Time Stamps

  • Understanding MASLD as a Systemic Disease 
  • MASLD vs MASH vs Met-ALD: Spectrum Steatotic Liver Disease
  • How to Screen for Fibrosis (FIB-4 & FibroScan)
  • Lifestyle Treatment & Weight Loss Targets
  • ESSENCE Trial: Semaglutide for MASH
  • MAESTRO-NASH Trial: Resmetirom
  • Future Treatments for MASH
  • Key Takeaways for Clinicians

Sponsor:  Oakstone CME

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Show Notes

What is MASLD?

MASLD (Metabolic dysfunction-associated steatotic liver disease)

  • Definition
    • Chronic systemic metabolic disorder characterized by hepatic steatosis in the setting of cardiometabolic dysfunction. 
      • MASLD replaced NAFLD (nonalcoholic fatty liver disease).
    • Why was NAFLD renamed to MASLD?
      • NAFLD was a diagnosis based on exclusion (“non-alcoholic”)
      • “Fatty liver” = stigmatizing to patients
      • Newer terminology emphasizes:
        • systemic metabolic dysfunction 
        • insulin resistance 
        • increased cardiometabolic risk, 
        • overlap with obesity, T2DM, dyslipidemia, and hypertension
  • MASLD Diagnostic Criteria
    • Evidence of hepatic steatosis (imaging, biopsy, or biomarkers)
    • At least one cardiometabolic risk factor:
      • Overweight/obesity
      • Type 2 diabetes mellitus
      • Hypertension
      • Hypertriglyceridemia
      • Low HDL cholesterol
    • Alcohol intake is below MetALD thresholds 
      • Females: <140 g/week, which equates to 10 drinks; 
      • Males: <210 g/week, which equates to 15 drinks 
    • MetALD: (Metabolic dysfunction–associated alcohol-related liver disease) 
      • Patients who meet MASLD criteria PLUS consume moderate amounts of alcohol 
        • >=140–350 g/week in females, and >= 210–420 g/week in men
  • Epidemiology

What is MASH? (Metabolic dysfunction-associated steatohepatitis)

  • Progressive form of MASLD characterized by:
    • steatohepatitis 
    • lobular inflammation
    • hepatocyte ballooning 
    • with or without fibrosis 
    • NOTE: MASH can accelerate progression to advanced fibrosis and cirrhosis 
      • It is often asymptomatic, which leads to underdiagnosis!
  • How is MASH diagnosed?
    • Generally requires liver biopsy for definitive diagnosis!
      • BUT most individuals with MASH are never biopsied! 
        • Screening of patient at high risk is essential
    • Screening for MASH: focuses on fibrosis 
      • BOTH non-invasive blood- and imaging-based assessments
        • Non-invasive blood-based: FIB-4 (Fibrosis-4)
          • Includes: age, AST, ALT, platelet count
          • Interpretation:
            • If <65 years old
              • <1.3 → low risk
              • ≄1.3 → additional testing recommended, often imaging-based
            • If ≄65 years
              • <2.0 → low risk
              • ≄2.0 → additional testing recommended, often imaging-based
            • If  >2.67, consider Hepatology referral
            • FIB-4 has good sensitivity for ruling out significant fibrosis
        • Imaging-based assessment: vibration-controlled transient elastography (VCTE)
          • Estimates liver stiffness via liver stiffness measure (LSM) 
          • Estimates steatosis via ultrasound-based continuous attenuation parameter  (CAP)
        • Limitations: 
          • Needs at least 4 hour fast 
          • Limited by excess adiposity
        • Interpretation:
          • Fibrosis (via LSM)
            • LSM of ≄<8 kPa rules out significant fibrosis
            • LSM 8-12 kPa intermediate zone, suggests significant fibrosis (F2)
            • LSM ≄12 kPa suggests advanced fibrosis (F3)
            • LSM ≄15 kPa suggests cirrhosis (F4)
  • What does a biopsy for MASH include? 
    • Fibrosis staging (F0–F4)
      • F0: fibrosis
      • F1: Perisinusoidal fibrosis
      • F2: Perisinusoidal + periportal fibrosis
      • F3: Bridging fibrosis
      • F4: Cirrhosis
    • NAFLD Activity Score (NAS) Total score range: 0–8
      • Steatosis (0–3)
        • 0: <5%
        • 1: 5–33%
        • 2: 34–66%
        • 3: >66%
      • Lobular inflammation (0–3)
      • Hepocyte ballooning (0–2)
    • These scores are commonly used in clinical trials
    • Major limitations of liver biopsy:
      • Sampling variability (patchy fibrosis distribution)
      • Interobserver and intraobserver variability
      • Thus two biopsies from different liver regions can produce different fibrosis stages

What are the lifestyle interventions for MASLD and MASH?

What drug trials have failed and are ongoing?

