Randomized Trial of Holding vs. Continuing Incretin-based Therapies Before Upper Endoscopy
Phase: PHASE4
Conditions: Diabetes Mellitus, Type 2, Obesity, Gastroparesis
Sponsor: The Cleveland Clinic

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Randomized trial of holding vs. continuing incretin-based therapies before upper 
endoscopy
Principal Investigator:  
Tilak Shah, M.D.
Email: shaht3@ccf.org
Address: 2950 Cleveland Clinic Blvd, Weston, FL 33331 
Background:
Incretin-based therapies include GLP-1 receptor agonists (GLP-1RAs) and dual GLP1-
RA and gastric inhibitory polypeptide (GIP) agonists. These drugs are commonly prescribed for 
diabetes and more recently, their use has risen exponentially as a primary therapy for weight 
loss. These medications can decelerate gastric emptying and diminish bowel motility by 
inhibiting peristalsis at the GLP-1 receptors situated in myenteric neurons.  Therefore, there 
exists a theoretic potential for gastroparesis, retained gastric contents, perioperative 
regurgitation, and pulmonary aspiration syndrome, and this is a concern for anesthesiologists and 
patients taking these medications. 
The American Society of Anesthesiologists recently released a consensus-based 
statement that recommends patients on daily dosing hold incretin-based therapy the day of the 
procedure, and those on weekly dosing hold the medication a week before the procedure. The 
evidence for these recommendations is based on retrospective studies and case reports, and 
therefore the conclusions may be overly proscriptive. Furthermore, holding incretin-based 
therapy poses a risk for worsening diabetes control and more importantly, could cause 
unnecessary delays in care if a patient’s procedure is postponed because they failed to hold the 
medication based on the recent recommendations (1-3).
Study Objective:
To assess whether holding incretin-based therapy before endoscopy reduces the likelihood of 
clinically relevant Residual Gastric Volume (RGV).
Hypothesis:
Holding incretin-based therapy is non-inferior to continuing incretin-based therapy for reducing 
the risk of clinically relevant RGV.

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Study design:
Randomized Non-Inferiority Controlled Trial.
Blinding:
Single-blind: endoscopist and anesthesia team will be blinded to study group assignment.
Primary Outcomes:
The primary outcome is clinically significant residual gastric volume defined as a composite of 
the following variables:
•
Residual gastric volume that precludes adequate endoscopic examination
•
Residual gastric volume that necessitates premature termination of the endoscopy 
procedure 
•
Need for endotracheal intubation due to stomach contents.
•
Occurrence of aspiration events requiring extended observation/monitoring, unplanned 
therapeutics, and/or hospital admission
Secondary Outcomes:
•
Presence of any solid food
•
Presence of moderate liquid content
•
Increased RGC defined as any amount of solid content or > 0.8 mL/Kg of fluid content 
(measured from the aspiration/suction canister).
•
Aspiration events up to 48 hours after endoscopy 
•
Differences in primary and secondary outcomes between different medications
Inclusion Criteria:
•
Patients using incretin-based therapies at a stable dose for more than 1 month.
•
Understand the study procedures and will be able to provide written informed consent to 
participate in the study. 
•
Patients scheduled for outpatient esophagogastroduodenoscopy (EGD), combined EGD 
and colonoscopy, endoscopic ultrasound (EUS), or endoscopic retrograde 
cholangiopancreatography (ERCP) under monitored anesthesia care (MAC) or moderate 
sedation.
Exclusion Criteria:
•
Documented history of gastroparesis (based on a 4-hour solid-phase gastric emptying 
study)

