#211 Breaking Down MASLD vs. MASH and the MAESTRO-NASH & ESSENCE Trials: Beyond Journal Club Segment

[SPEAKER_01]: By and large, we are numb to the noise of stayatotic liver disease. [SPEAKER_01]: You see it all of the time on every scan that is ordered. [SPEAKER_01]: An abnormal ALT is now normal. [SPEAKER_01]: A normal ALT is so rare in most of our patient panels, and what these studies and drug approvals mean, [SPEAKER_01]: is that this is the time to re-evaluate our own patients for their risk of liver related events. [SPEAKER_01]: So there's a lot of hope bound up in it.

[SPEAKER_01]: Now that we have things that we can do, it validates the condition. [SPEAKER_00]: That's Dr. Elliott Tupper at the Academic Chief's Epitology at the University of Michigan Health. [SPEAKER_03]: Welcome to Beyond Journal Club, a collaboration between Koir and any jam group. [SPEAKER_00]: The goal of B&R to clubs take landmark clinical trials and put them into contact, telling you the story of how we got to where we are, and then what it means to take care of our patients.

[SPEAKER_00]: I'm Dr. Scherbadi, an interdiscipate at EMC. [SPEAKER_04]: I'm Dr. Greg Katz, cardiologist at NYU. [SPEAKER_04]: I'm Dr. Clinton Lee, and that beef hospital isn't Boston, and it gets editor at NEJM. [SPEAKER_04]: And I'm Dr. LeCundergampos, and the drill fellow at NEJM. [SPEAKER_04]: All right, so today we're talking about Masold D, whereas some people call it Masold, and Masch, as well as two approved drugs that help improve liver fibrosis in these conditions.

[SPEAKER_00]: but here's the problem. [SPEAKER_00]: I think most of us don't actually have a mental model for stiototic liver disease. [SPEAKER_00]: So today, we're actually going to start with one a simple framework for why this disease happens. [SPEAKER_00]: Two had a screen and then wrist stratify. [SPEAKER_00]: And then three, the trials. [SPEAKER_00]: Essins and mystro-nash publish in the new lindronal of medicine in April 2025 and February 2024, respectively.

[SPEAKER_03]: 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 to completely different mechanisms of action.

[SPEAKER_03]: So bathtub analogy feels a little bit odd, but like, go with us. [SPEAKER_03]: And so, thank you to your body like a house and fat is water. [SPEAKER_03]: The bathtub is your storage of water, that subcutaneous fat. [SPEAKER_03]: And subcutaneous fat is designed to safely store access water that comes into the house. [SPEAKER_03]: Yeah, I'll make sure I get the first time I've heard of this analogy. [SPEAKER_04]: But what happens when this tub starts to overflow?

[SPEAKER_02]: Now, fat spills into places that dust will belong and starts to get into the walls, a defoundation, and other rooms. [SPEAKER_02]: In this analogy, that is deliver, muscle, pancreas, and around heart. [SPEAKER_00]: Yeah, and then here's the thing, every single person is born with a different size bathtub, right? [SPEAKER_00]: Their ability to accumulate different amounts of subcuhiness fat is different, and then [SPEAKER_00]: Now, visceral fat is different from subcutaneous fat.

[SPEAKER_00]: It is toxic stuff that is going to cause the problems. [SPEAKER_00]: The metabolic syndrome, the muscle D, the type of diabetes, these are all different expressions of the same underlying problem. [SPEAKER_00]: Too much water in the bathtub that's overflowing to the vital areas of the house or into our bodies. [SPEAKER_03]: So, massled metabolic dysfunction associated stiototic liver disease isn't really just a liver disease.

[SPEAKER_03]: It's what happens when the whole system gets overwhelmed. [SPEAKER_01]: So the first thing to recognize is that massled is a systemic disorder. [SPEAKER_01]: It is the liver manifestation of the metabolic syndrome. [SPEAKER_01]: Fat in the liver is just another risk factor for heart attack and stroke. [SPEAKER_00]: Right, and here's this key shift. [SPEAKER_00]: When we see hepatectatosis on imaging, we shouldn't be thinking, oh, this is a liver problem.

