Rare GLP1R variants attenuate weight loss with semaglutide but not tirzepatide

Weight loss with glucagon-like peptide-1 receptor agonists (GLP-1RAs) is heterogeneous across individuals, yet the genetic causes of this variation are not fully known. We integrated exome sequencing data with electronic health records within the Helix Research Network (n = 351,818). Here, we show that, among 13,725 GLP-1RA-treated adults, carriers of rare damaging GLP1R variants lose less weight with semaglutide than matched non-carriers but achieve a near-normal tirzepatide response. Carriers of rare variants in GIPR, which encodes the glucose-dependent insulinotropic polypeptide receptor, the second target of tirzepatide, also achieve normal weight loss responses. Our study demonstrates that rare GLP1R variants affect the response to semaglutide but not to tirzepatide. Rare GLP1R variants are shown to reduce weight loss with semaglutide but not tirzepatide, suggesting GLP1R genetic variation as a pharmacogenetic determinant of GLP-1 receptor agonist efficacy.