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Edited by
Luigi Santacroce
University of Bari Aldo Moro, Italy
Reviewed by
Xin Hai
Department of Pharmacy, First Affiliated Hospital of Harbin Medical University,
China
Marialetizia RASTELLI
Université de Lille, France
Wang Zhiyuan
Peking University, China
Table of contents

 * Abstract
 * Introduction
 * Methods
 * Results
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ORIGINAL RESEARCH ARTICLE

Front. Endocrinol., 06 December 2022
Sec. Gut Endocrinology
Volume 13 - 2022 | https://doi.org/10.3389/fendo.2022.1043789
This article is part of the Research Topic Endocrine Disruptors in Gut
Endocrinology View all 4 articles


ASSOCIATION BETWEEN DIFFERENT GLP-1 RECEPTOR AGONISTS AND GASTROINTESTINAL
ADVERSE REACTIONS: A REAL-WORLD DISPROPORTIONALITY STUDY BASED ON FDA ADVERSE
EVENT REPORTING SYSTEM DATABASE

Lulu Liu1,2Jia Chen1,3Lei Wang2Chen Chen4Li Chen1,5*
 * 1Department of Pharmacy and Evidence-Based Pharmacy Center, West China Second
   University Hospital, Sichuan University, Chengdu, China
 * 2School of Pharmaceutical Science and Technology, Tianjin University,
   Tianjin, China
 * 3Department of Pharmacy, Sichuan Provincial People’s Hospital Jinniu
   Hospital, Chengdu, China
 * 4West China School of Pharmacy, Sichuan University, Chengdu, China
 * 5Key Laboratory of Birth Defects and Related Diseases of Women and Children,
   Ministry of Education, Chengdu, China

Objective: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have
significantly improved clinical effects on glycemic control. However, real-world
data concerning the difference in gastrointestinal adverse events (AEs) among
different GLP-1 RAs are still lacking. Our study aimed to characterize and
compare gastrointestinal AEs among different marketed GLP-1 RAs (exenatide,
liraglutide, dulaglutide, lixisenatide, and semaglutide) based on real-world
data.

Methods: Disproportionality analysis was used to evaluate the association
between GLP-1 RAs and gastrointestinal adverse events. Data were extracted from
the US FDA Adverse Event Reporting System (FAERS) database between January 2018
and September 2022. Clinical characteristics, the time-to-onset, and the severe
proportion of GLP-1 RAs-associated gastrointestinal AEs were further analyzed.

Results: A total of 21,281 reports of gastrointestinal toxicity were analyzed
out of 81,752 adverse event reports, and the median age of the included patients
was 62 (interquartile range [IQR] 54–70) years old. Overall GLP-1 RAs were
associated with increased risk of gastrointestinal system disorders (ROR, 1.46;
95% CI, 1.44–1.49), which were further attributed to liraglutide (ROR, 2.39; 95%
CI, 2.28–2.51), dulaglutide (ROR, 1.39; 95% CI, 1.36-1.42), and semaglutide
(ROR, 3.00; 95% CI, 2.89–3.11). Adverse events uncovered in the labels included
gastroesophageal reflux disease, gastritis, bezoar, breath odor, intra-abdominal
hematoma, etc. Furthermore, it was observed that semaglutide had the greatest
risk of nausea (ROR, 7.41; 95% CI, 7.10–7.74), diarrhea (ROR, 3.55; 95% CI,
3.35–3.77), vomiting (ROR, 6.67; 95% CI, 6.32–7.05), and constipation (ROR,
6.17; 95% CI, 5.72–6.66); liraglutide had the greatest risk of abdominal pain
upper (ROR, 4.63; 95% CI, 4.12–5.21) and pancreatitis (ROR, 32.67; 95% CI,
29.44–36.25). Most gastrointestinal AEs tended to occur within one month.
Liraglutide had the highest severe rate of gastrointestinal AEs (23.31%), while
dulaglutide had the lowest, with a severe rate of 12.29%.

Conclusion: GLP-1 RA were significantly associated with gastrointestinal AEs,
and the association was further attributed to liraglutide, dulaglutide, and
semaglutide. In addition, semaglutide had the greatest risk of nausea, diarrhea,
vomiting, constipation, and pancreatitis, while liraglutide had the greatest
risk of upper abdominal pain. Our study provided valuable evidence for selecting
appropriate GLP-1 RAs to avoid the occurrence of GLP-1 RA-induced
gastrointestinal AEs.