[SPEAKER_00]: We should actually think, okay, our patients carry a metabolic risk just when up. [SPEAKER_03]: Yeah, so I co-sign that so strongly. [SPEAKER_03]: Masled crosses disciplines of medicine in a way that so few diseases do. [SPEAKER_03]: And so when I started cardiology fellowship, I would have never imagined a radiology report with the words of paddocks, the atosis, would make me better understand a patient's cardiometabolic risk, but it does. [SPEAKER_00]: Yeah, it's same here.

[SPEAKER_00]: I think the thing that trips me up though is that I definitely seen patients with a normal BMI who end up having massled or massled D.E. [SPEAKER_00]: And then I've definitely seen people who are obese that don't have it. [SPEAKER_04]: Yeah, I think the best way to explain this goes back to the analogy. [SPEAKER_04]: It's just that different people have different sized bathtubs, meaning everyone has a different capacity to store that fat sub-nutaneously.

[SPEAKER_02]: Yeah, a big tub means that someone can store a lot more at a prestigious opportunity before it overflows to the organs. [SPEAKER_02]: On the other hand, is Maltav means that overflow happens early. [SPEAKER_00]: 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 capacities store fat sub-bechanously.

[SPEAKER_00]: So, unfortunately, when there's excess fat, they're more likely to accumulate around visceral organs and, of course, that means higher cardiovascular metabolic risk. [SPEAKER_02]: In fact, that's one of the reasons why BMI alone can be misleading. [SPEAKER_03]: And the analogy has even more complexity. [SPEAKER_03]: I mean, after that overflow happens, not everyone develops the same damage, where the fact goes is different. [SPEAKER_03]: If it goes to the liver, that's massled.

[SPEAKER_03]: If it goes to the pancreatic beta cells, that inhibits our ability to produce insulin. [SPEAKER_03]: If it's deposited in the muscle, there may be more peripheral insulin resistance. [SPEAKER_04]: In other words, the capacity to handle excess out of post-issue is genetic, among other things, and so is which organs the extra fat goes to. [SPEAKER_04]: That's why the clinical picture can be so heterogeneous across different patients.

[SPEAKER_00]: Okay, so say your patient does have excess out of postissue. [SPEAKER_00]: That's gone to liver. [SPEAKER_00]: It could be muscle, it could be mesh, or another acronym that I'm forgetting where might not be invoked anymore. [SPEAKER_00]: How should we think about this?

[SPEAKER_01]: So metalty 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.

[SPEAKER_01]: If you see fat in the context of the metabolic syndrome, that is straight up metabolic dysfunction associated state type liver disease, which I will call [SPEAKER_01]: it's just totally random, and if it catches on fire, metabolic dysfunction associated, stay out of hepatitis.

[SPEAKER_02]: And willing to a graphic that breaks down to the Stingtians month, this did not agree with his thesis, but for the purpose of this episode, a simple word to think about is, mass-old equals fat and deliver, and mass equals fat plus information.

[SPEAKER_00]: Yeah, I always mix up those two and which one I should worry about more, but then you 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 after words and that's something we do not like, no ash, no mash. [SPEAKER_04]: I like that, Australia. [SPEAKER_04]: I think that's what I'm going to keep in my backpacker for the future.

[SPEAKER_00]: Yes. [SPEAKER_04]: And the whole reason we care about this is that MASH accelerates the progression to fibrosis dramatically. [SPEAKER_04]: And fibrosis, or scarring, of the liver, is what really determines clinical outcomes. [SPEAKER_04]: And advanced fibrosis in pairs liver function and can progress to list the poor outcomes we've all seen in the hospital.

[SPEAKER_04]: Like decompensitous rocis, not a cellular carcinoma, the need for liver transplant, higher risk of deaths, et cetera. [SPEAKER_02]: The news would get streaky, only 7 to 35% of patients with mass health develop mass each year. [SPEAKER_00]: Oh, so then most people with that deliver will never have mass or that active Stia hepatitis or that liver on fire, that's good news.

