Ozempic, Wegovy not associated with higher risk of suicidal ideation in large review of US health records

The researchers used a database that includes more than 100 million patient records to assess the risks of suicidal ideation among people using the drug, sold as Ozempic for type 2 diabetes and Wegovy for weight loss. The results were published Friday in the journal Nature Medicine.

Dr. Rong Xu, an author of the study and professor of biomedical informatics at Case Western Reserve University School of Medicine, said she decided to look into the issue after European regulators opened a probe into semaglutide and reports of suicidal thoughts last summer. The US Food and Drug Administration said this week that it’s also conducting its own investigation.

Xu and her fellow researchers, including National Institute on Drug Abuse Director Dr.Nora Volkow, compared cases of suicidal ideation among people taking semaglutide with those taking other medicines for weight loss or diabetes.

“We observed a lower incidence of suicidal ideations in patients who had taken semaglutide than in patients who were treated with non-GLP1R-targeting medications for the same conditions,” Volkow wrote in an email, referring to the way semaglutide works to mimic a hormone called GLP-1.

The analysis included more than 240,000 people with obesity and more than 1.5 million with type 2 diabetes. It looked at the risk of suicidal ideation within six months of starting the medicines, as well as at longer time points.

At six months, it found that among people taking the drug for weight loss, semaglutide was associated with a 73% lower risk of first-time suicidal ideation and a 56% lower risk of recurrent suicidal ideation. The comparator drugs included bupropion, naltrexone, orlistat, topiramate and phentermine.

For people with type 2 diabetes, the reductions were 64% and 49%, respectively. The comparator drugs included insulin, metformin and newer classes known as DPP-4 and SGLT-2 inhibitors.

The lower risks were observed out to three years.

A positive effect on mental health?

The comparator medicines work differently than semaglutide, which is a GLP-1 receptor agonist that has effects on insulin production, appetite and feelings of fullness. Researchers have noted that it also has effects on the brain.

As use of Ozempic and Wegovy has exploded over the past few years, Xu said, she noted anecdotal reports of people experiencing a reduction in addictive behaviors while taking them – less interest in things like alcohol or smoking – which made her wonder whether the medicines could also have a positive effect on mental health.

“It was kind of like a paradox,” Xu said. “The case reports from both sides”: the European investigation and these anecdotal reports.

With access to a database called the TriNetX platform, which includes de-identified electronic health records from 100.8 million people in 59 health systems across the US that’s updated “basically in real time, every day,” Xu decided to perform statistical analyses to assess the risk.

It’s an approach she says she used during the Covid-19 pandemic to evaluate the risk of the Omicron variant in real time.

Ozempic and Wegovy, along with similar drugs like Mounjaro and Zepbound, are now being prescribed to millions of patients in the US. In weight loss trials, Wegovy and Zepbound showed average body weight reductions of 15% and more than 20%, respectively. The most common side effects are gastrointestinal issues like nausea, vomiting and constipation, although reports of more serious potential side effects, like stomach paralysis, have more recently emerged.

The findings from the new study come days after the FDA said it was reviewing reports of suicidal ideation among people using semaglutide and similar medicines and evaluating the need for regulatory action.

The reports were from a database called the FDA Adverse Event Reporting System, or FAERS. The agency notes that a drug’s appearance there “means that FDA has identified a potential safety issue, but it does not mean that FDA has identified a causal relationship between the drug and the listed risk.”

The FAERS database lists more than 23,000 reports of various reactions among users of semaglutide; the most common are gastrointestinal disorders, with more than 10,000. There are 144 reports of cases of suicidal ideation.

“Those are case reports,” Xu said. “To derive a conclusion, you really need to perform a head-to-head comparison between similar patients.”

Possible effects on the brain

The European Medicines Agency said in July that it was reviewing 150 reports of possible cases of self-injury and suicidal thoughts among people taking semaglutide and similar medicines.

In December, the agency said that its Pharmacovigilance Risk Assessment Committee had reviewed available evidence and was seeking more information from the drugs’ makers.

“While at this point no conclusion can be drawn on a causal association, there are several issues that still need to be clarified,” the EMA said in a statement, without elaborating.

It said the safety committee would discuss the topic again in April.

Both Wegovy and Zepbound have warnings in their US prescribing information about the risk of suicidal behavior and ideation, noting that those risks have been reported in clinical trials with other chronic weight management products and recommending that patients be monitored for that risk.

The prescribing information for an older medicine, Saxenda – part of the same GLP-1 class – also contains a recommendation that patients should be monitored for depression or suicidal thoughts or behavior.

The information notes that clinical trials of Saxenda showed that nine of 3,384 adults, or 0.3% of those taking the medicine, reported suicidal ideation, compared with two of 1,941 adults on placebo, or 0.1%. One person on the drug attempted suicide. In a pediatric clinical trial, one patient of 125 taking the drug died by suicide. The information says “there was insufficient information to establish a causal relationship to Saxenda.”

The pivotal clinical trial of Wegovy excluded patients with a history of depression in the previous two years, a previous suicide attempt or severe suicidal ideation.

Volkow pointed to a previous weight-loss drug, rimonabant, that was withdrawn from the market in Europe in 2008 over concerns around suicidal thoughts as an example of weight-loss drugs potentially having these effects. She noted that that medicine works in a different way from semaglutide, blocking a cannabinoid type 1 receptor “that, when blocked, can trigger negative emotional states.”

She said it’s also possible that effects of abrupt weight loss could “make some people vulnerable” in a way that’s unrelated to the ways medicines might work.

And Volkow also pointed out the GLP-1 receptors that semaglutide binds to “are expressed in the brain’s dopamine reward system, and this could be a mechanism by which semaglutide might affect mood.”

A potential treatment for depression?

Even though semaglutide was associated with a lower risk of suicidal ideation in the study, Xu and Volkow wrote in a research briefing that the data “do not yet justify off-label treatment,” referring to the idea that doctors could prescribe the drug specifically to lower patients’ risk of suicidal thoughts.

The findings perhaps support future clinical trials to explore that possibility, Xu said, and Volkow pointed out that “there is interest on testing semaglutide as a potential treatment for depression.”

At least one trial is recruiting patients for that purpose, according to a federal database on clinical trials, assessing semaglutide as a treatment for cognitive dysfunction in major depressive disorder.

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