In Silico Exploration of Therapeutics for GLP-1 Receptor Agonist-Induced Nausea and Their in Vivo Validation in Mice

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are clinically used to control hyperglycemia and body weight in patients with type 2 diabetes mellitus and obesity. Despite their efficacy, GLP-1 RAs frequently induce nausea and vomiting as adverse effects, which are prominent factors for non-adherence to GLP-1 RAs. Therefore, new prophylaxes and treatments for GLP-1 RA-induced nausea are urgently needed. Here, we explored the U. S. Food and Drug Administration (FDA) Adverse Event Reporting System database to determine the effective drug combinations mitigating GLP-1 RA-induced nausea and vomiting in real-world settings. We further investigated the effects of the identified drugs on GLP-1 RA-induced pica behavior, a behavioral index of nausea in mice. Analysis of the FDA Adverse Event Reporting System revealed that therapeutics, including gabapentin and acetaminophen, significantly lowered the occurrence of nausea-related events in GLP-1 RA-treated patients. In mice, we confirmed that exenatide, a GLP-1 RA, significantly increased the pica behavior in a dose-dependent manner, without affecting the food intake. Finally, we found that co-treatment with gabapentin significantly decreased the pica behavior induced by exenatide. These results demonstrate the therapeutic efficacy of gabapentin against nausea and vomiting in patients administered GLP-1 RAs.

INTRODUCTION

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are clinically used to control hyperglycemia and body weight in patients with type 2 diabetes mellitus and obesity.¹⁾ Clinical studies have shown that GLP-1 RAs exhibit high glycemic efficacy with minimal risk of hypoglycemia, suggesting the superiority of GLP-1 RAs for the treatment of type 2 diabetes.^1–3) However, GLP-1 RAs frequently induce nausea and vomiting as adverse effects. A recent survey of patients treated with GLP-1 RAs has indicated that gastrointestinal side effects, including nausea and vomiting, are the prominent factors for non-adherence to GLP-1 RAs,⁴⁾ suggesting the necessity of effective prophylaxes and treatments against GLP-1 RA-induced nausea. Indeed, one in four people with type 2 diabetes (approximately 6.5 million people in the U.S.A.) does not fully benefit from the current U.S. Food and Drug Administration (FDA)-approved GLP-1 RA medications, and up to 50% of patients prescribed GLP-1 RAs (approximately 13 million people in the U.S.A.) experience nausea and vomiting.⁵⁾ These statistics further suggest that GLP-1 RA medications reducing nausea and vomiting show great potential for treating patients with type 2 diabetes and obesity.

Although mice are among the most frequently used experimental animals in preclinical studies, they do not exhibit vomiting behavior, hampering the precise analysis of nausea and vomiting in mice.⁶⁾ In contrast, mice show pica behavior, the persistent ingestion of non-nutritive substances such as kaolin, in response to emetic stimuli.^7,8) Previous reports have demonstrated that the pica behavior induced by the anti-cancer drug, cisplatin, is inhibited by treatment with clinically used 5-hydroxytryptamine type 3 (5-HT₃) receptor antagonists. Pica behavior is also caused by rotation with repeated acceleration and deceleration, which mimics motion sickness in mice.^9,10) Pica behavior is induced by radiation, anti-cancer drugs, and rotational stimulation and mitigated by 5-HT₃ receptor antagonists, glucocorticoids, and neurokinin-1 receptor antagonists, which are the representative prophylaxes and treatments for nausea in humans.¹¹⁾ Therefore, pica behavior can be used to establish a behavioral model of nausea and vomiting in mice with predictive validity. However, currently, there are no known drugs that can alleviate GLP-1 RA-induced pica behavior, indicating the need for new candidates for the prophylaxis of nausea and vomiting induced by GLP-1 RAs.

The FDA Adverse Event Reporting System (FAERS) consists of self-reports of drug-related adverse events. We and others have identified possible therapeutics for drug-induced adverse events through analysis of clinical big data, including FAERS data.^12–15) Zhao et al. reported that possible therapeutics may be identified through the analysis of FAERS; if the adverse events related to a certain drug were apparently mitigated by another concomitant drug, the drug may have the potential to treat drug-induced adverse effects.¹²⁾ Using this approach, we previously identified vitamin D as a concomitant drug that alleviates hyperglycemia induced by antipsychotics.¹³⁾ We also identified acetaminophen as a concomitant drug that improves tardive dyskinesia induced by the dopamine D₂ receptor antagonists.¹⁴⁾ Furthermore, Furuta et al. identified dexamethasone as a concomitant drug that prevents both fluoroquinolone-induced and age-related tendinopathy.¹⁵⁾ Collectively, clinical big data are a source of previously overlooked beneficial drug–drug interactions that directly lead to drug repurposing. In this study, we analyzed FAERS to seek the drug that may mitigate GLP-1 RA-induced nausea and vomiting. Then, we investigated the effects of the identified drug candidates on GLP-1 RA-induced pica behavior in mice.

