Fatty Liver & NASH in Clinical Trials
Podcast Transcript
Original Air Date: June 20, 2022
Introduction: Welcome to the MedEvidence podcast, hosted by Dr. Michael Koren and Michelle McCormick. MedEvidence, where we help you navigate the real truth behind medical research with both a clinical and research perspective. In this podcast, we'll have discussions with physicians that have extensive experience in patient care and research. How do you know that something works in medicine? We conduct clinical trials to see if things work. Now let's get the truth behind the data. Welcome to MedEvidence, powered by ENCORE Research Group. Go to Encoredocs.com.
Dr. Koren: Hello, my name is Dr. Michael Koren, and I am the moderator today for our MedEvidence Hour. And I also have the privilege of talking to my good friend and colleague, fellow researcher, gastroenterologist, and part-time guru, Dr. Bharat Misra. So we're delighted that he's joining us today, and we're having a great conversation. This is our third segment. We have learned a tremendous amount already about liver disease. You can't live without liver. L-I-V-E--R. So that's important to remember. We talked about Fibroscanning, which is this neat technology that uses ultrasonic elastography to look at the density of the liver and understand whether or not you're at risk for Fatty Liver or Cirrhosis. And we talked about the types of patients that may access this technology, including the difficulty of accessing the technology because the reimbursement levels are low and a lot of practices have not invested in this technology. So now let's move on to the actual diagnoses that we're going to make. And we talk a lot about NASH and NAFLD, so we’d like to define that for everybody. So again, I'm a cardiologist, so I don't keep up with these things. When I hear a NASH, the first thing I think about is a sitcom from the ‘70s, Bharat try to get us on the right track, or at least get me on the right track.
Dr. Misra: So Fatty Liver or NAFLD, which is non alcoholic, fatty liver disease is the first stage of this disease. And typically it's a condition in which the amount of fat in the liver increases to a point where it looks abnormal on imaging technology, or it causes abnormal liver tests. When this progresses to the next stage, it creates actual scar tissue in the liver. And the scarring is concerning because scar tissue, as you know, anywhere in the body is irreversible. And too much scarring in the liver can lead to an end-stage condition called Cirrhosis. We've all heard of the term Cirrhosis. So some patients with NAFLD, maybe a quarter, will progress to a more serious form called NASH. So a simple way to look at it is fatty liver is just excessive fat with maybe some liver damage. And NASH is where there is scar tissue, real liver damage, where we need to be more concerned.
Dr. Koren: Yeah. And so that stands for, correct me if I'm wrong for non alcoholic stato hepatitis.
Dr. Misra: That is correct. So when we first discovered NASH. It's exactly the same look on a liver biopsy as if you were drinking every day. But they realized this was happening in people who did not drink, and that's how the disease was originally diagnosed. And that's why nonalcoholic is in the name. In other words, for anybody who drinks excessive amounts of alcohol, for women, that's more than one glass a day. For men, it's more than two glasses a day. And the glasses are, by the way, smaller, not the 14-ounce glass of wine that we got used to. So you cannot have cannot be drinking alcohol when you make this diagnosis. So alcoholic liver disease looks exactly like NASH. So you have to exclude that by either getting patients to quit or excluding it in the first place.
Dr. Koren: So tell us about the stages of NASH. Are there any kind of nomenclature that's used to stage this disease?
Dr. Misra: Correct. So most diseases progress through more and more damage, and NASH is not an exception. And typically we classify it into four stages one, two, three, and four. Four is where you are at cirrhosis of the liver. So it's very important to understand that the liver is very unique. Its structure determine its function. So if you take a look, if you cut the liver and look at it, it's really very beautiful. It has all these hexagonal pieces in which the liver cells live and work, and through the center, the blood vessels traverse. There's quite a pretty organ under the microscope.
Dr. Koren: Spoken like a true gastroenterologist.
Dr. Misra: Yeah. I just love the structure of the liver, and I think the point I'm trying to make is the structure is critical for functioning. So when you get scar tissue, this beautiful beehivelike structure of the liver collapses. And so blood cannot flow, bile cannot flow, all other immune inflammation starts happening. And that is what happens in NASH. Its structure gets damaged. And the last stage of the damage, which is F for fibrosis, is the irreversible condition that we've talked about, cirrhosis of the liver. Once you go to that stage, even if you lose weight and do everything right, you're never going to go back to normal. In fact, you progress on a yearly rate to liver transplant or liver failure.
