Effect of Endoscopic Sleeve Gastroplasty in Patients With Obesity and MASH: A 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, and metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH). 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 lifestyle modification and the more recent Food and Drug Administration (FDA)-approved medication called resmetirom. Nevertheless, less than 10% of patients who undergo lifestyle modification experience at least 10% total weight loss (TWL), the threshold required for fibrosis regression. 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 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 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 sutures 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, 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.

Eligibility Criteria:
Inclusion Criteria:

1. 18 years or older
2. Obesity with a body mass index of 30-50 kg/m2
3. A diagnosis of MASH with stage 1 (F1), 2 (F2), or 3 (F3) fibrosis (on a scale of 0 \[no fibrosis\] to 4 \[cirrhosis\]). MASH is defined as the nonalcoholic fatty liver disease activity score (NAS) of 4 or higher, with a score of 1 or higher for each subcomponent: steatosis, hepatocyte ballooning and lobular inflammation). Grading and staging of biopsies for the purposes of enrollment are done by a liver pathologist at the site of enrollment.

Exclusion Criteria:

1. cirrhosis
2. excessive alcohol consumption (\>20 g per day for women; \>30 g per day for men)
3. active smoking
4. active malignancy
5. being on an anticoagulant or anti-platelet medication
6. being on a glucagon-like peptide-1 receptor agonist (GLP-1RA) or sodium-glucose cotransporter-2 (SGLT2) inhibitor of any dose
7. being initiated on an anti-obesity medication within 6 months prior to study enrollment or 12 months after study enrollment
8. history of bariatric surgery or bariatric endoscopy
9. changes in weight by greater than 5% within 6 months of study enrollment
10. hemoglobin A1c (HbA1c) ≥10%