GIP receptor agonism attenuates GLP-1 receptor agonist induced nausea and emesis in preclinical models

GIPR modulation can serve both to enhance the anorectic effects of GLP-1R agonism and facilitate additional weight loss through other putative mechanisms such as improvement in insulin sensitivity and reduction in GLP-1R mediated adverse gastrointestinal events.

“These data demonstrate that GIPR modulation can serve both to enhance the anorectic effects of GLP-1R agonism and facilitate additional weight loss through other putative mechanisms such as improvement in insulin sensitivity [30] and reduction in GLP-1R mediated adverse gastrointestinal events to permit increased GLP-1R engagement [39]”

GIP inhibits hindbrain neurons regulating emesis.

“Furthermore, GIP inhibits hindbrain neurons regulating emesis [25]”

GIP agonism reduces emesis caused by a GLP-1 receptor agonist in both rodent and human studies.

“and GIP agonism reduces emesis caused by a GLP-1 RA in both rodent and human studies [25, 26].”

In preclinical models, the addition of GIPR agonism to GLP-1R agonism attenuates emesis while increasing the amount of body weight reduction compared to GLP-1 agonism alone.

“In preclinical models, the addition of GIPR agonism to GLP-1R agonism attenuates emesis while increasing the amount of body weight reduction compared to GLP-1 agonism alone [98].”

Preclinical evidence indicates that GIPR agonism attenuates GLP-1R agonist-induced nausea and emesis.

“In fact there is evidence in preclinical studies that GIPR agonism attenuates GLP-1R agonist-induced nausea and emesis [98].”

Recent evidence suggests that GIPR activity may modulate GLP-1 dependent feeding behavior by reducing the emetic activity promoted by GLP-1R in the hindbrain.

“Recent evidence suggests that GIPR activity may modulate GLP-1 dependent feeding behavior by reducing the emetic activity promoted that GLP-1R in the hindbrain [39], an area of the brain relatively exposed to small circulating peptides.”

GIPR agonism helps to ameliorate the adverse nauseating effects of GLP-1R agonists in both clinical and preclinical settings.

“It has been reported in both clinical and preclinical settings that GIPR agonism helps to ameliorate the adverse nauseating effects of GLP-1R agonists [[39], [42]].”

The GIPRA GIP-085 almost totally prevented vomiting induced by the long-acting GLP-1RA GLP-140.

“the GIPRA GIP-085 almost totally prevented vomiting induced by a long-acting GLP-1RA GLP-140 (22).”

First-generation GLP-1R/GCGR co-agonists in animal obesity models produced greater weight loss, better glucose lowering, and reduced food intake than selective GLP-1R agonists.

“Once proven that full potency at each of the two receptors could be chemically assembled into a single chimeric peptide of comparable size to each native hormone, studies in animal models of obesity, utilizing first-generation GLP-1R/GCGR co-agonists, resulted in superior weight loss, enhanced glucose-lowering efficacy, as well as a reduction in food intake, when compared with selective GLP-1R Ag”

Data from the FDA Adverse Event Reporting System indicate a lower incidence of nausea and vomiting with tirzepatide, potentially due to GIP receptor-mediated neuronal inhibition in the area postrema, whereas constipation appears more frequent.

“Notably, data from the FDA Adverse Event Reporting System indicate a lower incidence of nausea and vomiting, potentially due to GIP receptor-mediated neuronal inhibition in the area postrema [149,150], whereas constipation appears more frequent, with the underlying mechanisms yet to be fully elucidated [151].”

Tirzepatide exhibits a safety profile comparable to that of GLP-1 receptor agonists.

“it is noteworthy that tirzepatide exhibits a safety profile comparable to that of GLP-1 RAs.”

GIP receptor agonism hindered malaise and vomiting related to GLP-1 receptor agonism in three animal models.

“as GIP receptor agonism hindered malaise and vomiting related to GLP-1 receptor agonism in three animal models [19].”

GIP receptors are expressed in GABAergic neurons of the area postrema of the brainstem and promote the inhibition of neurons responsible for nausea and emesis.

“GIP receptors are expressed in gamma-aminobutyric acid (GABA) ergic neurons of the area postrema of the brainstem and promote the inhibition of neurons responsible for nausea and emesis [19].”

One mechanism for tuning circuit activation within brainstem GLP-1R neuron populations is thought to contribute to clinical observations that tirzepatide elicits fewer discontinuation-inducing adverse gastrointestinal events than semaglutide, likely in part due to GIPR-expressing GABAergic area postrema neurons inhibiting area postrema and/or nucleus tractus solitarius neurocircuits which mediate

“One such mechanism for tuning circuit activation within brainstem GLP-1R neuron populations is thought to contribute to clinical observations that the GLP-1R/GIPR co-agonist tirzepatide elicits fewer discontinuation-inducing adverse gastrointestinal events than semaglutide (98, 99), likely in part due to GIPR-expressing GABAergic AP neurons inhibiting AP and/or NTS neurocircuits which mediate GLP-”