Dr. Koren: So we talked about some ways that people may get screened if they have risk factors being overweight or diabetic those risk factors if they happen to get a Cat scan for another reason. So they have abdominal pain to get a Cat scan and somebody knows it's fatty liver, they may want to explore that more. But another presenting reason that people may come to our attention is something that you and I share, is that people sometimes have increases in their liver function test when they take statins. And it's a fairly common drug, of course, and it's a fairly common implication of the use of that drug. So maybe a comment on that. Is that a reason to get a Fibroscan? Is that a reason to worry about NASH?
Dr. Misra: Yeah. So I think this is where Mike and I have a common area. So NASH is a part of a whole syndrome, the metabolic syndrome. And the biggest culprit in metabolic syndrome is heart disease. So we do refer quite often our patients with fatty liver or NASH just see a cardiologist, make sure the lipids are okay, blood pressure is okay, and if they're having any symptoms, get a stress test because that's a very common confounding variable. The key mistake that I think is made by both doctors and primary care physicians are they see somebody with fatty liver who's on a statin, they stop the statin immediately. All the data is that statins actually benefit fatty liver. And sometimes the liver enzyme goes up when you start the statin. But as you follow it, it normalizes. And then you can take the statins long-term. So statins are beneficial for patients with NASH. And NASH patients are at very high risk for heart disease. And so in the presence of symptoms, family history. It's good to see your favorite cardiologist. Mine happens to be sitting right next to me. So that thing is good advice.
Dr. Koren: Yes, I can't resist making a cardiology comment. But to your point, statins work by, “up-regulating” the liver's ability to remove cholesterol from circulation. So in the short run, you're making the liver work a little bit harder, but in the long run, you're actually getting fat out of the liver using statins. So, to your point great point. Statins should not be stopped if there is mileage to moderate increases in liver function tests. Very important point. In fact, statins may actually be a treatment for fatty liver disease. That's terrific. Okay, so let's talk about some other treatments for fatty liver disease. Obviously, statins are not designed specifically for that purpose, and there are other things out there. So maybe we always like to start with lifestyle issues and what to do about it. Is this something that can always go away with diet or are some people stuck with it? So why don't you comment on that?
Dr. Misra: So a couple of points here. First, it is a reversible condition until you get to cirrhosis. The liver has an amazing capacity to regenerate. And it regenerates very well as long as you take the offending agent away. So the first thing I tell my patients is get a detailed history about alcohol. Alcohol was the big kid on the block until fatty liver took away its number one position. But alcohol remains a hidden epidemic in the United States. Its numbers have gone up during COVID. People are drinking a lot more harder liquor, larger amounts. So the first thing you do is you got to quit alcohol because alcohol looks exactly like fatty liver on the biopsy. The second thing is we do recommend a very aggressive diet and exercise regimen to lose weight. Again, losing weight is the cure for fatty liver. Gaining weight is what causes the disease. And the vast majority, not all, but the vast majority of fatty liver in the United States is parallel to the obesity epidemic. So we consult them about a diet and exercise program, read, get a couple of books, try different methods. There is no single diet that works. It's really up to you to find out what works for you. But diet and exercise both have a very positive effect on fat in the liver and scar tissue in the liver. So that's the main treatment.
Dr. Koren: Are there certain cultures in the world that are less or more prone to fatty liver disease? Can we get insights about eating through cultures?
Dr. Misra: Yeah, so there is some genetic risk. So, for example, Hispanics are at very high risk of fatty liver. Native Americans are at very high risk of fatty liver. Southeast Asians and Asians, in general, get fatty liver at a much lower weight. We see southeast Asians were 15-pounds overweight, but they got fibrosis in the liver. So some cultures and some people, depending on their ethnicity and race, are at an increased rate of fatty liver and they have to be more careful. So that is true. Are some cultures protective? We don't know that for sure yet, but there are factors that may come into place.
Dr. Koren: Yes. So we always like to talk about Mediterranean-style eating, which is certainly beneficial for heart disease and certainly beneficial for metabolic syndrome. Do you know of any data on that particular type of eating style for liver disease?
