Effect of Endoscopic Sleeve Gastroplasty in Patients With Obesity and MASH: A Randomized Controlled Trial

Effect of Endoscopic Sleeve Gastroplasty on Patients With Obesity and Concomitant Metabolic Dysfunction-Associated Steatohepatitis (MASH): A Multicenter, Open-label, Randomized Controlled Trial

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease globally. While weight loss through lifestyle modification is the standard treatment, most patients regain weight limiting ultimate improvement in liver disease. On the other end of the spectrum, bariatric surgery has shown promise in the treatment of MASLD/metabolic dysfunction-associated steatohepatitis (MASH) due to its efficacy in inducing weight loss. Nevertheless, its adoption has been hindered by the perceived invasiveness of surgery.

Over the past decade, endoscopic sleeve gastroplasty (ESG) has gained recognition as a promising minimally-invasive approach to weight loss. The procedure involves utilizing a Food and Drug Administration (FDA)-authorized endoscopic suturing device to reduce the gastric volume by 70%. Studies reveal that ESG is associated with approximately 18.2% weight loss at one year after the procedure, with sustained results for at least 10 years. Nevertheless, the effect of ESG on MASH remains unknown.

In this study, the investigators will compare ESG + lifestyle modification versus lifestyle modification alone in treating histologic MASH. The study will randomize patients to one of two different treatment options: ESG + lifestyle modification or lifestyle modification alone.

The National Institutes of Health, the World Health Organization, and numerous other scientific organizations including the America Medical Association (AMA) recognize obesity as a chronic disease requiring primary therapy. Almost half of United States (U.S.) adults have obesity. The increasing prevalence of obesity in the U.S. has been accompanied by an increasing prevalence in its associated comorbid conditions including hypertension, diabetes, dyslipidemia, coronary heart disease, stroke, sleep apnea, osteoarthritis, gallbladder disease, GERD, and metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH). Obesity is associated with an increased risk of all-cause and cardiovascular mortality and accounts for about 2.5 million preventable deaths annually. The economic consequences of MASH are enormous, with the lifetime cost of care for all patients with MASH projected to be approximately $222 billion as of 2017.

Current treatment options for patients with MASLD/MASH are limited to weight loss via lifestyle modification and more recently, Food and Drug Administration (FDA)-approved medications, such as resmetirom and semaglutide, indicated specifically for patients with MASH and F2-F3 fibrosis. Nevertheless, less than 10% of patients who undergo lifestyle modification experience at least 10% total weight loss (TWL), the threshold required for hepatic fibrosis regression. The available pharmacological approaches for the treatment of obesity increase weight loss by 3% to 9% compared with lifestyle therapy alone, but some can be associated with unfavorable side effects, significant cost, and weight loss achieved by pharmacotherapy is rarely maintained upon withdrawal of the medication. On the other end of the spectrum, bariatric surgery, such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy, has shown promise in the treatment of MASLD/MASH due to its ability to induce significant and durable weight loss of at least 10% TWL. Nevertheless, its adoption has been limited with less than 2% of patients eligible for the surgery choosing to undergo the procedure. This is likely due to the perceived invasiveness of surgery, high costs, and limited access. More importantly, the majority of patients with mild to moderate (class I and class II obesity (BMI 30-40 kg/m2)), who do not qualify for bariatric surgery are left without an effective management, considering the modest effects seen with medications or lifestyle intervention alone and their ability to achieve >10%TWL only in the minority of patients. Yet, according to the global disability-adjusted life-years and deaths study, patients with mild to moderate obesity are the highest contributors to the burden on disease both in terms of co-morbidities and overall mortality. Therefore, both government agencies (the Agency for Healthcare Research and Quality [AHRQ]) and national societies (American Society of Bariatric and Metabolic Surgery [ASMBS], and American Society of Gastrointestinal Endoscopy [ASGE]) now recognize that a significant management gap exists for patients with mild to moderate obesity and have defined safety and efficacy thresholds for adoption of a new treatment category- endoscopic weight loss interventions.

Over the past decades, endoscopic bariatric and metabolic therapies (EBMTs) have been developed to fill the treatment gap for obesity and MASLD/MASH. Specifically, compared to lifestyle modification, EBMTs are associated with greater weight loss with a higher proportion of patients reaching the 10% TWL threshold. Additionally, given its non-surgical, minimally-invasive nature, the safety profile for EBMTs appears more favorable compared to bariatric surgery. To date, there are two EBMT devices and/or procedures that are approved or cleared by the Food and Drug Administration (FDA). These include intragastric balloons (IGBs) and endoscopic sleeve gastroplasty (ESG).

