Preoperative Glucagon-like Peptide-1 Therapy in Bariatric Surgery Patients With Morbid Obesity (PreMO): Rationale and Study Design for a Randomized Controlled Trial

Abstract

Introduction:

Bariatric surgery is the most effective treatment modality for individuals with morbid obesity, providing significant and durable weight loss and comorbidity resolution. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide receptor agonists have shown promise as weight loss drugs, in addition to their use in the treatment of metabolic disorders. While multimodal weight management is the standard of care for individuals with morbid obesity, the benefit of antecedent GLP-1 therapy prior to bariatric surgery has not been well-studied. The objective of this study is to conduct a clinical trial testing the hypothesis that preoperative treatment with a dual GLP-1/glucose-dependent insulinotropic polypeptide receptor agonist enhances preoperative weight loss and decreases tissue inflammation, resulting in improved postoperative outcomes.

Materials and methods:

We designed a randomized controlled trial (RCT) comparing preoperative treatment with tirzepatide versus standard medical care prior to minimally invasive bariatric surgery with a target enrollment of 50 patients randomized 1:1. For 3 mo preoperatively, the control arm will receive standard care in the form of dietary and lifestyle modification recommendations, whereas the treatment arm will receive weekly tirzepatide, in addition to standard care. Blood will be collected at enrollment through 12-mo postoperatively and analyzed for inflammatory and metabolic markers. Tissues (adipose, stomach, and liver) will be collected intraoperatively for transcriptome profiling and histological assessment.

Results:

This is an ongoing trial with no reportable results.

Conclusion:

Completion of this pilot RCT will provide data to support initiation of a multi-center RCT to determine therapeutic efficacy, and mechanisms of action, by which patients could benefit from preoperative treatment with tirzepatide.

Introduction

Obesity is defined by the World Health Organization as a chronic disease characterized by excessive fat deposits that can negatively affect health.¹ Currently, 43% of adults world-wide are overweight and 16% have obesity, more than doubling since 1990.¹ In the United States, the prevalence of obesity among adults is 41.9%.² Kentucky ranks second highest in the United States for obesity prevalence and has consistently ranked in the top 10 for the past 8 y.³

Chronic weight management strategies have traditionally included lifestyle changes combined with either pharmaco-therapy or metabolic and bariatric surgery (MBS). Common effective MBS procedures include gastric bypass (GBP), sleeve gastrectomy (SG), and biliopancreatic diversion. In head-to-head comparisons, randomized controlled trial (RCT) data have shown the superiority of MBS over lifestyle interventions or pharmacotherapy for weight loss, metabolic outcomes, and treatment of nonalcoholic steatohepatitis.^4–14 Observational studies have likewise shown that a modest degree of weight loss, achieved with diet/lifestyle changes before MBS may have clinically significant benefits including greater post-operative weight loss,^15,16 and reduced perioperative complication and mortality rates.¹⁷ On the other hand, some studies report no correlation between preoperative weight loss and outcomes after bariatric surgery.^18,19 Many comprehensive and multidisciplinary bariatric surgery programs consider preoperative weight loss a pre-requisite for surgery; however, it has not become standardized practice due to variability in patient responses.

