Impact GLP-1 Agonists Following Bariatric

Hypertension Clinical Trial

Official title: Biometabolic Impact of Continuation of GLP-1 Agonists Following Bariatric

Status Recruiting

Clinical Trial Summary

Glucagon-like peptide 1 (GLP-1) is a hormone that helps regulate blood glucose levels through improved insulin sensitivity and release of insulin from the pancreas, control hunger, induce satiety and plays a role in the metabolic health of a person. GLP-1 receptor agonists (GLP1-RAs) have been shown to be effective in achieving weight loss in patients with type 2 diabetes while improving blood glucose control. Bariatric surgical procedures have been shown to be effective in treating obesity as well as superior to best medical therapy for treatment of diabetes not just through restriction of calories but also through a positive impact in modifications of gut hormones, changes in circulating bile acids, modifications in the gut microflora as well as other undefined mechanisms. The combined benefits of GLP1-RAs with bariatric surgery have only been studied to a limited effect. In this randomized trial, the effects of continuation or discontinuation of GLP1-RA therapy in patients undergoing bariatric surgery will be determined. We will compare changes in weight, metabolic determinants including circulating bile acids and gut microbiome, psychological determinants of eating behavior, and adverse side effects in patients who continue vs discontinue therapy. Given differences in metabolic and clinical outcomes in patients undergoing vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB), both surgical groups will be examined. The study will be conducted at a high volume bariatric surgical program where patients will undergo randomization at the time of final clinic visit prior to surgery to continue or discontinue GLP1-RA. It is hypothesized that participants who continue GLP1-RA therapy after bariatric surgery will lose more weight with improved blood glucose control than those who discontinue therapy. Furthermore, changes in gut microbiome and circulating bile acids, known determinants of metabolic health, will be modified to a differential extent in those who are on GLP1-RAs vs those where GLP1-RAs are discontinued. Understanding the role these medications play in not only clinical outcomes after metabolic surgery but potential metabolic mechanisms by which surgery improves patient's metabolic health could help people with obesity and type 2 diabetes make informed decisions about their treatment options as well as advise providers on the continuation of these medications in the perioperative and postoperative period.

Clinical Trial Description

Preliminary Work To date we have established a randomized controlled clinical trial where we are comparing groups of patients with variable lengths of biliopancreatic limb lengths during gastric bypass. VSG patients serve as a control surgical group, and we have gathered both serum and stool in over 200 patients. We have collaborated with both the institutional metagenomics and proteomics centers to process samples and evaluate bile acid synthesis and stool microbiome content. This trial has successful IRB approval for the project through the University of Missouri-Columbia IRB (#2058104) as well as registered the study with clinicaltrials.gov (NCT04841057).

Recruitment and Randomization:

1. Meet inclusion criteria and do not have any exclusion criteria

2. Meet all criteria per standard practice to qualify for surgery

3. Taking a GLP-1 agonist at time of consenting as part of their medical care apart from the research protocol

4. Recruitment will occur at the time of the preoperative education class which is the final visit prior to surgery. At this point patients will have determined whether or not they desire to have a sleeve gastrectomy or gastric bypass. For those who are taking a GLP-1 agonist they will be offered the ability to participate in the study.

Randomization of patients and surgical technique. A total of two groups will be utilized. Eligible patients will include those taking a GLP-1 agonist at the time of surgery. These patient will be randomized to either continuation of the GLP-1 agonist or discontinuation of the GLP-1 agonist. Surgical patients will include those undergoing sleeve gastrectomy, gastric bypass, duodenal switch, or revisional surgery.

Recruitment Site Weight Management and Metabolic Center Preoperative and post-operative weight loss surgery patients as well as non-surgical weight management patients are seen by providers at the Weight Management and Metabolic Center, a part of MU Health Care. Patients will undergo standard screening for medical and surgical history per any preoperative weight loss surgery patient. Per our standard protocol all patients will have a full set of nutrition labs which includes basic labs including complete blood count and complete metabolic profile as well as vitamin and nutrient labs.

