Weight loss has long been a cornerstone of managing nonalcoholic steatohepatitis (NASH), now also known as metabolic dysfunction-associated steatohepatitis (MASH). However, with the recent FDA approval of resmetirom (Rezdiffra), a THR-β selective agonist, the treatment landscape is evolving. This article explores the role of Rezdiffra in MASH management, its relationship to weight loss, and how it compares to other therapies like GLP-1 agonists.
The Evolving Landscape of MASH Treatment
In the absence of pharmacologic treatments, weight loss served as the cornerstone of nonalcoholic steatohepatitis (NASH) management. Now that resmetirom has been granted accelerated approval for noncirrhotic NASH with moderate to advanced fibrosis, the role of glucagon-like peptide 1 (GLP-1)s has come into question, especially given their apparent lack of significant impact on fibrosis.
Resmetirom (Rezdiffra): A Liver-Directed Therapy
Resmetirom (Rezdiffra) is a brand-name prescription oral tablet used to treat a certain type of liver disease. It is not a weight-loss medication. Rezdiffra was approved by the Food and Drug Administration (FDA) in 2024 to treat a specific form of liver disease. It belongs to a class of drugs called thyroid hormone receptor-beta (THR-beta) agonists.
An oral, thyroid hormone receptor (THR)-β selective agonist, resmetirom was granted accelerated approval on March 14, following 18 clinical studies in its development program. Resmetirom’s safety and efficacy for adults with NASH has been demonstrated in phase 2 and 3 trials, the latest of which includes MAESTRO-NASH, an ongoing phase 3, double-blind, randomized, placebo-controlled trial, 1 of 4 phase 3 studies in resmetirom’s clinical development program supporting the approval for its use in adult patients with NASH and moderate to advanced (F2 - F3) fibrosis.
How Rezdiffra Works
Rezdiffra treats noncirrhotic nonalcoholic steatohepatitis (NASH) in adults with moderate to advanced liver fibrosis. NASH is a form of nonalcoholic fatty liver disease. With this condition, fat accumulates in the liver, which leads to inflammation and damage. These changes cause liver fibrosis, which is scarring of the liver. Liver fibrosis prevents the liver from working as well as it should.
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Rezdiffra treats NASH by attaching to a protein called THR-beta. This helps reduce the stored fat from the liver, reducing liver inflammation and damage.
Clinical Trial Evidence
The safety and efficacy of Rezdiffra was evaluated based on an analysis of a surrogate endpoint at month 12 in a 54-month, randomized, double-blind placebo-controlled trial. The surrogate endpoint measured the extent of liver inflammation and scarring. The sponsor is required to conduct a postapproval study to verify and describe Rezdiffra’s clinical benefit, which will be done through completing the same 54-month study, which is still ongoing. To enroll in the trial, patients needed to have a liver biopsy showing inflammation due to NASH with moderate or advanced liver scarring.
At 12 months, liver biopsies showed that a greater proportion of subjects who were treated with Rezdiffra achieved NASH resolution or an improvement in liver scarring as compared with those who received the placebo. A total of 26% to 27% of subjects who received 80 milligrams of Rezdiffra and 24% to 36% of subjects who received 100 milligrams of Rezdiffra experienced NASH resolution and no worsening of liver scarring, compared to 9% to 13% of those who received placebo and counseling on diet and exercise. The range of responses reflects different pathologists’ readings. In addition, a total of 23% of subjects who received 80 milligrams of Rezdiffra and 24% to 28% of subjects who received 100 milligrams of Rezdiffra experienced an improvement in liver scarring and no worsening of NASH, compared to 13% to 15% of those who received placebo, depending on each pathologist’s readings.
Important Considerations
- Rezdiffra is not for people with cirrhosis.
- Use of Rezdiffra should be avoided in patients with decompensated cirrhosis.
- Using Rezdiffra at the same time as certain other drugs, in particular statins for lowering cholesterol, may result in potentially significant drug interactions.
The Role of Weight Loss in MASH Management
For years, weight loss has been a critical part of managing conditions like nonalcoholic steatohepatitis (NASH/MASH). Weight loss is an important element of the overall approach to managing MASH. It's indicated that losing 3-5% of your body weight can help reduce liver fat. Therefore, losing weight will likely remain a part of your treatment plan.
Is Rezdiffra a Weight Loss Medication?
No. Resmetirom is focused on reducing fat from the liver, but not from other body parts. Improving fat metabolism in the liver can have a positive effect on overall body fat reduction. However, this is a potential secondary benefit of resmetirom, rather than a main effect.
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No, Rezdiffra is not approved for weight loss. Also, weight loss was not reported as a side effect in studies of the drug.
Rezdiffra is approved only to treat MASH in adults with moderate to advanced liver fibrosis. It works by helping the liver store less fat, but it’s not used to reduce fat in other parts of the body.