  • Early trials in the 2000s = Multiple trials  that started to show benefits of: 
    • PPAR agonists 
    • vitamin E

Failed Trials: RESULTS

  • PIVENS Trial 
    • Vitamin E and pioglitazone
      • Vitamin E: Improved NASH histology in non-diabetic patients
      • Pioglitazone: Improved some histologic parameters 
        • but did not meet the predefined primary endpoint
      • Neither demonstrated clear fibrosis benefit
  • RESOLVE-IT Trial
    • Elafibranor: Dual PPAR-α/ÎŽ agonist
      • Early phase studies suggested improvements in steatosis and inflammation
      • Phase 3 trial failed the primary endpoint of NASH resolution without worsening fibrosis
  • FALCON 1 and FALCON 2
    • Pegbelfermin: FGF21 analogue
      • Early reductions in steatosis and biomarkers
      • Failed to meet primary histologic endpoints in later-stage studies
  • ALPINE 1 and ALPINE 2
    • Aldafermin: FGF19 analogue
      • Showed reductions in liver fat and some biomarker improvements
      • Failed to consistently achieve key histologic endpoints

FDA Approved Drugs for MASH and Fibrosis

    • Resmetirom =selective thyroid hormone receptor-beta (THR-ÎČ) agonist 
      • Located predominantly in the liver
        • Avoids systemic thyrotoxic effects mediated through THR-α
        • Increases hepatic fat metabolism
        • Enhances lipid oxidation
        • Reduces intrahepatic triglycerides
        • Lowers LDL cholesterol and triglycerides
    • Trial Design
      • Phase 3 randomized controlled trial
      • Population
        • Adults with biopsy-confirmed MASH and F2–F3 fibrosis
        • Exclusion: Cirrhosis (F4)
        • Sample size: 966 patients
      • Intervention Arms
        • Resmetirom 80 mg vs. resmetirom 100 mg vs. placebo
      • Duration
        • 52 weeks (interim analysis)
      • Co-Primary Endpoints
        • MASH resolution without worsening fibrosis
        • ≄1-stage fibrosis improvement without worsening MASH
    • Results
      • MASH resolution
        • 29.9% with 100 mg
        • 25.9% with 80 mg
        • 9.7% with placebo
      • Fibrosis improvement
        • 25.9% with 100 mg
        • 24.2% with 80 mg
        • 14.2% with placebo
    • Adverse Effects
      • Mostly mild:
        • Diarrhea, nausea, small reductions in free T4
    • Limitations
      • Histologic surrogate endpoints, no clinical endpoints
    • FDA Approval
      • Resmetirom became the first FDA-approved liver-directed therapy for MASH in March 2024.
  • ESSENCE Trial (Semaglutide)
    • Semaglutide =GLP-1 receptor agonist 
      • Promotes weight loss and improves insulin resistance.
        • Importantly: Liver does not appear to contain significant GLP-1 receptor expression
    • Trial Design
      • Phase 3 randomized controlled trial
      • Population
        • Adults with biopsy-confirmed MASH and F2–F3 fibrosis
        • Sample size: 1,197 patients
        • Randomization 2:1 to semaglutide 2.4 mg or placebo
      • Duration
        • 72-week interim analysis
      • Co-Primary Endpoints
        • MASH resolution without worsening fibrosis
        • ≄1-stage fibrosis improvement without worsening MASH
    • Results 
      • MASH resolution
        • 62.9% with semaglutide
        • 34.3% with placebo
      • Fibrosis improvement
        • 36.8% with semaglutide
        • 22.4% with placebo
      • Adverse Effects
        • Mainly GI-related AEs: nausea, vomiting, constipation, diarrhea
    • Limitations
      • Histologic surrogate endpoints, no clinical outcomes
      • Significant response in the placebo group
    •  

Ongoing Trials: INTERVAL RESULTS

  • HARMONY Trial (Phase 2b)
    • Efruxifermin: FGF21 analogue
      • Significant improvements in:
        • fibrosis 
        • MASH resolution 
        • noninvasive biomarkers
      • Benefits persisted through 96 weeks in some analyses
      • NEXT STEPS: Moved to phase 3
  • ENLIVEN Trial (Phase 2b)
    • Pegozafermin: FGF21 analogue
      • Significant improvements in:
        • fibrosis 
        • MASH resolution
      • NEXT STEPS: Moved to phase 3 development
  • NATIVE Trial (Phase 2b)
    • Lanifibranor: Pan-PPAR agonist (α/ÎŽ/Îł)
      • Met the primary endpoint of ≄2-point reduction in SAF-A score
      • Demonstrated improvements in: 
        • MASH activity 
        • fibrosis
        • composite histologic endpoints
      • NEXT STEPS: Currently in Phase 3

What Questions Remain?

  • Do these therapies improve clinical outcomes?
    • Trials are ongoing and will assess liver-related outcomes including progression to cirrhosis
  • How to select between agents?

Take-home points

  • MASLD = systemic metabolic disease and an important cardiovascular risk factor 
  • MASH = inflammatory liver injury and accelerates fibrosis progression
    • It is often asymptomatic and underdiagnosed!
  • Remember to screen for fibrosis when steatosis is present! 
    • Especially in the presence of other risk factors 
      • alcohol intake, cardiometabolic comorbidities, etc 
    • FIB-4 is the first-line screening tool and can be followed by elastography to confirm. 
    • Technically, biopsy is required to diagnose MASH or fibrosis, 
      • But these diagnoses are often made non-invasively now!
  • Lifestyle interventions are key in the management of steatotic liver disease 
    • Weight loss can improve:
      • steatosis 
      • steatohepatitis
      • fibrosis
  • Resmetirom and semaglutide are the beginning of a major therapeutic shift in MASH!

