How Do Selective Thyroid Hormone Receptor-Beta Agonists Work?

Selective thyroid hormone receptor-beta (THR-B) agonists are medications used in the treatment of adults with noncirrhotic nonalcoholic steatohepatitis (NASH), who have moderate to advanced scarring (fibrosis) of liver tissue. NASH is a severe and advanced form of nonalcoholic fatty liver disease (NAFLD).

Nonalcoholic fatty liver disease is a condition caused by accumulation of fat in the liver. It is known as NASH when NAFLD progresses and causes inflammation and damage to the liver. NAFLD and NASH are silent diseases that usually cause few or no symptoms, and when they do, it is generally tiredness and abdominal discomfort, but these liver diseases can cause fibrosis and cirrhosis, and affect liver function.

Thyroid hormones play an important role in many physiological processes including helping the liver break down fats. Thyroid hormones work by stimulating molecules known as thyroid hormone receptors (THRs) in the body. THR-alpha isoform is primarily found in brain, heart and bone, while the liver, kidney, thyroid and other organs have THR-beta isoform.

Patients with NAFLD or NASH have reduced activity of THR-B activity, which is the primary underlying cause for fat accumulation in the liver. Selective THR-B agonists specifically bind to THR-B and enhance their activity, which promotes breakdown of liver fat and reduces the accumulation of triglycerides in the liver.

Currently, the first and only drug in selective THR-B agonists class of drugs is resmetirom (brand name Rezdiffra), approved by the FDA on March 14, 2024, under accelerated approval based on improvement of NASH and fibrosis. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.

Selective thyroid hormone receptor-beta agonists are oral tablets approved by the FDA for the treatment of noncirrhotic nonalcoholic steatohepatitis, along with diet and exercise, in adults who have F2 to F3 stages of fibrosis in the liver tissue. TR-beta agonists are not indicated for use in patients with decompensated cirrhosis.

Common side effects of selective thyroid hormone receptor-beta agonists include the following:

• Diarrhea
• Nausea
• Vomiting
• Constipation
• Abdominal pain
• Itching (pruritus)
• Dizziness
• Liver toxicity (hepatotoxicity)
• Increase in levels of liver enzymes ALT and AST
• Increase in total bilirubin levels
• Hypersensitivity reactions including:
• Rash
• Hives (urticaria)
• Gallbladder-related side effects such as:
• Gallstones (cholelithiasis)
• Acute gallbladder inflammation (cholecystitis)
• Pancreas inflammation due to gallstones (obstructive pancreatitis)

Less common side effects of selective thyroid hormone receptor-beta agonists include the following:

• Decrease in appetite
• Abnormal stools
• Gas (flatulence)
• Taste disorder (dysgeusia)
• Vertigo
• Palpitations
• Irregular heart rhythm (arrhythmia)
• Tendon disease (tendinopathy)
• Skin redness (erythema)
• Low blood sugar (hypoglycemia)
• Abnormal uterine bleeding
• Depression 

Information contained herein is not intended to cover all possible side effects, precautions, warnings, drug interactions, allergic reactions, or adverse effects. Check with your doctor or pharmacist to make sure these drugs do not cause any harm when you take them along with other medicines. Never stop taking your medication and never change your dose or frequency without consulting your doctor.

Generic and brand names of selective thyroid hormone receptor-beta agonists include:

• resmetirom
• Rezdiffra