As blogged previously, rare post marketing case reports of suicidality have emerged amongst people taking GLP1 receptor agonists for diabetes or obesity, prompting a review of this class of medications by regulators around the world. 

A recent real world study evaluated electronic health records of people with overweight or obesity, drawn from a large American database, who were prescribed semaglutide (a GLP1 receptor agonist called Ozempic for type 2 diabetes and Wegovy for weight management), looking at new and recurrent suicidal ideation, compared to (propensity score-matched) people who were prescribed non-GLP1 receptor agonist obesity medication (bupropion, naltrexone, orlistat, topiramate, phentermine, and setmelanotide. (Note that of these, only phentermine, orlistat and setmelanotide are approved stand-alone obesity medications.) 

On evaluation of over 240,000 people with overweight or obesity, over a 6 month time period from the initial prescription, semaglutide was associated with a 73% lower risk of new suicidal ideation, and a 56% lower risk of recurrent suicidal ideation, compared to people prescribed other weight management medication.  These findings were consistent across gender, age, and ethnicity.  At baseline (before being prescribed semaglutide), people in both groups were on other weight management medication (per the list above) and were propensity score matched to balance this, but we don’t know how many people prescribed semaglutide had the other medications stopped, or had them continued with semaglutide added on.

They also analyzed data in over 1.5 million people with type 2 diabetes prescribed semaglutide vs only non GLP1 receptor agonist diabetes medication (insulin, metformin, sulfonylurea, DPP4 inhibitors, SGLT2 inhibitors, thiazolidinediones, and alpha glucosidase inhibitors).  At baseline, patients were propensity-matched to balance the proportion in each group on each of these other medications.   At 6 months, a prescription for semaglutide was associated with a 64% lower risk of new suicidal ideation, and a 49% lower risk of recurrent suicidal ideation, compared to people prescribed other non-GLP1 diabetes medication.  At 3 years, there was a 42% lower risk of new suicidal ideation and 42% lower risk of recurrent suicidal ideation with semaglutide compared to people prescribed non-GLP1 diabetes treatments.

As a retrospective observational database study, there are inherent limitations to these data, including potential for misdiagnosis, unmeasured or uncontrolled confounders like disease severity or other medical conditions, self-selection for a particular medication, reverse causality, lack of information on adherence or dosage, and so on.  Controlled clinical trials are a much more rigorous way to assess for any outcome, and the clinical trials of GLP1 receptor agonists have not show an increased risk of suicidal ideation.  As an addition to our clinical trial information, this large, real-world database analysis is reassuring that semaglutide is not associated with increased suicidality.

So where are the regulatory agencies at with their analysis?

The American FDA’s preliminary evaluation has not found evidence that GLP1s cause suicidal thoughts or actions.  They are continuing to look into this issue by way of analysis of additional data, and will provide a further update when their further analysis is complete.

The European Medicines Agency Pharmacovigilance Risk Assessment Committee (PRAC) states that while at this point no conclusion can be drawn for a causal association, there are several issues that still need to be clarified by the makers of these medications.  They have asked for additional information from the makers of GLP1RAs and will review the topic again in April 2024.

The United Kingdom Medicine and Health Care Products Regulatory Agency (MHRA) is also conducting an independent investigation on this topic.

BOTTOM LINE:  This large retrospective database analysis does not support a higher risk of suicidal ideation with semaglutide, and in fact suggests that the risk may be lower.  Health agencies around the world continue their evaluation of the GLP1 class, and we look forward to their updates as they become available.

ImportantIf you have concerns about your mood or feel in any danger of self harm, reach out to your health care provider, government support hotlines/services, or attend emergency care.  In Canada, help for suicide crisis and prevention can be found here.

Disclaimer: I am/have been an investigator in clinical trials of semaglutide.  I receive honoraria as a continuing medical education speaker and consultant from the makers of semaglutide (Novo Nordisk).

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