Transcript

Dr. Elliot Tapper: By and large, we are numb to the noise of steatotic liver disease. You see it all of the time on every scan that is ordered. An abnormal ALT is now normal. A normal ALT is so rare in most of our patient panels. And what these studies and drug approvals mean is that this is the time to reevaluate our own patients for their risk of liver related events. So there’s a lot of hope bound up in it. Now that we have things that we can do, it validates the condition.

Dr. Shreya Trivedi: That’s Dr. Elliot Tapper, the Academic Chief of Hepatology at the University of Michigan Health.

Dr. Gregory Katz: Welcome to Beyond Journal Club, a collaboration between Core IM and NEJM group.

Dr. Shreya Trivedi: The goal of Beyond Journal Club is to take landmark clinical trials and put them into context, telling you the story of how we got to where we are and then what it means to take care of our patients. I’m Dr. Shreya Trivedi, an internist at BIDMC.

Dr. Gregory Katz: I’m Dr. Greg Katz, a cardiologist at NYU.

Dr. Clement Lee: I’m Dr. Clem Lee, a med-peds hospitalist in Boston and a guest editor at NEJM.

Dr. Alejandro Campos Rodriguez: And I’m Dr. Alejandro Campos, a Editorial Fellow at NEJM

Dr. Clement Lee: All right. So today we’re talking about MASLD, whereas some people call it MASLD and MASH, as well as two approved drugs that help improve liver fibrosis in these conditions.

Dr. Shreya Trivedi: But here’s the problem. I think most of us don’t actually have a mental model for steatotic liver disease. So today, we’re actually going to start with one, a simple framework for why this disease happens. Two, how to screen and then risk-stratify. And then three, the trials. ESSENCE and MAESTRO-NASH were published in the New England Journal of Medicine in April 2025 and February 2024, respectively.

Dr. Gregory Katz: And it’s important to cover it like this because once you understand the model, the trials and the mechanisms just make sense, including how two different drugs can tackle the same disease through completely different mechanisms of action.

A SYSTEMIC DISEASE

Dr. Shreya Trivedi: All right, let’s start with one question. Why does fat even end up in the liver at all?

Dr. Alejandro Campos RodrĂ­guez: The simplest way to understand this is the Bathtub analogy.

Dr. Gregory Katz: So, the bathtub analogy feels a little bit odd, but go with us. And so think of your body like a house, and fat is water. The bathtub is your storage of water that’s subcutaneous fat, and subcutaneous fat is designed to safely store excess water that comes into the house.

Dr. Clement Lee: Yeah, I’ll admit, Greg, this is the first time I’ve heard of this analogy. But what happens when this tub starts to overflow?

Dr. Alejandro Campos Rodriguez: Now, fat spills into places it doesn’t belong and starts to get into the walls at the foundation and other rooms. In this analogy, that is the liver, muscle, pancreas, and around the heart.

Dr. Shreya Trivedi: Yeah. And then here’s the thing. Every single person is born with a different-sized bathtub. Their ability to accumulate different amounts of subcutaneous fat is different. And then once that bathtub is filled, we start adding visceral fat. Now, visceral fat is different from subcutaneous fat. It is toxic stuff that is going to cause the problems. The metabolic syndrome, the MASLD, the type 2 diabetes. These are all different expressions of the same underlying problem: too much water in that bathtub that’s overflowing to the vital areas of the house or into our bodies.

Dr. Gregory Katz: So MASLD, Metabolic Dysfunction Associated Steatotic Liver Disease, isn’t really just a liver disease. It’s what happens when the whole system gets overwhelmed.

Dr. Elliot Tapper: So the first thing to recognize is that MASLD is a systemic disorder. It is the liver manifestation of the metabolic syndrome. Fat in the liver is just another risk factor for heart attack and stroke.

Dr. Shreya Trivedi: Right. And here’s this key shift. When we see hepatic steatosis on imaging, we shouldn’t be thinking, “Oh, this is a liver problem”. We should actually think, “Okay, our patient’s cardiometabolic risk just went up.”

Dr. Gregory Katz: Yeah. So I co-signed that so strongly. MASLD crosses disciplines of medicine in a way that so few diseases do. And so when I started cardiology fellowship, I would’ve never imagined a radiology report with the words hepatic steatosis would make me better understand a patient’s cardiometabolic risk, but it does.

Dr. Shreya Trivedi: Yeah, same here. I think the thing that trips me up though, is that I’ve definitely seen patients with a normal BMI who end up having MASLD or MASLD. And then I’ve definitely seen people who are obese that don’t have it.

Dr. Clement Lee: Yeah. I think the best way to explain this goes back to the analogy. It’s just that different people have different-sized bathtubs, meaning everyone has a different capacity to store that fat subcutaneously.

Dr. Alejandro Campos Rodriguez: Yeah. A big tub means that someone can store a lot more adipose tissue subcutaneously before it overflows to the organs. On the other hand, a small tub means that overflow happens early.

