Rezdiffra Reduces Cardiovascular, Liver-Related Risk Markers in MASH

In March 2024, the FDA approved Rezdiffra (resmetirom) for the treatment of adults with metabolic dysfunction-associated steatohepatitis (MASH) with moderate-to-advanced liver scarring (fibrosis), to be used along with diet and exercise—marking the first pharmacologic therapy available for this indication. Now, a new analysis shows that the drug reduces cardiovascular and liver-related markers in MASH.^1,2

“New analyses from the Phase 3 MAESTRO program and a growing body of real-world evidence reinforce Rezdiffra’s position as the foundational therapy for MASH,” David Soergel, MD, chief medical officer of Madrigalm, said in the news release.² “The data we are presenting at the EASL Congress give us new insight into Rezdiffra’s potential to reduce clinically significant portal hypertension risk in patients with well-compensated MASH cirrhosis, a population with no approved therapies.”

Resmetirom for MASH

The FDA estimated that approximately 6 to 8 million people in the US have MASH with moderate to advanced liver scarring, with that number expected to increase. The condition can progress to cirrhosis, liver failure, liver cancer, and the need for transplantation. MASH is the leading cause of liver transplantation in women and the second leading cause of all liver transplantation in the US.¹

Resmetirom is a once daily, oral, liver-directed thyroid hormone receptor (THR)-β agonist designed to address key underlying causes of MASH. As a partial activator of the THR, the drug reduces liver fat accumulation. Dosing is weight-based, including patients weighing 100 kilograms (kg) or more receiving 100 mg once daily and those weighing less than 100 kg receiving 80 mg once daily.³

The FDA approved resmetirom under its accelerated approval pathway based on a surrogate endpoint—the extent of liver inflammation and scarring at 12 months—in a 54-month, randomized, double-blind, placebo-controlled trial. At month 12, 26% to 27% of patients receiving 80 mg and 24% to 36% receiving 100 mg achieved MASH resolution with no worsening of liver scarring, compared with 9% to 13% of placebo recipients. A confirmatory 54-month outcomes trial remains ongoing.¹

Cardiovascular and Liver Risk Markers

Two years after approval, a growing body of clinical and real-world evidence was presented at the European Association for the Study of the Liver Congress 2026, held May 27 to 30 in Barcelona, Spain, spanning eight poster presentations.²

A secondary analysis of the phase 3 MAESTRO-NASH and MAESTRO-NAFLD-1 trials examined resmetirom's effects on atherogenic lipids and lipoproteins in patients stratified by baseline statin use. Among statin-treated patients (n = 473) receiving resmetirom 100 mg, 44.4% of those with a baseline low-density lipoprotein-C (LDL-C) of 70 mg/dL or higher shifted below that threshold at week 52, and 50% of those with a baseline LDL-C of 100 mg/dL or higher fell below that level.²

Among patients with elevated baseline Lp(a) receiving resmetirom 100 mg without statins (n = 493), 45.4% of those with a baseline Lp(a) of 30 mg/dL or higher and 62.5% of those with 50 mg/dL or higher shifted below those thresholds.²

"Cardiovascular disease is the leading cause of death in people with MASH, so the secondary analysis from the phase 3 MAESTRO program demonstrating that Rezdiffra improved LDL-C, ApoB, and Lp(a) is highly relevant for clinicians and patients,” Meena B. Bansal, MD, FAASLD, system chief of the division of liver diseases and director of the MASH/NASH Center of Excellence at the Icahn School of Medicine at Mount Sinai, said in a news release.² "This is particularly important because statins are not known to meaningfully lower certain lipoproteins such as Lp(a)."

A separate analysis applied the ANTICIPATE-NASH risk model—a noninvasive stratification tool integrating liver stiffness measurements, platelet count, and body mass index to estimate clinically significant portal hypertension (CSPH) risk—to patients with well-compensated MASH cirrhosis treated with resmetirom for up to 2 years. Results showed the proportion of patients classified as high risk for CSPH decreased from 75% at baseline to 54.5% at year 2, and mean ANTICIPATE-NASH scores declined by up to 37.6% over the treatment period.²

Real-World Performance Aligns With Trial Data

Multiple real-world analyses demonstrated that patients treated with resmetirom for up to 12 months in routine clinical practice achieved clinically meaningful improvements in biomarkers of liver disease and cardiometabolic risk.²

In one analysis of a large gastroenterology practice, 48.6% of patients achieved a 25% or greater reduction in liver stiffness over a mean follow-up of approximately 9 months. Discontinuation due to treatment-related adverse events was less than 1%. In a separate electronic health record analysis of 728 patients treated over 12 months, statistically significant reductions in alanine aminotransferase and aspartate aminotransferase were observed across all subgroups, irrespective of baseline type 2 diabetes status, obesity, or concurrent glucagon-like peptide-1 receptor agonist and statin use.²

Drug Interactions and Patient Monitoring

Pharmacists dispensing resmetirom play a critical role in counseling patients on several clinically significant drug interactions and safety signals.

Resmetirom should be avoided in patients taking gemfibrozil. Concurrent use with statin medications—including atorvastatin, pravastatin, rosuvastatin, and simvastatin—and with clopidogrel warrants clinical attention, as these interactions may require dose adjustment.³

Serious but less common adverse effects include drug-induced liver toxicity (hepatotoxicity) and gallbladder-related problems such as cholelithiasis, cholecystitis, and obstructive pancreatitis.^1,3 Patients should be counseled to report symptoms of liver injury—including jaundice, fatigue, nausea, vomiting, fever, rash, or right upper abdominal pain—promptly.² Use of resmetirom should be avoided in patients with decompensated cirrhosis or moderate to severe liver disease.^1,3

The most commonly reported adverse effects in clinical trials were diarrhea and nausea. Additional adverse effects reported in postmarketing surveillance include constipation, dizziness, itching, and unusual menstrual bleeding.^1,3

Resmetirom has not been studied in the pediatric population, and its safety during breastfeeding has not been established. Pregnant patients or those planning pregnancy should be directed to the manufacturer's pregnancy registry.²

REFERENCES

1. US Food and Drug Administration. FDA approves first treatment for patients with liver scarring due to fatty liver disease. News release. FDA. March 14, 2024. Accessed June 30, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-liver-scarring-due-fatty-liver-disease

2. Madrigal Pharmaceuticals, Inc. Madrigal presents data demonstrating Rezdiffra reduced markers of cardiovascular and liver-related risk in patients with MASH. News release. Madrigal Pharmaceuticals. May 27, 2026. Accessed June 30, 2026. https://ir.madrigalpharma.com/news-releases/news-release-details/madrigal-presents-data-demonstrating-rezdiffra-reduced-markers

3. Mayo Clinic. Resmetirom (oral route). Mayo Clinic. June 1, 2026. Accessed June 30, 2026. https://www.mayoclinic.org/drugs-supplements/resmetirom-oral-route/description/drg-20566734