Resmetirom plus maximally tolerated therapy lowers LDL in heterozygous FH vs. placebo
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In patients with heterozygous familial hypercholesterolemia already taking maximally tolerated lipid-lowering medication, resmetirom lowered LDL, triglycerides, apolipoprotein B and lipoprotein(a) levels vs. placebo, researchers reported.
“Heterozygous familial hypercholesterolemia (HeFH) is an autosomal dominant genetic disorder, with an estimated prevalence of approximately one in 200 to 250, leading to elevated LDL cholesterol plasma levels and increased risk of atherosclerotic coronary vascular disease,” G. Kees Hovingh, MD, professor of internal medicine at the University of Amsterdam Faculty of Medicine, and colleagues wrote in a research letter to the Journal of the American College of Cardiology. “Lowering LDL cholesterol is the cornerstone treatment for patients with HeFH.”
Resmetirom (Madrigal) is a liver-directed, orally active thyroid hormone receptor-beta agonist with an estimated 28-fold selectivity for thyroid hormone receptor-beta over thyroid hormone receptor-alpha compared with triiodothyronine, according to the study.
In a prior phase 1 trial with healthy participants, researchers found that resmetirom 50 mg to 200 mg per day lowered LDL up to 30% within 10 to 12 days of initiation compared with placebo.
For the present phase 2, double-blind trial, researchers randomly assigned 116 patients (mean age, 57 years; 53% men; 99% white) with a genetic HeFH-causing variant who were not at guideline-recommended LDL levels while taking maximally tolerated lipid-lowering therapy to 12 weeks of resmetirom or placebo.
Overall, 81.9% of participants were on high-intensity statins and 67.2% were on ezetimibe.
After 12 weeks of resmetirom, the researchers observed an 18.8% reduction in LDL compared with placebo (95% CI, –27.8 to –9.8; P < .0001; mean difference, –27 mg/dL; 95% CI, –38.4 to –15.5; P < .0001). The LDL reduction was dose-dependent, according to the study.
Resmetirom also lowered triglycerides, ApoB levels and Lp(a) levels compared with placebo (P for all < .0001).
Researchers reported that resmetirom was well tolerated and adverse events were generally mild and self-limiting. Adverse events, including diarrhea (19.2% vs. 10.5%) and nausea (20.5% vs. 5.3%), were more common among participants taking resmetirom compared with placebo.
“Limitations of this study include small sample size, short duration and homogeneous population,” the researchers wrote. “Resmetirom added to existing therapy appears to be safe and well tolerated in a group of HeFH patients. Further studies are needed to evaluate the potential role of resmetirom in the management of hyperlipidemia.”
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