Dr. Shreya Trivedi: Yeah. Speaking of small bathtubs, I am so jealous of people with big bathtubs. I recently learned that certain populations, particularly many Asian populations, have less capacity to store fat subcutaneously. So, unfortunately, when there’s excess fat, they’re more likely to accumulate around visceral organs, and of course, that means higher cardiometabolic risk.

Dr. Alejandro Campos Rodriguez: In fact, that’s one of the reasons why BMI alone can be misleading.

Dr. Gregory Katz: And the analogy has even more complexity. I mean, after that overflow happens, not everyone develops the same damage. Where the fat goes is different. If it goes to the liver, that’s MASLD. If it goes to the pancreatic beta cells that inhibits our ability to produce insulin. If it’s deposited in the muscle, there may be more peripheral insulin resistance.

Dr. Clement Lee: Yeah. In other words, the capacity to handle excess adipose tissue is genetic, among other things, and so is which organs the extra fat goes to. That’s why the clinical picture can be so heterogeneous across different patients.

SPECTRUM STEATOTIC LIVER DISEASE

Dr. Shreya Trivedi: Okay. So, say your patient does have excess adipose tissue that’s gone to the liver. It could be MASLD, it could be MASH or another acronym that I’m forgetting or might not be in vogue anymore. How should we think about this?

Dr. Elliot Tapper: So, Met-ALD is when you have fat attributable to the metabolic dysfunction, and there’s some ongoing alcohol use, but at some point, alcohol consumption is such that we now say that’s the primary or if the sole driver, that’s alcohol-related liver disease. If you see fat in the context of the metabolic syndrome, that is straight up metabolic dysfunction associated steatotic liver disease, which I will call MASLD. Some people like MASL-D. It’s just totally random. And if it catches on fire, metabolic dysfunction-associated steatohepatitis.

Dr. Alejandro Campos Rodriguez: And we’ll link to a graphic that breaks down the distinctions among the statietic liver diseases, but for the purpose of this episode, a simple way to think about it is MASLD equals fat in the liver, and MASH equals fat plus inflammation.

Dr. Shreya Trivedi: Yeah, I always mix up those two and which one I should worry about more, but then I remember that MASH ends with ASH, and that can help me remember, okay, MASH is the one where the liver is on fire because ASH could be like the inflammation that happens afterwards, and that’s something we do not like. No ASH, no MASH.

Dr. Clement Lee: I like that, Ashreya. I think that’s one I’m going to keep in my back pocket for the future.

Dr. Shreya Trivedi: Yes.

Dr. Clement Lee: And the whole reason we care about this is that MASH accelerates the progression to fibrosis dramatically, and fibrosis or scarring of the liver is what really determines clinical outcomes. And advanced fibrosis impairs liver function and can progress the list of poor outcomes we’ve all seen in the hospital, like decompensated cirrhosis, hepatocellular carcinoma, the need for liver transplant, higher risk of death, et cetera.

Dr. Alejandro Campos Rodriguez: And you need the word gets tricky. Only 7% to 35% of patients with MASLD develop MASH each year.

Dr. Shreya Trivedi: Oh, so then most people with fatty liver will never have MASH or that active steatohepatitis or that liver on fire. That’s good news.

Dr. Gregory Katz: And that heterogeneity is because some people’s liver cells are just more vulnerable to lipotoxic injury. And so to keep going with our house bathtub analogy, their wiring is just more fragile. And unfortunately, we can’t yet identify ahead of time who’s going to have fragile wiring and who doesn’t, and that’s where screening comes in.

Dr. Shreya Trivedi: Ah, yes. Great segue to screening and staging. But before we do, let us summarize. So in terms of spectrum, if you see MASLD, that means there’s fat in the liver. If you see Met-ALD, there’s some alcohol involved also. Both of these, though, can lead to MASH. And remember, the ASH in MASH means that their liver is on fire, there is inflammation, and that is particularly bad because MASH accelerates fibrosis. And fibrosis, as Clem mentioned, is what we care about because it’s shown to be the primary determinant of all the bad things, right? Cirrhosis, hepatocellular carcinoma and other badness. 

Dr. Shreya Trivedi:  So clinically, what I’m taking away is that we all need to make a mental shift that when we do see steatosis on that long imaging report, the next question should be, “Does my patient have fibrosis? And if so, how much?” Because it’s that fibrosis that’s tied to outcomes.

Dr. Alejandro Campos Rodriguez: And this first step is to calculate something called a fibrosis four index or FIB-4 index. All you need is the patient’s age, the platelet count and AST and ALT values. It has good sensitivity for ruling out significant fibrosis when the score is low.

Dr. Elliot Tapper: If the number is less than 1.3, then you’re good to go. If the number is over 1.3, you might want to do another test like elastography, but if the number is over 2.67, that’s the highest risk person.

Dr. Clement Lee: All right, I think I can remember that less than 1.3 means a low risk for fibrosis.

Dr. Gregory Katz: And one age-related nuance is that the FIB-4 uses age as a component, and that inflates the score in older patients. A score over two in someone over 65 is about equivalent to a score of 1.3 in a younger patient. And so we need to keep that in mind before we reflexively send every older patient for elastography.