[SPEAKER_03]: And that heterogeneity is because some people's liver cells are just more vulnerable to lipotoxic injury. [SPEAKER_03]: And so to keep going with our house, spath tobenology, their wiring is just more fragile. [SPEAKER_03]: And unfortunately, we can't yet identify a head of time who's going to have fragile wiring and who doesn't. [SPEAKER_03]: And that's where screening comes in. [SPEAKER_00]: Ah, yes, great segue to screening and staging, but what we do, let us summarize.

[SPEAKER_00]: So in terms of spectrum, if you see muscle, that means there's fat in a liver, if you see metalde, there's some alcohol involved also. [SPEAKER_00]: Both of this though can lead to mash and remember, the ash and mash means that their liver is on fire, there is inflammation, and that is particularly bad because mash accelerates fibrosis.

[SPEAKER_00]: and fibrosis, let's climb and mention is what we care about because it's shown to be the primary determinant of all the bad things, right? [SPEAKER_00]: Cerosis, hepatocelicarsinoma, and other badders.

[SPEAKER_00]: So clinically, what I'm taking away is that we all need to make a mental shift that when we do see stiotosis on that long imaging report, the next question should be, does my patient have fibrosis? [SPEAKER_00]: And if so, how much? [SPEAKER_00]: Because it's that fibrosis that's tied to outcomes. [SPEAKER_02]: And this first step is to calculate something called a fibrosis for index, or feed for index.

[SPEAKER_02]: All you need is the patient's age, the playlet count, and ASTNAL two values. [SPEAKER_02]: And it has good sense to be for really outstanding significant fibrosis one. [SPEAKER_02]: This course, low. [SPEAKER_01]: If the number is less than 1.3, then you're good to go. [SPEAKER_01]: If the number is over 1.3, you might want to do another test like Elastography. [SPEAKER_01]: But if the number is over 2.67, that's the highest risk person.

[SPEAKER_04]: All right, so I think I can remember that less than 1.38 means a low risk for fibrosis. [SPEAKER_03]: Yeah, and one age-related nuance is that the fib for uses ages of component and that inflates the score on older patients. [SPEAKER_03]: Score over 2 and someone over 65 is about equivalent to a score of 1.3 in a younger patient. [SPEAKER_03]: And so we need to keep that in mind before we reflexely send every older patient for your lastography.

[SPEAKER_00]: Yeah. [SPEAKER_00]: So I guess what I'm taking away is if I see a thin force or over 1.3 in someone younger than 65, or if I see a thin force or over 2 in a patient, over 65 years old, that means yes, go ahead proceed to less photography, and there's many different times of less photography, and I think the one that most of us are familiar with, or we'll hear about is the fibroscan.

[SPEAKER_01]: I go to is vibration control, triasing teleastography, which has a brand name of Fibroskin, although there are other alternatives that assess the viscoalastic properties of the liver. [SPEAKER_01]: 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 hyprotensive events.

[SPEAKER_00]: Uh, I don't know why that visual of like, we're just seeing how the liver jiggles is so memorable to me and I have since explained that just so many patients and they're like, okay, let's go see how my liver jiggles and if it's stiff or not, anyways, I just it's so cute, but then once you order it and you get the test results back, in terms of interpreting that less photography, they're thankfully the good way to remember the cutoffs and what it means.

[SPEAKER_01]: And this is how this has transformed our way of communicating to patients the rule of five. [SPEAKER_01]: Five, Stone Cold Normal, okay? [SPEAKER_01]: Less than 10, low risk. [SPEAKER_01]: 10 or above, you're at high risk for something called compensated advanced chronic liver disease. [SPEAKER_01]: So 10, substance up. [SPEAKER_01]: 15, cirrhosis.

[SPEAKER_01]: This is like 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. [SPEAKER_01]: 20 is cirrhosis and 25 is cirrhosis and you actually think that the person has portal hypertension. [SPEAKER_03]: But the key limitation we should be explicit about is what the PIV-4 in Elastography can and cannot tell us.

