Resmetirom Significantly Reduces LDL-C, Restore Thyroid Hormones in NASH with Fibrosis


New analyses from the phase 3 MAESTRO-NASH support the oral daily drug's benefit for cardiovascular and hormonal outcomes over 1 year.

Resmetirom Significantly Reduces LDL-C, Restore Thyroid Hormones in NASH with Fibrosis

Naim Alkhouri, MD

Credit: Twitter

Resmetirom may be able to restore thyroid hormone levels,1 as well as reduce and maintain lipid/lipoprotein levels in patients with nonalcoholic steatohepatitis (NASH),2 according to findings from a pair of phase 3 assessments.

In 2 separate abstracts presented at The Liver Meeting 2023 from the American Association for the Study of Liver Diseases (AASLD) in Boston this weekend, phase 3 MAESTRO-NASH data indicated a myriad of hormone and cardiovascular benefits with resmetirom for patients with NASH and fibrosis. The latest findings from the late-stage trial come 2 months after Madrigal Pharmaceuticals announced a New Drug Acceptance (NDA) from the US Food and Drug Administration (FDA) for resmetirom for the treatment of NASH with liver fibrosis.3

Resmetirom is an oral liver-targeted thyroid hormone receptor (THR)-β selective agonist. At the time of the NDA acceptance in September, Madrigal chief medical officer and president of research & development Becky Taub, MD, described the agent as being supported by a “compelling data package” to support its clinical benefit in patients with NASH and liver fibrosis.

“The NDA is supported by the positive efficacy results observed in our pivotal Phase 3 trial, the large safety database we have established through the MAESTRO program, and two ongoing outcomes studies that are designed to verify clinical benefit following a potential accelerated approval,” Taub stated.

Cardiovascular Benefit

The first abstract, presented by Naim Alkhouri, MD, chief medical officer, chief of Transplant Hepatology and director of the Fatty Liver Program at Arizona Liver Health, sought to analyze 54-month MAESTRO-NASH data demonstrating the effect of 2 resmetirom doses on atherogenic lipid and lipoprotein levels.2

Resmetirom was previously demonstrated to significantly improve such lipid profiles in patients with presumed NASH. For this analysis, Alkhouri and colleagues analyzed patients with metabolic risk factors, liver stiffness, hepatic fact, NASH with F1B-F3 fibrosis confirmed by biopsy, and a nonalcoholic fatty liver disease (NAFLD) activity score (NAS) >4.

Patients were randomized 1:1:1 to either once-daily oral 80 mg or 100 mg resmetirom, or placebo. The analysis’s key endpoint was percent change in LDL-C from baseline to week 24, while tertiary endpoints included percent change in patients’ triglycerides, apoB, apoCIII and Lp(a) from baseline.

Mean LDL-C was 106.6 mg/dL and 102.9 mg/dL among patients receiving resmetirom 80 mg and 100 mg, respectively. At 24 weeks, investigators observed mean reductions of 13.6 mg/dL in patients receiving 80 mg doses, and 16.3 mg/dL in patients receiving 100 mg doses, versus a 0.1 mg/dL mean LDL-C score increase among patients receiving placebo.

Treatment difference in LDL-C reduction was -13.7 mg/dL (95% CI, -17.5 to -10.0; P <.0001) for 80 mg resmetirom versus placebo. The difference was even greater for patients with 100 mg doses (-16.4 mg/dL; 95% CI, -20.1 to -12.6; P <.0001).

Over 52 weeks, investigators observed maintained differences in reduced LDL-C among patients on both 80 mg (-13.3 mg/dL; 95% CI, -17.3 to -9.3; P <.0001) and 100 mg doses (-19.0 mg/dL; 95% CI, -23.0 to -15.1; P <.0001) versus placebo.

Alkhouri and colleagues additionally observed significantly improved reductions in mean patient triglycerides, ApoB, ApoCIII, and Lp(a) for both resmetirom doses versus placebo over 24 and 52 weeks as well.

“The effect of potential NASH therapies on cardiovascular risk factors, including atherogenic lipids/lipoproteins, is important to consider as cardiovascular disease is a common cause of mortality in patients with NASH and fibrosis,” the team concluded.

Hormone Benefit

In the second abstract, presented by Stephen A. Harrison, MD, medical director of Pinnacle Clinical Research, investigators analyzed MAESTRO-NASH data for the effect of both 80 mg and 100 mg once-daily resmetirom on thyroid hormone levels over 52 weeks. The team noted that (THR)-βis responsible for regulating multiple metabolic pathways in the liver.1

“However, patients with NASH have diminished hepatic THR-β signaling (due to decreased conversion of prohormone T4 to active hormone T3 in favor of increased conversion of T4 to inactive metabolite reverse T3 [rT3]),” they wrote. “Resmetirom…may address this underlying pathophysiology.”

Harrison and colleagues evaluated circulating thyroid hormone levels including thyroid-stimulating hormone (TSH), FT3, FT4, and rT3 across 3 cohorts from the MAESTRO-NASH population—overall patients, thyroxine-treated patients, and euthyroid patients—at week 52.

Investigators reported significant reductions in FT4 and rT3 levels among both resmetirom treatment arms versus placebo at week 52 (P <.0001), as well as significantly increased Ft3/rT3 ratios in both treatment arms versus placebo (P <.0001). Similar effects were observed in each of the overall, thyroxine-treated, and euthyroid populations.

The team did not observe, however, any significant change in TSH or FT3 levels with either dose of resmetirom versus placebo at 52 weeks. Nonetheless, investigators remarked positively on the analysis’ findings.

“Resmetirom treatment significantly reduced FT4 and rT3 levels consistent with increased conversion of T4 to active hormone T3 and decreased conversion of T4 to the inactive metabolite rT3, Overall, these data suggest resmetirom treatment may restore thyroid hormone levels within the liver of patients with NASH and fibrosis.”


  1. Bedossa P, Guy CD, Schattenburg JM, Loompa R, et al. 2463-C: RESMETIROM TREATMENT HELPS RESTORE THYROID HORMONE LEVELS IN PATIENTS WITH NONALCOHOLIC STEATOHEPATITIS: 52-WEEK DATA FROM THE PHASE 3 MAESTRO-NASH TRIAL. Paper presented at: The Liver Meeting. Boston, MA. November 10 - 14, 2023.
  3. Madrigal Pharmaceuticals. Madrigal Pharmaceuticals Announces NDA Acceptance and Priority Review of the New Drug Application for Resmetirom for the Treatment of NASH with Liver Fibrosis. Press release. Published September 13, 2023.
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