Dr. Shreya Trivedi: Yeah. So I guess what I’m taking away is if I see a FIB-4 score over 1.3 in someone younger than 65, or if I see a FIB-4 score over two in a patient over 65 years old, that means yes, go ahead, proceed to elastography. And there’s many different types of elastography. And I think the one that most of us are familiar with, or we’ll hear about, is the FibroScan.

Dr. Elliot Tapper: Our go- to is vibration control transient elastography, which has a brand name of FibroScan, although there are other alternatives that assess the viscoelastic properties of the liver. So we need to jiggle the liver to see how stiff it is, and that stiffness correlates with the presence of cirrhosis, yes, no, but also prognostically, whether or not that person will go on to develop liver cancer or portal hypertensive events.

Dr. Shreya Trivedi: I don’t know why that visual of we’re just seeing how the liver jiggles is so memorable to me, and I’ve since explained that to so many patients and like,”Okay, let’s go see how my liver jiggles and if it’s stiff or not”. Anyways, it’s so cute. But then once you order it and you get the test results back in terms of interpreting that elastography, there thankfully is a good way to remember the cutoffs and what it means.

Dr. Elliot Tapper: And this is how this has transformed our way of communicating to patients: the rule of fives. 5, stone called normal, okay? Less than 10, low risk. 10 or above, you’re at high risk for something called compensated advanced chronic liver disease. So 10, something’s up. 15 cirrhosis. Some people over 15 don’t have cirrhosis. They have stiff liver because of inflammation, and some people below 15 have cirrhosis, but 15, the test characteristics are pretty good. 20 is cirrhosis, and 25 is cirrhosis, and you actually think that the person has portal hypertension.

Dr. Gregory Katz: But the key limitation we should be explicit about is what the FIB-4 and elastography can and cannot tell us. And so they still don’t have any ability to detect active inflammation non-invasively. So MASH still requires a biopsy

Dr. Alejandro Campos Rodriguez: And this really matters. Take two patients with identical FIB-4 elastography scores. One may have active MASH with fibrosis, while the other may only have fibrosis. So in that scenario, a biopsy is the only way to distinguish them.

Dr. Gregory Katz: And if a patient has active inflammation, that distinction between inflammation and fibrosis matters because active inflammation means damage is ongoing and intervening is much more urgent than if there’s just fibrosis without inflammation, where it’s kind of like the damage has already been done.

Dr. Elliot Tapper: The FDA requires that, in order to achieve approval, these drugs must show unpaired liver biopsy that there is a reduction in the steatohepatitis without a worsening of the fibrosis.

Dr. Clement Lee: All right, but there is a problem with doing these invasive tests of biopsy on everyone with concerning FIB-4 or elastography results, and that’s because even biopsy results aren’t that reliable.

Dr. Elliot Tapper: If you took a biopsy from a patient’s left lobe and from their right lobe, many people will have the same fibrosis stage, but at least on four will not. And if you gave the same biopsy to two different pathologists, they will often disagree about the stage. And here’s the problem. Sometimes you’ll give that same biopsy to the same pathologist on two different days, and they will disagree with themselves. So for all those reasons and more, I am not going to require a liver biopsy to manage a patient, and I will arrive at a place that might be more certain using elastography.

Dr. Shreya Trivedi: And Dr. Tapper even acknowledged that what he does in practice might be different from another hepatologist.

Dr. Elliot Tapper: So there’s this drugs that have been approved are now based on biopsy, and some insurers or integrated healthcare systems have followed the letter of the law. After all, if this drug was approved based on a liver biopsy finding, then I should only be dispensing this drug for people with that liver biopsy finding, and you have to sometimes play by that rule.

Dr. Alejandro Campos Rodriguez: So here’s the biopsy paradox. In clinical trials, biopsy is the gold standard, but in clinical practice, we can often manage patients non-invasively using the FIB-4 and elastography. So when we’re thinking about who qualifies for these new drugs, that’s where this tension actually matters.

Dr. Shreya Trivedi: Yeah. And hold that thought because that is a great segue to management. But first, let’s recap the diagnostic tools that we do have. My takeaway is next time if I see steatosis on a long radiology read, I’m going to go ahead and calculate that FIB-4 score. And if it’s over 1.3 in someone who is younger than 65 years old, or if it’s over two in someone older than 65, I’m going to go ahead and advocate for them to get an elastography. And most commonly, you’ll see the FibroScan, which the wonderful Dr. Elliot Tapper says. It’s that special ultrasound to see how much that liver jiggles to assess fibrosis.

Dr. Clement Lee: Yeah. And then we cannot detect inflammation or fibrosis without a biopsy. And the problem is that there can be variability based on where the sample is collected and which pathologist is reading it that day.

Dr. Gregory Katz: So there’s a lot of different layers of uncertainty here. And so this discrepancy among pathologists down the road opens the door to a potential paradigm shift in how we treat the disease. And it makes me wonder, how much do we truly know about the way we’re managing this condition versus how much of how we do things clinically are just based on educated guesses with our current understanding of the physiology.

Dr. Clement Lee: Yeah. I think what you’re describing, Greg, is the tension between being accurate and precise about who truly has fibrosis, but then recognizing that our gold standard isn’t really the gold standard because it’s patchy.