Dr. Misra: Yes, I believe there is a considerable amount of data that a Mediterranean diet is very helpful for patients with fatty liver. So in general, a diet that helps diabetes helps fatty liver. So you have to cut out simple sugars, and simple carbs. That's very helpful. You have to moderate the total amount of carbs. That's helpful. You have to increase the amount of good fats and decrease the amount of bad fats. That means less fried chicken, more avocado, more nuts, and omega three, omega six balance is restored. Omega three fatty acids are helpful. And then, of course, your total calories have to be lower than they should be. So these dietary changes help fatty liver and this considerable amount of evidence. Now, here's a very important point about diet and exercise. Most people think they have to lose a significant amount of weight. The data suggests that at 5% of total body weight loss, fatty liver starts to melt away. And somewhere between ten and maybe 14%, it goes away completely. So the amount of weight we're talking about is between five to 15%. So 10% goal. So if you're about 200 lbs and say, 5ft 11, you got to lose 20 lbs and your fatty liver will go away. So that's a message I want to leave people with. We're not talking about supermodel slim people. We're talking about just modest amounts of weight loss.
Dr. Koren: Let me make a comment about other drugs and other therapies that we use based on current technology and current research.
Dr. Misra: So if you're not a diabetic, taking 800 international units of vitamin E has been shown to reduce fatty liver. Other than that, there are no other.
Dr.Koren: That's interesting because it's a fat-soluble vitamin.
Dr. Misra: It is. It's not just the fat. It's fat plus inflammation. And vitamin E has an anti-inflammatory effect on the body. Now, you do have to be careful because there are some data that high amounts of vitamin E actually increase your cancer risk overall. So it's a balance that you should discuss with your primary care physician. So other than vitamin E, there are no approved medications for fatty liver. Now, if you're a diabetic, then there are two classes of drugs that really help fatty liver. One is pioglitazone and the other is GLP-1. These are all technical terms for a drug called Semiglutide. So that is helpful. If you have, for example, high cholesterol, statins are very helpful. So for diabetics, there are a couple of medications that help. If you have high cholesterol, some medications help, but other than that, it is disappointing that there are no approved therapies yet for fatty liver disease.
Dr. Koren: We're going to dig into that a little bit more. So Bharat, tell us a little bit about the scope of the things that are being investigated for fatty liver disease in clinical research,
Dr. Misra: This is the genius of American democracy. When we have a problem, we throw our best resources. What are our best resources? It's our universities and our scientists and at every GI meeting I go to the number of papers on fatty liver and NASH, the number of new products to treat them is growing exponentially. This is the primary reason for this podcast we want to leave you with the message that there is hope. And that hope comes from clinical trials. And I tell all my patients the next miracle drug is in a clinical trial somewhere today and you might be able to get it five years before anybody else has even access to it, free of cost. How do you do that? You try to enroll in a clinical trial. So there are many drugs targeting a very complex system, from deposition of fat in the liver to the fat causing inflammation, then the inflammation leading to scar tissue, and the scar tissue eventually leading to a collapse of the liver architecture, causing cirrhosis. So the drugs that are targeting the disease process targeted at different times, different places in this very complex mechanism. So, for example, one of the trials we have coming up uses a drug called Semiglutide. Semiglutide is a GLP-1 agonist. In other words, it stimulates this particular molecule and it's actually approved for diabetes.
Dr. Koren: And now we're looking at it for weight loss.
Dr. Misra: It's actually a weight loss drug. And just to let you know, just a week ago, another semiglutide, the results were published. Patients lost 55lbs on the drug,
Dr. Koren: And it's marketed under the name Ozempic and Rubelsis.
Dr. Misra: Correct. Ozempic and Rubelsis are the brand name for this class of drug. So that seems to be the most popular class because there's a lot of evidence that it helps you lose weight and helps diabetes if you're a diabetic. So that's one class of medication work study.
Dr. Koren: And to give our organization a little pat on the back, we have been very involved with these studies from the get go. And what's interesting, in fact, about this particular diabetes drug is that the original studies were looking at cardiovascular safety. So ten years ago, there was a concern that while certain drugs can lower blood sugar and diabetics, did it do good or harm when you were trying to prevent cardiovascular complications? So the FDA and its wisdom mandated that these companies do studies on these diabetes drugs. And lo and behold, we're learning that some of them have these remarkable side effects, including weight loss and getting rid of fatty liver and Smaglitide is one of those type of drugs.
Dr. Misra: Yeah, that's actually one of the benefits of doing clinical trials. You find out what else good. We always worried about the side effects of drugs, while there are positive effects of drugs that you figure out during a clinical trial. So you know how it's gone from looking at heart disease to diabetes to NASH to now weight loss. In other words, these are all kind of linked together in a drug that helps one condition actually helps all the others. We have four upcoming clinical trials at ENCORE Borland Groover Clinic.
Dr. Koren: Beautiful.
Dr. Misra: And they all work at different mechanisms, and we will be enrolling patients shortly in the next couple of months. So I think if I had to look at what is the most exciting area of research currently, it is the treatment of fatty liver and NASH.
