In a new study published in eClinicalMedicine, researchers have found that the use of semaglutide, a medication primarily prescribed for type 2 diabetes, does not increase the risk of developing neurological or psychiatric conditions. Surprisingly, semaglutide may even offer protection against cognitive deficits and nicotine misuse. These findings were derived from analyzing the electronic health records of tens of thousands of patients over a one-year period.
Semaglutide is the active ingredient in several medications, including Ozempic. It functions by mimicking a hormone called glucagon-like peptide-1 (GLP-1), which helps to regulate blood sugar levels. Beyond its glucose-lowering effects, semaglutide has also been recognized for its potential benefits in weight management, leading to its approval for treating obesity as well. The medication has gained significant attention due to its efficacy in improving metabolic health, reducing cardiovascular risks, and aiding weight loss.
The motivation behind the new study stemmeds from both its expanding use and emerging concerns about its safety profile. While randomized controlled trials have confirmed the benefits of semaglutide on metabolic and cardiovascular health, there have been reports of potential adverse neuropsychiatric effects, such as worsening mood and suicidal behavior.
These reports prompted regulatory agencies like the European Medicines Agency and the United Kingdom’s Medicines and Healthcare products Regulatory Agency to review the safety of GLP-1 receptor agonists, including semaglutide. The United States Food and Drug Administration also conducted a preliminary evaluation but found no causal link. Despite this, the concerns persisted within the medical community and the public.
Given these concerns, the researchers aimed to provide a more comprehensive assessment of the risks associated with semaglutide by analyzing electronic health records from a large population of patients.
“I became interested in studying glucagon-like peptide-1 receptor agonists (GLP1-RAs) for neuropsychiatric disorders about 4 years ago when, serendipitously, I saw a patient being started on one of these medications for their diabetes, who also improved in their psychiatric symptoms,” said study author Riccardo De Giorgi, a clinical lecturer at the University of Oxford.
“I started planning an experimental medicine trial, currently ongoing, to investigate this matter in healthy volunteers. Meanwhile, regulatory agencies such as the EMA and the MHRA started an enquiry into GLP1-RAs following some reports of possible adverse neuropsychiatric events in people taking these medications for diabetes or weight loss. We thought therefore that we could leverage existing data on a platform called TriNetX to contribute to this research.”
The TriNetX US Collaborative Network is a comprehensive database containing anonymized electronic health records of over 100 million patients across 62 healthcare organizations in the United States. The study focused on patients aged 18 and above who had been diagnosed with type 2 diabetes and received a first prescription of semaglutide between December 2017 and May 2021. The researchers compared these patients to three other groups, each prescribed a different antidiabetic medication: sitagliptin, empagliflozin, or glipizide.
The cohorts were meticulously matched based on 179 variables, including demographics, socioeconomic factors, lifestyle, healthcare utilization, comorbidities, and other medication use. This rigorous matching ensured that the comparison between the groups was as fair and unbiased as possible.
The researchers tracked the occurrence of 22 neurological and psychiatric outcomes, including conditions such as cognitive deficits, dementia, epilepsy, depression, anxiety disorders, and substance misuse. They also examined all-cause mortality within the year following the first prescription. The incidence of these outcomes was analyzed using statistical methods that allowed for a detailed comparison between semaglutide and the other medications.
The results revealed that semaglutide was not associated with an increased risk of any of the neurological or psychiatric conditions studied. In fact, semaglutide was linked to a lower risk of cognitive deficits and nicotine misuse compared to sitagliptin and glipizide.
Specifically, the risk of cognitive deficits was significantly lower in patients taking semaglutide compared to those taking sitagliptin (hazard ratio of 0.72) and glipizide (hazard ratio of 0.72). Additionally, the risk of nicotine dependence was lower in the semaglutide group compared to all three comparator drugs.
These findings are in line with another recent study, which found that people with type 2 diabetes treated with glucagon-like peptide-1 agonists, such as Ozempic, have a reduced risk of developing dementia. The
“In addition to the lack of safety problems, we were pleased to see that semaglutide use seemed positively associated with a lower risk for cognitive deficit and nicotine use,” De Giorgi told PsyPost. “This is because there are several other studies that have been looking at mechanisms of action of this medication, and they quite consistently suggest that semaglutide may have neuroprotective activity while also working on regulating the reward system of our brain.”
“These mechanisms, when faulty, are likely implied in the disorders mentioned above. Therefore, it was nice to witness how evidence from pre-clinical and clinical research line up with each other.”
The study also found that semaglutide was associated with a lower risk of all-cause mortality compared to sitagliptin, glipizide, and empagliflozin. This finding is particularly noteworthy, although it should be interpreted with caution due to potential limitations in the completeness of death registry linkage in the database used.
“The main takeaway is that semaglutide appears safe from a neurological and psychiatric perspective in people who take it for the treatment of their diabetes,” De Giorgi said. “Aside from sugar control and weight loss, this medication may have some more benefit on the brain health of these patients, but we need clinical trials that can confirm this.”
While these findings are promising, it is important to recognize the limitations of the study. The primary limitation is that the study is observational, meaning it can identify associations but cannot establish causality. Therefore, while the results suggest that semaglutide may have protective effects on cognitive health and nicotine misuse, it cannot be definitively stated that semaglutide causes these benefits.
“We should not make the mistake of inferring causality between the exposure (semaglutide) and the outcomes (neurological and psychiatric disorders) measured,” De Giorgi noted. “Therefore, we must be careful before considering any clinical recommendation. However, this study contributes to a growing body of research that provides reassurance regarding potential adverse neuropsychiatric effects of semaglutide and similar medications.”
Future research should focus on confirming these findings through randomized controlled trials and exploring the mechanisms by which semaglutide may exert its protective effects on cognitive health and substance misuse. Clinical trials including biomarkers of disease progression and longer follow-up periods would be valuable in understanding the potential neuroprotective and anti-inflammatory effects of semaglutide.
Despite these limitations, this study provides valuable insights into the safety profile of semaglutide and its potential benefits beyond glycemic control in patients with type 2 diabetes. These findings are particularly relevant given the high burden of mental health issues in patients with diabetes and the growing use of GLP-1 RAs for various health conditions.
“There is much interest in investigating the potential of semaglutide and similar medications at the moment,” De Giorgi explained. “Some important studies in this context are for example: ISAP and EVOKE Plus for cognitive disorders, and STAR-T for alcohol use disorder. As mentioned above, my research group is also looking at better understanding cognitive mechanisms behind semaglutide action in healthy people – the OxSENSE study.”
“This is an exciting area of clinical research, but we must proceed with caution,” he added. “Drugs such as semaglutide may be powerful tools for a range of health conditions, but they are novel drugs and we need more investigations. Moreover, these medications are unlikely to be one-size-fits-all remedies, so a significant research investment may be needed to better identify who are the people that are more likely to benefit from them, and who are the people who may experience undesirable effects.”
The study, “12-month neurological and psychiatric outcomes of semaglutide use for type 2 diabetes: a propensity-score matched cohort study,” was authored by Riccardo De Giorgi, Ivan Koychev, Amanda I. Adler, Philip J. Cowen, Catherine J. Harmer, Paul J. Harrison, and Maxime Taquet.