Recently glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) as well as dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) RAs have revolutionized weight management strategies.^20–22 The SURMOUNT-1 study, a phase three double blind RCT involving over 2500 patients, examined the effects of three different doses of dual GLP-1/GIP therapeutic agent, tirzepatide (Mounjaro).²³ Average weight reduction, compared to placebo, ranged from 16 to 22% total body weight after 72 wk of treatment. The results of this trial showed greater mean weight loss than the 15% weight reduction seen with semaglutide (Ozempic) over 68 wk in the STEP-1 study.²⁴ One of the major concerns with medical weight management revolves around the durability of weight loss. There is limited but strong evidence from at least three RCTs showing significant weight regain after initial loss, following discontinuation of GLP-1 RA therapy.^14,25,26 The STEP-1 extension study showed that participants regained two-thirds of their weight lost within 1 y of stopping a 68-wk treatment regimen with semaglutide.²⁵ Combining GLP-1/GIP pharmacotherapy with MBS has potential to provide a benefit to patients, especially those with morbid obesity. However, prospective trials combining weight loss drugs and surgery are lacking. Existing studies are mostly retrospective in nature with no treatment standardization and a focus on weight loss alone.^27,28 GLP and GIP are thought to act on multiple tissues and cells through their independent receptors with potential effects far beyond weight loss.²⁹ To our knowledge, there are no studies that have prospectively evaluated the impact of preoperative treatment with dual GLP-1/GIP RA medication on tissue level inflammation or metabolic outcomes, in addition to weight loss, in patients undergoing MBS.

GLP-1 receptor signaling exerts broad anti-inflammatory actions across multiple organ systems, including adipose tissue, liver, kidney, intestine, vasculature, and the brain.^30,31 GLP-1 receptor activation reduces proinflammatory cytokine production, shifts macrophages toward a more anti-inflammatory phenotype, and attenuates NF-κB—mediated inflammatory pathways. These anti-inflammatory effects complement the more well-known metabolic actions of GLP-1—based therapy and can occur independently. For example, a single dose of exenatide or semaglutide was found to reduce tumor necrosis factor alpha (TNFα) and interleukin 1-beta levels in rodent models of inflammation and in human peripheral blood mononuclear cells from treated patients.^32–34 Further, a 2021 systematic review and meta-analysis of 40 RCTs, reported that therapy with GLP-1RAs compared to standard diabetes treatments or placebo was associated with significant reductions in serum C-reactive protein (CRP), TNFα and malondialdehyde, and a significant increase in adiponectin, providing clinical support for the anti-inflammatory role of GLP-1 RAs.³⁵

We have initiated an RCT to test the effects of preoperative tirzepatide treatment on tissue-level inflammation and evaluate the association of these changes with postoperative improvements in weight loss, inflammation, and cardiovascular and metabolic outcomes after bariatric surgery. We hypothesize that participants on tirzepatide preoperatively will have a decrease in inflammatory markers and improved overall weight loss and metabolic outcomes after MBS compared to those not antecedently treated with the study drug. The outcome of this study could impact therapeutic guidelines for the multimodal treatment of obesity.

Study Design

We initiated an RCT at the University of Kentucky (UK) with plans to recruit 50 adult patients who have enrolled in the multidisciplinary MBS program at the UK HealthCare Weight Loss Surgery Clinic and are candidates to undergo laparoscopic or robotic SG, or gastric bypass surgery (either primary or conversion of SG to GBP for weight recurrence). Our enrollment goal is based mostly on feasibility, although a power analysis was performed by the study statistician (G. S. H.) using nQuery 9.3.1 (Statistical Solutions Ltd.; Cork, Ireland). Using a two-sided significance level of 0.05, we estimated that a sample size of 20 competing participants in each group would yield 80% power to detect between-group differences of at least 0.91 standard deviations in quantitative outcomes. Although this represents a relatively large effect size, the pilot nature of this RCT prioritizes feasibility in preparation for the initiation of a higher-powered multicenter RCT in the future. Five patients per group were added to account for potential withdrawals, differences in drug and procedure being tested, and the single-center nature of the study, arriving at 25 patients per treatment group for a total of 50 planned enrollments. Detailed Inclusion and Exclusion criteria are listed in Table 1. This ongoing trial is registered at clinicaltrials.gov (NCT06721507, https://clinicaltrials.gov/study/NCT06721507 , date of registration: March 12, 2024). The proposed dates of enrollment are March 2025 through March 2027, or until full recruitment is achieved. All potential participants identified using approved recruitment methods will complete an informed consent process prior to enrollment in the study (UK Institutional Review Board protocol #97933).