Dr. Koren: We'll definitely get into some more specifics, but just remind everybody you can call 904-730-0166 to talk to somebody who can help you figure out if you're a candidate for a clinical trial, help you get a free fibroscan if you're interested in that. Or you can contact us at www.encoredocs.com. And that's another way to learn more about us.
Dr. Misra: That is correct. And you can go on to the website, fill out your information, and somebody will get back to you for a fibroscan appointment, answer interest questions about trials or just general information. And we have access to this in Jacksonville now.
Dr. Koren: Yeah. And northeast Florida and in the Tampa suburbs. In different parts of Florida. But again, don't freak out. That was one of our words of wisdom in a previous version of this podcast, and there's help there. But you just got to figure it out. And it might start with getting that fibroscan to determine where you stand. You may have trivial problems or maybe more severe ones. Of course, every once in a while, people have put off these evaluations for a period of time. We may find that there is significant fibrosis and maybe even cirrhosis. But putting your head in the sand will not help you figure this out. We will help you figure it out with a free fibroscan to start, if necessary. And then if you're an appropriate candidate, we will get you involved in clinical research. So, getting to clinical research, Bharat, might you talk to us a little bit more about another area? Just basic concepts of how we're trying to approach this problem.
Dr. Misra: So, for example, let's look at diet and exercise are the most effective treatment, but they're hard to do. As everybody who's been on diet knows, very hard to do. Clinical trials are where they come in. So we have another trial, in which we're looking at a combination molecule. So we know GLP-1 agonists, like semiglutide health. Well, what if you combine them with glucagon receptor agonists and two is sometimes better than one? That's how we figured out how to beat HIV. That's how we figured out how to beat hepatitis C. And at least two of these clinical trials are multimodality treatments. In other words, they target fatty liver at different points.
Dr. Koren: And glucagon, for the audience, is a starch that's made out of sugars in our body, and we have to have a mechanism to break that down. But again, if we overwhelm the liver's ability to process all these foods and substances, ultimately something's going to go wrong. The other thing this gets a little bit into the cardiology space is that there's a focus on triglycerides. And triglycerides are another form of blood fats. And there's some thinking that perhaps certain drugs that help your body get rid of triglycerides will also get rid of fatty liver. And if you have a comment about that or any experience
Dr. Misra: Yeah, no, at the start we said fatty liver is actually part of a very complex disease called metabolic syndrome. High triglycerides are a marker for metabolic syndrome, as is a risk for diabetes, as is blood pressure, as is the presence of heart disease and fat in the liver truncal, obesity, and increased risk for many cancers, including uterus and colon cancer. So I think targeting triglycerides has been somewhat hard, I think, with current medications. But in general, if you can lower triglycerides by changing your diet and exercising, I think it helps your metabolic syndrome.
Dr. Koren: Yes. So there's another thing that kind of sounds like a science fiction thing. It's called the pharmacoid X receptor agonist. And as I understand it, that's a molecule that can maybe prevent basic liver disease from becoming more advanced have you been involved in those types of trials?
Dr. Misra: Yeah, I believe we have an upcoming trial for a foreign soil X receptor. So, as I said, there are different ways you can target it. So, for example, if you have fatty liver and you never get scar tissue, you never have to worry about fatty liver. And I believe this particular trial targets farcinoid X inhibitor, along with another medication to prevent fibrosis. So this is a whole kitchen sink approach. We don't know which one of these drugs will be effective and safe. And so pharmaceutical companies, to their credit, are targeting all these different modalities to prevent scaring.
Dr. Koren: So a patient comes in, they get their fibroscan, they have moderate fatty liver disease. How do you advise them to get involved in a clinical trial? How do you choose a clinical trial? Give us a little insight into your approach with a patient.
Dr. Misra: Sure. The first thing is we sit down with them and talk to them about fatty liver, and then we emphasize diet and exercise to lose weight. Even though it's not very effective, it is always the first step. You try and of course, you have them stay off the alcohol. And then if we bring them back for a follow-up, was it, say, in a couple of months, they've tried everything, they're unsuccessful. Then you talk to them. If they're diabetic, you take them in one direction. If they have high cholesterol, you take them in another direction. But typically at that follow-up visit, if patients are frustrated at their lack of progress, you visit clinical trials with them. And the way I choose my patients for clinical trials is I have a list of the trials and which patients qualify on my desk. So it depends on your age, on your weight, on whether you're diabetic or not, whether you have scar tissue or not, whether you have cirrhosis or not. Most clinical trials do not want just patients with fatty liver. They want patients who are at risk. They have more scar tissue in the liver, typically F2 fibrosis and above. So the Fibroscan helps them decide that. Very few trials want patients with just fatty liver. They do exist, but most of our current clinical trials want somebody with some damage to the liver. So based on these factors, I have a cheat sheet and I look at them and say, oh, it looks like you qualify for these two. I pick up the phone and we call our coordinator and we refer the patient, and then the coordinator, with the patient's permission, goes through their entire chart. Takes a long time to look at it, drugs, medications, and whether they qualify. And if they qualify at that initial screen, they bring them in for a formal visit. And that is the visit at which we go through all the checkboxes and see if a patient will qualify for a clinical trial.
