The diabetes and obesity drug semaglutide does not increase the risk of an initial diagnosis of a neurological or psychiatric condition – in fact it lowers the risk, research shows.
Semaglutide is a glucagon-like peptide 1 receptor agonist (GLP1-RA) used for type 2 diabetes mellitus and obesity.
GLP1-RAs have been hailed as the scientific breakthrough of the year 2023. Healthcare spending on these medications is predicted to expand further as novel indications, formulations, and related molecules become available.
The research team, from NIHR Oxford Health Biomedical Research Centre, noted that pre-clinical evidence had suggested that these medications promoted neurobiological activity, including protection against neuronal degeneration and inflammation, as well as modulating dopamine-related reward mechanisms.
Because of this, semaglutide had been under consideration for use in neurological, psychiatric and substance use disorders.
But in July last year, the European Medicines Agency and the UK Medicines and Healthcare products Regulatory Agency began a review of these medications’ safety, following reports of worsening mood and suicidal behaviour in GLP1-RAs users.
While the US FDA has issued a preliminary evaluation suggesting no causal link but concerns over adverse neuropsychiatric events still resonate within the media and with the public. The safety profile of semaglutide, and GLP-1 RAs more broadly, remains under assessment; a better clarification of it is necessary to inform patients, prescribers, and policymakers.
Dr Paul Harrison from Oxford University said that whether semaglutide had positive or negative effects on brain health needed to be determined.
Research showed the risk of cognitive deficits was significantly lower after semaglutide compared to sitagliptin and glipizide, but similar between semaglutide and empagliflozin.
One possibility is that any protective effect of GLP1-RAs on cognition is mediated by their effect on cardiovascular morbidity. However, the lack of consistent association with ischaemic strokes suggests that other mechanisms might also be at play.
These might include other neuroprotective and anti-inflammatory mechanisms, supported by measurements of systemic inflammation in people exposed to semaglutide. As these are partly shared with SGLT2I, this hypothesis would also explain why no difference in cognitive outcomes were observed when semaglutide was compared with the SGLT2I empagliflozin.
Similarly, the risk of dementia was lower after semaglutide compared to sitagliptin and glipizide, although this did not reach significance after correction, but similar between semaglutide and empagliflozin.
Secondly, the risk of nicotine dependence was found to be significantly lower after semaglutide compared to glipizide and empagliflozin, and lower compared to sitagliptin, although not after correction for multiple testing.
The association of semaglutide with lower risks of nicotine use disorder was robust and consistent across comparisons.
Other significant results included a lower risk of a first diagnosis of depression and ischaemic stroke compared to sitagliptin. The risk of all-cause mortality was lower after semaglutide compared to sitagliptin, glipizide, and empagliflozin.
“In summary, semaglutide use was not associated with higher risks of onset or recurrence of neurological and psychiatric outcomes in the following 12-months compared to other commonly prescribed antidiabetic agents,” Dr Harrison said.
“In contrast, semaglutide has a potential benefit for cognition and nicotine misuse.”