Dr. Shreya Trivedi: Oh, is that a pun, patchy, like patchy areas of fibrosis? Well, that’s what you literally are saying, right?

Dr. Clement Lee: Yeah. So now that we have a way to identify risk and understand the biopsy paradox, let’s move on to the management of MASLD

Dr. Elliot Tapper: And the first thing to know is that as weight loss proceeds, the fat will be removed from the liver and with it eventually, the inflammation and even a remodelling of the fibrosis. So, around 5% body weight loss is enough to start to drain fat from the liver. Around 7.5% body weight loss, you have an extinguishing of that fire, the MASH or metabolic dysfunction-associated steatohepatitis. And then, around 10 to 12.5% body weight loss, you’ll actually see a reduction in the fibrosis.

Dr. Gregory Katz: So that statement is so biologically powerful. Patients so often feel like 10 pounds isn’t an amount of weight loss that’s worth celebrating, but 5% of body weight for a 220 pound patient is 11 pounds. And at that threshold, you’re already starting to see improvements in the liver. This is meaningful biology, and even if it doesn’t show up in the mirror or the way someone’s clothes fit, it’s worth celebrating.

Dr. Shreya Trivedi: I love this idea so much of giving our patients a target, as someone who personally is like a numbers person and very mission-oriented. I love the idea of being like, “Hey, if you lose 7.5% of your weight, we can actually reverse inflammation of the liver.” Or “if we get to 10% weight loss, we can actually see reduction in terms of the stiffness, the fibrosis of the liver.” I think that’s huge enough. I find it very motivating.

Dr. Clement Lee: Yeah, Shreya, I feel like we’re always playing good cop, bad cop in these episodes because I sort of want to say, yeah, 10% weight loss, that feels like a lot. Just through lifestyle alone, I’m not sure that’s very commonly achievable or doable for our patients.

Dr. Gregory Katz: And that discrepancy between what is ideally achievable and what is actually achievable is the whole setup for these trials. We just haven’t had the tools to help our patients produce this weight loss reliably and durably until now.

Dr. Shreya Trivedi: And now onto the two trials, they test two different medicines with the same idea. Fat is toxic, and if we reduce it, then we can reverse the disease, but they do this in two different ways.

Dr. Gregory Katz: Let’s get back to that bathtub analogy. Our tub is overflowing into the liver and causing damage. And if we want to reverse that damage, we can either turn down the rate that the water is draining into the liver or we can take that water out of the liver directly.

Dr. Alejandro Campos Rodriguez: And that’s exactly what these drugs do. Semaglutide slowing down the water coming into the bathtub while resmetirom drains delivered directly.

Dr. Clement Lee: So let’s start with semaglutide, the first of those drugs, which was studied in the ESSENCE trial, and I had to go to clinicaltrials.gov to really find what it stood for, ESSENCE that stands for the Effect of Semaglutide in Subjects with Non-cirrhotic Non-alcoholic Steatohepatitis. This study was registered in 2021, so I’m not taking off too many points for them using the old nomenclature NASH. However, I don’t love that they were calling the participant subjects. It kind of feels sterile. So I’m just going to give this acronym a six out of 10. Final answer.

Dr. Alejandro Campos Rodriguez: I didn’t give it a list an eight. I actually liked it. So talking about the trial, so the ESSENCE trial included about 1200 patients randomized to a 2:1 ratio to semaglutide, 2.4 milligrams versus placebo. And all of these participants had biopsy confirm MASH with F2, F3 fibrosis.

Dr. Shreya Trivedi: Yeah. And then just for context, fibrosis is stage from 0 to 4 with 4 being cirrhosis and then F2, F3, which is these patients in the trial, that is moderate to advanced fibrosis on biopsy.

Dr. Clement Lee: And as Dr. Tapper mentioned before, the co-primary endpoints in these trials are improvement of either MASH or fibrosis without worsening of the other.

Dr. Alejandro Campos Rodriguez: Yeah, and the results were pretty impressive. At 72 weeks with semaglutide, 63% of patients had MASH resolution versus 34% with placebo and 37% had fibrosis improvement with semaglutide versus 22% with placebo.

Dr. Gregory Katz: And the part that I found pretty wild is that semaglutide hasn’t even been proven to directly act on the liver.

Dr. Elliot Tapper: There are no GLP-1 receptors in the liver. When semaglutide is able to produce in a randomized controlled trial, a reduction in fibrosis, it is doing so through general metabolic health, and it is a sign that the liver is basically a bystander in a systemic process.

Dr. Gregory Katz: And so this is the bathtub analogy playing out in the trial data. Semaglutide reduces water in the whole house and thus overflow from the bathtub. And so, that leaves the liver a chance to heal. This tells us something really profound to me. And so fibrosis and MASLD is potentially reversible if you address the upstream metabolic problem, even if you don’t target the liver directly, I mean at least to a point.

Dr. Shreya Trivedi: Oh, fair. But I just want to pause for a second. Did we just say that the placebo arm had 34% resolution of MASH and 22% of the patients had improvement fibrosis with just placebo?

Dr. Elliot Tapper: This is what you see in virtually all drugs that have been studying this because there’s a lot of variability in biopsy reads. There’s a lot of variability in the liver, and of course, people are getting a standard of care lifestyle management, and there might also be regression to the mean.

