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Glucagon-like peptide-1 receptor agonism and suicide risk: evidence from Mendelian randomization

Accepted version
Peer-reviewed

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Authors

Zhao, Steven Sizheng 
Gill, Dipender 

Abstract

Glucagon-like peptide-1 receptor agonists (GLP1Ra) have proven efficacious for treating type 2 diabetes (T2D), obesity, and cardiovascular disease (1). However, suicidal thoughts and self-injury have been reported following treatment with semaglutide, leading to investigations by the European Medicines Agency, and the Medicines and Healthcare Products Regulatory Agency in the United Kingdom. It remains unclear whether these potential adverse events are attributable to semaglutide, the GLP1Ra drug class, the underlying conditions, or other factors. A large observational study found that semaglutide use was associated with lower risk of incident and recurrent suicidal ideation, compared with other anti-obesity or anti-diabetes medications (2). However, it is difficult to draw causal inference from traditional epidemiological associations due to the potential for residual confounding and reverse causation. For this reason, it is important to triangulate evidence using methods that make orthogonal assumptions. Here, we applied Mendelian randomization (MR) to investigate whether there is human genetic evidence for a causal effect of GLP1Ra on suicide risk. This paradigm uses randomly allocated genetic variants as instrumental variables for studying the effect of GLP1Ra, and is therefore less vulnerable to the environmental confounding and reverse causation bias that can hinder causal inference in traditional epidemiological designs.

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Journal Title

Journal of the American Heart Association

Conference Name

Journal ISSN

2047-9980
2047-9980

Volume Title

Publisher

Wiley

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Sponsorship
Wellcome Trust (225790/Z/22/Z)