Patients' genetics shape response to GLP1 drugs

Two genetic variants affect the response to glucagon-like peptide 1 (GLP-1) receptor agonist drugs, according to a new large-scale study by the 23andMe Research Institute.

Injectable weight-loss medications such as semaglutide (eg Ozempic) and tirzepatide (eg Mounjaro) have recently become widely available for individuals who are overweight or obese. These drugs act by mimicking gut hormones that regulate appetite, insulin release and digestion, but how well they work and are tolerated can differ greatly between patients.

'While there is high interest in GLP-1 medications, there is significant variation in how well they work for different people,' said Dr Noura Abul-Husn, chief medical officer at the 23andMe Research Institute and contributor to the study. 'The market is crowded with weight loss support and medications, but the approach to weight management is typically one of trial and error. This can lead people to leap into treatment with a high degree of uncertainty and unrealistic expectations about efficacy and possible side effects.'

The researchers performed a genome-wide association study, scanning millions of genetic variants from 27,885 individuals who also self-reported their experience with GLP-1 treatments. The results, published in Nature, help pinpoint genetic signatures associated with the drugs' performance and side-effects.

The analysis showed that patients who carried a variant called rs10305420 in the gene encoding the primary receptor targeted by GLP-1 drugs lost slightly more weight than those without this mutation. Similar results were obtained based on electronic health records from 4,855 individuals in the All of Us cohort, showing concordance between self-reported and clinical data.

Another variant was associated with how well patients could tolerate tirzepatide: those who had a substitution known as rs1800437 in the gene that codes for the receptor GIPR experienced more nausea and vomiting. No such association was found for rs1800437 carriers who took semaglutide, which, unlike tirzepatide, does not act on GIPR.

Finally, the researchers built models of treatment response that combined genetic information with clinical factors such as age, sex, dose, and treatment duration and whether patients had type 2 diabetes. While these models could help predict how individuals would benefit from GLP-1 drugs, the overall impact of genetic factors remained small.

Dr. Marie Spreckley, an obesity expert from the University of Cambridge, UK, who was not involved in the study said to the Guardian: 'Overall, this is an important step toward understanding variability and the potential for future precision approaches, but the effects are modest and the evidence is not yet sufficient to support using genetic information to guide treatment decisions in routine clinical practice.'