Rare GLP1R variants attenuate weight loss with semaglutide but not tirzepatide.

Rare damaging GLP1R variants in 13,725 GLP-1RA–treated adults are linked to less weight loss with semaglutide, while tirzepatide weight loss remains near-normal in carriers.

• Why it matters: Weight loss from GLP-1 receptor agonists varies across people, but the genetic basis for differences in drug response is not well defined.
• What they did: Using exome sequencing linked to electronic health records from the Helix Research Network (n = 351,818), the study compared weight-change outcomes in carriers versus matched non-carriers after semaglutide or tirzepatide.
• The result: Carriers of rare damaging GLP1R variants show attenuated semaglutide response but not reduced tirzepatide response, and rare GIPR variant carriers also show normal weight loss with tirzepatide.

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