CHICAGO — Semaglutide emerged superior to resmetirom on multiple measures of cost-effectiveness, including total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios, for treating adults with non-cirrhotic metabolic dysfunction-associated steatohepatitis (MASH) and F2 to F3 fibrosis, a new study showed.

“Because not all of us are economists, one might ask what these economic terms mean,” said study author Sarpong Boateng, MD, MPH, a resident at Yale New Haven Health/Bridgeport Hospital in Bridgeport, Connecticut, who presented the findings at Digestive Disease Week (DDW) 2026.

“These are different ways of answering one simple question: Are we getting enough clinical benefit for our cost?” he explained.

Phase 3 trials have shown that both medications improve fibrosis and steatosis, he added; however, “they differ in their mechanism, cost, and most importantly, extrahepatic benefits, particularly cardiovascular outcomes with semaglutide.”

Cost-Effectiveness Matters

Critical gaps in knowledge remain, said Boateng.

These therapies have been evaluated individually, “but there’s just no direct head-to-head comparison to guide treatment selection between these two high-cost options,” he explained. “And when this happens, it creates uncertainty for clinicians, payers, and policymakers.”

Cost-effectiveness matters because the prevalence of MASH is high. It affected an estimated 350 million people worldwide in 2024 “and is projected to rise substantially in the coming decades,” the researcher explained. In the US, there were more than 30,000 deaths related to MASH in 2020. Furthermore, cases of MASH with F2 or higher stages of fibrosis are expected to increase from 6.7 million in 2020 to 11.7 million by 2050.

“Importantly, MASH is now a leading driver of cirrhosis, HCC [hepatocellular carcinoma], and death, with an estimated $76 billion in direct costs and even higher societal costs. As such, any treatment decision becomes not only clinical but also an economic and population-level decision,” said Boateng.

To learn more, Boateng and his colleagues compared data from the ESSENCE trial for semaglutide with those from the MAESTRO-NASH trial for resmetirom to help guide value-based treatment strategies. They used a model to simulate disease progression across nine health states ranging from fibrosis to cirrhosis, HCC, liver transplantation, and death.

ESSENCE and MAESTRO-NASH featured similar designs and patient populations. Both are phase 3, double-blind, placebo-controlled studies assessing patients with F2 or F3, non-cirrhotic MASH. Patients had similar BMIs around 35 and a similar prevalence of diabetes around 60%.

“The number that matters most is fibrosis improvement; it was around 26% for both,” Boateng reported.

Key Findings

Multiple economic metrics in the study favored semaglutide over resmetirom. For instance, the incremental cost-effectiveness ratio at 10 years for semaglutide vs resmetirom was around $44,000 vs more than $100,000. Semaglutide also emerged superior on net monetary benefit, which assesses health outcomes by combining effectiveness and cost at a specific willingness-to-pay threshold.

“We see that at low willingness-to-pay thresholds, semaglutide quickly becomes the most cost-effective option and rapidly approaches 100%,” Boateng said. Measures of QALYs also favored semaglutide over resmetirom in the study.

In terms of clinical outcomes, both therapies reduced cirrhosis, HCC, and mortality. “But semaglutide offered the best balance of cost, liver outcomes, and cardiovascular benefits,” he said. “This shows that efficacy alone is not enough, but value also matters.”

Limitations of the study included using data from clinical trials, which may not reflect real-world adherence or outcomes, Boateng said. “However, the findings remained robust across several sensitivity analyses, which gives us an assurance that our study findings are likely valid.”

“Semaglutide is the most cost-effective strategy for treating non-cirrhotic MASH with moderate-to-advanced fibrosis,” he told meeting attendees. “The value improves even further with cardiovascular benefits, and then it supports semaglutide as first-line therapy for F2 to F3 fibrotic MASH.”

Cardiovascular Effects of Resmetirom?

During the Q&A, session co-moderator Mazen Noureddin, MD, a hepatologist at Houston Methodist Hospital in Houston, said one big issue was concluding that cardiovascular outcomes with semaglutide are superior to resmetirom.

“You took a very large cardiovascular study for semaglutide [the SELECT study] and used it as positive evidence. But you presume that resmetirom has no cardiovascular events, and I’m not claiming it does, but there are no trials yet on that,” he said.