Table 1 –

Study inclusion and exclusion criteria.

Inclusion criteria

Adults (age greater than or equal to 18 y)

Must be enrolled in the multidisciplinary metabolic and bariatric surgery program at the UKHC weight loss surgery clinic

BMI ≥40 kg/m2 with one or more obesity-related comorbidities

Demonstrated abstinence from any form of nicotine use, confirmed by serum nicotine and metabolite testing

Expressed preference and are deemed a suitable candidate for laparoscopic or robotic vertical sleeve gastrectomy, or gastric bypass

Enrollment in the ADORE bariatric tissue bank

Exclusion criteria

Any contraindication to the use of tirzepatide (per package insert)

1 Personal or family history of medullary thyroid carcinoma.

2 Patients with multiple endocrine neoplasm syndrome type 2.

3 Hypersensitivity to tirzepatide.

4 History of pancreatitis.

5 Type 1 diabetes.

6 Patients with active, untreated, or symptomatic cholelithiasis or jaundice.

Current use of a GLP-1 or GLP-1/GIP receptor agonist, or consistent use within past 90 d

Diagnosed autoimmune disease

Current use of immunosuppressive agents or use within the past 30 d

Moderate or severe substance use disorder according to DSM-5 criteria

Uncontrolled significant psychiatric disorder as assessed by specialized bariatric psychologist

Female participant who is pregnant, breast-feeding, or intends to become pregnant with in 1 y following surgery

Prisoners

ADORE = Alliance for Diabetes Research; BMI = body mass index; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; GIP = glucose-dependent insulinotropic polypeptide; GLP-1 = glucagon-like peptide-1; UKHC = University of Kentucky HealthCare.

The study workflow is depicted in Figure. Participants will be randomized to receive standard of care (SOC) alone or SOC with preoperative tirzepatide treatment for 3 mo prior to surgery. The statistician (G. S. H.) will perform the randomization for each patient adaptively, using a Microsoft Excel macro-based scheme designed to prioritize the balance of age, body mass index, and diabetes in each group, while still retaining a sizable element of randomness for each patient’s assignment. The study team will not be blinded to assigned arm, given the lack of placebo control in this pilot trial. SOC consists of consultation with the multidisciplinary MBS team and surgeon, bariatric clinic nursing staff, registered dietician, and a certified behavioral health provider. Patients attend a group nutrition class where in-depth education and counseling regarding dietary and lifestyle modification is provided. Study subjects are then seen for monthly visits to assess progress and compliance with dietary and lifestyle modifications before surgery can be scheduled. Study subjects randomized to receive 3 mo of tirzepatide treatment will be seen in the UK HealthCare Endocrinology Clinic to undergo education and counseling regarding self-injection of the medication as well as side effect monitoring. Participants will self-administer weekly injections of tirzepatide subcutaneously and undergo monthly visits in the Endocrinology Clinic to assess for tolerance and monthly dose escalation per clinical guidelines and provider assessment. Monthly visits will be coordinated with the monthly MBS SOC clinic visits.

Fig.

— Study workflow: Collaborative study workflow between UKHC Weight Loss Surgery Clinic, UKHC Endocrine Clinic, ADORE Bariatric Tissue Bank, and basic science research labs at University of Kentucky College of Medicine.