Dr. Clement Lee: Yeah, that’s fair. It goes back to what we were saying. These biopsies aren’t perfect, but even with that, if you just look at the numbers, 63% versus 34% or 37% versus 22%, I mean, these are large treatment effects by any standard.

Dr. Shreya Trivedi: Yeah. Okay. All right. So that’s the ESSENCE trial and what we saw in terms of data and outcomes. Let’s move on to the second approach to tackle MASLD: resmetirom. This is a thyroid hormone receptor beta agonist. So basically it’s targeting thyroid receptors in the liver, and I was today years old when I learned that there are thyroid receptors in all your liver.

Dr. Clement Lee: Okay. Me too, Shreya.

Dr. Shreya Trivedi: Yes. Thank you for the solidarity.

Dr. Alejandro Campos Rodriguez: Yeah. It’s almost like a liver-specific thyrotoxic state where the liver cells spit up their metabolism and oxidize intrahepatic lipids, which basically burns the accumulated fat.

Dr. Clement Lee: Yeah. What you’re describing sounds like targeted fat reduction in one organ. So you get the metabolic benefits of thyroid hormone in the liver, but you don’t turn the rest of the body thyroid toxic. I mean, that sounds like a win to me.

Dr. Gregory Katz: So, hearing about this mechanism is one of those times when I marvel at just how freaking clever pharmaceutical companies can be. I mean, in the fitness world, this spot reduction idea, this is the concept that you can target fat loss in a specific body area through exercise or intervention. Spot reduction is considered a myth. You don’t do crunches and selectively burn belly fat. You don’t do tricep extensions, and suddenly your arms become thinner. Fat mobilization during exercise is systemic, not local. And so resmetirom, to my knowledge, represents the first time any kind of intervention, pharmacologic or otherwise, has achieved something biologically equivalent to spot reduction, selectively clearing fat from one specific organ, the liver, without requiring systemic weight loss. I mean, it’s like miraculous. It’s just astounding how clever this is.

Dr. Shreya Trivedi: Yeah, Greg, now that you say it out loud, I’m like, yeah, I didn’t think about that. But then, so how did the resmetirom actually do in real life when it came to this trial?

Dr. Alejandro Campos Rodriguez: Yeah, they randomized about 1,000 patients to resmetirom versus placebo and looked at the same endpoints as the ESSENCE trial. They showed mass resolution in 30% with the 100 milligram dose, 26% with the 80 milligram dose and 10% with placebo.

Dr. Gregory Katz: And that 100 milligram dose showed a 52% reduction in liver fat fraction as seen on MRI. And so it emphasizes a lot of the benefits here are probably through the reduction of liver fat.

Dr. Clement Lee: Yeah. So let’s take a look at the fibrosis. Fibrosis improvement occurred in about 26% of patients taking resmetirom 100 milligrams, 24% with 80 milligrams and 14% with placebo.

Dr. Shreya Trivedi: Okay. There is some signal beyond placebo, but what about the safety data? Because I don’t know something about you guys, telling me that a part of our body is becoming thyrotoxic makes me a little nervous.

Dr. Clement Lee: Yeah, it made me a little wary, too, Shreya, but I’ll be honest, a safety profile looks pretty reassuring. Most patients had only mild gastrointestinal side effects, and then there were small decreases in free T4 that remained within the normal range and there were no major thyroid or cardiac signals, which is obviously all of our major concern. And that said, longer-term data will be important for us to watch for additional side effects that pop up.

Dr. Alejandro Campos Rodriguez: Well, now that we’re talking about caveats, I do want to say something about accessibility. Resmetirom costs about $48,000 per year. That’s roughly $170 per tablet.

Dr. Gregory Katz: So that’s like a thousand patients for like 12 generations of rosuvastatin and metformin. Hearing those numbers is the first time I think literally in my whole life I have ever felt sympathy for the person on the other end of that prior authorization phone call.

Dr. Shreya Trivedi: It’s painful on all sides.

Dr. Gregory Katz: Yeah. But once we get past all of those caveats and obstacles, let’s take a step back and look at MASLD and MASH from an intellectual perspective. We have this condition that has been kind of impossible to treat for a generation, except when patients get sick enough to need a liver transplant. And now we have two drugs, two totally different mechanisms, no overlap in how they work and both of them lead to improvement or even remission of this condition. We’ve had so many wow moments when we talk about new medical research on this podcast, but these two trials, MAESTRO-NASH and ESSENCE, these are wow moments for me.

Dr. Shreya Trivedi: Yeah. And then the fact that both of them work is just strong evidence for that underlying hypothesis being correct, that hypothesis that liver fat is toxic. And so if you reduce it in whatever way you can, if we reduce that fat, we can reverse inflammation and even fibrosis, which is a pretty remarkable validation for that excess fat toxicity model.