[SPEAKER_03]: And so they still don't have any ability to detect active inflammation noninvacely, so MASH still requires a biopsy. [SPEAKER_02]: Yeah, and this really matters. [SPEAKER_02]: Like, take two patients with identical PIV-4 and Elastography's course. [SPEAKER_02]: One may have active MASH with fibrosis, well, the other may only have fibrosis. [SPEAKER_02]: So in that scenario, BAHPS is the only way to this Tinguish time.

[SPEAKER_03]: And if a patient has active inflammation, that distinction between inflammation and fibrosis matters, because active inflammation means damage is ongoing. [SPEAKER_03]: And intervening is much more urgent than if there's just fibrosis with that inflammation, where it's kind of like the damage has already been done.

[SPEAKER_01]: the FDA requires that in order to achieve approval, these drugs must show unpaired liver biopsy that there is a reduction in this stiato hepatitis without a worsening of the fibrosis. [SPEAKER_04]: All right, but there's a problem with doing these invasive tests of biopsy on everyone with concerning fit for or elastography results. [SPEAKER_04]: And that's because even biopsy results aren't that reliable.

[SPEAKER_01]: If you took a biopsy from a patient's left load and from their right load, many people will have the same fibrosis stage, but at least one in four will not. [SPEAKER_01]: And if you gave the same biopsy to two different pathologists, they will often disagree about the stage. [SPEAKER_01]: And here's the problem. [SPEAKER_01]: Sometimes you'll give that same biopsy to the same pathologist on two different days. [SPEAKER_01]: and they will disagree with themselves.

[SPEAKER_01]: So for all of 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. [SPEAKER_00]: And Dr. Tapri, even acknowledge that what he does in practice might be different from another hepatologist. [SPEAKER_01]: So, there's this drugs that have been approved, are now based on biopsy, and some insurers or integrated healthcare systems are followed the letter of a law.

[SPEAKER_01]: 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. [SPEAKER_02]: So here's the biopsy paradox. [SPEAKER_02]: In clinical trials, biopsy is the goal standard burning. [SPEAKER_02]: Clinical practice we can often manage patients non-invasively using the fit for and L's topography.

[SPEAKER_02]: So when we're thinking about who qualifies for these new drugs, that's where these tension actually matters. [SPEAKER_00]: Yeah, and hold that thought because that is a great segue to management. [SPEAKER_00]: But first, let's recap the diagnostic tools that we do have. [SPEAKER_00]: My takeways next time, if I see stiotosis on a long radiology read, I'm going to go ahead and cathode that fifth force core.

[SPEAKER_00]: And if it's over one way or three in someone who is younger than 65 years old, or if it's over two in someone older than 65, [SPEAKER_00]: I'm going to go ahead and advocate for them to get an illustrationography and most commonly you'll see the fibroscan, which the wonderful doctor, Elliott Taber says, it's that special ultrasound to see how much that lever jiggles to assess fibrosis. [SPEAKER_04]: Yeah, and then we can not detect inflammation or fibrosis without a biopsy.

[SPEAKER_04]: And the problem is that there can be variability based on where the sample is collected in which pathologist is reading it that day. [SPEAKER_03]: So there's a lot of different layers of uncertainty here. [SPEAKER_03]: And so this discrepancy among pathologists down the road opens the door to a potential paradigm shift in how we treat the disease.

[SPEAKER_03]: 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. [SPEAKER_04]: 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.

[SPEAKER_00]: Oh, is that a pun patchy like patchy areas of fibrosis? [SPEAKER_00]: Well, that's what you literally are saying, right? [SPEAKER_04]: Yeah.

[SPEAKER_04]: So now that we have a way to identify risk and understand the biopsy paradox, let's move on to the management of massled. [SPEAKER_01]: 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 remodeling of the fibrosis. [SPEAKER_01]: So, around 5% body weight loss is enough to start to drain fat from the liver.

[SPEAKER_01]: Around 7.5% body weight loss, you have an extinguishing of that fire the mesh, or metabolic dysfunctional socioecia, or hepatitis. [SPEAKER_01]: And then, about around 10 to 12.5% body weight loss, you'll actually see a reduction in the fibrosis. [SPEAKER_03]: So that statement is so biologically powerful. [SPEAKER_03]: Patients so often feel like 10 pounds isn't an amount of weight loss that's worth celebrating.