MATERIALS AND METHODS

Mice

All animal experiments were approved by the Kyoto University Animal Research Committee (Approval Number: 19–41) and were performed in accordance with the ethical guidelines of the Kyoto University Animal Research Committee. Male C57BL/6J mice (6–10 weeks old; 20–28 g; Nihon SLC, Shizuoka, Japan) were used in this study. The mice were kept at a constant ambient temperature (22 ± 2°C) under a 12/12 h light/dark cycle with free access to food and water, unless otherwise stated.

Drugs

Kaolin and gum arabic were purchased from Sigma-Aldrich (St. Louis, MO, U.S.A.). Cisplatin and gabapentin were purchased from the Tokyo Chemical Industry (Tokyo, Japan). Exendin-4 (exenatide) and acetaminophen were purchased from Enzo Life Sciences (Farmingdale, NY, U.S.A.) and Nacalai Tesque (Kyoto, Japan), respectively. Dosages of gabapentin and acetaminophen were determined based on human equivalent doses of these drugs. Dosage of exenatide was determined experimentally. Exenatide and the concomintant drugs (exenatide and gabapentin) were not mixed in the same solution but were prepared separately and administered in series.

Quantification of Pica Behavior

Throughout the experiments, the mice had free access to laboratory chow pellets (MF; Oriental Yeast, Tokyo, Japan), kaolin pellets, and water. Kaolin pellets were prepared according to a previously reported method.⁸⁾ Kaolin was mixed with 1% (w/w) gum arabic in distilled water to form pellets similar in size to the laboratory chow pellets, and the pellets were dried at room temperature for 7 d. The mice were adapted to the kaolin pellets for 2 weeks before quantification of their pica behavior. On the day of the experiment, the mice were intraperitoneally (i.p.) injected with cisplatin (7.5 mg/kg), exenatide (1, 10, and 100 μg/kg), gabapentin (50 and 100 mg/kg), or acetaminophen (50 and 100 mg/kg). Control mice received saline injections (1 mL/100 g body weight, i.p.). Then, kaolin and food intakes over 24 h were measured.

Quantification of the Two-Axis Rotation-Induced Pica Behavior

Rotating device was prepared according to a previous report.¹⁶⁾ The mice were placed in 50-mL conical tubes on the upper plane, with their heads 25 cm outward from the axis, and rotated at 80 rpm counter-clockwise around the axis. The axis of the upper plane was located 25 cm from the axis of the lower plane. The lower plane was simultaneously rotated clockwise with an angular acceleration of 9.9°/s² until the angular velocity reached 25 rpm and subsequently decelerated at the same angular acceleration until the rotation stopped. Alternations of acceleration and deceleration were continued for 1 h. Control mice stayed in home cages or were placed in 50-mL conical tubes without rotation for 1 h. Then, kaolin and food intakes over 24 h were measured.

Analysis of the FAERS Database

Analysis of FAERS was conducted according to previous reports.^13–15) Briefly, FAERS adverse event reports were obtained from the FDA website (http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/). Duplicate reports amounting to 13632002 reports (2004/Q1-2019Q4) were deduplicated according to the FDA recommendation for adopting the most recent case number. After deduplication, we analyzed the remaining 11438031 reports. Drug names (generic names, trade names, and their abbreviations) were mapped to the unified generic names according to the previous reports.^13–15) Adverse event signals were evaluated by calculating the reporting odds ratio (ROR) with 95% confidence interval (CI). Reports of nausea-related adverse events were defined using the preferred terms “nausea” and “vomiting.” Individuals in the FAERS database were divided into the following 4 groups: (a) records where nausea-related events were reported, and the drug of interest was prescribed; (b) records where nausea-related events were not reported, and the drug of interest was prescribed; (c) records where nausea-related events were reported, and the drug of interest was not prescribed; and (d) records where nausea-related events were not reported, and the drug of interest was not prescribed. ROR with 95% CI and Z score were calculated as follows:

  

$$\text{ROR}=\frac{\raisebox{1ex}{$a$}\!\left/ \!\raisebox{-1ex}{$b$}\right.}{\raisebox{1ex}{$c$}\!\left/ \!\raisebox{-1ex}{$d$}\right.}$$

  

$$95\text{\% CI}=\exp \{\log \left(\mathrm{R}\mathrm{O}\mathrm{R}\right)\pm 1.96\sqrt{\frac{1}{a}+\frac{1}{b}+\frac{1}{c}+\frac{1}{d}}\}$$

  

$$Z\text{\hspace{0.17em}score}=\frac{\log \left(\mathrm{R}\mathrm{O}\mathrm{R}\right)}{\sqrt{\frac{1}{a}+\frac{1}{b}+\frac{1}{c}+\frac{1}{d}}}$$

where the variables from a to d indicate record numbers in each group, and log refers to the natural logarithm. For the identification of possible therapeutics for GLP-1 RA-induced nausea, the above-mentioned analysis was performed on records using GLP-1 RAs (exenatide, liraglutide, dulaglutide, semaglutide, albiglutide, and lixisenatide).

Statistical Analyses

Statistical analyses were performed using GraphPad Prism 10 (GraphPad, San Diego, CA, U.S.A.). Data are represented as the mean ± standard error of the mean. Student’s t-test was used for the analysis of 2 groups. Data from more than or equal to three groups were compared using one-way ANOVA, followed by a post hoc test. In all cases, differences with p < 0.05 were considered statistically significant.

RESULTS

GLP-1 RAs Exhibit High RORs for Nausea-Related Adverse Events in FAERS

We analyzed FAERS to investigate whether GLP-1 RAs increase the signals associated with the occurrence of nausea-related adverse events (Table 1; Supplementary Table 1). We found that GLP-1 RAs, such as exenatide and liraglutide, as well as apremilast, a phosphodiesterase-4 inhibitor, and varenicline, an α4β2 nicotinic acetylcholine receptor agonist, increased the occurrence of nausea-related adverse events. As apremilast and varenicline are reported to increase the risk of nausea in humans,^17,18) it is suggested that this analysis successfully demonstrated drug-induced nausea.

Table 1. Drugs Associated with Nausea-Related Adverse Events in the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) Database

Drug	Nausea with drug (%)	Nausea without drug (%)	Odds ratio (95% CI)	Z score
Varenicline	16215/80340 (20.18)	593346/11357691 (5.22)	4.59 (4.51–4.67)	171.34
Exenatide	15240/72246 (21.09)	594321/11365785 (5.23)	4.85 (4.76–4.93)	171.23
Apremilast	15443/88413 (17.47)	594118/11349618 (5.23)	3.83 (3.76–3.90)	149.96
Ondansetron	16146/107799 (14.98)	593415/11330232 (5.24)	3.19 (3.13–3.24)	134.19
Ribavirin	14186/101868 (13.93)	595375/11336163 (5.25)	2.92 (2.87–2.97)	117.10
Liraglutide	7107/37804 (18.80)	602454/11400227 (5.28)	4.15 (4.04–4.26)	107.56
Duloxetine	14948/127064 (11.76)	594613/11310967 (5.26)	2.40 (2.36–2.44)	99.52
Peginterferon alfa-2a	8652/58289 (14.84)	600909/11379742 (5.28)	3.13 (3.06–3.20)	97.22
Acetaminophen	47216/580648 (8.13)	562345/10857383 (5.18)	1.62 (1.60–1.64)	96.68
Telaprevir	6283/36288 (17.31)	603278/11401743 (5.29)	3.75 (3.65–3.85)	94.80

Identification of Drugs Decreasing the RORs for GLP-1 RA-Associated Nausea-Related Events in FAERS

Next, we analyzed the FAERS database to explore the concomitant drugs that can mitigate nausea-related adverse events in GLP-1 RA-treated patients. We found that therapeutics for type 2 diabetes decreased the occurrence of nausea-related adverse events, which may be explained by reduced GLP-1 RA dosing. Therefore, we focused on other drugs and found that several medications, including pregabalin, gabapentin, prednisone, and acetaminophen, significantly decreased the occurrence of nausea-related adverse events in GLP-1 RA-treated patients (Table 2; Supplementary Table 2).