Dr. Elliot Tapper: By and large, the person with MASH with F2 or F3 fibrosis, what that person really needs is a resolution of the underlying condition that led their liver to be sick in that way. And that’s why weight loss is number one through whatever means possible. If it happens through diet, fantastic. If it happens through bariatric surgery or pharmacologic therapy, also awesome. And then in sequence, if that person still has a high risk for cirrhosis or F3 fibrosis, that’s a person that definitely needs one of these liver-directed therapies, the resmetiroms, the epruxifirmin. You’ll have some people advocate that you can use both drugs in combination. But again, our goal is to reduce overall morbidity and mortality. It begins with treating the underlying cause, the insulin resistance, the cardiovascular risk. And then if you’re still stuck with liver risk, and you would address that, that’s my opinion.

Dr. Gregory Katz: So I just want to point out in the vein of understanding morbidity, mortality, the totality of how these drugs work, that we don’t actually have data about how these drugs are going to impact HCC risk or even all-cause mortality. Patients might not necessarily care about their liver histology until we have evidence that we have benefit of these other outcomes. And so these trials are really, really promising and exciting, but they’re not definitive.

Dr. Alejandro Campos Rodriguez: Actually, more to come on that. Both of these trials will look at long-term clinical outcomes and liver-related events, including progression to cirrhosis. And I just have to add, when researching for this episode, I was amazed by how much more is coming. There are ongoing studies looking at FGF21 analogues, PPAR agonists, and other incretin mimetics like tirzepatide.

Dr. Elliot Tapper: It was in the trial of tirzepatide that we saw the most robust reductions in fibrosis. And lo and behold, what was the body weight loss that was observed on average? 10%.

Dr. Shreya Trivedi: Again, hearing how powerful that 10% weight loss is just makes someone like me who’s a numbers person really excited. I love a goal, I love a mission, yes. But unfortunately, it hits home personally for me because my mom, I don’t know why she had this right precaution ultrasound so many years ago, but there was some steatosis noted, and I so wish I’d known this, that I could have used that in terms of motivation for weight loss for her. And sadly, the issue just got swept under the radar for years. And even as I learned more about MASH and remember something about steatosis, I still felt like I didn’t know how to manage it and how and when things should be repeated.

Dr. Gregory Katz: So I look at a patient like your mom, and I look at these two trials, and to me, this is really good evidence that a patient like your mom should be followed longitudinally over time. It doesn’t necessarily need action at this moment, but now that we have these treatment options, we should be following people and making clinical decisions about when to intervene pharmacologically.

Dr. Elliot Tapper: You are fully empowered to repeat that FibroScan a year or two later and then celebrate with the patient or demonstrate that things have gotten more serious. The stakes are higher. You went from 10 to 14. Okay, what didn’t we do since the last time that we met? Or you went from an 11 to a 6, you can fire your hepatologist.

Dr. Clement Lee: Wow, I feel like that’s revolutionary that thought that you might be able to fire a hepatologist or graduate from a liver clinic. I mean, this makes me think a lot about the future of MASLD.

Dr. Elliot Tapper: So, what I think the future is, is that earlier liver disease, like what the Biopsy would’ve said at F210, maybe elevated ALT. This is not going to be a hepatology patient. This is going to be someone that is managed through easily prescribed, largely well-tolerated medications firmly within the wheelhouse of primary care clinicians who are likely or honestly superior in motivational interviewing and lifestyle management compared to a hepatologist. Then the hepatologist, as regards MASH, NASH are going to become cirrhosisologists where your non-invasive tests that you either knew about or were clued into through things like best practice advisories that were wired into the electronic health record would identify the patient who is at risk for liver cancer or decompensation and ought to be followed by a hepatologist.

Dr. Shreya Trivedi: That is a great premonition to put out there that the hepatologists are going to be mostly cirrhosisologists. But I think for any of this to happen, the big knowledge translation piece here and something I definitely have to get better at doing is that when we do see steatosis on some long radiology read, we need to go ahead and plug in that patient’s age, AST, ALT, platelet count, and make sure they are at low risk for fibrosis.

Dr. Elliot Tapper: And so what I would say for most clinicians is to make sure that your patient is at low risk for advanced fibrosis, and if they are at higher risk for it, to intensify management and now and in the future, there will be increasingly more tools available to address this problem.

Dr. Gregory Katz: And so let’s look at ESSENCE and MAESTRO-NASH as calls to action. MASLD and MASH are finally treatable conditions. And so when we are on the front lines, we see steatosis on imaging and ALT of 55. Even if we’re not treating it immediately, this is something to talk about to the patient or flagging it in a discharge summary as something that should be looked at and monitored down the road. If we can identify people for risk for cirrhosis, that’s a win. I mean, cirrhosis sucks, and we’ve all seen people who have miserable lives and miserable deaths who have cirrhosis when they’re in the hospital. And so this is something that I personally am transitioning from nihilism to optimism about treating.

Dr. Shreya Trivedi: Yeah, definitely. I think it’s so great that we have more tools to help us along the way and more options to manage this durably over time. I think, as Dr. Tapper said, beginning, it validates this disease in a way that hopefully can move the needle forward.

Dr. Gregory Katz: And with that, that’s a wrap for today’s episode. If you got something from this episode, please send it to somebody that you work with and share it with them so that they can learn too.

Dr. Shreya Trivedi: And as always, we love hearing feedback. Please email us at hello@coreimpodcast.com. Opinions expressed are our own and do not represent the opinions of any affiliated institutions. Thank you and take care.

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