By WileyJanuary 24, 20251 Comment3 Mins Read

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Popular examples of GLP-1 receptor agonists (GLP1RA) include semaglutide (Ozempic, Wegovy), liraglutide (Victoza, Saxenda), and dulaglutide (Trulicity). These medications mimic the GLP-1 hormone to stimulate insulin secretion, reduce glucagon release, and slow gastric emptying, promoting blood sugar control and weight loss. They bind to GLP1 receptors in the pancreas and brain, enhancing satiety and improving glucose regulation.

A study on GLP1RA medications found that behavioral side effects likely do not result from direct action on GLP1R.

Glucagon-like peptide 1 receptor agonists (GLP-1RAs), widely used medications for managing type 2 diabetes and obesity, have recently gained attention for their rising popularity as weight loss drugs. However, these medications have been associated with behavioral side effects. A large population-based study published in Diabetes, Obesity and Metabolism explored whether specific genetic variants could help explain these effects.

GLP-1RAs work by mimicking the GLP-1 hormone, which regulates insulin secretion, blood glucose levels, and feelings of satiety. The GLP-1 hormone binds to the GLP1R receptor located on cells in the brain and pancreas.

In the study, researchers analyzed common genetic variations in the GLP1R gene across diverse populations, including 408,774 individuals of white British ancestry, 50,314 of white European ancestry, 7,667 South Asians, 10,437 of multiple ancestries, and 7,641 African-Caribbean individuals.

Variants in the GLP1R gene had consistent associations with cardiometabolic traits (body mass index, blood pressure, and type 2 diabetes) across ancestries. GLP1R variants were also linked with risk-taking behavior, mood instability, chronic pain, and anxiety in most ancestries, but the results were less consistent. The genetic variants influencing cardiometabolic traits were separate from those influencing behavioral changes and separate from those influencing expression levels of the GLP1R gene.

Behavioral Effects and GLP1R Variants

The findings suggest that any observed behavioral changes with GLP1RA are likely not acting directly through GLP1R.

“Whilst it is not possible to directly compare genetic findings to the effects of a drug, our results suggest that behavioral changes are unlikely to be a direct result of the GLPRAs. Exactly how these indirect effects are occurring is currently unclear,” said corresponding author Rona J. Strawbridge, PhD, of the University of Glasgow, in the UK.

Reference: “Association of GLP1R locus with mental ill-health endophenotypes and cardiometabolic traits: A trans-ancestry study in UK Biobank” by Madeleine M. E. Hayman, Waneisha Jones, Alisha Aman, Joey Ward, Jana Anderson, Donald M. Lyall, Jill P. Pell, Naveed Sattar, Paul Welsh and Rona J. Strawbridge, 22 January 2025, Diabetes, Obesity and Metabolism.
DOI: 10.1111/dom.16178

DiabetesGeneticsObesityPublic Health