The novel dual glucose‐dependent insulinotropic polypeptide and glucagon‐like peptide‐1 (GLP‐1) receptor agonist tirzepatide transiently delays gastric emptying similarly to selective long‐acting GLP‐1 receptor agonists

Abstract

The effect of dual glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) receptor agonist (RA) tirzepatide on gastric emptying (GE) was compared to that of GLP‐1RAs in non‐clinical and clinical studies. GE was assessed following acute and chronic treatment with tirzepatide in diet‐induced obese mice versus semaglutide or long‐acting GIP analogue alone. Participants [with and without type 2 diabetes (T2DM)] from a phase 1, 4‐week multiple dose study received tirzepatide, dulaglutide or placebo. GE was assessed by acetaminophen absorption. In mice, tirzepatide delayed GE to a similar degree to that achieved with semaglutide; however, these acute inhibitory effects were abolished after 2 weeks of treatment. GIP analogue alone had no effect on GE or on GLP‐1's effect on GE. In participants with and without T2DM, once‐weekly tirzepatide (≥5 and ≥4.5 mg, respectively) delayed GE after a single dose. This effect diminished after multiple doses of tirzepatide or dulaglutide in healthy participants. In participants with T2DM treated with an escalation schedule of tirzepatide 5/5/10/10 or 5/5/10/15 mg, a residual GE delay was still observed after multiple doses. These data suggest that tirzepatide's activity on GE is comparable to that of selective GLP‐1RAs.

Effects on weight loss and glycemic control with SAR441255, a potent unimolecular peptide GLP-1/GIP/GCG receptor triagonist

“…Since gastric emptying effects with long-acting GLP-1 agonists attenuate over time (Umapathysivam et al, 2014;Urva et al, 2020), we believe this phenomenon will not play a significant role in long-term glucose control, and the insulinotropic character of the three involved principles will become the major driving force for glucose control.…”

I-M-150847, a novel GLP-1 and GIP receptor dual agonist, improves glycemic control and reduces obesity in the rodent model of type 2 diabetes and obesity

“…However, the mechanism of the I-M-150847-mediated regulation of the gut-brain axis is presently unexplored. Reduced gastric emptying and delayed intestinal motility have been reported in the case of long-acting GLP-1R agonists (48) as well as GLP-1R GIPR dual agonist Tirzepatide (49).GIPR is present in key feeding centers at the hypothalamus and intracerebroventricular administration of acyl GIP causes acute neural activation in the feeding centers that includes the arcuate nucleus, dorsomedial hypothalamic nucleus, ventromedial nucleus of the hypothalamus, and lateral hypothalamus (50). Future research is needed to explore whether I-M-150847 causes similar neural activity in the feeding centers to trigger early induction of satiety.…”

Tirzepatide: A Useful Addition for Treatment of Type 2 Diabetes and Obesity

“…When compared with semaglutide 1.0 mg, GI adverse effects were slightly more common with the highest dose of terzipatide (15 mg) (table 1). Nausea and vomiting are attributed in part to delay in gastric emptying, which usually subsides after several weeks [17]. In fact, Urva et al [17] have shown that tirzepatide caused delay in gastric emptying that was similar in magnitude to the selective GLP-1 agonist dulaglutide.…”