New Study Shows Keto Intervention Slashes Liver Disease Risk

Adam: 
MASLD, which is the most common liver condition, has a prevalence of 25 to 34% in the American population. So, that’s 80 to 90 million people. So, this is preventable. And it’s widespread, and I’m glad we’re talking about it

Bret: 
Welcome to the Metabolic Mind Podcast. I’m your host, Dr. Bret Scher. Metabolic Mind is a non-profit initiative of Baszucki Group, where we’re providing information about the intersection of metabolic health and mental health and metabolic therapies, such as nutritional ketosis as therapies for mental illness.

Thank you for joining us. Although our podcast is for informational purposes only and we aren’t giving medical advice, we hope you will learn from our content and it will help facilitate discussions with your healthcare providers to see if you could benefit from exploring the connection between metabolic and mental health.

Metabolic disease, metabolic dysfunction, you hear that term all the time. And it’s talked about as if it’s one thing, when really it is diffuse in our body. It affects our brains. It affects our liver. It affects our blood sugar. It affects our hearts, our kidneys. It can affect every aspect of our bodies.

And today, I’m joined by Dr. Adam Wolfberg, who’s the Chief Medical Officer at Virta Health, to talk about this impressive new study that was just published in the Journal of Hepatology, specifically looking at the ketogenic intervention for liver disease and the prevention of liver disease. So, not just the treatment, but preventing it from happening in the first place.

And we go through a lot of different terms, MASLD, MASH. It used to be all called NASH, or it used to be called NAFLD, non-alcoholic fatty liver disease, because it looks like alcoholic liver disease with all the fat infiltration, but it’s not. It’s because of metabolic dysfunction. So, it’s metabolic dysfunction-associated steatotic liver disease.

It’s a mouthful that even I can’t pronounce. And then, that can progress to metabolic dysfunction-associated steatohepatitis, which is the more advanced one. So, MASLD and MASH. Now, I know, I apologize for all the details, but what this study looks at was that a ketogenic intervention could be a preventive treatment for that.

So, that’s pretty dramatic. So, I hope you enjoy this interview to learn more about metabolic dysfunction, about liver disease with Dr. Adam Wolfberg. Many of the interventions we discuss can have potentially dangerous effects if done without proper supervision. Consult your healthcare provider before changing your lifestyle or medications.

In addition, it’s important to note that people may respond differently to ketosis, and there isn’t one recognized universal response.

Dr. Adam Wolfberg, welcome back to Metabolic Mind. It’s great to see you again. 

Adam: 
You as well, Bret. Thanks for inviting me. 

Bret: 
Yeah, I definitely had to have you back to talk about this paper, that you were a co-author on, about basically the Virta intervention with a ketogenic intervention for preventing liver disease, metabolic associated, I can’t even say it, MASLD.

Preventing MASLD, which I thought was really interesting because the preventions part of it, which is so important. So, we’ll talk about this in more detail. But first, as I like to start, I want to hear from you. What is, in your opinion, the biggest misconception within medicine that you really wish was different?

Adam: 
I think the biggest misconception is that you can treat metabolic diseases individually. And in my opinion, metabolic diseases are interrelated. They have some of the same causative factors, many of the same risk factors, and as physicians the best approach we can take is to recommend prevention and treatment of all of them together using a combination of nutrition and traditional therapeutics.

Bret: 
Yeah, I love that answer because one of the main complaints about the whole medicine institution is that we’re so siloed, right? There is a joke that in cardiology that you’re the LAD expert or you’re the left ventricle expert, or like how narrow can you get it?

Or you’re a left kidney expert for nephrology. We get so narrow focused that we forget it’s the whole body. And like you’re saying, the metabolic dysfunction affects so much of it, which is why talking about this study is perfect. You could say, from Virta, where you are the Medical Director, that maybe it started as a diabetes intervention company, right?

And then, broadened into weight loss. And then, now, into metabolic disease. And now, we’re talking about liver disease. So, take a minute just to tell us about that scope and that interrelatedness between liver disease, type 2 diabetes, obesity, metabolic dysfunction, how you see it as one. 

Adam: 
I think that’s just right, Bret. And honestly, at Virta, we were led by the evidence.

Virta started as, I’m sure your listeners know, from a type 2 diabetes focused nutritional intervention designed to prevent or reverse type 2 diabetes. And it was based on a clinical trial of patients with type 2 diabetes. A significant majority of them reversed their disease. But along the way, as we analyzed the data from that trial and from many others, and we’re going to talk about the liver specific trial today, or the liver specific data today.

What we learned was that a host of adjacent metabolically-related conditions were impacted by the low-carb approach that Virta recommends. Liver disease, kidney disease, cardiovascular disease. We’ve also seen the impact in behavioral conditions and so many others. And so, it led us at Virta to recognize that the impact on metabolic disease is really quite broad.

Bret: 
Yeah, I think that’s well said. All right, so first, let’s set the stage here. Liver disease is this broad category, but we’re specifically talking about metabolically-associated liver disease. So, set the stage for the prevalence, like how common is this? How many people are living with this?