Boateng agreed that a future study should evaluate cardiovascular outcomes for resmetirom. “But I must say that even after taking away the cardiovascular benefits, semaglutide still outperforms.”

Asked to comment, session co-moderator Cynthia A. Moylan, MD, a gastroenterologist and assistant professor of medicine at Duke University School of Medicine and chief of hepatology at the Durham Veterans Affairs Medical Center in Durham, North Carolina, critiqued the study for relying on clinical trial data.

“If you’re using these phase 3 trials, it’s hard to kind of expand what the populations would be in the real world.” She added, however, that the cost-effectiveness findings make sense because semaglutide is a less expensive treatment.

GLP-1s vs SGLT2s in MASLD

In another study presented during the same session at the meeting, investigators compared long-term outcomes between people initiating a GLP-1 receptor agonist or an SGLT2 inhibitor after diagnosis with metabolic-associated steatotic liver disease (MASLD). The study included 90,030 people in each treatment group identified from the TriNetX Global Collaborative Network. 

At 1 year, GLP-1s were associated with significantly lower all-cause mortality compared with SGLT2 inhibitors (1.36% vs 2.13%; relative risk [RR], 0.69; 95% CI, 0.62-0.77; P < .001). Similar benefits were observed for all-cause mortality at 3 years (4.11% vs. 4.76%; RR, 0.76; 95 % CI, 0.71-0.82; P < .001).

The cirrhosis risk was similar at 1 year (RR, 1.01; 95% CI, 0.88-1.16; P = .92) and at 3 years (RR, 1.02; 95% CI, 0.92-1.13; P = .75); and the risks of hepatocellular carcinoma risk were also comparable at 1 year (RR, 0.96; 95% CI, 0.69-1.33; P = .80) and at 3 years (RR, 0.98; 95% CI, 0.77-1.24; P = .86).

Furthermore, GLP-1s were linked to lower ascites at 1 year (RR, 0.76; 95% CI, 0.65-0.89; P = .001) and at 3 years (RR, 0.84; 95% CI, 0.75-0.94; P = .002), as well as lower emergency hospitalizations at 1 year (RR, 0.92; 95% CI, 0.89-0.95; P < .001) and at 3 years (RR, 0.96; 95% CI, 0.94-0.98; P < .001).

“GLP-1s help promote weight loss, improve insulin resistance, and reduce hepatic and adipose inflammation,” said Asifa Manzoor, MBBS, internal medicine resident at Aiken Regional Medical Centers, in Aiken, South Carolina. “These effects may reduce the physiologic stress that triggers ascites and acute hospitalization.” 

“Our study does not say that SGLT2 inhibitors are a weak comparator,” Manzoor emphasized. “SGLT2s already have known benefits in reduction of cardiometabolic risk, hepatic steatosis, and fibrosis markers.”

Moylan praised the researchers for comparing high numbers of people with MASLD; however, she noted that the study is retrospective and based on International Classification of Diseases codes, which limits some of the data that could be included in the study. 

“It’s food for thought,” she added. 

The study was independently supported. Boateng reported having no relevant financial relationships. Noureddin disclosed he is a scientific/medical advisory board member: Akero, Aligos, Altimmune, AstraZeneca, Boehringer Ingelheim (BI), Boston Pharma, Curve Biosciences, CytoDyn, GSK, Histoindex, Lilly, Madrigal, Merck, Novo Nordisk, Rivus, Sagimet, Takeda, and Terns; research grant site principal investigator: Allergan, Altimmune, Akero, BI, Bristol Myers Squibb, Boston Pharma, Conatus, Corcept, Enanta, Galectin, Genfit, Gilead, GSK, Kowa, Lilly, Madrigal, Merck, Novartis, Novo Nordisk, Rivus, Shire, Takeda, Terns, Viking, and Zydus; private stock shareholder: Akero, Kriya, OPKO, and Rivus; and speakers bureau: Madrigal and Novo Nordisk. Moylan disclosed being a research grant site principal investigator for Exact Sciences, GSK, and Madrigal; scientific/medical advisory board member for BI; and a consultant for Novo Nordisk. Manzoor had no relevant financial disclosures.

Damian McNamara is a freelance contributor to Medscape Medical News. He worked full-time for Medscape and WebMD from 2018 to 2024. Damian has a BA in chemistry and an MA in science, health and environmental reporting/journalism.