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

2024; Wiley; Volume: 26; Issue: 11 Linguagem: Inglês

10.1111/dom.15875

1463-1326

Filip K. Knop, Shweta Urva, Mallikarjuna Rettiganti, Charles T. Benson, William C. Roell, Kieren J. Mather, Axel Haupt, Edward Pratt,

Gastric Cancer Management and Outcomes

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. This randomized, placebo-controlled, investigator- and participant-blind, crossover phase 1 study (NCT05444569) conducted at one centre in Singapore enrolled healthy male or female participants aged 21-60 years who were considered overtly healthy as determined through medical evaluation, and with a body weight of 55 kg or higher and a body mass index (BMI) within the range of 23-40 kg/m2. The full study design, including key exclusion criteria and study procedures, is included in the supplemental appendix (see the supporting information). The protocol was approved by the local ethical review board and was conducted in accordance with the Declaration of Helsinki guidelines on good clinical practice. This study consisted of two treatment periods in a crossover design (Figure 1). Participants were randomly assigned 1:1 using a randomization table to receive a single subcutaneous dose (day 1) of either LY (25 mg) or placebo (PBO) (comparable volume), with the alternative blinded treatment administered on day 1 of the second treatment period. The half-life of LY is approximately 11-14 days.6 For both treatment periods, this injection was followed by once-daily dosing of liraglutide, in a dose-escalation paradigm that increased daily from 0.6 mg subcutaneously (sc) (day 2) to 2.4 mg sc (day 5), followed by daily dosing at 2.4 mg through day 9. An 8-week washout period separated the two treatment periods in the crossover study. Participants, investigators and clinic staff were blinded to LY versus PBO treatment assignment; only the clinic pharmacist was unblinded. Liraglutide was open label. The total number (in all participants by treatment condition) and proportion of participants who experienced at least one GI treatment-emergent AE (TEAE) were reported. These included abdominal discomfort, abdominal distension, constipation, decreased appetite, diarrhoea, dyspepsia, early satiety, eructation, flatulence, gastro-oesophageal reflux, haematochezia, nausea and vomiting (preferred terms from Medical Dictionary for Regulatory Activities [MedDRA] version 25). Analyses were performed on the safety analysis set, that is, all participants enrolled who received at least one dose of the study intervention, and incidence was compared between the two treatment periods. A generalized linear model assuming a negative binomial distribution was used to compare the total/mean number of TEAEs between LY and PBO. For comparing all GI TEAEs, an initial statistical model was fit by including the sequence and period terms. These were not found to be statistically significant and therefore these terms were not included in the final model, which compared the total number of GI events (all GI events and individual GI events) between LY and PBO. An unstructured variance covariance matrix was used to model the correlation among repeated measures on the same participant. The proportions of participants with AEs were compared between LY and PBO using McNemar's test. All analyses should be considered exploratory and a P value of less than .05 was assumed to indicate statistical significance. Statistical analysis for this paper was generated using SAS Enterprise Guide version 7.15. Among 34 healthy participants enrolled, 32 received at least one dose of study treatment. The study population for cohorts initially receiving PBO or LY, respectively, comprised 94% and 100% males with mean ages of 42.3 and 40.3 years. The baseline clinical characteristics were well balanced between the two treatment sequence groups, with mean weights of 82.2 and 85.0 kg and mean BMIs of 28.6 and 29.0 kg/m2, respectively, for cohorts that received PBO or LY in the first treatment period (Table S1). One participant randomized to PBO/LY completed dosing in the first (PBO) treatment period, but withdrew because of scheduling conflicts after 7 days of liraglutide dosing in the second (LY) treatment period, reaching the maximal liraglutide dose (2.4 mg) on day 5. Thirty-two participants completed the PBO period and 31 completed the LY period. There were no adverse events reported on day 1 of LY or PBO administration. The earliest report of GI TEAEs occurred on day 2 (the first day of liraglutide administration) for either treatment period. The total number of GI TEAEs across all participants was significantly lower in the LY versus PBO treatment conditions (41 vs. 75; P = .022) (Figure 2A). The proportion of participants with at least one GI TEAE was numerically lower for LY (56%) versus PBO conditions (72%) (P = .197) (Figure 2B). The number of GI TEAEs and the proportion of participants with at least one GI TEAE were also summarized among the subgroups of participants with baseline BMIs of 30 kg/m2 or higher and less than 30 kg/m2 for all GI TEAEs, and the following common individual GI TEAEs: nausea, vomiting and diarrhoea (Table S2). No formal analyses were performed, however, there was no evident difference in treatment effect by BMI grouping. For individual GLP-1 RA-related GI TEAEs, there were numerical reductions in the incidences comparing LY versus the PBO treatment conditions, except for early satiety, diarrhoea and eructation (Figure 2). The total number of gastro-oesophageal reflux events and the corresponding proportion of patients affected by gastro-oesophageal reflux was significantly lower for the LY versus PBO treatment circumstance (5 vs. 14; P = .005 [Figure 2A] and 13% vs. 34%; P = .020 [Figure 2B]). No deaths or severe adverse events were reported in the study. The most frequent TEAEs, reported in more than 35% of participants, were decreased appetite, catheter-site bruising, nausea, gastro-oesophageal reflux and catheter-site erythema. All TEAEs were mild in severity. Among participants who experienced at least one GI TEAE, the median time to first event was 3 days when treated with PBO as opposed to 4.5 days when treated with LY. Overall, 8/32 participants (25%) experienced at least one nausea or vomiting TEAE when treated with LY, as opposed to 12/32 participants (37.5%) when treated with PBO. The median time to first nausea or vomiting event for participants who experienced such an event was also greater after treatment with LY compared with treatment with PBO (Table S2). 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. The authors thank the participants, caregivers and investigators. We thank Eli Lilly and Company employees Eric A. Rodriguez for medical writing and editorial support, and Paul J. Emmerson for critical review of the manuscript. This study was funded by Eli Lilly and Company. Filip K. Knop is currently employed at Novo Nordisk A/S, Bagsværd, Denmark. The reported work was performed prior to Dr. Knop's employment at Novo Nordisk, and the analyses and reporting of results are independent from Novo Nordisk A/S. 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. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.15875. Lilly provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has received first regulatory authorization and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, and blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org. Data S1. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.