Hypophagia and body weight loss by tirzepatide are accompanied by fewer GI adverse events compared to semaglutide in preclinical models

Jun 18, 2025Science advances

Tirzepatide reduces eating and body weight with fewer digestive side effects than semaglutide in animal studies

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Abstract

GIPR agonism in rats and shrews blocks emesis while promoting weight loss and improved glucose tolerance.

GLP-1R/GIPR agonistic analogs may enhance glycemic control and weight management more effectively than GLP-1R agonists alone.
GIPR agonism is associated with antiemetic effects, potentially reducing nausea and vomiting from GLP-1R activation.
Tirzepatide, a GLP-1R/GIPR agonist, induced significantly fewer side effects compared to equipotent doses of semaglutide.
Combined activation of GLP-1R and GIPR may improve therapeutic outcomes for obesity and diabetes treatments.

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Glucagon-like peptide-1 receptor (GLP-1R)/glucose-dependent insulinotropic peptide receptor (GIPR) agonistic analogs have yielded superior results in enhancing glycemic control and weight management compared to GLP-1R agonism alone. Intriguingly, GIPR agonism appears to induce antiemetic effects, potentially alleviating part of the nausea and vomiting side effects common to GLP-1R agonists like semaglutide. 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.

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Hypophagia and body weight loss by tirzepatide are accompanied by fewer GI adverse events compared to semaglutide in preclinical models

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