The MAESTRO-NASH post hoc results reinforce the hepatic selectivity of resmetirom with limited systemic thyroid hormone signalling effects.In a post hoc analysis of the phase III MAESTRO-NASH trial presented at ADA 2026, systemic thyroid function remained stable with resmetirom, supporting its extrahepatic safety in individuals with metabolic dysfunction-associated steatohepatitis (MASH).
“At week 52, thyroid parameters showed minimal changes from baseline overall, regardless of baseline thyroxine replacement therapy status,” the investigators said.
Over 52 weeks, both resmetirom doses resulted in modest reductions in FT4* as early as week 4 without compensatory increases in TSH** or FT3*. TSH was generally stable, indicating preserved hypothalamic-pituitary-thyroid (HPT) axis feedback. Changes in FT3 were minimal, with levels remaining within normal range, they noted.
Baseline thyroxine therapy status
In participants who were not on thyroxine replacement therapy at baseline, the least-squares mean changes from baseline (LSM CFB) in FT3/FT4 were –0.01/–0.16 ng/dL with resmetirom 80 mg, –0.08/–0.21 ng/dL with resmetirom 100 mg, and –0.02/0.02 ng/dL with placebo. Similar patterns were observed among those who received thyroxine replacement therapy (0.04/–0.18 ng/dL, –0.03/–0.26 ng/dL, and –0.02/0.02 ng/dL, respectively).
Resmetirom also did not significantly affect TSH levels in participants who did (LSM CFB, –0.63 and –0.13 mIU/L for 80 and 100 mg, respectively) and did not receive thyroxine replacement therapy (LSM CFB, –0.23 and –0.20 mIU/L). For placebo, the corresponding values were –0.22 and –0.08 mIU/L.
Moreover, the LSM CFB in rT3*** levels were similar between resmetirom 80 and 100 mg in participants who did (–5.1 and –6.3 ng/dL, respectively) and did not receive thyroxine replacement therapy (–4.5 and –4.9 ng/dL). [ADA 2026, abstract 1806-P]
Cardiovascular parameters
Both resmetirom 80- and 100-mg doses yielded small reductions in systolic blood pressure (SBP; mean CFB, –3.83 and –4.38 mm Hg, respectively) and diastolic BP (DBP; mean CFB, –1.57 and –2.12 mm Hg) at week 52. The reductions with placebo were minimal (mean CFB, –0.94 and –1.55 mm Hg for SBP and DBP, respectively).
There were no clinically meaningful effects in pulse rate at week 52 (mean CFB, 0.13, –0.46, and –0.06 bpm for resmetirom 80 mg, resmetirom 100 mg, and placebo, respectively).
“The cardiovascular parameters remained generally stable across treatment groups,” the researchers said.
Thyroid hormone signalling modulator
Resmetirom is approved in the US for the treatment of adults with noncirrhotic MASH with moderate-to-advanced (F2–F3) liver fibrosis, alongside diet and exercise. [https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-liver-scarring-due-fatty-liver-disease, accessed 15 June 2026]
“As a liver-directed thyroid hormone receptor-β agonist that modulates thyroid hormone signalling, resmetirom warrants evaluation for its potential effects on systemic thyroid function, including HPT parameters,” the investigators explained.
MAESTRO-NASH included 966 patients with biopsy-confirmed MASH (fibrosis stage F1B, F2, or F3) and ≥3 metabolic risk factors. Individuals with asymptomatic subclinical hypothyroidism and those who are on stable thyroxine replacement therapy at >75 µg/day following thyroidectomy were allowed to participate. The participants were randomized 1:1:1 to resmetirom 80 mg, resmetirom 100 mg, or placebo QD.
The post hoc analysis included MAESTRO-NASH participants with F2 or F3 disease and available thyroid function data (n=888; mean age 56.8 years, 56 percent women). Approximately two-thirds of participants had F3 disease, and 14 percent were on thyroid replacement therapy at screening, the most common being thyroxine ≤75 mcg/day (10.4 percent). The mean FT3, FT4, and rT3 levels were 3, 1.1, and 18.8 ng/dL, respectively. The mean TSH level was 2 mIU/L.
“[Taken together,] the findings reinforce the hepatic selectivity of resmetirom with limited systemic thyroid hormone signalling effects,” the investigators concluded.