INTRODUCTION

According to the reports of the International Diabetes Federation, there were
537 million patients with diabetes worldwide in 2021, and the prevalence of
diabetes was estimated at 10.5% (1). Glucagon-like peptide-1 receptor agonists
(GLP-1 RAs) have been increasingly recommended in the treatment of type 2
diabetes (T2DM) due to their favorable effects on improving glycemic control and
reducing the risk of cardiovascular events (2, 3). GLP-1RAs lower the blood
glucose of patients with diabetes through transient glucose-dependent
stimulation of insulin, and suppression of glucagon secretion and gastric
emptying (4, 5). So far, a total of seven GLP-1 RAs, including exenatide,
liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, and
tirzepatide, have been approved by the US Food and Drug Administration (FDA) for
treatment of T2DM.

With the extensive use of GLP-1 RAs, adverse drug reaction (ADR) reports are
increasing gradually, which has attracted the attention of clinicians and drug
administrations. The most frequently reported adverse events (AEs) of GLP-1 RAs
were gastrointestinal adverse drug reactions, including nausea, vomiting, and
abdominal pain, which were closely related to activation of central and
peripheral GLP-1 receptors (6, 7).

In a recent network meta-analysis, overall GLP-1 RAs significantly increased the
incidence of gastrointestinal AEs compared with placebo or conventional
treatment, and the odds ratios for nausea, vomiting and diarrhea from GLP-1 RAs
were 11.8 (95% CI, 2.89–46.9), 51.7 (95% CI, 7.07–415), and 4.93 (95% CI,
1.75–14.7), respectively (8). Other meta-analyses have also reported similar
results (6, 9–11). Moreover, some gastrointestinal adverse reactions with low
incidence but severe consequences are also notable. Some observational studies
showed that treatment with GLP-1 RAs was associated with an increased OR value
(2.24–29.4) of pancreatitis (12–14). However, the differences in
gastrointestinal toxicities among different GLP-1 RAs are still not known. These
problems pose concerns for physician about how to choose the safest and most
appropriate medication therapy. In addition, there have been no recent
systematic review updates, and further research on the seriousness and
time-to-onset of various GLP-1-related gastrointestinal AEs is needed. Thus,
this study aimed to characterize and compare gastrointestinal AEs of different
marketed GLP-1RAs based on real-world data to provide evidence for physicians on
the safety profiles of various GLP-1 RAs and how to choose the most appropriate
GLP-1 RA medication.


METHODS


DATA SOURCES

This retrospective pharmacovigilance study was conducted based on the FDA
Adverse Event Reporting System (FAERS) database. FAERS is a publicly available
post-marketing safety surveillance database that contains adverse event reports,
medication error reports, and product quality complaints reported by health
professionals, pharmaceutical manufacturers, lawyers, and individual patients
(15, 16). Although FAERS is a US database, it receives AEs reports from all over
the world. Therefore, the large size and global coverage of this open database
make it particularly suitable for the analysis of spontaneous data reporting
(15). FAERS database includes the following eight types of files: demographic
and administrative information (DEMO), drug information (DRUG), adverse events
(REAC), patient outcomes (OUTC), report sources (RPSR), start and end dates for
reported drugs (THER), indications for use (INDI), and invalid reports
(DELETED). All files recorded “primaryid” and “caseid” variables; therefore, the
information about patients and AEs could be obtained by linking these variables
in all files. DRUG and THER files recorded “drug_seq” variables; therefore,
information about drug use and therapy could be obtained by linking “drug_seq”
variables in these two files. All files are available at the FDA website
(https://fis.fda.gov/extensions/FPDQDE-FAERS/FPD-QDE-FAERS.html).

All reports between 1 January 2018 and 30 June 2022 were extracted for this
analysis. We chose 2018 as the starting year because the most recent approved
GLP-1 RA (semaglutide) except for tirzepatide was marketed in 2017, and the
ending date was set as the most recent quarter when data were available. The
study period was also the data analysis period, given that our research was a
cross-sectional study. During the study period, a total of 7,927,000 reports
were retrieved from the FAERS database. According to FDA’s recommendations, a
two-step deduplication process was used to ensure the unique report: 1)
selecting the higher “primaryid” when the “caseid” and “fda_dt” were the same,
2) selecting the latest “fda_dt” when “caseid” were the same, where “primaryid”
was an unique number for identifying a AE report, “caseid” was an unique number
for identifying a case, and “fda_dt” was the date when FDA received a case (17).
Then, the expurgated data from the DELETED file was downloaded from FAERS to
delete the invalid reports, finally reducing the number of reports to 6,803,529
(Figure 1).


