Vertical Sleeve Gastrectomy for Treatment of NASH: a pilot randomized control

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Abstract Nonalcoholic fatty liver disease (NAFLD) is a chronic liver condition that impacts 83 million Americans and is characterized by fat (steatosis) of the liver. Twenty-five percent of individuals with NAFLD also have associated liver cell inflammation and cell damage in a condition known as nonalcoholic steatohepatitis (NASH). Particularly in the presence of type 2 diabetes (T2DM), NASH leads to liver fibrosis, cirrhosis, the need for liver transplant, and an increase in mortality. There are no approved medications to treat NASH but its strong association with obesity supports prioritization of weight loss as therapy. Lifestyle interventions (LI) that produce weight loss, especially when close to 10% total body weight loss, can reduce the core components of NASH and fibrosis. There are significant challenges with adherence to LI programs outside of the research setting, highlighting the need for alternative therapies. The most common weight loss surgical procedure, the vertical sleeve gastrectomy (VSG), reliably achieves 20% total body weight loss. The VSG not only offers significant durable weight loss but also impacts the microbiome and metabolic regulators such as bile acids that can influence the progression of NASH. Single-site uncontrolled studies using the liver biopsy to evaluate NASH demonstrate improvement in both NASH and fibrosis. However, there is no level 1 evidence to recommend the use of bariatric surgery for NASH. Controlled studies are essential as significant NASH and fibrosis improvement have been observed in the placebo arms of pharmaceutical trials. From a definitive trial of VSG compared to LI, we will gain important information on the safety and medium-term effect on NASH and fibrosis improvements as well as longer term reduction in clinically meaningful events such as cirrhosis and mortality. We will also learn who will respond to the VSG and what biomarkers might be prioritized to predict VSG or LI outcomes to support personalized approaches for NASH therapy. At present, there is no therapy known to improve clinical outcomes in patients with T2DM and NASH. Before a trial of this nature can be initiated, we plan to initiate a 12 month pilot and feasibility randomized controlled trial (RCT) of VSG versus LI for treatment of NASH in patients with prediabetes or T2DM with 3 aims to (1) Determine the relative effectiveness of VSG on histologic improvements of the components NASH (steatosis, inflammation, cellular damage, and fibrosis) to inform sample size calculations for a definitive trial. (2) Demonstrate that we can recruit briskly, ensure protocol adherence, and retain participants who will undergo 12-month liver biopsies. (3) Demonstrate that we can reliably collect and analyze potential biomarker samples, prioritizing the microbiome, to predict and correlate with histologic outcomes. We leverage two sites with diverse populations in order to increase generalizability of our findings. This proposal of an explanatory therapeutic pilot RCT in response to PAS-20-160 will provide the information needed for a large-scale hypothesis-driven RCT of VSG for the definitive management of NASH and T2DM.