Comparative effectiveness of pharmacotherapies and bariatric surgery for metabolic dysfunction associated steateohepatitis

The National Institute of Diabetes and Digestive and Kidney Diseases awarded the Seattle Institute for Biomedical and Clinical Research $272,400 on September 1, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to execute target trial emulation studies comparing the effectiveness of pharmacotherapies and bariatric surgery for metabolic dysfunction associated steatohepatitis (MASH).

The award funds high-quality observational studies using the National VA EHR supplemented by CMS-Medicare and community care data to determine whether semaglutide and tirzepatide reduce the risk of major adverse liver outcomes (MALOS)—including cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, and liver transplantation—in patients with MASH and stage 2–4 fibrosis. The research will evaluate these GLP-1 receptor agonists against other antihyperglycemic agents and compare their effectiveness to bariatric surgery. Secondary outcomes include major adverse cardiovascular events (MACE). The studies target patients with MASH in the setting of type 2 diabetes or obesity.

Performance of work occurs in Seattle, Washington, with a period of performance through May 31, 2030. This is a project grant, a form of research assistance funding focused on discrete investigative effort.

Abstract

Metabolic dysfunction associated steatohepatitis (mash) is projected to become the most common cause of cirrhosis, decompensated cirrhosis and hepatocellular carcinoma in the world. Two pharmacotherapies have received accelerated U.S. Food and drug administration (FDA) approvals for the treatment of adults with mash and stage 2-3 fibrosis based on randomized controlled trials (rcts) demonstrating reduction in hepatic fibrosis after 12-18 months of treatment. Resmetirom (rezdiffra), a liver-directed thyroid hormone receptor beta (thrβ) agonist, was approved in march 2024 and semaglutide (wegovy), a GLP-1 receptor agonist, in august 2025. Tirzepatide, a dual GLP-1/GIP receptor agonist, was shown in phase 2 rcts to reduce fibrosis, but has not been tested yet in phase 3 rcts. To date, no pharmacotherapies have been demonstrated in rcts to reduce major adverse liver outcomes (malos) in patients with mash, which include cirrhosis, decompensated cirrhosis, hepatocellular carcinoma and liver transplantation. Target trial emulation (TTE) involves specifying the critical elements of the study design of an RCT and explicitly attempting to emulate each of these elements in an observational dataset. Our overall objective is to execute high-quality ttes using the national VA EHR, supplemented by CMS-medicare and community care data, to determine the effectiveness of semaglutide and tirzepatide in reducing the risk of malos as the primary outcome and mace as the secondary outcome in patients with mash, in the setting of T2D or obesity, under the following specific aims: SA1. In patients with mash and stage 2-4 fibrosis, determine the comparative effectiveness of semaglutide in reducing the risk of malo (primary outcome) and mace (secondary outcome) compared to (a) other antihyperglycemic agents (SGLT2I, pparγ agonists and DPP-4I) in patients with T2D, (b) other weight loss medications (phentermine-topiramate, naltrexone-bupropion) in patients with obesity without T2D, and (c) bariatric surgery in patients with obesity (with or without T2D). SA2. In patients with mash, stage 2-4 fibrosis, determine the comparative effectiveness of tirzepatide in reducing the risk of malo (primary outcome) and mace (secondary outcome) compared to (a) other antihyperglycemic agents (semaglutide, SGLT2I, pparγ agonists and DPP-4I) in patients with T2D, and (b) bariatric surgery in patients with obesity (with or without T2D). Exploratory aim. If a sufficient number of resmetirom initiations accrue, we will determine the comparative effectiveness of resmetirom in mash with stage 2-3 fibrosis versus other medications (tirzepatide, semaglutide, SGLT2I, pparγ agonists and DPP-4I) against malo (primary outcome) and mace (secondary outcome). Subgroups: in both SAS, we will explore if the comparative effectiveness varies in clinically meaningful subgroups according to: a. Cirrhosis; b. BMI; c. Age; d. HBA1C%; e. Concomitant use of glucose-lowering medications; f. SEX; g. Genetic polymorphisms in 3 masld-related genes (PNPLA3, TM6SF2 and MBOAT7).