[SPEAKER_03]: But 5% of body weight for 220 pound patients is 11 pounds. [SPEAKER_03]: And at that threshold, you're already starting to see improvements in the liver. [SPEAKER_03]: This is meaningful biology. [SPEAKER_03]: And even if it doesn't show up in the mirror or the way someone's clothes fit, it's worth celebrating.

[SPEAKER_00]: Yeah. [SPEAKER_00]: I love this idea so much of giving our patients a target as someone who personally is like a numbers person and I'm like very mission oriented. [SPEAKER_00]: I love the idea of being like, hey, if you lose 7.5% of your weight, we can actually reverse information on the liver. [SPEAKER_00]: Or if we get to 10% weight loss, we can actually see reduction in terms of the stiffness of the fibrosis of the liver. [SPEAKER_00]: I think that's huge enough.

[SPEAKER_00]: I find it very motivating. [SPEAKER_04]: Yeah, sure. [SPEAKER_04]: 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 like just through lifestyle alone. [SPEAKER_03]: I'm not sure that's very commonly achievable or doable for a patient's and that discrepancy between what is ideally achievable and what is actually achievable is the whole setup for these trials.

[SPEAKER_03]: We just haven't had the tools to help our patients produce this weight loss reliably and derbly until now. [SPEAKER_00]: And now onto the two trials, they test two different medicines of same idea. [SPEAKER_00]: Fat is toxic, and if we reduce it, then we can reverse the disease. [SPEAKER_00]: But they do this in two different ways. [SPEAKER_03]: Let's get back to that bathtub analogy. [SPEAKER_03]: Our tub is overflowing into the liver and causing damage.

[SPEAKER_03]: 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. [SPEAKER_02]: and that's exactly what these drugs do. [SPEAKER_02]: Some magulitate works by slowing down. [SPEAKER_02]: The water coming into the bathtub, while resmetterone trains delivered directly.

[SPEAKER_04]: So let's start with the Magatide, the first of those drugs, which was studied in the essence trial, and I had to go to clinical trials.gov to really find what it stood for, essence. [SPEAKER_04]: But it stands for the effect of some agatite in subjects with non-serotic, non-Akohalic, state of hepatitis. [SPEAKER_04]: This study was registered in 2021, so I'm not taking up too many points for them using the old nomenclature, Nash.

[SPEAKER_04]: However, I don't love that they were calling the participant subjects, it kind of feels sterile. [SPEAKER_04]: So I'm just gonna give this acronym a six at a time, [SPEAKER_02]: I didn't give it a least to me, but I actually liked it. [SPEAKER_02]: So talking about the trial, so the essence trial, included about 1200 patients, randomized to the one ratio, to the semacolytide, to 0.4 milligrams versus placebo.

[SPEAKER_02]: And all of this participants had bioticum for mash with F2F3 fibrosis. [SPEAKER_00]: And then just for context fibrosis, the stage from zero to four with four being cirrhosis, and then F2F3, which is, you know, these patients in the trial, that is moderate to advanced fibrosis on biopsyden. [SPEAKER_04]: And as Dr. Tapper mentioned before, the co-primer endpoints in these trials are improvement of either mesh or fibrosis without worsening of the other.

[SPEAKER_02]: Yeah, and the results were pretty impressive. [SPEAKER_02]: At 72 weeks with tobacco type, 63% of patients had mass resolution versus 34% with placebo. [SPEAKER_02]: And 37% had fibrosis and proven with tobacco type versus 22% with placebo. [SPEAKER_03]: And the part that I found pretty wild is that semadoutide hasn't even been proven to directly act on the liver. [SPEAKER_01]: There are no GOP-1 receptors in the liver.

[SPEAKER_01]: When semi-glutide is able to produce an randomized control 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. [SPEAKER_03]: And so, this is the bathtub analogy playing out in the trial data. [SPEAKER_03]: Samagotide reduces water in the whole house and dusts overflow from the bathtub. [SPEAKER_03]: And so, lat leaves the liver a chance to heal.