For all enrolled participants, blood will be collected at enrollment (baseline), at the end of study drug treatment (~3months later for both arms), and during the postoperative period (1, 6, and 12 mo). Blood will be processed to obtain plasma, serum, and PMBCs which will be cryopreserved for future use. The surgical procedure will be minimally invasive (laparoscopic or robotic) performed by one of three surgeons, and sleeve size is calibrated around either a 40 or 56 French bougie based on individual surgeon’s established technique. Oversewing of the staple line and omentopexy is performed by two out of the three surgeons. We partnered with the Alliance for Diabetes and Obesity Research Bariatric Tissue Project (UK IRB #69767) to collect tissue samples intra-operatively. This biorepository functions as an important research resource for investigators focusing on diabetes and/or obesity by providing abdominal tissues collected intra-operatively including subcutaneous and visceral adipose tissue, liver, and stomach which are harvested by the surgeon or collected from histopathological specimens. Tissues are collected as follows. A core needle liver biopsy is obtained using a soft core automatic biopsy gun under direct laparoscopic visualization followed by hemostasis using electrocautery, a wedge omental fat biopsy is obtained using advanced bipolar energy device, and a subcutaneous fat biopsy is obtained using electrocautery to excise a 1-2 cm wide and 3-5 mm thick disc of tissue from one of the larger trocar site incisions. These specimens are collected fresh from the operating room, processed to a size for storing in 2 mL cryovials, preserved on dry ice, and stored in an ultra-low temperature freezer at − 80°C. At the time of SG, a small portion of the excised partial gastrectomy specimen and, based on operative technique variations, occasionally a small specimen of gastric pouch or small intestine at the time of GBP are collected and sent to the clinical pathology lab. From there, a clinical pathologist will provide discarded specimens to the study team which are preserved in 10% formalin or frozen on dry ice. Collectively, these samples (blood and tissue) will be used to assess changes in inflammatory and metabolic health markers. Proposed blood tests are centered around inflammatory biomarkers or molecules which modulate inflammation, metabolism, and energy balance. CRP, interleukin-6, and TNFα are common inflammatory biomarkers which are positively associated with obesity and have been used to assess inflammation in prior studies for both GLP-1 therapy and bariatric surgery.^35–42 Adiponectin and leptin are fat-derived hormones frequently used to assess metabolic health.^40–44 The renin-angiotensin-aldosterone system is a hormonal system with multiple components whose alterations are linked to inflammation and energy balance.^45–47 The effects of tirzepatide therapy on changes at the tissue level will be characterized by histological assessment of H&E-stained tissue sections and gene expression profiling using bulk RNA sequencing. The collective tissue-level and systemic inflammatory profiles will be analyzed for association with postoperative clinical and metabolic outcomes (Table 2). All lab analysis will be performed in blinded fashion with deidentified samples.

Table 2 –

Planned data points.

Patient characteristics*	Standard of care blood tests†
Age	CBC w/differential
Sex	CMP
Ethnicity	Lipid profile
Height	Prealbumin
Weight	Hemoglobin A1c
Body mass index	TSH
Body composition (fat and muscle mass)	Free T4
	iPTH
Blood pressure
Comorbidities
Blood tests and samples for research†	Tissues banked during surgery
PBMCs isolated from blood	Visceral adipose tissue
Insulin	Subcutaneous adipose tissue
CRP	Liver
IL-6	Stomach
TNFα
Leptin
Adiponectin
Calcitonin
RAAS profile
Postoperative data‡
30-d postoperative	Comorbidity improvement
complications §	Blood pressure
Death	Hemoglobin A1c
Surgical site infection	Plasma triglycerides
Anastomotic/staple line leak	Need for T2D medications
Venous thromboembolism
Anastomotic/staple line bleeding
Emergency department visit

CBC = complete blood count; CMP = comprehensive metabolic panel; CRP = C-reactive protein; IL-6 = interleukin-6; iPTH = intact parathyroid hormone; PBMC = peripheral blood mononuclear cell; RAAS = renin-angiotensin-aldosterone system; T2D = type 2 diabetes; T4 = thyroxine 4; TNF = tumor necrosis factor; TSH = thyroid-stimulating hormone.

^*Obtained at each bariatric clinic visit.

^†Obtained at baseline (enrollment), after 3 mo on study drug (preoperative), 1, 6, and 12 mo postoperatively.

^‡Obtained at each postoperative bariatric clinic visit up to 12 mo.

^§Based on Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) criteria.