The ESG procedure is an endoscopic minimally-invasive weight loss procedure where a commercially available, FDA-approved, full-thickness endoscopic suturing device (Overstitch; Boston Scientific, Marlborough, MA) is used to reduce the stomach volume by 70% through the creation of a restrictive endoscopic sleeve. This is accomplished by a series of endoluminally placed full-thickness stitches through the gastric wall, extending from the distal gastric body to the proximal gastric body. The investigators currently perform this procedure as a standard of care at Brigham and Women's Hospital (BWH). Our previous studies have demonstrated that ESG not only leads to significant weight loss of at least 10% TWL, but also improves non-invasive tests (NITs) of liver steatosis and fibrosis, as well as MASH histologic features in patients with obesity and concomitant MASH. Nevertheless, it remains unclear if ESG is superior to lifestyle modification alone.

Clinical Data to Date

The feasibility of ESG was first demonstrated in humans in the US in 2013. Since then, the technique has gained wide clinical adoption in the US and worldwide with thousands of cases performed. Multiple single-arm prospective and retrospective studies have demonstrated the safety and minimally invasive nature of the technique and reported %TWL of about 16% to 18% at 12 months. Furthermore, studies have demonstrated physiologic perturbations resulting from creation of the ESG and its association with increased satiation and metabolic effects that are potentially important to control the metabolic dysregulation associated with obesity. In a recent randomized controlled trial including 209 participants, subjects were randomized to either ESG combined with lifestyle modification (n=85) or lifestyle modification alone (n=124). At 12 months, the ESG group achieved significantly greater weight loss of 13.6% TWL, compared to 0.8% in the control group. ESG-related serious adverse events occurred in only 2% of participants, with no instances of mortality, intensive care, or surgery required. While ESG has demonstrated both safety and efficacy for weight loss, no RCTs have yet assessed its impact on obesity-related comorbidities.

Inclusion Criteria:

1. Age ≥ 18 (male or female)
2. BMI ≥30 kg/m2 or ≥27 kg/m2 with at least one obesity-related comorbidity
3. Self-reported stable weight (no weight change >5%) for 6 months prior to the first study visit
4. Willingness to follow protocol requirements, including signed informed consent, routine follow-up schedule, completing laboratory/imaging/additional tests, and completing diet counseling
5. Willingness to NOT start a new anti-obesity medication for the following 12 months
6. Residing within a reasonable distance from the investigator's office and able to travel to the investigator to complete routine follow-up visits
7. Ability to give informed consent
8. Women of childbearing potential (i.e., not post-menopausal, nor surgically sterilized) must agree to use adequate birth control methods

Exclusion Criteria:

1. Known history of other chronic liver diseases (viral hepatitis, autoimmune hepatitis, drug-induced hepatitis, and genetic)
2. Treatment with vitamin E (at doses ≥800 IU/day), pioglitazone, obeticholic acid, or resmetirom <90 days before the first study visit
3. History of foregut or gastrointestinal (GI) surgery (except uncomplicated fundoplication, cholecystectomy or appendectomy)
4. Prior bariatric surgery
5. Prior endoscopic sleeve gastroplasty
6. Any inflammatory disease of the GI tract, including severe (LA Grade C or D) esophagitis, Barrett's esophagus with dysplasia, gastric ulceration, duodenal ulceration, cancer or specific inflammation such as Crohn's disease
7. Potential upper gastrointestinal bleeding conditions such as esophageal or gastric varices, congenital or acquired intestinal telangiectasis, or other congenital anomalies of the gastrointestinal tract such as atresias or stenoses
8. Severe gastroesophageal reflux disease (GERD)
9. A structural abnormality in the esophagus or pharynx, such as a stricture or diverticulum, that could impede passage of the endoscope.
10. Achalasia or any other severe esophageal motility disorder
11. Chronic abdominal pain
12. Gastroparesis or intractable constipation
13. Hepatic insufficiency or cirrhosis
14. Severe coagulopathy
15. Insulin-dependent diabetes (either type 1 or type 2) or a significant likelihood of requiring insulin treatment in the following 12 months or HgbA1C ≥ 12%
16. Patients on an anti-platelet agent, anticoagulant agent or chronic/routine use of NSAIDs
17. Patients on corticosteroids, immunosuppressants, or narcotics
18. Patients on an anti-seizure or anti-arrhythmic medication
19. Patients who are pregnant or breastfeeding
20. Excessive alcohol consumption (>20 g per day for women; >30 g per day for men)
21. Active smoking
22. History of poorly controlled hypertension, coronary artery disease, congestive heart failure, cardiac arrhythmia
23. History of respiratory diseases such as chronic obstructive pulmonary disease (COPD) requiring steroids, pneumonia, or cancer
24. History of autoimmune connective tissue disorder such as lupus, scleroderma or immunocompromised disease
25. History of active malignancy
26. History of genetic or hormonal causes for obesity, such as Prader Willi syndrome
27. History of endocrine disorders affecting weight, such as uncontrolled hypothyroidism
28. Eating disorders, including night eating syndrome, bulimia, binge eating disorder or compulsive overeating
29. Active psychological issues preventing participation in a lifestyle modification program as determined by a psychologist