[SPEAKER_03]: This tells us something really profound to me. [SPEAKER_03]: And so, fibrosis and massled is potentially reversible if you address the upstream metabolic problem. [SPEAKER_03]: Even if you don't target the liver directly, but I mean, it'll at least two a point. [SPEAKER_00]: Oh, fair. [SPEAKER_00]: But I just want to pause for a second, like, do we just say that the placebo arm had 34% resolution of mash and 20% of the patients had improvement fibrosis with just placebo?

[SPEAKER_01]: This is what you see in virtually all drugs that have been studying this because there's a lot of variability in biopsy reads. [SPEAKER_01]: There's a lot of variability in the liver and, of course, people are getting a standard of care, lifestyle management, and it might also be like regression to the meat. [SPEAKER_04]: Yeah, that's fair. [SPEAKER_04]: It goes back to what we were saying.

[SPEAKER_04]: These biopsies aren't perfect, but even with that, if you just look at the numbers, 63% versus 34% or 37% versus 22%. [SPEAKER_04]: I mean, these are large treatment effects by any standard.

[SPEAKER_00]: Yeah, okay. [SPEAKER_00]: All right. [SPEAKER_00]: So that's the essence trial and what we saw in terms of data and outcomes. [SPEAKER_00]: Let's move on to the second approach to tackle massled Resbetteron. [SPEAKER_00]: This is a thyroid hormone receptor beta-agnes. [SPEAKER_00]: So basically, it's targeting thyroid receptors in the liver. [SPEAKER_00]: And I was today years old when I learned that there are thyroid receptors in your liver. [SPEAKER_02]: Okay, me too, Shraya.

[SPEAKER_00]: Yes. [SPEAKER_00]: Thank you for the solidarity. [SPEAKER_02]: Yeah, it's like almost like a liver-specific thyratoxic state, or the liver, cells, spit up their metabolism and oxidize inter-happotic lipids, which basically burns the accumulated fat. [SPEAKER_04]: 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 thyratoxic.

[SPEAKER_04]: I mean, that sounds like a win to me. [SPEAKER_03]: 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. [SPEAKER_03]: Spot reduction is considered a myth. [SPEAKER_03]: You don't do crunches and selectively burn belly fat.

[SPEAKER_03]: You don't do trisepic extensions and suddenly your arms become thinner. [SPEAKER_03]: Fat mobilization during exercise is systemic, not local, and so resmeterum to my knowledge represents the first time any kind of intervention pharmacologic or otherwise has achieved something biologically equivalent to spyroduction, selectively clearing fat from one specific organ, the liver, without requiring systemic weight loss. [SPEAKER_03]: I mean, it's like miraculous.

[SPEAKER_03]: It's just astounding out clever. [SPEAKER_03]: This is [SPEAKER_00]: Yeah, Greg, now that you say it out loud and like, yeah, I didn't think about that, but then so how did the res matter on actually do in real life when it came to this trial? [SPEAKER_02]: Yeah, they randomized about a thousand patients to risk matter numbers as placebo and looked at the same endpoints as the essence trial.

[SPEAKER_02]: They showed mass resolution in 30% with the 100 million dose, 26% with the 80 million dose, and 10% with placebo. [SPEAKER_03]: And that 100 million gram dose showed a 52% reduction in liver fat fraction as seen on MRI. [SPEAKER_03]: And so it emphasizes like a lot of the benefits here are probably through the reduction of liver fat.

[SPEAKER_04]: Yeah, so let's take a look at the fibrosis fibrosis improvement occurred in about 26% of patients taking risk matter on 100 milligrams, 24% with 80 milligrams and 14% with placebo. [SPEAKER_00]: Okay, there is some signal beyond placebo, but what about the safety data? [SPEAKER_00]: Because I don't know something about you guys telling me that a part of our bodies becoming thyrotoxic makes feel little nervous.