FIGURE 1

Figure 1 The flow diagram of selecting GLP-1 RA-associated AEs from FAERS
database.



FAERS is a publicly available and anonymous database. Therefore, approval and
written informed consent were waived by the ethics review board of the Ethical
Committee of West China Second University Hospital of Sichuan University.


DATA EXTRACTION

The generic and brand names of GLP-1 RAs approved by the FDA were used to
identify adverse events of GLP-1 RAs in the DRUG files, including exenatide
(BYETTA, BYDUREON), liraglutide (VICTOZA, SAXENDA), dulaglutide (TRULICITY),
lixisenatide (ADLYXIN, SOLIQUA), and semaglutide (OZEMPIC, RYBELSUS, WEGOVY). Of
note, albiglutide (TANZEUM) and tirzepatide (MOUNJARO) were not included in our
study, given that albiglutide has been discontinued in the United States market
since 26 July 2017, and tirzepatide was approved by the FDA in May 2022. The
data for tirzepatide were too immature to support the analysis. The summary of
approval dates for these GLP-1RAs is listed in Supplementary Table 1.

The AEs in REAC files are encoded by the preferred terms (PTs) in the Medical
Dictionary for Regulatory Activities (MedDRA) terminology, which is comprised of
27 system organ classes (SOCs) (16). The structural hierarchy of MedDRA
terminology has five levels: SOC (system organ class), HLGT (high level group
term), HLT (high level term), PT (preferred term), and LLT (lowest level term)
(17). Accordingly, the latest version of MedDRA 25.0 was used to classify AEs in
reports at the relevant SOC level. In our study, all GLP-1 RA-induced PTs were
analyzed, and we found that gastrointestinal AEs were most frequently reported
in GLP-1 RAs. Therefore, the PTs of GLP-1 RAs below the SOC for gastrointestinal
system disorders (SOC: 10017947) were analyzed. Gastrointestinal-related AEs
were defined by 905 PTs, including nausea, vomiting, etc. The role codes for AEs
had been assigned by reporters, including primary suspected (PS), secondary
suspected drug (SS), concomitant (C), and interacting (I). To guarantee GLP-1
RAs were most likely to cause AEs during drug use, analysis reports were limited
to those in which the “role_cod” of the drug was “PS” (primary suspected) in the
DRUG files (18).

Demographics (gender, age), reporting characteristics (reporting region, year,
occupation of reporters), and indications of reports of GLP-1 RA-associated
gastrointestinal toxicities were analyzed. In addition, we calculated the
time-to-onset of gastrointestinal AEs and the proportion of AE outcomes that
were caused by different GLP-1 RAs. The calculation method of time-to-onset is
the interval between the start time of GLP-1 RAs’ utilization and the time of AE
occurrence (19). Reports with date errors (drug use time later than event
occurrence time) and missing date data were excluded. Severe outcomes included
death (grade 5), life-threatening conditions (grade 4), and outcomes causing
hospitalization, disability, or a congenital anomaly (grade 3) (20). The
proportion of reports with severe outcomes was calculated by dividing the number
of reports with severe outcomes by the total number of reports.


DATA MINING AND STATISTICAL ANALYSIS

All characteristics and outcome measures of AE reports regarding GLP-1 RAs were
evaluated descriptively. Categorical variables were reported as frequencies and
percentages, and continuous variables were summarized as means and standard
deviations or medians with interquartile ranges depending on the data
distribution.

A disproportionality analysis model was performed to detect the potential
signals of gastrointestinal AEs caused by GLP-1 RAs at both the class level and
the drug generic name level (21). When a target drug is more likely to induce a
target AE than all other drugs, it will typically get a higher score due to
higher disproportionality (e.g., when semaglutide causes more gastrointestinal
AEs than other drugs, it will get a higher disproportionality score) (21). Both
frequentist methods (reporting odds ratio [ROR] (22) and proportional reporting
ratio [PRR] (23)) and Bayesian methods (information component [IC] (24) and
empirical Bayes geometric mean [EBGM] (25)) of disproportionality analysis were
applied to investigate the association between a gastrointestinal AE and GLP-1
RAs. The equations and corresponding criteria of the four disproportionality
algorithms are listed in Supplementary Table 2.