We will collect data on surgical outcomes, weight loss, and metabolic outcomes (improvement of hypertension, glycemic control, dyslipidemia, and need for type 2 diabetes medications). Patients will be seen back in the MBS clinic at 2 wk, 1-, 3-, 6- and 12-mo post operatively at which time they will undergo anthropometric measurements including body composition analysis.

Analysis Plan

The primary outcome will be post-tirzepatide tissue and circulating inflammatory markers at the time of surgery, and their relationship with postoperative metabolic and inflammatory profiles. Secondary outcomes will include clinical/surgical outcomes, including percent excess weight loss, comorbidity improvement/resolution, and 30-d surgical complications. Differences between treated and nontreated patients will be assessed using linear and logistic mixed models (for continuous or binary outcomes with repeated measurements per patient) or using two-sample t-tests and chi-square or Fisher’s exact tests (for continuous or categorical outcomes with single measurements per patient). All model assumptions, including normality, will be assessed using a combination of visual plots and formal testing. Likelihood ratio testing and Akaike Information Criterion will be used to select an appropriate covariance structure for each mixed model, and a Kenward—Roger adjustment will be used to correct for negative bias in the standard error and degrees of freedom calculations in these models. Across all analyses, a statistical significance level of α = 0.05 will be used. Given the low enrollment goal for this pilot trial, including patients in the treatment arm that do not actually complete the treatment could significantly skew results. Thus, the primary analysis will be performed per-protocol; patients who do not move forward with the surgery or do not complete the medication protocol will be withdrawn. Intention-to-treat analysis will only be performed as a sensitivity analysis.

Limitations

This trial is centered on a single academic medical center experience and is not generalizable to larger groups or more diverse patient populations. Additionally, our design is limited to a 3-mo treatment window prior to MBS. Longer duration and reinstatement of use postoperatively may improve long-term outcomes. Finally, our pilot RCT is limited to 50 participants.

Conclusions/Anticipated Outcomes

There is an increased focus on multimodal management for obesity. Injectable GLP-1 RAs have become popular in recent years as they accomplish weight loss with ease of use and result in improvement of metabolic and cardiovascular parameters. With medications alone, long-term efficacy, affordability and sustained metabolic benefit especially for higher BMI patients remain questionable as long-term data are lacking. For severe obesity, MBS remains the most effective and durable independent treatment modality with a high safety profile. This study seeks to test the hypothesis that incorporating preoperative GLP-1/GIP RA as a neo-adjuvant therapy might improve perioperative surgical, metabolic, and weight loss outcomes. There is abundant literature on the role of GLP-1 RAs in reducing circulating inflammatory mediators^30,33,48,49; however, their effect on tissue-level inflammation in humans has not been studied due to inaccessibility of tissue samples. This study capitalizes on the opportunity to collect tissue samples intraoperatively in a unique surgical population that is also eligible for GLP1 therapy. Limited data at the tissue-level, along with lack of clinical outcome data on concurrent use of injectable GLP-1 RAs with MBS highlight the novelty of this study. We expect that treatment with tirzepatide in a multidisciplinary setting with close clinical monitoring, nutritional support, and lifestyle changes will result in additional preoperative weight loss, improved fatty liver changes, and reduced systemic and tissue level inflammation which will result in reduced surgical complications, increased overall weight loss, and improved cardiovascular and metabolic outcomes.

Future Directions

Pending analyses of preliminary data from this pilot RCT, we aim to develop a larger multicenter RCT encompassing a broader patient cohort undergoing primary MBS to gain further insight into which patients would benefit from preoperative treatment with tirzepatide and most appropriate treatment duration. Whether certain patients would further benefit from postoperative GLP-1 therapy is another question of interest to follow-up in subsequent trials.

Data Availability

Due to the nature of the study, participants were assured that raw data would remain confidential. Deidentified data will be shared on clinicaltrials.gov.