[SPEAKER_04]: Yeah, it made me a little wary too, Shreya, but I'll be honest, a safety profile looks pretty reassuring. [SPEAKER_04]: Most patients had only mild gastrointestinal side effects, and then there were small decreases in free G4 that remained within the normal range. [SPEAKER_04]: And there were no major thyroid or cardiac signals, which is obviously all of our major concern.

[SPEAKER_02]: And that said, longer term data will be important for us to watch for additional side effects I've helped up. [SPEAKER_02]: Well, now that we're talking about caveats, I do want to say something about accessibility. [SPEAKER_02]: There's a matter I'm cost about $48,000 per year. [SPEAKER_02]: That's roughly $170 per tablet. [SPEAKER_03]: Yeah, so that's like a thousand patients for like 12 generations of Rusus that in a minute format. [SPEAKER_03]: Here are those numbers.

[SPEAKER_03]: 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. [SPEAKER_00]: Uh, it's painful on all sides. [SPEAKER_00]: Oh, yeah. [SPEAKER_03]: But once we get past all of those caveats and obstacles, let's take a step back and look at mass-old and mash from an intellectual perspective.

[SPEAKER_03]: 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. [SPEAKER_03]: 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.

[SPEAKER_03]: We've had so many wow moments when we talk about new medical research on this podcast, but these two trials, mystronash, and essence, like these are wow moments for me.

[SPEAKER_00]: Yeah, and then the fact that both of the work is just strong evidence for that underlying hypothesis being correct, right, that hypothesis, 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. [SPEAKER_01]: By and large, the person with mesh with F2 or F3 fibrosis.

[SPEAKER_01]: But that person really needs is a resolution of the underlying condition that led their liver to be sick in that way. [SPEAKER_01]: And that's why weight loss is number one through whatever means possible. [SPEAKER_01]: If it happens through diet, fantastic. [SPEAKER_01]: If it happens through bariatric surgery or pharmacologic therapy, also awesome.

[SPEAKER_01]: And then in sequence, if that person still paths, [SPEAKER_01]: a high-risk for cirrhosis or F3 fibrosis, then a person that definitely needs one of these liver-directed therapies, the resumerums, the effects of fern. [SPEAKER_01]: You'll have some people advocate that you can use both drugs in combination, right? [SPEAKER_01]: But again, our goal is to reduce overall morbidity and mortality.

[SPEAKER_01]: 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. [SPEAKER_01]: That's my opinion.

[SPEAKER_03]: So I just want to point out, in the vein of understanding morbidity and 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. [SPEAKER_03]: Patients might not necessarily care about their liver histology until we have evidence that we have benefit of these other outcomes. [SPEAKER_03]: And so these trials are really, really promising and exciting, but they're not definitive.

[SPEAKER_02]: Actually, more to come on that, both of these trials will look at long-come-click-aloud counts and live a related events, including progression to cirrhosis. [SPEAKER_02]: And I just have to add, when research in for this episode, I was amazed by how much more is coming. [SPEAKER_02]: There are ongoing studies looking at FGF21 analogs, PPR agonists, and other engine medics like Dersepadach.

[SPEAKER_01]: It was in the trial of Thursday that we saw the most robust reductions in fibrosis and lower and behold, what was the body weight loss that was observed on average 10%. [SPEAKER_00]: Again, hearing how powerful that 10% weight loss is just makes someone like me who's like a numbers person really excited. [SPEAKER_00]: Like I love a goal. [SPEAKER_00]: I love a mission. [SPEAKER_00]: Yes. [SPEAKER_00]: But unfortunately, it's home personally for me. [SPEAKER_00]: It is my mom.

[SPEAKER_00]: I don't know why she had this right [SPEAKER_00]: But there were some Stiatosis 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, like the issue just got swept on the radar for years, and even as I learned more about Mazel and remember something about Stiatosis, like I still felt like it didn't know how to manage it, and how and when things should be repeated.

[SPEAKER_03]: 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 doesn't necessarily need action at this moment. [SPEAKER_03]: But now that we have these treatment options, we should be following people and making clinical decisions about when to intervene pharmacologically.