To improve the reliability of signals and avoid occurring false positive
signals, a signal was regarded as positive only when it met all criteria of four
algorithms simultaneously (26). Then, the signal strength of the top six most
frequently reported gastrointestinal AEs of overall GLP-1 RAs in the FAERS
database was ranked among different GLP-A RAs, and the top six AEs are nausea,
vomiting, diarrhea, upper abdominal pain, constipation, and pancreatitis,
respectively. A Kruskal–Wallis test was performed to compare the time-to-onset
of gastrointestinal outcomes in different GLP-1 RAs. The severe proportion of
gastrointestinal events in different GLP-1 RAs was compared using Fisher’s exact
test or Pearson’s chi-squared test. Two-sided P-values of <0.05 were considered
statistically significant. Data extraction was conducted by MySQL 8.0, and
statistical analyses were performed using R 4.10.


RESULTS


DESCRIPTIVE ANALYSIS

From January 2018 to June 2022, a total of 231,730 GLP-1 RA-associated AEs
reports were recorded, of which 21,281 reports of gastrointestinal AEs were
identified. Of these, 1,956 gastrointestinal reports were for exenatide (9.19%),
2,891 for liraglutide (13.58%), 10,757 for dulaglutide (50.55%), 182 for
lixisenatide (0.86%), and 5,567 (26.16%) for semaglutide (Figure 1).

The characteristics of AE reports for different GLP-1 RAs are presented in
Table 1. More male patients reported gastrointestinal AEs from GLP-1 RAs
(54.19%). The median age (interquartile range) of patients was 62 (54–70) years.
The region with the highest number of reports was North America (91.40%),
followed by Europe (4.10%), and Asia (2.55%). The number of gastrointestinal AEs
steadily increased from 4,163 in 2018 to 5,048 in 2021, which reflected the
increasingly clinical application of GLP-1 RAs. These AEs were mainly reported
by consumers (74.28%) and physicians (11.04%). Gastrointestinal AEs were most
frequently reported for unknown indications (50.37%) and diabetes mellitus
(41.07%). The median time-to-onset of gastrointestinal AEs was 1 (IQR 0–24)
days, and 77.44% of the AEs occurred within 30 days after excluding invalid
reports. Outcomes causing hospitalization, disability, or a congenital anomaly
(2,933, 13.78%) account for the most frequent outcomes in all cases.


TABLE 1

Table 1 The characteristics of GLP-1 RAs-associated gastrointestinal reports.




AE SIGNALS ASSOCIATED WITH DIFFERENT GLP-1 RAS

All adverse events signals of GLP-1 RAs were detected by using four algorithms
and their corresponding criteria. A total of 619 positive signal for GLP-1 RAs
were observed, and the most AEs of positive signal were distributed in
gastrointestinal system (Figure 2).


FIGURE 2

Figure 2 Proportion of positive signal for different GLP-1 RAs in system organ
level.



Within the SOC level, gastrointestinal system disorders in overall GLP-1 RAs
were overreported compared with the background frequency (ROR 1.46, PRR 1.33, IC
0.41, EBGM 1.33), which were further attributed to liraglutide (ROR 2.39, PRR
1.84, IC 0.88, EBGM 1.33), dulaglutide (ROR 1.39, PRR 1.28, IC 0.36, EBGM 1.25),
and semaglutide (ROR 3.00, PRR 2.10, IC 1.07, EBGM 2.10), while exenatide (ROR
0.57, PRR 0.63, IC −0.68, EBGM 0.63) and lixisenatide (ROR 0.51, PRR 0.57, IC
−0.81, EBGM 0.57) did not show the association with gastrointestinal AEs
(Table 2).


TABLE 2

Table 2 Signal detection for GLP-1 RAs-associated gastrointestinal adverse
events.



