DAY 1: Cardiometabolic Profiles Matter When Selecting Therapies for Metabolic Dysfunction-Associated Steatohepatitis

Clinicians may need to look beyond hepatic fibrosis and consider cardiovascular risk when selecting therapeutic options for people with metabolic dysfunction-associated steatotic liver disease (MASLD) or metabolic dysfunction-associated steatohepatitis (MASH). Considering the cardiometabolic profiles of different therapies is particularly important when managing individuals with dyslipidemia and other cardiovascular risk factors, according to real-world data presented at the 2026 Annual Scientific Meeting of the American College of Gastroenterology (ACG 2026) in Nashville, Tennessee.

Individuals living with MASLD or MASH have an increased risk for subclinical cardiovascular disease and may experience major adverse cardiovascular events (MACE) even before the onset of advanced liver disease [Prikhodko VA et al. Biomedicines 2026;14:909]. Recently-approved therapies for MASH have shown potential to address coexisting cardiometabolic comorbidities, in addition to their effects on hepatic fibrosis. Resmetirom, a liver-targeted selective thyroid hormone receptor-beta (THR-β) agonist approved in March 2024 for patients with MASH and moderate-to-advanced liver fibrosis (stage F2 or F3), has been shown to improve both liver histology and cardiometabolic parameters. Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is frequently prescribed in patients with MASLD or MASH because it addresses core cardiometabolic drivers like obesity and type 2 diabetes in addition to improving liver histology and reducing hepatic fat.

A propensity-matched analysis designed to compare cardiovascular outcomes in adults with MASLD or MASH and hepatic fibrosis treated with either resmetirom or semaglutide showed that resmetirom reduced the risk for MACE (defined as myocardial infarction, ischemic stroke, or all-cause mortality) by 50% compared with semaglutide over 1 year of treatment. The odds of all-cause mortality and heart failure were also significantly lower in patients treated with resmetirom compared with the semaglutide cohort, while the rates of myocardial infarction and atrial fibrillation were similar between the two groups, each including 4,253 patients. Furthermore, the analysis showed that the MACE and mortality reduction benefit was maintained through 2 years of follow-up.

“What’s driving this mortality and heart failure signal without a difference in myocardial infarction suggests that this is not primarily about preventing plaque rupture,” said lead author Jalal Samhoun, MD, an internal medicine resident at Florida Atlantic University in Boca Raton, Florida. “It’s more [likely mediated by] resmetirom’s effects on low-density lipoprotein cholesterol, apolipoprotein B, and triglycerides, along with reduced hepatic inflammation. These benefits emerged within 1 year and persisted through 2 years of follow-up, providing early real-world evidence that resmetirom may confer cardiovascular benefits beyond its established hepatic effects.”

Samhoun noted that semaglutide is not “a passive competitor,” as it has its own proven cardiovascular benefits. “Finding an advantage over an active cardioprotective drug is notable,” he added. Prospective trials with cardiovascular endpoints may provide clarity on the distinct cardiometabolic profiles of patients who are prescribed resmetirom or semaglutide, two agents that target metabolic pathways through entirely different mechanisms.

Clinical trial data presented at ACG 2026 reinforced previous findings that resmetirom can provide critical cardioprotective benefits alongside its primary indication for treating MASH. A meta-analysis including 22 randomized, controlled trials evaluating 38 interventions for biopsy-confirmed MASH showed that resmetirom 100 mg daily achieved greater reductions in low-density lipoprotein cholesterol and triglyceride levels compared with semaglutide 2.4 mg once weekly and other emerging therapies for people with MASH. While, in phase 2 trials, tirzepatide (15 mg once weekly) and pegozafermin (15 mg once weekly) ranked best in terms of histologic improvement of MASH, the findings suggested that resmetirom 100 mg may yield unique benefits when it comes to atherogenic lipid reduction. The analysis also showed that semaglutide achieved a greater weight reduction than other agents, underscoring its metabolic benefits.

“These findings suggest that treatment selection in MASH may increasingly be individualized according to fibrosis burden, metabolic profile, and treatment goals,” said presenting author Muhammad Arsalan, MD, an internal medicine physician at St. Luke’s Hospital in Chesterfield, Missouri, noting that the cardiometabolic profile of a therapeutic option should play a pivotal role in clinical decision-making, alongside histologic efficacy.