Consent Process:

Each patient will be approached before the weight loss or bariatric surgery or during their care for medical weight loss or when being evaluated for non-weight loss surgery. In addition, Written Consent and HIPPA form consent will be provided for the patient to review, and one of the research staff listed on the local IRB will be available to answer any questions after the patient has sufficient time to review the consent.

Number of anticipated subjects:

Sample size for randomization to two groups will be 150 patients. This is based on power analysis to have an 80% power to detect a difference in percentage of excess body weight loss with a probability of a Type 1 error rate of 5%. This will provide adequate patients given several different procedures that will be performed on patients in each group and an attrition rate of 30% who do not follow through with either follow-up appointments or adherence to their randomization status/group.

Sample size was determined based on previously published literature. This is an appropriate number to demonstrate a statistical difference in weight loss, the primary end goal.

Study Procedures/ Design/ Treatment Plan:

Patients will be recruited for approximately 5 years to gather the appropriate sample size. Because each patient will have samples collected for 5 years, it will be approximately 10 years from last patient enrolled until study is completed.

Surgical Procedures Each patient will decide which surgical procedure he/she desires after the initial consultation with the surgeon.

A gastric bypass will be performed using our standard technique. In brief, all procedures will be performed laparoscopically as is standard practice. Specifically, at our institution, the gastric pouch will be constructed with a linear stapler approximately 5 cm long and 3 cm wide. The gastrojejunostomy anastomosis will be constructed either with a 25 mm circular stapler or a linear stapler. The linear stapler common gastroenterotomy will be closed in a running 2 layer manner to narrow to approximately 13-15 mm. The jejunojeunostomy will be created with a liner stapler after creation of BPL length of 100 cm and an alimentary limb length of 125 cm which will be connected to the gastric pouch via the gastrojejunostomy. The remaining small bowel, which will represent the common small bowel channel will also be measured. Measurements will be achieved in a standard manner.

Patients undergoing a sleeve gastrectomy will undergo a procedure to laparoscopically resect and remove approximately 80% by volume of the outer portion of the stomach. At our institution, specifically the sleeve gastrectomy is performed using a bougie as an intraluminal template for sizing purposes. The bougie is either 36 or 40 French per our usual practice.

Medication Use Protocol

1. Currently, continuation or discontinuation of GLP-1 agonists after bariatric surgery has not been established as standard of care and is at the discretion of the medical team (surgical or medical). No GLP-1 agonists will be initiated postoperatively if not taking one of these medications when having bariatric surgery.

2. All GLP-1 agonists will be stopped 1 weeks before bariatric surgery in line with current recommendations by the American Society of Anesthesiologists.

3. Following bariatric surgery to avoid missing a dose, the dose the patient is currently taken will be continued.

4. In the event the patient develops significant side effects that are intolerable by the patient and outline below, appropriate dose modification will occur

5. Only patients who are taking GLP-1 agonists as part of routine medical care will be included in the study. The current standard of care regarding continuation or cessation of GLP-1 agonists has not been established and is up to individual providers including primary care physicians or specialists prescribing these medications or the surgeon performing the bariatric procedure.

Preoperative and Postoperative Visits

• Routine care: all patients will have preoperative visits required to qualify for weight loss surgery. These visits are part of routine care. At one of the final visits prior to the procedure, routine laboratory studies will be performed. When the patient is able labs will be drawn at the time of routine laboratory studies. The additional labs will be paid for by the study and the routine studies billed to patient/insurance company

• Postoperative visits will be performed as per routine care at 1 week, 1 month, 3 months, 6 months and then annually thereafter. Data from these visits will be used for the research study

• Blood will be drawn at 3 month visit, 6 month visit and annual visits.

Specimen Collection

• Samples will be collected based on the below protocols. Samples including blood, stool, and solid tissue will be collected from all groups. Following collection, samples will be transferred to the laboratory using the labs well established protocol.