Furthermore, the positive signals of gastrointestinal AEs were classified as PT
level (Supplementary Table 3). The top six most common gastrointestinal reports
were nausea (8,988, 42.23%), diarrhea (4,666, 21.93%), vomiting (4,660, 21.90%),
upper abdominal pain (2,082, 9.78%), constipation (1,790, 8.41%), and
pancreatitis (1,752, 8.23%). All gastrointestinal AEs in the label of GLP-1 RAs
were found in our study, which confirmed the reliability of this study. However,
there were five disproportional signals that were not covered on the label that
were detected for liraglutide (gastroesophageal reflux disease, gastritis,
bezoar, breath odor, and intra-abdominal hematoma), one for dulaglutide
(duodenogastric reflux), and three for semaglutide (breath odor, pancreatic
failure, and mesenteric panniculitis).

Simultaneously, the signals of the top six common gastrointestinal AEs (nausea,
diarrhea, vomiting, upper abdominal pain, constipation, and pancreatitis) for
different GLP-1 RAs were detected and compared (Table 3). The results showed
that semaglutide had the greatest risk of nausea (ROR, 7.41; 95% CI, 7.10–7.74),
diarrhea (ROR, 3.55; 95% CI, 3.35–3.77), vomiting (ROR, 6.67; 95% CI,
6.32–7.05), and constipation (ROR, 6.17; 95% CI, 5.72–6.66); liraglutide had the
greatest risk of upper abdominal pain (ROR, 4.63; 95% CI, 4.12–5.21). In
addition, it was observed that use of any GLP-1 RA was associated with the risk
of pancreatitis, and the signal strength of pancreatitis was ranked as follows:
liraglutide (ROR, 32.67; 95% CI, 29.44–36.25) > semaglutide (ROR, 19.10, 95% CI,
17.26–21.13) > dulaglutide (ROR, 12.63; 95% CI, 11.76–13.56) > lixisenatide
(ROR, 6.78; 95% CI 4.26–10.80) > exenatide (ROR, 4.91; 95% CI, 4.12–5.85).


TABLE 3

Table 3 The difference of signal strength in the top six most frequently
reported gastrointestinal adverse events among different GLP-1 RAs.




TIME-TO-ONSET AND SEVERE PROPORTION

The time-to-onset of gastrointestinal system disorders for each GLP-1 RA regimen
is shown in Table 4. The result showed the time-to-onset of GLP-1 RAs had a
statistical difference (p <0.001, Kruskal–Wallis χ2 = 109.90). The longest
median time-to-onset was 4 (IQR 0–40) days for semaglutide, while the shortest
was 0 (IQR 0–11) day for lixisenatide, 1 (IQR 0–19.75) day for exenatide, 1 (IQR
0–7) day for dulaglutide, and 3 (IQR 0–36.75) days for liraglutide,
respectively.


TABLE 4

Table 4 Time-to-onset of GLP-1 RA-associated gastrointestinal AEs.



To explore the prognosis of patients with gastrointestinal AEs after using GLP-1
RAs, this study evaluated the outcome of reports by severe proportions of
outcomes. The corresponding results were presented in Table 1 and Figure 3, and
they showed a statistical difference in the severe proportions of GLP-1
RA-related gastrointestinal AEs among different GLP-1 RAs (p <0.001, Pearson’s
χ2 = 11,227). In all GLP-1 RAs, liraglutide (23.31%, 657 severe outcomes out of
2,819 cases) had the highest severe proportion of GLP-1 RA-associated
gastrointestinal AEs, and the lowest for dulaglutide (12.29%, 1,322 severe
outcomes out of 9,435 cases).


FIGURE 3

Figure 3 The case severe rate for GLP-1 RA-related gastrointestinal AEs.




DISCUSSION

In this large real-world study, we found that GLP-1RAs are associated with an
increased risk of gastrointestinal AEs, which were mainly attributed to
liraglutide, dulaglutide, and semaglutide. The most frequently reported GLP-1
RA-induced gastrointestinal AE was nausea (8,988, 42.23%), diarrhea (4,666,
21.93%), and vomiting (4,660, 21.90%) in FAERS. This is consistent with prior
studies, and a system review reported that ADRs of GLP-1 RAs tend to arise from
the gastrointestinal system, with nausea, diarrhea, and vomiting occurring in up
to 51%, 20%, and 19% of patients, respectively (27). These gastrointestinal AEs
are related to the inhibition effect of GLP1-RAs on delay in gastric emptying
and stimulation of neural circuitry (9, 28, 29).