Adam: 
So, we’re talking about liver disease that isn’t associated with an infection or alcohol consumption. But it’s related to metabolism, and it’s hugely common, Bret. MASLD, which is the most common liver condition, that’s the metabolic dysfunction-associated steatotic liver disease. That’s a mouthful, I know.

That one has a prevalence of 25 to 34% in the American population. So, that’s 80 to 90 million people. That’s kind of the precursor for more severe liver disease, MASH, which has about a 20% prevalence within that MASLD population, but it’s still 15 to 20 million people. And these are individuals who are at risk for serious long-term complications, including liver cirrhosis and related health hazards.

So this is preventable, and it’s widespread, and I’m glad we’re talking about it. 

Bret: 
Yeah, and that’s in the general population. And then, if you narrow down to people with type 2 diabetes, the incidence is even higher, isn’t it? 

Adam: 
That’s right. I don’t have that statistic at my fingertips, but you’re right.

In patients there are risk factors for these conditions, and number one is obesity, and number two is type 2 diabetes. 

Bret: 
And so in analyzing those earlier studies, your team saw that liver function tests got better. And that was just part of the standard testing. We’re going to test everybody’s liver function test, and lo and behold, with no quote-unquote “liver-focused treatment,” the liver function test got better.

So, I guess that was probably part of the impetus to say, “Let’s study this further and see what the impact really is on liver health and liver disease.” 

Adam: 
That’s just right. the original prospective study demonstrated that ALT was reduced by 30% in the study group and AST by 21%. Those are the sort of core liver enzymes or liver tests.

And so, we had data from the very beginning that liver disease would be impacted. 

Bret: 
Yeah. And so the setup of this one is really interesting, that it looked like 5,000 individuals who were Virta clients and matched them with 5,000 individuals who were usual care in the community, matched as closely as could be.

But what’s interesting about this is you weren’t treating liver disease. Again, you were just treating metabolic disease and seeing who progressed to liver disease, which I thought was really interesting. So, what did you think about the setup of that study? Tell us a little bit about the background there.

Adam: 
Yeah, if you let me geek out a little bit on the technical approach to this study, I’ll provide some background for your listeners. We worked with an organization called Komodo. They maintain a very large warehouse of claims data from lots and lots of payers around the United States, and it’s extremely well-protected to maintain patient confidentiality.

And what we did was we went looking in a, there’s a mechanism to look without identifying individual patients. We went looking for Virta patients in that warehouse, and I just want to be super clear that we never knew the identities of the patients whose data we were evaluating. What Komodo also did at the same time was that they created a very well-matched control group.

These were individuals who were matched on the basis of their age, their diagnoses, their geography, the medications they were taking. And in this warehouse of data, we found data on just over 5,000 patients who had been subjected to the Virta treatment. And hence, they created an identically-sized matched control group. And we were able to analyze these data in the aggregate in large groups and to look at the diagnoses that developed over time. And also, the cost of taking care of these patients over time.

And so, we have analyses coming out on some other conditions, kidney disease and cardiovascular disease, and those have yet to be published. But the data on liver disease was published a couple weeks ago in the Journal of Hepatology. 

Bret: 
Yeah, and I find that so interesting. So, it’s not a true randomized controlled trial, but sounds like as close as you could get to being one without actually being one.

So ,still might not be considered the quote-unquote “gold standard” but pretty close. Like, how do you see that in terms of where it stands in the ranking of evidence quality? 

Adam: 
Sure. This was very high quality claims research. I think the number one objection to the results we’re going to discuss today is that the control group, while they look identical to the Virta group, they’re just out there in the wild. And they’re not necessarily doing anything to improve their health.

We honestly don’t know. Maybe they’re exercisers, maybe they’re not. Maybe they’re eating a low-calorie diet, maybe they’re not. We just don’t really know very much about them except for the baseline conditions that created them as the match control group. The sort of demographic factors that I described a minute ago.

And so, the objection is that the Virta group is doing Virta, and the control group is doing we don’t know what. And so, naturally, those who are engaged in a health-related behavior are likely to have better results. And I think there’s some validity to that objection. I also think that as physicians, our job is to encourage patients to do right by their own healthcare. And so, that’s called selection bias that I was describing a minute ago, and we’re all about selection bias in medicine.

If we can get the more selection bias, the better because it leads to better patient results. 

Bret: 
Yeah. And we’ve been referring to Virta. I’m sure most people are familiar with Virta. We think of Virta as a low carb and ketogenic diet intervention. but it’s more than that, right?

It’s also an online coaching relationship with your coach and check-ins. So, people could say, maybe you just get better from that as well? So, it is a two-pronged approach from the Virta side. 

Adam: 
Absolutely. As many of your listeners know, we make sure that every patient has an individual relationship with their health coach, with their physician or nurse practitioner. And then, they also have access to the digital tools and content that helps them to improve their nutrition.

Bret: 
Yeah, and if we fast-forward here to the results, they were pretty impressive. A lower incidence of any liver-related diagnosis of 27 compared to almost 43 per thousand person years. So not percentage, but per thousand person years. But then, looking specifically at the, I guess you could say, more advanced metabolic associated steatohepatitis. So, the sort of more advanced liver disease, 4.2 versus 10, for advanced liver disease.