Table 2. Drugs Decreasing the Reporting Odds Ratios of GLP-1 RA-Induced Nausea-Related Adverse Events in the FAERS Database

Drug	Nausea with drug (%)	Nausea without drug (%)	Odds ratio (95% CI)	Z score
Pregabalin	198/1792 (11.05)	28261/146845 (19.25)	0.52 (0.45–0.60)	−8.61
Gabapentin	412/3111 (13.24)	28047/145526 (19.27)	0.64 (0.58–0.71)	−8.39
Cholecalciferol	493/3476 (14.18)	27966/145161 (19.27)	0.69 (0.63–0.76)	−7.49
Rosuvastatin	495/3485 (14.20)	27964/145152 (19.27)	0.69 (0.63–0.76)	−7.46
Reveroxaban	36/530 (6.79)	28423/148107 (19.19)	0.31 (0.22–0.43)	−6.84
Prednisone	152/1288 (11.80)	28307/147349 (19.21)	0.56 (0.47–0.67)	−6.64
Metoprolol	706/4591 (15.38)	27753/144046 (19.27)	0.76 (0.70–0.83)	−6.57
Adalimumab	83/821 (10.11)	28376/147816 (19.20)	0.47 (0.38–0.59)	−6.45
Acetaminophen	629/4106 (15.32)	27830/144531 (19.26)	0.76 (0.70–0.83)	−6.30
Allopurinol	231/1727 (13.38)	28228/146910 (19.21)	0.65 (0.56–0.75)	−6.08

Effects of Cisplatin and Double-Axis Rotation on the Food and Kaolin Intakes in Mice

To assess nausea- and vomiting-like behaviors in mice, we examined the effects of anti-cancer drugs and double-axis rotation stimuli, which are well-known emetic stimuli, on pica behavior. We found that acute treatment with cisplatin (7.5 mg/kg, i.p.) significantly increased the intake of kaolin over 24 h but decreased the food intake (kaolin: t₂₆ = 4.544, p < 0.001, n = 14 mice/group; food: t₂₆ = 2.126, p < 0.05, n = 14 mice/group; Figs. 1A, 1B). A previous study in rats demonstrated that double-axis rotation with repeated acceleration and deceleration increases the kaolin intake.¹⁶⁾ Therefore, we tested whether double-axis rotation affects the kaolin and food intakes in mice. The mice subjected to double-axis rotation for 1 h consumed more kaolin than the naïve mice and those constrained in a plastic tube. On the other hand, neither double-axis rotation nor constraint to a plastic tube affected the food intake (kaolin: F_2,45 = 17.85, p < 0.0001, Tukey’s multiple comparisons test [naïve vs. tube: p = 0.1862, naïve vs. rotation: p < 0.0001, and tube vs. rotation: p < 0.001], n = 16 mice/group; food: F_2,45 = 1.118, p = 0.336, n = 16 mice/group; Figs. 1C, 1D). These results confirmed the successful measurement of nausea- and vomiting-like behaviors in mice.

Fig. 1. Effects of Cisplatin and Double-Axis Rotation on the Food and Kaolin Intakes in Mice

(A, B) Cisplatin (7.5 mg/kg, intraperitoneal [i.p.]) or saline was administered to mice. Then, food (A) and kaolin (B) intakes over 24 h were measured. * p < 0.05 and *** p < 0.001 vs. saline-treated mice via unpaired Student’s t-test. n = 14 mice. Data are represented as the mean ± standard error of the mean (S.E.M.) of intake. (C, D) Mice were subjected to double-axis rotation (rotation), constrained to tubes (tube), or not provided any intervention (naïve). Then, food (C) and kaolin (D) intakes over 24 h were measured. *** p < 0.001 and **** p < 0.0001 via ordinary one-way ANOVA, with Tukey’s multiple-comparison post hoc test. n = 16 mice. Data are represented as the mean ± S.E.M. of intake.

Effects of the GLP-1 RA, Exenatide, on the Food and Kaolin Intakes in Mice

In this setting, we examined the effects of the GLP-1 RA, exenatide (exendin-4; 1–100 μg/kg, i.p.), on kaolin and food intakes in mice. We found that exenatide significantly increased the kaolin intake in a dose-dependent manner but did not affect the food intake (kaolin: F_3,36 = 6.493, p < 0.01, Dunnett’s multiple comparisons test [saline vs. exenatide{1 μg/kg}: p = 0.4575, saline vs. exenatide{10 μg/kg}: p < 0.05, and saline vs. exenatide{100 μg/kg}: p < 0.001], n = 10 mice/group; food: F_3,36 = 1.711, p = 0.182, n = 10 mice/group; Figs. 2A, 2B).