• These samples will be stored in the following manner:

• Following sample collection, the samples will be labelled with a deidentified label and sample code entered into a database. A separate database will be maintained by research staff

• Any other clinical data will be kept in a separate database with corresponding code to the pathologic specimen database. This clinical database will be maintained by research staff in the Department of Surgery. REDCap™ is a secure online web-based application that can be used to store clinical information to create a clinical database. REDCap will include a field that corresponds to the code entered into the tissue database maintained by research staff

• Blood collection: at a hospital clinical lab located at University Hospital or affiliated institutions

• For stool collection, the patient will be provided a collection kit to collect the sample. They will be instructed to collect a sample and mail it to the research lab using institution approved methodology.

• For liver specimen collection, electrocautery or ultrasonic dissector will be used to excise a small wedge of liver specimen during the patient's weight loss procedure or other operation.

• For omentum collection, this will be harvested with electrocautery or ultrasonic dissector during the patients' operation.

• For subcutaneous fat, this will be harvested with electrocautery during the patient's operation from a skin incision created for completion of the operation.

• For small bowel, it will be taken only during those operations where bowel is routinely removed and discarded, such as during the gastric bypass.

• Bile will be collected from gallbladder during cholecystectomy or small bowel during gastric bypass. Bile will only be removed from the gallbladder when the patient is undergoing a cholecystectomy. After removal of the gallbladder, 10 cc of bile will be collected for research purposes.

• For stomach removed during sleeve gastrectomy this is removed at the time of the operation. A portion of the stomach will be removed for research specimen and the rest sent as a surgical specimen to the pathology laboratory

Clinical Data Collection

• A prospective clinical database will be maintained with relevant clinical data.

• In order to have relevant clinical data to allow for identification of the specimen and if relevant for planned research the research staff as mentioned above research staff listed on IRB will collect a limited amount of clinical data including name, date of birth, medical record number and procedure performed or medical weight loss as relevant.

• Any additional clinical data will be maintained by research staff within the Department of Surgery using RedCap TM or a spreadsheet located on a HIPAA compliant University of Missouri approved, cloud-based platform.

• The clinical database and specimen codes will be maintained research staff of the Department of Surgery at the University of Missouri School of Medicine where it will be maintained in a secure manner to protect identifiable patient data.

• This database will be deidentified for all HIPAA protected personal health information. This HIPAA protected health information will be kept in a separate database in a separate location that is password protected. It will also be maintained in a cloud-based platform. The two databases will be linked by a code with corresponding code linking the samples kept secure in a cloud-based platform and maintained by research staff

• Only research staff listed on IRB will have access to the key that allows identification of protected health information in the database

• Patients will be unblinded to which group they are in with regards to continuation or discontinuation of a GLP-1 agonist. Surgeons performing the operation will also be unblinded.

All patients will be performed for patients per routine care provided through metabolic and bariatric clinic. Regarding GLP-1 agonist therapy there is currently no standard of care whether to continue or discontinue their use after bariatric surgery.

Data Safety Monitoring Plan

The following additional variables will be included in the prospective database at the following follow-up visits (3 month, 6 months, 12 month, 24 months, 36 months, 48 months, and 60 months follow-up) and used to monitor for complications or adverse events:

1. Diagnosed protein calorie malnutrition

2. Presence of adverse GI side effects

3. Presence of excessive weight loss defined as BMI less than 20

4. Vitamin or micronutrient deficiencies ;

Related Conditions & MeSH terms

• Diabetes Mellitus
• Hypertension
• Metabolic Syndrome
• Morbid Obesity
• Obesity, Morbid
• Obstructive Sleep Apnea of Adult
• Sleep Apnea Syndromes
• Sleep Apnea, Obstructive

• NCT number: NCT06132477
• Study type: Interventional
• Source: University of Missouri-Columbia
• Contact: Lori Wilcox, EdD, MS
• Phone: 573-882-9500
• Email: muresearchirb@missouri.edu
• Status: Recruiting
• Phase: Phase 4
• Start date: February 1, 2024
• Completion date: July 2028