Resmetirom Tied to Lower MACE vs Semaglutide in Real-World MASLD Analysis

Patients with metabolic dysfunction-associated steatotic liver disease (MASLD) or metabolic dysfunction-associated steatohepatitis (MASH) and hepatic fibrosis who received resmetirom had lower rates of major adverse cardiovascular events (MACE) and all-cause mortality than matched patients receiving semaglutide, according to findings from a real-world analysis presented at the American College of Gastroenterology (ACG) 2026 Annual Scientific Meeting in Nashville, Tennessee.¹

The poster, presented by Jalal Samhoun, MD, Florida Atlantic University, addresses a gap the investigators identified: there are no comparative cardiovascular outcome data between the 2 therapies, even though cardiovascular disease contributes heavily to morbidity and mortality in MASLD and MASH.¹

How Resmetirom and Semaglutide Compare for MASH With Fibrosis

Resmetirom is an oral, liver-directed, thyroid hormone receptor-β agonist. In March 2024, the US Food and Drug Administration (FDA) granted it accelerated approval for noncirrhotic MASH with moderate to advanced fibrosis. It was the first drug approved for the disease. In the phase 3 MAESTRO-NASH trial, MASH resolution without worsening of fibrosis occurred in 25.9% and 29.9% of patients receiving resmetirom 80 mg and 100 mg, respectively, versus 9.7% with placebo. Low-density lipoprotein cholesterol fell by 13.6% and 16.3% at week 24.²

Semaglutide 2.4 mg received accelerated approval for the same population in August 2025 based on part 1 of the phase 3 ESSENCE trial, in which 62.9% of patients receiving semaglutide achieved steatohepatitis resolution without worsening of fibrosis, versus 34.3% with placebo.³ Unlike resmetirom, semaglutide has a dedicated cardiovascular outcome trial. In SELECT, it reduced MACE by 20% versus placebo in adults with established cardiovascular disease and overweight or obesity without diabetes.⁴

TriNetX Study Design and Cardiovascular Outcomes With Resmetirom

Investigators used the TriNetX Global Collaborative Network to identify adults with MASLD or MASH and hepatic fibrosis receiving resmetirom or semaglutide. They performed 1:1 propensity score matching on demographics, cardiovascular risk factors, metabolic comorbidities, liver disease characteristics, medications, and laboratory values.¹

The final cohorts included 4253 patients each. The primary outcome was MACE, defined as myocardial infarction (MI), ischemic stroke, or all-cause mortality. Secondary outcomes were all-cause mortality, MI, atrial fibrillation (AF), and heart failure (HF).¹

At 1 year, resmetirom was associated with lower risks of MACE (hazard ratio [HR], 0.50; 95% CI, 0.32-0.80; P = .003), all-cause mortality (HR, 0.29; 95% CI, 0.16-0.54; P <.001), and HF (HR, 0.64; 95% CI, 0.42-0.99; P = .04). The 2 groups did not differ significantly in MI or AF.¹

At 2 years, the lower risks of MACE (HR, 0.61; 95% CI, 0.41-0.89; P = .01) and all-cause mortality (HR, 0.33; 95% CI, 0.20-0.55; P <.001) persisted. AF showed a nonsignificant trend favoring resmetirom (HR, 0.66; 95% CI, 0.41-1.07; P = .09), and MI rates remained similar.¹

What the Resmetirom Findings Mean and What Remains Unknown

Investigators described the findings as early real-world evidence that resmetirom may confer cardiovascular benefits beyond its established hepatic effects. The lower risks they observed emerged within the first year and persisted through 2 years of follow-up.¹

The analysis is retrospective and drew on electronic health records, so it can show associations but cannot establish causation. Propensity matching accounts only for variables recorded in the database, and residual confounding cannot be excluded. All-cause mortality was included in the MACE composite, while rates of MI did not differ between groups.1 Additionally, semaglutide has shown cardiovascular benefit in a randomized trial, but no randomized cardiovascular outcome data for resmetirom have been published.^2,4

References

1. Samhoun J, et al. Cardiovascular outcomes of resmetirom versus semaglutide in patients with MASLD/MASH: a propensity-matched real-world analysis. Presented at: American College of Gastroenterology 2026 Annual Scientific Meeting; October 9-14, 2026; Nashville, TN.

2. Harrison SA, Bedossa P, Guy CD, et al. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med. 2024;390(6):497-509. doi:10.1056/NEJMoa2309000

3. Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis. N Engl J Med. 2025;392(21):2089-2099. doi:10.1056/NEJMoa2413258

4. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389(24):2221-2232. doi:10.1056/NEJMoa2307563