Genetics can blunt Ozempic

Weight-loss shots copy a gut hormone that tells the body to release insulin, slow digestion and curb appetite, but some people seem genetically less able to hear that signal. (nature.com) Two studies published in April 2026 point to DNA as part of the reason. A Nature paper from 23andMe analyzed 27,885 people who reported using glucagon-like peptide-1 receptor agonists, while a Genome Medicine study led by Stanford Medicine examined blood-sugar response in clinical trials, human experiments and mice. (nature.com) (stanford.edu) The Stanford-led team reported that roughly 10% of the general population carries variants linked to what the researchers call “glucagon-like peptide-1 resistance,” meaning hormone levels are higher but the biological effect is weaker. The study was published April 10 and focused on diabetes treatment rather than weight loss. (stanford.edu) (link.springer.com) In some drug trials, carriers of those variants lowered blood glucose less effectively after six months on glucagon-like peptide-1 drugs than non-carriers did, Stanford said. The variants are in the PAM gene, which helps process hormones including glucagon-like peptide-1. (stanford.edu) (link.springer.com) The 23andMe paper looked at a different question: why people on semaglutide and tirzepatide lose very different amounts of weight and get different side effects. It found a variant in the GLP1R gene tied to greater weight-loss response, with an extra 0.76 kilograms of expected loss per copy of the effect allele. (nature.com) (mediacenter.23andme.com) That same analysis also linked variation in GLP1R and GIPR to nausea and vomiting, and the GIPR signal appeared only in people using tirzepatide, not semaglutide. Tirzepatide acts on both glucagon-like peptide-1 and gastric inhibitory polypeptide pathways, while semaglutide targets glucagon-like peptide-1 alone. (nature.com) (mediacenter.23andme.com) The papers do not show that every disappointing result on these drugs is genetic. The Nature study relied on self-reported outcomes, and Stanford said it is still unclear whether the PAM variants that blunt blood-sugar control also reduce weight loss from higher-dose obesity drugs such as Wegovy and Zepbound. (nature.com) (stanford.edu) What the studies do add is a clearer biological explanation for at least some non-response. Both groups said the findings could support precision medicine, where a genetic test helps doctors choose a drug, estimate likely weight loss and flag side-effect risk before treatment starts. (nature.com) (stanford.edu)