In our study, semaglutide had the highest risk for nausea (ROR, 7.41; 95% CI,
7.10–7.74), vomiting (ROR, 6.67; 95% CI, 6.32–7.05), diarrhea (ROR, 3.55; 95%
CI, 3.35–3.77), and constipation (ROR, 6.17; 95% CI, 5.72–6.66) when compared
with background drugs. Semaglutide is a new generation of long-acting GLP-1RAs
with a longer half-life than liraglutide after subcutaneous administration (183
vs 11–15 h) (30). Hence, the effects of gastrointestinal motility and neural
circuitry of semaglutide may be more significant compared with those using other
GLP-1 RAs. Our results were similar to those of previous studies, which reported
that semagulutide had a higher risk of nausea, vomiting, diarrhea, and
constipation compared with liraglutide (15).

Physician and patients have been expressed the concerns regarding a possible
association of GLP-1 RAs treatment with pancreatitis. In our study, pancreatitis
were the same disproportionality signals for all different GLP-1 RAs. These
results were similar with prior studies. A cohort study revealed an increased
risk of pancreatitis, and 36% of patients who used GLP-1 RAs or DPP- 4
inhibitors had elevated serum amylase or lipase (or both) levels compared with
18% of patients not taking these agents (31). Another case-control study showed
that the use of incretin-mimetic therapies within 30 days (OR: 2.24, 95% CI:
1.36–3.68), or ranging from 30 days to 2 years was associated with an increased
risk of acute pancreatitis (OR: 2.01, 95% CI: 1.37–3.18) compared with nonusers.
Our study found that the signal strength of pancreatitis for different GLP-1 RA
was ranked as following: liraglutide (ROR = 32.67) > semaglutide (ROR = 19.10) >
dulaglutide (ROR = 12.63) > lixisenatide (ROR = 6.78) > exenatide (ROR = 4.91).
It is suggested that patients being at risk of pancreatitis should not use any
GLP-1 RAs, especially for liraglutide and semaglutide.

Our studies showed GLP-1 RA-associated gastrointestinal toxicities occurred 30
days (3,234, 77.44%) after the initiation of GLP-1RAs, and the median
time-to-onset was 1 (IQR 0–24) days with a significant difference between
different GLP-1 RA regimens. A systematic review was consistent with our
results: gastrointestinal toxicities tended to occur early after treatment
initiation with fluctuation over time, both in a type 2 diabetic population and
a more general population (9). Time-to-onset analysis of gastrointestinal AEs
may have been dependent upon the pharmacokinetic and pharmacodynamic properties
of different GLP-1RAs. A “start low, go slow” strategy when initiating GLP-1
receptor agonists may reduce the likelihood of patients experiencing these
events (32).

To further assess the severity of gastrointestinal AEs related to different
GLP-1RAs, the severe proportion was compared among different GLP-1RA treatments.
We observed that the severe rates had statistical significance in different
GLP1- RAs. It was worth noting that liraglutide had the highest severe rate
(23.31%, 657/2,819). Therefore, physicians should pay close attention to the
health status of patients after AEs to avoid the progression to severe outcomes.
LEADER trial showed that 32.2% patients experienced severe AEs in the
liraglutide group for 4.5 years follow-up period, while these AE not only
limited to gastrointestinal (33).

Although our study had significant advantages based on the FAERS database and
data mining technology, there were also some limitations inherent to its
observational design. First, the FAERS database is a self-reporting system with
reporting randomness (e.g., existing selective, incomplete, inaccurate,
untimely, and unverified reporting) and massive missing data (e.g., age and
dosage). It is difficult to consider some confounders (such as dosage, duration
of use, comorbidities, and drug combinations) that may influence the occurrence
of gastrointestinal toxicity. Second, because the FAERS only contains cases with
adverse events, the total number of patients receiving GLP-1RA treatment was
low. Hence, the incidence rate of gastrointestinal AEs associated with GLP-1RA
use cannot be estimated. Third, we focus only on gastrointestinal toxicity, and
the deep relationship between GLP-1RAs and other system organ classes remains
unknown. Further clinical trials or observational studies are needed to confirm
our results. Finally, disproportionality analysis based on FAERS showed neither
causality nor quantified risk due to the lack of pharmacological mechanism study
but only showed an evaluation of the signal strength, which was just a
statistical association (34). Like other pharmacovigilance studies, Frequentist
and Bayesian are indexes of increased risk in AE reports, whether a causality
exists and needs to be further validated by basic research.


