medications.

Against the above background, Riccardo De Giorgi, Department of Psychiatry, University of Oxford, Warneford Hospital, Warneford Lane, Oxford, United Kingdom, and colleagues aimed to estimate the risks of neurological and psychiatric outcomes within one year of a first semaglutide prescription in T2DM patients, and compare them with those arising after a first prescription of three other common antidiabetic medications.

For this purpose, they conducted a propensity-score-matched cohort study based on EHR data from 100 million people in the USA. Three cohorts of patients with type 2 diabetes prescribed semaglutide between December 1, 2017, and May 31, 2021, were matched using propensity scores (1:1) with those receiving sitagliptin, empagliflozin, and glipizide, utilizing a greedy nearest-neighbor algorithm with a caliper distance of 0.

Cox regression analysis evaluated the risks of 22 neurological and psychiatric outcomes within one year of the index prescription. These outcomes included encephalitis, parkinsonism, cognitive deficits, dementia, epilepsy/seizures, migraines, insomnia, nerve disorders, myoneural junction/muscle diseases, intracranial hemorrhage, ischemic stroke, and various substance misuses (alcohol, opioids, cannabis, stimulants, nicotine), as well as psychosis, bipolar disorder, depression, anxiety, obsessive-compulsive disorder, and suicidality. Negative control outcomes (NCOs) were employed to assess potential unmeasured confounding.

The study led to the following findings:

· Each matched cohort included 23,386 (semaglutide versus sitagliptin), 22,584 (versus empagliflozin), and 19,206 (versus glipizide) patients.

· Semaglutide was not associated with an increased risk of neurological and psychiatric outcomes.

· After multiple-testing correction, semaglutide was associated with reduced risk for several such outcomes, notably cognitive deficit compared to sitagliptin (HR 0.72) and glipizide (HR 0.72), dementia compared to sitagliptin (HR 0.52), and nicotine misuse across most comparisons (HR 0.72 against glipizide; HR 0.77 against empagliflozin; HR 0.82 against sitagliptin, though the latter was no longer statistically significant after adjustment for multiple comparisons).

· Empagliflozin showed the fewest differences from semaglutide.

· No differences in NCOs were observed between cohorts.

"Our findings can guide current regulatory investigations and public health initiatives while encouraging clinical trials to explore the role of semaglutide in the treatment and prevention of cognitive deficits and substance misuse," the researchers concluded.

Reference:

Riccardo De Giorgi, Ivan Koychev, Amanda I. Adler,et al. 12-month neurological and psychiatric outcomes of semaglutide use for type 2 diabetes: a propensity-score matched cohort study. EClinicalMedicine (2024). DOI: 10.1016/j.eclinm.2024.102726

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(24)00305-5/fulltext