It’s unlikely that Rezdiffra causes weight gain. In studies of the drug, weight gain was not reported as a side effect. But this doesn’t mean weight gain can’t occur during Rezdiffra treatment.
Lifestyle Modifications
Even small changes can help support your liver health.
- Eat well.
- Watch your alcohol intake.
- Get active.
- Be careful with supplements.
- Be mindful about your weight.
Also remember that managing MASH is about more than the number on the scale.
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GLP-1 Agonists vs. Resmetirom: A Comparative Look
Harrison discusses the role of GLP-1-based therapies in NASH management and situations where resmetirom may be a better option following its recent FDA approval. “GLP-1 based therapy targets weight and gets at the core tenet of the root cause of many different diseases, including MASLD or steatotic liver disease,” Stephen Harrison, MD, founder and chairman of Pinnacle Clinical Research and Summit Clinical Research, explained in an interview with HCPLive. “For all the good things that GLP-based therapies do, there is no evidence that you're doing anything positive on fibrosis.”
Although Harrison was careful to note GLP-1 agonists improve insulin sensitivity and address key drivers of fibrosis, he also pointed out most patients cannot stay on therapy long enough to see the potential fibrosis benefit. Citing the uptick in complications from liver disease seen at F2, he emphasized the need for liver-directed therapies with a faster, more direct impact on fibrosis. This, he explained, is where resmetirom comes into play.
When to Consider Each Therapy
For patients with F0 or F1, Harrison said he would continue to use GLP-based therapies. For patients with F2, he noted this is where the “crossroad” begins: “If they're on [a GLP-1], I'm going to keep them on it and add resmetirom. If they're not on it, then I think I have a little bit of play. But at F3, I think we really need to start with liver-directed therapy.”
“The issue really becomes as you advance beyond F2 and you get to F3 or even early stage F4,” Harrison explained. “Then, I worry a little bit about GLP-1-based therapy because we really need to pull those people back from the brink of falling over the cliff into decompensation. Our effort really should be on halting and reversing fibrosis, first and foremost. Weight loss at that point is secondary.”
Potential Combination Therapy
To maximise the effect of MASH therapy, especially in patients where obesity is also present, weight loss medicines can be used together with Rezdiffra.
Emerging Therapies: Semaglutide and Tirzepatide
As indicated by recent clinical trials, GLP-1 antagonists such as semaglutide may even have the potential to be stand-alone MASH treatments. According to a recent press release, Novo Nordisk will apply for FDA approval and EMA approval for Wegovy (semaglutide) as a treatment for metabolic dysfunction-associated steatohepatitis (MASH). After 72 weeks of follow-up, 37% of patients treated with semaglutide saw their liver scarring improve. 63% of semaglutide patients saw their MASH resolve without scarring getting worse.
Mounjaro's manufacturer, Eli Lilly, has also been studying the medicine in the context of fatty liver with fibrosis (MASH). After 52 weeks of treatment, 10% of patients in the placebo group had their MASH resolved without worsening of the fibrosis. These results point to a potential role tirzepatide could play as a treatment for MASH in the future.
Rezdiffra vs. Semaglutide: Mechanism of Action
If Wegovy (semaglutide) gets approval for treating MASH, it's important to understand how it compares to Rezdiffra.
- Mechanism of action.
- Liver fat reduction.
- Insulin sensitivity.
- Anti-inflammatory action.
As you can see, the two medicines have a different approach to MASH treatment. It may be that they will be relevant for a different subset of the patient population.
Accessing Rezdiffra and Patient Support
Rezdiffra is a recently approved medicine and as such, it's not yet available in most countries. If you have MASH and your doctor believes you could benefit from Rezdiffra (and weight loss medicines), then you can directly buy and import the medicines. Even if they're not approved or available in your country yet.
Your Rezdiffra prescription will be delivered directly to your doorstep through a specialty pharmacy. The specialty pharmacy or Madrigal Patient Support will call you to review your prescription, confirm your insurance, and discuss financial assistance options. A specialty pharmacy stocks medications and treatments that are not typically found at your local retail pharmacy.
Madrigal Patient Support
Madrigal Patient Support can help you manage the insurance process. They can identify financial assistance options, help you understand costs and coverage, and provide support getting started and throughout treatment. Have questions? You can access Madrigal Patient Support services when you begin treatment with Rezdiffra.
Understanding the Cost
While the cost of Rezdiffra depends on your insurance coverage and eligibility for support programs, the price has been adjusted for those with commercial insurance and who qualify for the Rezdiffra Copay Assistance Program.
Connecting with Others
Other people have been where you are-and it’s normal to have questions. Ask your liver specialist to connect you with a local support group. The Rezdiffra Patient Welcome Kit is sent to patients who are new to Rezdiffra. It includes a variety of educational materials and helpful resources to support you throughout your treatment journey.