[SPEAKER_01]: You are fully empowered to repeat that five is going to year or two later, and then celebrate with the patient or demonstrate that things have gotten more serious, like the stakes are higher. [SPEAKER_01]: You went from 10 to 14? [SPEAKER_01]: Okay, like what didn't we do when since the last time that we met or you went from an 11 to a six, you can fire your epitologist. [SPEAKER_04]: Wow, I feel like that's for evolutionary.

[SPEAKER_04]: That's not that you might be able to fire and have a tallad just for a graduate from liver clinic. [SPEAKER_04]: It just makes me think a lot about the future of Masold. [SPEAKER_01]: So what I think the future is is that earlier liver disease, like what the biopsy would have said in F2-1-0, right, maybe elevated ALT. [SPEAKER_01]: This is not going to be a hepatology patient, right?

[SPEAKER_01]: 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

[SPEAKER_01]: And then the epitologist, as regards, mash, mash, are going to become cirrhosisologist, 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 epitologist.

[SPEAKER_00]: Uh, that is a great premonition put out there that the hepatologists are going to be mostly cirrhosisologist, but I think for any of this to kind of happen, the big knowledge translation piece here and something I definitely have to get better at doing is that when we do see stytosis on some long radiology read, we need to go ahead and plug in that patient's age, AST, ailed, platelet count, and make sure they are at low risk for fibrosis.

[SPEAKER_01]: 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. [SPEAKER_01]: And now and in the future there will be increasingly more tools available to address this problem. [SPEAKER_03]: So let's look at Essence and MysterNash as calls to action. [SPEAKER_03]: Masled and Mash are finally treatable conditions.

[SPEAKER_03]: And so when we are on the front lines, we see Stiatose's Unimaging and ALT of 55. [SPEAKER_03]: Even if we're not treating it immediately, this is something to talk about to the patient or flagging into discharge summary as something that should be looked at and monitored down the road. [SPEAKER_03]: If we can identify people for risk for cirrhosis, that's a win.

[SPEAKER_03]: 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. [SPEAKER_03]: And so this is something that I personally have transitioning from nihilism to optimism about treating. [SPEAKER_00]: Yeah, definitely. [SPEAKER_00]: I think it's so great that we have more tools to help us along the way, and more options to manage this terribly over time.

[SPEAKER_00]: I think as Dr. Tapper said, beginning to evaluate his disease in a way that hopefully can [SPEAKER_03]: I'm with that. [SPEAKER_03]: That's a wrap for today's episode. [SPEAKER_03]: 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 to. [SPEAKER_00]: And as always, we love hearing feedback. [SPEAKER_00]: Please email us at helloacquariempotcast.com.

[SPEAKER_00]: Appingings Express are our own and do not represent the opinions of any affiliate institutions. [SPEAKER_00]: Thank you and take care. [SPEAKER_00]: Okay, mash is the one that is more badness. [SPEAKER_00]: It's all badness, but worse of the badness. [SPEAKER_03]: I should not say free to do that. [SPEAKER_03]: That's okay. [SPEAKER_03]: No. [SPEAKER_03]: I mean, you could probably say badness one fewer times.

[SPEAKER_03]: Yeah. [SPEAKER_00]: I felt myself judging myself when I was doing it. [SPEAKER_00]: I was like, okay, let me try it again. [SPEAKER_04]: But then recognizing that our gold standard isn't really the gold standard because it's patchy. [SPEAKER_00]: Is that a pun, patchy, like patchy, or is a pie process? [SPEAKER_00]: Well, it's what you literally are saying, right? [SPEAKER_04]: Yeah. [SPEAKER_04]: It sounds better to better release my lens.

[SPEAKER_00]: I'm not sure what the pun is, but it's literally patchy. [SPEAKER_04]: Well, just have you say that in a little sweeper. [SPEAKER_03]: We should have you explain the joke because a joke that is well-explained usually lands you'll be well. [SPEAKER_03]: We're going to have you explain the joke. [SPEAKER_03]: Like if you have been one whole minute having you explain the joke. [SPEAKER_00]: It's like me out a minute. [SPEAKER_00]: Okay. [SPEAKER_00]: Go for it.