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•
Known history of achalasia 
•
Surgical or genetically altered foregut anatomy
•
Known gastric outlet obstruction or pre-procedure imaging suggestive of gastric outlet 
obstruction.
•
Patients who did not follow the standard NPO (nil per oral) instructions.
•
Patients who have planned endotracheal intubation (ETT) during their upper endoscopy 
procedure (EGD, EUS, or ERCP).
•
Ongoing opiate use
•
Unable or unwilling to give written consent
Randomization:
•
Patients will be randomly assigned to either continue incretin-based therapy as prescribed 
(“continue” group) or to hold therapy as outlined in the ASA guidance recommendations 
(“hold” group). 
•
Simple randomization will be applied post-enrollment, utilizing REDCap serial numbers 
with pre-determined interventions (“continue” vs. “hold”). The randomization table of 
allocation will be completed by a statistician on REDCap to ensure concealed allocation.
Study Operation:
•
The candidates for the study will be determined either during the gastroenterology clinic 
visit OR based on review of records by a member of the research team of patients 
scheduled for upper endoscopy, EUS, and ERCP cases three to four weeks in advance 
•
Patients’ invitation 
o
For patients who are scheduled for the procedure through the gastroenterology 
clinic, the patient’s clinic provider will invite the patient for the study during the 
office visit or with a phone call. 
o
For patients who are not scheduled via the above route, a letter of invitation will 
be sent to the patient from the physician completing the procedure through the US 
mail or MyChart. 
•
Patient consent 
o
Interested patients in the clinic setting will be given the option to complete a 
research encounter during the same day, including in-person consent if interested, 
or complete the process remotely over the phone and through MyChart Electronic 
consent, or DocuSign.
o
Patients who are not identified in clinic but through chart review will receive a 
phone call and phone encounters will be completed with interested potential 
participants and will include an explanation of the study and the consent process 
(phone scripts attached). MyChart Electronic consent process or DocuSign will be 
used to send the study consent to the participants.
•
After obtaining consent, the patient information will be entered into the REDCap which 
will give the patient a REDCap serial number. 

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•
A randomization tool in the REDCap will determine the intervention (The randomization 
table of allocation will be completed by a statistician on REDCap to ensure concealed 
allocation).
•
The patient will be informed about the intervention during the clinic visit by a study 
member (not the endoscopist) or over the phone. 
•
A few days before the intervention, the patient will receive a call as a reminder of the 
intervention and instruction from a study member (not the endoscopist). 
•
On the endoscopy day, the proceduralist and anesthesia team will be blinded to the 
patient's group assignment. To ensure that blinding is maintained, a sticker will be placed 
on the patient physical chart to remind the provider to avoid asking about the study 
intervention.
•
A research coordinator/investigator will confirm intervention compliance and record the 
variables of interest for the study.
•
Information will be directly entered into the Redcap data collection sheet or recorded on a 
physical paper-based collection sheet and transferred immediately to Redcap on the same 
day. The physical sheets will be shredded on the day of the procedure. 
•
A phone call to the patient within the first week after the procedure to follow up and 
exclude aspiration events. If patient cannot be contacted, then a member of the study 
team will review patient records to identify any emergency department visits or 
hospitalizations related to a post-procedure aspiration event.
Electronic Consent operation
-
An investigator or research coordinator will contact the invited candidates over the phone 
2-4 weeks before the scheduled procedure. The study purpose, intervention, adverse 
events, and consenting process will be discussed over the phone. The encounter will be 
documented in the patient chart as a phone encounter.
-
Subjects interested in the study will be provided with consent through MyChart 
Electronic consent or DocuSign with instructions to complete online consent signing.
-
After all parties complete the consent, a randomization of the study intervention will be 
done through Redcap. 
-
A follow-up phone call will be made to communicate the instructions to the participants. 
Rational for electronic consent (E-consent)
The study is not feasible with conventional consent, especially for open access procedures for the 
following reasons:
•
The duration for participant involvement in the study is short, and the study intervention 
is only applied one week before the procedure, which would make it impractical to bring 
the patient for an extra encounter and would decrease the chance for enrollment.

