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Here, we show in rats and shrews that GIPR agonism blocks emesis and attenuates other malaise behaviors elicited by GLP-1R activation while maintaining reduced food intake and body weight loss and improved glucose tolerance. The GLP-1R\/GIPR agonist tirzepatide induced significantly fewer side effects than equipotent doses of semaglutide. These findings underscore the therapeutic potential of combined pharmaceutical strategies activating both incretin systems, leading to enhanced therapeutic index and reduced occurrence of nausea and vomiting for obesity and diabetes treatments.<\/jats:p>","DOI":"10.1126\/sciadv.adu1589","type":"journal-article","created":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T14:00:58Z","timestamp":1750255258000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":16,"title":["Hypophagia and body weight loss by tirzepatide are accompanied by fewer GI adverse events compared to semaglutide in preclinical models"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9438-695X","authenticated-orcid":true,"given":"Tito","family":"Borner","sequence":"first","affiliation":[{"name":"Department of Biobehavioral Health Sciences, University of Pennsylvania, School of Nursing, Philadelphia, PA, 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