Dr. Koren: So I'm going to guess that there are at least 28 compounds that are in development for fatty liver disease.
Dr. Misra: Yeah, I believe that is right on the money.
Dr. Koren: Now. Of course, I cheated. He told me that before he got on the air.
Dr. Misra: These are an actual clinical trial
Dr. Koren: And probably another 28 or more that are in a lab somewhere being evaluated.
Dr. Misra: That is correct. As I said, this is a very fruitful area of research, so we have a lot of upcoming clinical trials. So I think the message again if you do have fatty liver, there is hope.
Dr. Koren: Yeah. And there is hope, even in the research realm. I had a patient, a cardiology patient, who was referred for one of the GI trials, ex-marine, tough guy, nice guy. And he felt vulnerable maybe for the first time in his life because he learned about the development of fibrosis. And he participated in a trial and has done extraordinarily well. So that can't be underestimated that we are all destructible. It doesn't matter how tough you are. We're all destructible. And one of the ways of destroying yourself relatively slowly but surely is to develop fatty liver disease that ultimately becomes cirrhosis. And you have educated me already by telling me that fatty liver and the complications of fatty liver are now the number one reason people get liver transplants.
Dr. Misra: That is correct. Very soon, fatty liver and its complications will overtake hepatitis C and alcohol.
Dr. Koren: So we'll leave the audience with two very important thoughts. One is that if you're worried about fatty liver, give us a call and get a fibroscan or get some other assessment that will help you facilitate. ENCORE Research, members are able to get these fatty liver assessments with fibroscans for free. So it's a nice service for the community, both here in Northeast Florida where we're sitting right now as well in the Tampa area. And then two is to learn about clinical research because there are not great options for fatty liver disease right now, but on the horizon, there may be tremendous advances in this area, and you can be part of those tremendous advances by just calling us. That number would be 904-73-0016 or encoredocs.com.
Dr. Misra: That's correct. And I'd like to summarize, patients ask me, why should I participate in a clinical trial? Doctor Misra, I don't want to be a guinea pig. We haven't used guinea pigs in trials for so long, I’ve actually never seen one. But that's what everybody thinks about. So I tell them, first is, as I said before, the next miracle drug is out there. The next drug that can cure hepatitis C has been in a clinical trial for ten years before it was approved by the FDA. So if you want access to that technology, you have to participate in a clinical trial. The second reason is you get very good clinical care. In this busy day, both Mike and I see patients every day. In fact, my clinic starts in about 20 minutes. So we don't have enough time to sit down with patients, talk to them and educate them. In a clinical trial, you get what I call white glove medicine. A coordinator will look at you carefully all your medications, your labs, and your weight. At every visit, they measure you. They take your blood pressure, draw blood, and doctors will talk to you. In other words, you get very careful attention, which is, I think, a very great reason to be in a clinical trial. The third reason is you make a difference. Something you're doing is going to help maybe 25 to 100 million people.
Dr. Koren: That's pretty cool.
Dr. Misra: In other words, sit back in your nursing home and when you're 80 with your feeding tube, you can say, I contributed to that drug you're taking, which cost $5,000. I was part of that. And then there is a minor advantage we'd like to tell people. We do reimburse you for your time and effort. So there's a small stipend involved to make it a little pleasant for you to come. So those are the reasons.
Dr. Koren: Just don't use that money on alcohol. Bharat, thank you for your insights, as always, you're amazing. We're going to have to change gastroenterologist to guru on your jersey there.
Dr. Misra: I will petition my group for that immediately.
Dr. Koren: Yes, and you're a delight. I learned so much and I hope the audience did as well.
Michelle McCormick: I'm your host, Michelle McCormick, and we want to thank Dr. Michael Koren for his clinical and research perspective behind the science in this episode of MedEvidence, the truth behind the data.
