A long-acting glucose-dependent insulinotropic polypeptide receptor agonist improves the gastrointestinal tolerability of glucagon-like peptide-1 receptor agonist therapy

Tirzepatide, a novel long-acting glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 (GIP/GLP-1) receptor agonist (GIP/GLP-1 RA), has shown greater clinical efficacy in reducing HbA1c and body weight compared with placebo or selective GLP-1 RAs.^{1, 2} Mechanisms by which GLP-1R agonism contributes to chronic weight management and glycaemia are well understood. The contributions of GIPR agonism to the clinical efficacy of tirzepatide are less well known.

GLP-1 RA use is associated with gastrointestinal (GI) tolerability challenges, including nausea and emesis, that potentially limit efficacy and compliance.³ The beneficial and adverse effects of GLP-1R agonism are ascribed to signalling in regions of the hind brain, which also express GIP receptors. This may suggest potential overlapping central regulation of emetic responses. In animal experiments, GIPR agonism reduced GI adverse effects (AEs) induced by chemotherapeutic agents or GLP-1R agonism.^{4, 5}

Here, we explore the potential benefit of GIPR agonism to offset GI AEs associated with GLP-1R agonism in a clinical setting. We investigate the effect of a single dose of the long-acting, selective GIPRA, LY3537021 (LY), on GI AEs in healthy volunteers in the context of daily dosing and rapid dose escalation with liraglutide, a selective GLP-1 RA. We hypothesize that concurrent exposure to liraglutide and a GIPRA would produce fewer GI AEs than exposure to liraglutide alone.

Here, we show that co-exposure to a GIPRA can reduce the incidence of GI AEs that are commonly seen with GLP-1 RA treatment. With the main exception of diarrhoea, GIPR agonism provided numerical reductions in each of the main recognized GI AEs associated with the use of GLP-1 RAs.

These observations are concordant with animal experiments that show pretreatment with GIPR agonists reduces chemotherapy-induced and GLP-1 RA-induced GI AEs, including vomiting.^{4, 5} Treatment with GIPR agonism attenuated GLP-1 RA-induced nausea and emesis in shrews, and peptide YY-induced nausea in mice.^{4, 5, 7} A recently presented study of a long-acting GIPRA added to semaglutide also showed a numerical reduction of GI events in the combination versus semaglutide alone, mainly driven by nausea and vomiting events, in alignment with the current findings.⁸

The beneficial effects of GLP-1 RAs to reduce food intake are mediated by their action on an integrated neuronal network originating in the hypothalamus and hind brain, namely, the arcuate nucleus of the hypothalamus and the area postrema in the brainstem.^{9, 10} GI AEs such as GLP-1 RA-induced nausea are thought to be mediated by GLP-1 RA action, primarily in the area postrema.¹⁰ Notably, the GIPR is also expressed in these brain regions, suggesting that there may be overlapping regulation of central nervous system-mediated anorexigenic and emetic behaviours by GIPRAs.^{10, 11} The integrated response to GLP-1 RAs and GIPRAs in these areas of the brain may provide the neuronal substrate mediating the prior observations in animals and the current observations in humans.

The limitations of this study include the small number of female participants and the limited ethnic diversity, which may limit the generalizability of the observations. Women may be more prone to GLP-1–related AEs, so the efficacy of GIPRAs to reduce these AEs in women may differ.¹² This study was not powered to detect efficacy signals for individual GI event types, nor was it powered to evaluate efficacy by differing weight status.

The current study findings suggest a means by which the GIPR-activating aspect of tirzepatide action may contribute to its overall efficacy, namely by improving the tolerability of its GLP-1R–activating aspect.¹³ This potentially enables greater GLP-1R engagement and function by tirzepatide with less GI distress, contributing to efficacy and adherence.

AH, KJM, EJP, and WCR wrote the first draft of the manuscript. All authors contributed to the content. CTB, AH, FKK, KJM, EJP, WCR, and SU contributed to the study design. EJP contributed to the data collection. All authors contributed to the analyses.

This study was funded by Eli Lilly and Company. The funder of the study, Eli Lilly and Company, was involved in study design, data collection, data analysis, data interpretation, and writing of the report.

FKK is employed at and shareholder of Novo Nordisk A/S, Bagsværd, Denmark. SU, MR, CTB, WCR, KJM, AH and EJP are employees and shareholders of Eli Lilly and Company, Inc., Indianapolis, IN.