A new study has found a link between the popular diabetic and weight loss drug Ozempic and a disproportionately high risk of suicidal thoughts. While the researchers cannot establish causation, they say the link needs to be investigated further so that people can be informed of the potential risks.
The hype around Ozempic has been unavoidable. Semaglutide, its generic name, is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) that has revolutionized diabetes and weight management treatments by its ability to lower blood sugar levels and suppress appetite. Between 2015 and 2019, the percentage of type 2 diabetics treated with GLP-1 RAs, including semaglutide, increased from 3.2% to 10.7%.
Recent research has highlighted the drug’s ‘bonus’ therapeutic benefits, including a reduced risk of kidney complications in type 2 diabetics, reduced heart risks in overweight non-diabetics, and its potential as a treatment for addiction. However, a recently published study has found a darker link between semaglutide and suicidal thinking.
After reports of suicidal or self-harming thoughts associated with the GLP-1 RAs semaglutide (Ozempic and Wegovy) and liraglutide (Saxenda) surfaced in 2023, a group of American, Italian and Swiss researchers examined data from a global World Health Organization (WHO) database of individual case safety reports with over 28 million reports of suspected adverse drug reactions (ADRs).
They searched for reports of suicidal or self-harm ADRs associated with semaglutide and liraglutide between July 2011 and August 2023 and grouped indications for the drugs’ prescription into categories: diabetes, weight management, possible off-label indication, and any other indication. ‘Off-label use’ is using an approved drug for an unapproved use. For example, before the introduction of Wegovy, which is indicated for the management of obesity, doctors would prescribe Ozempic, an approved diabetes treatment, for an unapproved indication – weight loss. (They’re the same drug sold under different brand names; the difference is in the amount of semaglutide in each pen dispenser and what they’re approved for.) Off-label prescribing is both common and legal.
Before moving on to the researcher’s findings, it’s necessary to explain the statistical analyses they performed. Pharmacovigilance is an important scientific area concerned with detecting, assessing, understanding, and preventing ADRs. After a drug has been market-approved, the main source for detecting new ADRs is a database of individual case safety reports recording suspected ADRs, such as the WHO database used here. However, while spontaneous reporting of suspected ADR events is considered the best way to evaluate them, their value is limited by under- and selective reporting.
Disproportionality analyses using reports of suspected ADRs are the most commonly used quantitative methods for detecting so-called ‘safety signals,’ potential signs of risk that warrant further investigation. Disproportionality analyses are statistical methods that aim to quantify the association between a drug and an ADR event by comparing the number of observed patient safety reports recording both the drug and the event with the number of reports that would be expected in the absence of an association between the drug and the event, based on the underlying drug and event rates within the same patient safety database. If the observed-to-expected metric significantly exceeds a predefined threshold, it generates a signal of disproportionate reporting or SDR. However, because of the issue of under- and selective reporting already mentioned, SDRs can’t, in and of themselves, be reported as conclusive scientific evidence of a causal relationship between a drug and an adverse event.
From 36,172,078 reports in the database, the researchers identified a total of 107 unique cases of suicidal and/or self-harm ADRs associated with semaglutide and 162 associated with liraglutide. The main reason for prescribing the drugs was possible off-label use (31.8% for semaglutide and 33.9% for liraglutide), followed by weight management (26.2% and 24.7%) and diabetes (24.3% and 20.4%).
However, analyses only detected significant disproportionality for semaglutide-associated suicidal ideation compared with other antidiabetic medications and detected no signals for any other ADR of interest. The disproportionality remained when certain medications were taken alongside semaglutide, highlighting the interplay between it and mental illness.
“The disproportionality remained significant when focused on co-reported antidepressants or benzodiazepines, suggesting that people with anxiety and depressive disorders may be at higher probability of reporting suicidal ideation when medicated with semaglutide,” said the researchers. “When repeating the analysis after excluding cases in which antidepressants were co-reported, we did not detect a disproportionality signal. In contrast, when repeating the analysis after excluding cases in which benzodiazepines were co-reported, the disproportionality remained significant. This is consistent with an interaction between baseline psychopathology and semaglutide effects and warrants further investigation.”
Based on their analyses, the researchers suggested that people with diabetes and/or obesity without co-existing psychiatric conditions may not be at high risk of semaglutide-associated suicidal ideation. The researchers did not detect any signals for liraglutide-associated suicidal and/or self-harming ADRs.
The study’s findings have generated reactions from experts. Dr Trevor Steward, senior research fellow at the University of Melbourne’s School of Psychological Sciences, voiced concerns about issues raised by the study.
“The study raises key questions about whether additional precautions are needed when prescribing semaglutide to patients with mental health issues and if warning about the increased risk of suicidal thoughts for some people should be included on the medication’s labels,” he said. “The rise in off-label prescribing of these medications is concerning, and there is an urgent need for larger studies to understand any potential risks related to both the patient and the medication itself … Given that these medications have become so popular, this study should be seen as a wake-up call on the importance of supporting larger studies that aim to understand how these medications may impact the brain, who they are safe for, and who might be at risk.”
The researchers are unable to say that semaglutide caused a higher risk of suicidal thoughts, and they point out the study’s limitations. For example, that suicidal ideation may have existed before GLP-1 treatment. Adjustments for potential confounders such as alcohol and substance misuse were limited because of the relatively small number of reports found. There was a lack of details about off-label prescribing the researchers were unable to qualify the extent to which prescribing was off-label and its impact on the results. Data on treatment duration until ADR was only available in a few patient reports. There was also a high proportion of cases with missing medication dose data, preventing a dose-response analysis.
Despite these limitations, the researchers say that the link between semaglutide and suicidal thoughts raised by their study needs to be investigated further.
The study was published in JAMA Network Open.
Source: Scimex