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•
Many procedures are scheduled in an open-access fashion, which means that the patient 
is scheduled for the procedure by a provider other than the performing physician and/or 
from a different department.
•
The intervention for the study must be completed one week before presenting to the 
procedure, which requires that the patient be enrolled before the procedure date.
Sample Size Determination:
•
Previous retrospective studies indicate that 5-7% of GLP-1RA users have increased RGV 
compared to less than 0.5% in non-users.
•
If there is a significant difference in favor of the experimental (“hold”) group of 7%, then 
120 patients are needed (60 in each group) to be 80% certain that the upper limit of a one-
sided 95% confidence interval (or equivalently a 90% two-sided confidence interval) will 
exclude a difference in favor of the standard group of more than 3% (the non-inferiority 
limit) using Farrington-Manning’s score test. 
•
Because estimates from previous retrospective studies are for the outcome of residual 
gastric volume, they may not accurately reflect our primary outcome, which is a more 
pragmatic and clinically useful outcome. Therefore, we plan to conduct an interim 
analysis at 20% recruitment and may adjust sample size if necessary, based on point 
estimates derived from the interim analysis. 
Study Variables 
Date of birth, gender, race, body mass index (BMI), type of incretin-based therapy used, incretin 
therapy dose, pre-endoscopy clinical symptoms, presence of diabetes, last HBA1c if available, 
detailed endoscopic reports, gastric residual content on endoscopy, and RGC-related events as 
described above. Please refer to the data collection sheet for details of the variables above.
Study Statistics 
The Statistics will be done with the help of a Clevland Clinic statistician. Data will be extracted 
in deidentified form directly from Redcap for analysis.
Once data has been collected, we will use STATA version 14.1 (STATA Corp, College Station, 
TX, USA) for statistical analysis. We will use statistics of central tendency (mean, median, and 
mode) for most values. Data normality will be tested using Kolmogorov–Smirnov test. We will 
use Pearson’s chi-square tests for categorical variables and T-test for continuous variables. A P-
value of < 0.05 will be considered significant for all statistical analyses. The primary outcome 
will be calculated using chi-square or Mann-Whitney test. For the primary outcome, an 
intention-to-treat analysis will be utilized. 

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Interim Analysis and Data Monitoring Committee (DMC)
The study DMC will include the following: The gastroenterology program director at Weston, a 
gastroenterologist, and a Cleveland Clinic statistician. Meetings will be held at 20%, 50, and 
100% of recruitment to ensure data security compliance, appropriate rate of recruitment, and 
study adverse events monitoring. A report of each meeting will be sent to the IRB. The DMC 
will not be blinded for study groups. Interim analysis will be conducted after 20 and 50% of 
recruitment on the second DMC meeting, and the study will be stopped if inferiority is 
confirmed. 
Data Security 
Data, including patient information and consent, will be stored electronically in the Redcap 
system\DocuSign which is password-protected and on the secure Cleveland Clinic network. If 
physical paper sheets were used, the physical paper sheets' information would be transferred to 
Redcap and shredded on the day of data gathering.
Possible Harm to Subjects and Adverse Events
The study risk is related to continuing incretin-based therapy in the periprocedural time. 
Medication continuation has a theoretical risk of increased residual gastric content, although 
there is no strong evidence to support that.  Increased gastric residual content can lead to 
prolonged monitoring time, increased procedure time, premature termination of the procedure, 
unexpected urgent endotracheal intubation, or aspiration events.  
Breach of confidentiality is another potential harm, and it will be minimized by the data security 
plan described above. The study does not involve prescribing incretin-based therapy.
All serious unexpected adverse events will be recorded and reported to the IRB in a timely 
fashion. Adverse events (study outcome) will be reported to the IRB after each DMC meeting.
References
1- Kobori T, Onishi Y, Yoshida Y, et al. Association of glucagon-like peptide-1 receptor 
agonist treatment with gastric residue in an esophagogastroduodenoscopy. J Diabetes 
Investig. 2023;14(6):767-773. doi:10.1111/jdi.14005
2- Silveira SQ, da Silva LM, de Campos Vieira Abib A, et al. Relationship between 
perioperative semaglutide use and residual gastric content: A retrospective analysis of 
patients undergoing elective upper endoscopy. J Clin Anesth. 2023;87:111091. 
doi:10.1016/j.jclinane.2023.111091

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3- Joshi G, Abdelmalak B, Weigel W, et al. American Society of Anesthesiologists 
Consensus-Based Guidance on Preoperative Management of Patients (Adults and 
Children) on Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists.  Released June 
29, 2023.  Accessed from asahq.org on January 16, 2024.