Fig. 2. Effects of the Glucagon-Like Peptide-1 Receptor Agonist (GLP-1 RA), Exenatide, on the Food and Kaolin Intakes in Mice

(A, B) Exenatide (1–100 μg/kg, i.p.) or saline was administered to mice. Then, food (A) and kaolin (B) intakes over 24 h were measured. * p < 0.05 and *** p < 0.001 vs. saline-treated mice via ordinary one-way ANOVA, with Dunnett’s multiple-comparison post hoc test. n = 10. Data are represented as the mean ± S.E.M. of intake.

Effects of Gabapentin and Acetaminophen on the Food and Kaolin Intakes in the Presence of the GLP-1 RA, Exenatide

Although we identified the concomitant drugs that apparently decreased the occurrence of nausea-related adverse events in FAERS, it is unclear whether these drugs mitigate the nausea-related behaviors with minimal effect on appetite. In this study, we focused on gabapentin and acetaminophen because previous studies indicate the potential usefulness of these drugs to suppress nausea. To verify this, we administered exenatide (100 μg/kg) with or without gabapentin (50 and 100 mg/kg, i.p.) and acetaminophen (50 and 100 mg/kg, i.p.) and measured the food and kaolin intakes over 24 h. We found that co-treatment with gabapentin (100 mg/kg) significantly reduced the kaolin intake induced by exenatide, and co-treatment with acetaminophen (100 mg/kg) also tended to reduce the increased kaolin intake induced by exenatide (F_5,54 = 5.191, p < 0.001, Dunnett’s multiple comparisons test [exenatide{100 μg/kg} vs. saline: p < 0.0001, exenatide{100 μg/kg} vs. exenatide with gabapentin{50 mg/kg}: p = 0.1993, exenatide{100 μg/kg} vs. exenatide with gabapentin{100 mg/kg}: p < 0.05, exenatide{100 μg/kg} vs. exenatide with acetaminophen{50 mg/kg}: p = 0.8645, and exenatide{100 μg/kg} vs. exenatide with acetaminophen{100 mg/kg}: p = 0.1194], n = 10 mice/group; Fig. 3B). By contrast, there were no significant effects of gabapentin and acetaminophen on the food intake (F_5,54 = 0.5460, p = 0.7406; Fig. 3A). Finally, we tried to rule out the possibility that gabapentin and acetaminophen may reduce the efficacy of GLP-1 RAs in the JMDC Claims database. We compared HbA1c values among patients treated with GLP-1 RAs in the presence and absence of acetaminophen and gabapentinoids. GLP-1 RAs significantly decreased HbA1c values regardless of concomitant use of acetaminophen and gabapentinoids (Supplementary Fig. 1). These results indicate the possible usefulness of acetaminophen and gabapentin in the real-world setting.

Fig. 3. Effects of Gabapentin and Acetaminophen on the Food and Kaolin Intakes in the Presence of the GLP-1 RA, Exenatide

(A, B) Saline, exenatide (100 μg/kg, i.p.) with vehicle, exenatide with gabapentin (50 and 100 mg/kg, i.p.), or exenatide with acetaminophen (50 and 100 mg/kg, i.p.) was administered to mice. Then, food (A) and kaolin (B) intakes over 24 h were measured. * p < 0.05 and **** p < 0.0001 vs. exenatide-alone via ordinary one-way ANOVA, with Dunnett’s multiple-comparison post hoc test. n = 10. Data are represented as the mean ± S.E.M. of intake.

DISCUSSION

In this study, we confirmed that GLP-1 RAs increased the occurrence of nausea-related adverse events through analysis of the FAERS database. Then, we identified concomitant drugs, including gabapentin and acetaminophen, as possible therapeutics for GLP-1 RA-induced nausea through exploration of the FAERS database. Finally, we found that gabapentin mitigated the pica behavior induced by the GLP-1 RA, exenatide, in mice without affecting their food intake. To the best of our knowledge, this is the first report to show the inhibitory effect of gabapentin on pica behavior induced by GLP-1 RAs.

