Resmetirom reduces bad cholesterol, restores thyroid hormones in NASH

Treatment with resmetirom significantly reduced low-density lipoprotein cholesterol (LDL-C) and other atherogenic lipids, as well as restored thyroid hormone (TH) levels in patients with nonalcoholic steatohepatitis (NASH), according to two subgroup analyses of the MAESTRO-NASH trial presented at The Liver Meeting 2023.

“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,” said Dr Naim Alkhouri from Arizona Liver Health in Tucson, Arizona, US.

This ongoing, double-blind, placebo-controlled, phase III trial analysed 966 patients with biopsy-confirmed NASH and F1B-F3 fibrosis who had a nonalcoholic fatty liver disease activity score of ≥4 at baseline. Participants were randomized in a 1:1:1 ratio to receive resmetirom 80 mg (n=322) or 100 mg (n=323) once daily or placebo (n=321) for 52 weeks.

At week 24, patients receiving the 80 mg doses had an LDL-C reduction of 13.6 mg/dL and 16.3 mg/dL in those receiving 100 mg doses (p<0.0001 for both). In contrast, a 0.1 mg/dL increase in LDL-C was observed among those treated with placebo. [The Liver Meeting 2023, abstract 2462-C]

Similarly, levels of apolipoprotein B (ApoB) decreased by 16.8 mg/dL and 19.8 mg/dL and apolipoprotein CIII (ApoCIII) by 10.6 mg/dL and 14.1 mg/dL with resmetirom 80 and 100 mg, respectively. With placebo, ApoB and ApoCIII levels increased by 0.4 mg/dL and 8.1 mg/dL, respectively.

Greater reductions in triglycerides (-22.7 mg/dL [80 mg] and -21.7 mg/dL [100 mg] vs -2.6 percent) and lipoprotein(a) ([Lp(a)]; -30.4 mg/dL [80 mg] and -35.9 mg/dL [100 mg] vs -0.8 mg/dL) were also observed with resmetirom over placebo.

“Overall, resmetirom 80 and 100 mg significantly reduced atherogenic lipid/lipoprotein levels from baseline, including triglycerides, ApoB, ApoCIII, and Lp(a), by week 24 … These improvements in the lipid/lipoprotein profile were maintained through week 52,” he concluded.

Resmetirom may restore TH levels

“Patients with NASH have diminished thyroid hormone receptor [THR]-β signaling within their liver due to decreased conversion of prohormone T4 to active hormone T3 in favour of increased conversion of T4 to inactive metabolite reverse T3 [rT3],” said Dr Stephen Harrison from the University of Oxford, Oxford, UK, who presented findings on the effect of resmetirom on TH levels.

“Resmetirom, an oral liver-targeted THR-β selective agonist in development as a potential treatment for NASH, may address this underlying pathophysiology,” he noted.

The researchers evaluated circulating TH levels (TSH, free T3 (FT3), free T4 (FT4), and rT3) as well as the FT3/rT3 ratio, at week 52 in the overall, thyroxine-treated, and euthyroid populations from the MAESTRO-NASH trial. [The Liver Meeting 2023, abstract 2463-C]

In the overall population, patients treated with resmetirom 80 or 100 mg had significant reductions in FT4 level relative to those treated with placebo at week 52 (-13.9 percent and -18.1 percent, respectively, vs 2.6 percent; p<0.001).

The rT3 level also decreased from baseline to week 52 in the resmetirom group compared with the placebo group (-4.6 percent [80 mg] and -5.1 percent [100 mg] vs 0.17 percent; p<0.001).

In addition, FT3/rT3 ratio significantly increased with resmetirom vs placebo at week 52 (0.06 percent each for 80 mg and 100 mg vs 0 percent; p<0.001).

However, there was no significant difference in the TSH or FT3 levels between the resmetirom and placebo groups.

The effects observed in the thyroxine-treated and euthyroid populations were similar to that in the overall population.

“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,” said Harrison.

“These data suggest resmetirom treatment may restore TH levels in patients with NASH and fibrosis,” he added.