CONCLUSION

We explored the relationship between GLP-1 RAs and gastrointestinal AEs from
various perspectives and quantified the potential risks based on a comprehensive
and systematic retrospective analysis of the FAERS database. GLP-1 RAs were
significantly associated with gastrointestinal AEs, and the association was
further attributed to liraglutide, dulaglutide, and semaglutide. In addition,
semaglutide had the greatest risk of nausea, diarrhea, vomiting, constipation,
and pancreatitis, while liraglutide had the greatest risk when it came to upper
abdominal pain. Furthermore, the time-to-onset and severe outcomes of GLP-1
RAs-induced gastrointestinal AEs were also discussed, which was helpful for
clinical practice and drug monitoring to a certain extent. Our study provided
valuable evidence for early clinical interventions and the identification of the
risk of gastrointestinal toxicities.


DATA AVAILABILITY STATEMENT

The raw data supporting the conclusions of this article will be made available
by the authors, without undue reservation.


ETHICS STATEMENT

Ethical approval was not provided for this study on human participants because
FAERS (FDA Adverse Event Reporting System) is publicly available and anonymous
database, so approval and written informed consent were waived by the ethics
review board of the Ethical Committee of West China Second University Hospital
of Sichuan University. Written informed consent from the participants’ legal
guardian/next of kin was not required to participate in this study in accordance
with the national legislation and the institutional requirements.


AUTHOR CONTRIBUTIONS

LC and LL contributed to conception and study design, and took responsibility
for the collection, integrity, and accuracy of the data. All authors drafted the
manuscript, participated in data analyses and interpretation, and revisions of
the manuscript and approved the final version.


FUNDING

This study was supported by a grant from the National Natural Science Foundation
of China (No. 82073921).


ACKNOWLEDGMENTS

All authors thank the US Food and Drug Administration Adverse Event Reporting
System for using their database.


CONFLICT OF INTEREST

The authors declare that the research was conducted in the absence of any
commercial or financial relationships that could be construed as a potential
conflict of interest.


PUBLISHER’S NOTE

All claims expressed in this article are solely those of the authors and do not
necessarily represent those of their affiliated organizations, or those of the
publisher, the editors and the reviewers. Any product that may be evaluated in
this article, or claim that may be made by its manufacturer, is not guaranteed
or endorsed by the publisher.


SUPPLEMENTARY MATERIAL

The Supplementary Material for this article can be found online at:
https://www.frontiersin.org/articles/10.3389/fendo.2022.1043789/full#supplementary-material


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Keywords: GLP-1 receptor agonists, gastrointestinal toxicities, adverse drug
reactions, pharmacovigilance, data mining

Citation: Liu L, Chen J, Wang L, Chen C and Chen L (2022) Association between
different GLP-1 receptor agonists and gastrointestinal adverse reactions: A
real-world disproportionality study based on FDA adverse event reporting system
database. Front. Endocrinol. 13:1043789. doi: 10.3389/fendo.2022.1043789

Received: 14 September 2022; Accepted: 21 November 2022;
Published: 07 December 2022.

Edited by:

Luigi Santacroce, University of Bari Aldo Moro, Italy

Reviewed by:

Marialetizia Rastelli, Université de Lille, France
Wang Zhiyuan, Peking University, China
Xin Hai, First Affiliated Hospital of Harbin Medical University, China

Copyright © 2022 Liu, Chen, Wang, Chen and Chen. This is an open-access article
distributed under the terms of the Creative Commons Attribution License (CC BY).
The use, distribution or reproduction in other forums is permitted, provided the
original author(s) and the copyright owner(s) are credited and that the original
publication in this journal is cited, in accordance with accepted academic
practice. No use, distribution or reproduction is permitted which does not
comply with these terms.

*Correspondence: Li Chen, chenl_hxey@scu.edu.cn



Disclaimer: All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their affiliated organizations, or
those of the publisher, the editors and the reviewers. Any product that may be
evaluated in this article or claim that may be made by its manufacturer is not
guaranteed or endorsed by the publisher.




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