Fatty liver, now known as Metabolic Associated Steatohepatitis, or MASH, now has 2 FDA-approved medications for its treatment. (This disease state was formerly known as NAFLD or NASH, but I like MASH.  If visceral adiposity has led to someone becoming shaped like a potato, they may have MASH and end up with French Fry-brosis of the liver unless we intervene).

One of the medications for MASH is, somewhat unsurprisingly, semaglutide, while the other medication is called Resmetirom (brand name Rezdiffra).  Since the spotlight seems to always be on semaglutide, I think it’s high time we gave Resmetirom a little bit of love by discussing its unique mechanism and its fairly significant effect on…LIPIDS!!!

Resmetirom is an agonist of thyroid hormone receptor beta (THR-β), which is the most prevalent receptor for thyroid hormone in the liver.  So not only does Resmetirom help “melt the fat” in folks with MASH by increasing fatty acid oxidation, in THIS STUDY it led to a decrease of roughly 25% in both LDL-C and ApoB along with an approximate 20% reduction in triglycerides!

So why does this medication work?  Let’s take a step back and talk about THYROID HORMONE, since modulation of a liver-specific receptor is the key to Resmetirom’s efficacy.

Thyroid hormone activates sterol regulatory element binding protein 2 (SREBP2), which increases LDL receptor expression (increasing LDL clearance) and also enhances LPL activity.  So when someone is HYPOTHYROID, his or her LDL-C will be a bit higher than normal due to decreased LDL receptor activity, and oftentimes triglycerides will also be elevated due to the decreased LPL.  Logically, Lipid Specialists are trained to watch out for hypothyroidism as a secondary cause of hyperlipidemia.

Studies of thyroid hormone replacement for those who were previously hypothyroid show about a 10 mg/dL drop in LDL-C, and there are some studies that also show around a 20% drop in Lp(a), although this effect is variable.  Additionally, hypothyroidism is a risk factor for statin-associated myopathies; essentially since your global metabolic processes are sluggish, the drug can remain in your system longer and potentially lead to increased side effects.  Overall, the effects of thyroid hormone replacement on lipid levels are quite modest, and if your baseline cholesterol metrics are stratospheric AND you’re concurrently hypothyroid, you’re probably not going to be living in that much safer of a Lipid Neighborhood even if your thyroid gets properly regulated.  Part of this is likely due to the rather modest effect of thyroid hormone on activating SREBP2 compared to other target genes.  Thyroid hormone has a lot to do, and it can only contribute modestly to lipid homeostasis without neglecting or messing up other physiologic functions. 

Conversely, those with HYPERTHYROIDISM have secondary HYPOBETALIPOPROTEINEMIA (low cholesterol).  But don’t think these folks are feeling smug about their low ApoB.  Due to the thyroid hormone excess, they feel like they are having an internal anxiety attack at all times. They’re hot, sweaty, and feel like they’ve drank a 12 pack of Monster Energy Drinks; they may be losing a bunch of weight, but not in a good way, and they might even go into atrial fibrillation and get osteoporosis.  And this is due to the effect of thyroid hormone binding to thyroid hormone receptor alpha (THR-α), the predominant isoform in the heart, bone, and in many other tissues.

So because there are thyroid hormone receptors EVERYWHERE in the body and too much thyroid hormone will ruin your life, giving folks thyroid hormone for their fatty liver or to help them move to a safer Lipid Neighborhood is too dirty of a game plan. (Thyroid hormone was actually tried as a therapeutic approach in the Coronary Drug Project with dextrothyroxine, but it unfortunately just killed people).  However, what’s DIFFERENT about RezDIFFra is that since its THR-β agonism is more liver-specific, the beneficial effects of thyroid hormone on fatty acid oxidation and LDL receptor expression can be leveraged without the off-target toxicities seen in hyperthyroidism.

So will Resmetirom be routinely used for ApoB lowering?  I doubt it…but the science is pretty cool! The effects on MASH are great…the lipid-lowering is just gravy!