MASH: Understanding the Disease
MASH is a chronic, serious, and progressive liver disease and everyone’s experience with Rezdiffra is different. Take Rezdiffra every day, with or without food, for as long as your liver specialist tells you to.
Yes, MASH and NASH refer to the same condition. The following summary explains what “MASH” and “NASH” represent and why the condition name changed.
As noted previously, MASH occurs when fat builds up in the liver. The buildup causes liver damage and inflammation, which leads to liver scarring (fibrosis).
MASH doesn’t progress at the same rate for everyone. Some people may stay in the early stages for years, while others may see faster progression-especially if they have health factors like type 2 diabetes, obesity, or high cholesterol. That’s why regular testing is important.
Risk Factors and Prevalence
Fatty liver disease is a buildup of fat in liver cells. If it goes unmanaged, the fat can become toxic, triggering inflammation in your liver. This can lead to MASH with liver scarring (fibrosis). A liver with mild scarring is considered stage F1.
Studies show that Latino adults are more likely to develop MASH. One study that looked at results from several smaller studies found that, compared to other groups, Latinos have a 50% higher risk of MASLD and a 42% higher risk of MASH. They may also be more likely to experience more severe liver scarring. If you're Latino and have associated conditions like type 2 diabetes, obesity, high blood pressure, high triglycerides, or high cholesterol, talk to your doctor about getting tested for liver scarring-even if you feel fine.
Symptoms and Diagnosis
MASH is often silent, which means you may not feel any symptoms. Your liver specialist may order blood tests (like FIB-4 or ELF), imaging tests (like FibroScan® or MRI), or, in some cases, a liver biopsy to check for inflammation and scarring.
Over time, MASH can cause liver scarring-also called fibrosis-which can get worse if not addressed. Scarring is measured in stages, from F0 (no scarring) to F4 (severe scarring or cirrhosis). The good news? You can take action. Ask your liver specialist about getting tested for liver scarring.
Monitoring and Testing
If you’ve been diagnosed with MASH with liver scarring, regular monitoring is important, especially if you have other health factors like type 2 diabetes, high cholesterol, high blood pressure, high triglycerides, or obesity.
Blood-based tests such as FIB-4, ELF, or ALT/AST. ALT and AST are blood tests that help check for liver damage. Imaging tests such as FibroScan®, MRI, or ultrasound are also noninvasive liver tests. Liver biopsy may be necessary to give your liver specialist a clear result. A liver enzyme test alone cannot diagnose your stage or level of scarring. Additional tests may be needed depending on your health history and results. Once you get your results, schedule a follow-up with your liver specialist to discuss next steps. If your test shows moderate to advanced scarring, sometimes called F2 or F3, ask if Rezdiffra could be part of your treatment plan.
Potential Side Effects of Rezdiffra
Like other medications, Rezdiffra can cause mild to serious side effects.
Mild Side Effects
Rezdiffra can cause some mild side effects, as shown in the list. If you have questions about these or other side effects, talk with your doctor or pharmacist or refer to the drug’s prescribing information.
Mild side effects of Rezdiffra may include:
- Diarrhea
- Constipation
- Nausea
- Vomiting
- Abdominal pain
- Itchiness
- Dizziness
Keep in mind that these mild side effects are usually temporary and go away as your body adjusts to the medication.
Serious Side Effects
While not common, Rezdiffra may also cause serious side effects. If you’re experiencing a serious side effect from Rezdiffra, call your doctor right away. If the side effect feels life threatening or you think you’re having a medical emergency, call 911. Or call your local emergency number right away.
Serious side effects of Rezdiffra may include:
- Liver damage, which can cause symptoms such as:
- Nausea
- Vomiting
- Abdominal pain
- Jaundice
- Gallbladder problems, which can cause symptoms such as:
- Fever
- Abdominal pain
Some symptoms associated with serious side effects of Rezdiffra may resemble those of its mild side effects. If you’re concerned about any or have side effects that aren’t going away, tell your doctor right away.
Gallbladder Problems
Rezdiffra may cause serious side effects. Gallbladder problems: Gallbladder problems such as gallstones, or inflammation of the gallbladder, or inflammation of the pancreas from gallstones can occur with MASH and may occur if you take Rezdiffra. Call your healthcare provider right away if you develop any signs or symptoms of these conditions, including nausea, vomiting, fever, or pain in your stomach area (abdomen) that is severe and will not go away.
Initiating a Conversation with Your Doctor
Questions about Rezdiffra? This indication is approved based on improvement of MASH and liver scarring (fibrosis). The first step is talking with a liver specialist. Keep in mind, Rezdiffra is not for people with cirrhosis. You have every right to start the conversation. When it comes to your liver health, your voice matters most.
Before taking Rezdiffra, tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Know the medicines you take.
This doctor discussion guide can help you prepare to request a test for liver scarring.