We confirmed that exenatide, a GLP-1 RA, induced the pica behavior in mice, consistent with a previous report.¹⁹⁾ Our analysis showed increased nausea-related adverse events in FAERS. However, the mechanism underlying GLP-1 RA-induced nausea is not yet fully understood. Evidence has revealed the mechanisms and neural substrates of nausea and vomiting. Specifically, vestibular nuclei mediate the nausea induced by motion sickness. The cerebral cortex and limbic system play central roles in the nausea induced by cognitive and emotional inputs. Area postrema senses emetic agents, such as anti-cancer drugs, in the blood. Nucleus tractus solitarius (NTS) receives inputs from these brain regions, integrates the nausea-related information, and activates the autonomic nervous system responses, leading to nausea.²⁰⁾ GLP-1 receptors are abundantly expressed in various brain regions, including the NTS and area postrema.²¹⁾ Intracardially injected ¹²⁵I-labeled GLP-1 binds to the area postrema and subfornical organ, where the blood–brain barrier was not tight.²²⁾ By contrast, previous reports have demonstrated the presence of fluorescently labeled exenatide in the NTS and area postrema after systemic injection.^23,24) Taken together, these results suggest that GLP-1 receptors in the area postrema and NTS play key roles in nausea and vomiting induced by GLP-1 RAs.

We found that gabapentin and acetaminophen decreased the occurrence of nausea-related adverse events in GLP-1 RA users in FAERS and inhibited the pica behavior induced by exenatide in mice; however, the underlying mechanisms have not yet been elucidated. Gabapentin is clinically used as an antiepileptic and antinociceptive drug.^25,26) Although its action mechanism is not yet fully understood, its primary site of action is suggested to be the α2δ subunit of voltage-dependent calcium channels.^27,28) In addition to these therapeutic effects, recent clinical studies have indicated that gabapentin improves chemotherapy-induced and postoperative nausea and vomiting.²⁹⁾ Although decreased tachykinin neurotransmission and calcium influx in the area postrema have been speculated to underlie this antiemetic efficacy, the precise mechanisms remain to be elucidated. Therefore, further mechanistic investigations are necessary to determine the inhibitory effect of gabapentin on pica behavior induced by GLP-1 RAs.

Several studies have demonstrated that GLP-1 RAs induce appetite suppression and weight loss in humans and rodents.^30,31) However, we found no significant difference in food intake between the exenatide-injected and control mice. This discrepancy may be due to the relatively short in vivo half-life of exenatide and our measurement schedule. In this study, we simultaneously measured the food and kaolin intakes for 24 h, according to a previous report on the time course of pica behavior in mice.³²⁾ Half-life of exenatide is 2–3 h.³³⁾ Appetite suppression by exenatide is time-dependent, and a decrease in food intake by low-dose exenatide is observed only during cumulative food intake for 1–8 h, but not 24 h.³⁰⁾

In the FAERS database, acetaminophen reduced the occurrences of nausea and vomiting-associated events in GLP-1R agonist users. Although not significant, acetaminophen tended to decrease kaolin intake induced by exenatide in mice. Previous reports indicate that CB₁ receptor agonists show antiemetic effects in ferrets and shrews.^34,35) Acetaminophen is metabolized to AM404 that exerts antinociceptive effects through CB₁ receptor activation³⁶⁾; thus, it is possible that CB₁ receptor activation may mediate acetaminophen-induced antiemetic effects.

In conclusion, GLP-1 RAs increased the occurrence of nausea-related adverse events, which were mitigated by the concomitant use of gabapentin in humans and rodents. These findings indicate the possible use of gabapentin as a prophylactic or therapeutic for GLP-1 RA-related nausea and vomiting.

Acknowledgments

This work was supported by JST FOREST (Grant number JPMJFR2268 (K.N.)), JSPS KAKENHI (Grant numbers JP20H04774 (K.N.), JP20K07064 (K.N.), JP24K22019 (K.N.), JP24K02352 (K.N.), and JP20H00491 (S.K.)), and AMED (Grant numbers JP20ak0101088h0003 (S.K.) and JP21ak0101153h0001 (S.K.)). Grants were also received from the Lotte Research Promotion Grant (K.N.), Senri Life Science Foundation (K.N.), Mochida Memorial Foundation for Medical and Pharmaceutical Research (K.N.), Suzuken Memorial Foundation (K.N.), and Takeda Science Foundation (K.N.).

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

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