A new study has found a link between the popular diabetes drug and weight-loss medication Ozempic and a disproportionately high risk of suicidal thoughts. Although researchers can't establish causation, they say the link needs to be studied further so people can be informed about the potential risks.
The hype around Ozempic was inevitable. Its generic name, semaglutide, is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) that has revolutionized diabetes and weight management treatments with its ability to lower blood sugar levels and suppress appetite. Between 2015 and 2019, the percentage of people with type 2 diabetes treated with GLP-1 RAs, including semaglutide, increased from 3.2% to 10.7%.
Recent research has highlighted the drug's 'bonus' therapeutic benefits, such as reducing the risk of kidney complications in people with type 2 diabetes, reducing heart risks in overweight non-diabetics, and its potential as a treatment for addiction. However, a recently published study found a darker link between semaglutide and suicidal ideation.
After reports emerged in 2023 of suicidal or self-harm thoughts associated with the GLP-1 RAs semaglutide (Ozempic and Wegovy) and liraglutide (Saxenda), a group of American, Italian, and Swiss researchers examined data from a global World Health Organization (WHO) database of individual case safety reports containing more than 28 million reports of suspected adverse drug reactions (ADRs).
They looked for reports of suicide or self-harm ADRs associated with semaglutide and liraglutide between July 2011 and August 2023, and categorized the indications for prescribing the drugs: 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 launch of Wegovy, which is indicated for obesity management, doctors would prescribe Ozempic, an approved diabetes treatment, for an unapproved indication — weight loss. (These are the same drugs sold under different brand names; the difference is in the amount of semaglutide in each pen dispenser and what they are approved for.) Off-label prescribing is both common and legal.
Before moving on to the researchers’ findings, it is necessary to explain the statistical analyses they performed. Pharmacovigilance is an important scientific field concerned with the detection, evaluation, understanding and prevention of ADRs. Once a drug is on the market, the main source for detecting new ADRs is a database of individual case safety reports that record suspected ADRs, such as the WHO database used here. However, while spontaneous reporting of suspected ADR events is considered the best way to assess them, their value is limited by inadequate and selective reporting.
Disproportionality analyses, which use reports of suspected ADRs, are the most commonly used quantitative methods to detect so-called 'safety signals', which are indications of potential risk that require 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 drugs. observed patient safety reports recording both the medication and the event, along with the number of reports to be reported expected based on baseline rates of drugs and events in the same patient safety database when there is no association between the drug and the event. If the observed-expected metric significantly exceeds a predefined threshold, it generates a disproportionate reporting or SDR signal. However, due to the previously mentioned problem of inadequate and selective reporting, SDRs cannot by themselves be reported as definitive scientific evidence of a causal relationship between a drug and an adverse event.
Of the 36,172,078 reports in the database, researchers identified a total of 107 unique cases of suicide and/or self-harm ADRs associated with semaglutide and 162 cases associated with liraglutide. The main reason for prescribing the medications 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 suicidal ideation associated with semaglutide compared with other antidiabetic drugs and no signal for any other ADR of interest. Disproportionality persisted when certain drugs were taken with semaglutide, highlighting the interaction between semaglutide and mental illness.
“The disproportionality remained significant when focusing on concomitantly reported antidepressants or benzodiazepines, suggesting that people with anxiety and depressive disorders may be more likely to report suicidal ideation when treated with semaglutide,” the researchers wrote. “When we repeated the analysis excluding cases where antidepressants were concomitantly reported, we did not detect a disproportionality signal. In contrast, when we repeated the analysis excluding cases where benzodiazepines were concomitantly reported, the disproportionality remained significant. This is consistent with an interaction between core psychopathology and semaglutide effects and warrants further investigation.”
Based on their analysis, the researchers suggested that patients with diabetes and/or obesity without comorbid psychiatric disorders may not be at increased risk for semaglutide-related suicidal ideation. The researchers did not detect any signals for liraglutide-related suicide and/or self-harm ADRs.
The study's findings have drawn criticism from experts, with Dr Trevor Steward, a senior research fellow at the University of Melbourne's School of Psychological Sciences, expressing concern about the issues raised by the study.
“The study raises important questions about whether additional precautions are needed when prescribing semaglutide to patients with mental health problems and whether a warning about an increased risk of suicidal thoughts in some people should be added to the drug’s label,” he said. “The increase in off-label prescribing of these drugs is concerning and there is an urgent need for larger studies to understand the potential risks to both the patient and the drug itself… Given that these drugs have become so popular, this study should be seen as a warning about the importance of supporting larger studies aimed at understanding how these drugs may affect the brain, who they are safe for and who may be at risk.”
Researchers have investigated semaglutide Why did it happen? They point to a higher risk of suicidal ideation and limitations of the study. For example, this suicidal ideation may have been present before GLP-1 treatment. Adjustment for potential confounders, such as alcohol and substance abuse, was limited by the relatively small number of reports found. There was a lack of detail about off-label prescribing; researchers were unable to characterize the extent to which prescribing was off-label and its impact on outcomes. Data on duration of treatment until ADR were available only in a few patient reports. There was also a high proportion of cases with missing drug dose data, precluding dose-response analysis.
Despite these limitations, the researchers say the link between semaglutide and suicidal thoughts uncovered in their study needs to be investigated further.
The study was published on: JAMA Network Open.
Source: Scimex