And what I liked was looking at the number needed to treat of 65 people per year to prevent any liver related diagnosis. So, I guess that’s what I would lay out as what stood out to me. Is that kind of what stood out to you, or were there other findings that really jumped out to you as well?

Adam: 
I think you covered it. Significantly lower risk of developing significant liver disease over a relatively short period of time. 

Bret: 
Yeah, and importantly, these were not people with liver disease. So, this was a true sort of prevention and which is so important because treating it is one thing. And now, of course, they’re talking about FDA-approved medications that are quite expensive and have side effects and so forth, which could be beneficial. But here we’re talking about a lifestyle intervention to prevent it with a number needed to treat of 65 for prevention.

Now, if you compare that to a lot of medications that have number needed to treat in the 200, 300, 400 for prevention, it really stands out. But yet, it’s not front page news. Do you think that’s part of this lifestyle versus drug bias, or why do you think it’s not getting the attention a drug would for a 65 number needed to treat to prevent liver disease?

Adam: 
I think we’re beginning to gain attention and get traction, honestly. I think that so many of the medications, and take GLP-1s, for example, are supposed to be taken by patients in combination with a lifestyle and exercise program. And I think that latter part, the lifestyle and exercise program, gets dropped or gets forgotten so often.

But I think that we’re bringing it back. And I think that, to your point, when you have a relatively low NNT, number needed to treat, that has garnered a lot of attention and says to providers, and says to payers particularly, that this is a low-cost approach that is very cost-effective and clinically impactful.

Bret: 
Yes, you mentioned cost-effectiveness. What were some of the cost data that turned up in this study? 

Adam: 
I don’t have those at my fingertip, Bret. But what I can say, in general, and we’re going to be publishing a paper on this specifically, is that the total cost of care for the Virta group goes down dramatically relative to the match control group.

And that includes the price of Virta. So, for health plans or employers that are investing in a prevention program or in a disease treatment program, this is music to their ears. It’s music to ours as well. 

Bret: 
Yeah, and it’s a little counterintuitive that medicine doesn’t. Medicine, I use medicine as a whole, which obviously is not quite accurate. But most commercial health insurances and most medical practices don’t do the upfront investment in prevention.

And I wonder if it’s because they’ve just been burned too many times? There’s not enough adherence or whatever? But when you’re on the hook for the cost as a company, as a self-employed company or whatever, and those are the ones doing it, and those are the ones seeing benefit, then I would think that would set the stage that everybody would perk their ears up and say, “Hey, maybe we should be doing that, too?”

So, you have a very unique model at Virta. Maybe tell us a little bit about that, and how you see that maybe catching fire a little bit.

Adam: 
The challenge I think, Bret, from the employer, the health plan’s perspective, is that they are responsible for the cost of care for their members or their employees, honestly, for a relatively short period of time.

When they run the numbers, they know that they’re likely to be responsible for these individuals for two or three years on average. And so, investing in prevention is good for the individual but bad for the business because the savings are realized too far down the road for them to accrue to the person who’s footing the bill.

And honestly, I think that’s really one of the real problems with American medicine. That’s like a structural problem in the way that we pay for it, is that the payer isn’t set up to benefit from investment in prevention. I think that at Virta, we acknowledge that, and we focus on delivering long-term value, but also delivering short-term value.

Honestly, it’s a necessity that we prove to our clients that we can deliver economic value within one year and two years. But I realize that we’re part of a solution that may not have a great economic reward mechanism given the structure of the American healthcare system. 

Bret: 
Yeah, which is a problem.

But when you talk about the health of the person, it’s clear it’s making a significant difference. Now, I guess the questions that remain, though, is it the coaching? Is it the keto is intervention? Is it the weight loss? Is it just eating better? And this doesn’t truly answer those questions.

I’m sure the patients don’t care. The patients are better. They’re not getting liver disease. They’re happy either way. But how do you address those questions that come up? 

Adam: 
The paper answers a couple of those questions. One of the questions it answers is that the more weight that the participants lost, the greater the impact.

So, the benefit for those who lost more weight was greater than the benefit for those who lost less weight. Interestingly, and the analysis was pretty limited given the availability of these data, the beta-hydroxybutyrate data didn’t really show a difference. So, those who were in a greater degree of nutritional ketosis didn’t see greater benefit compared to those who had lower degrees of nutritional ketosis.

And that’s, honestly, a little puzzling scientifically. But I think that from a intervention perspective or a public health perspective, what that says to me is that more people can succeed here. More people can access a low-carb diet without getting into extreme degrees of nutritional ketosis and still see the preventive benefits related to liver and other conditions.

Bret: 
Yeah, I think that part’s really interesting. And at Metabolic Mind, obviously, we talk a lot about brain-based disorders. And the brain can actively use ketones as fuel, and I think that’s why we see, on average, more benefit with higher ketone levels up in the two to three range.

But for general metabolic health, for preventing liver disease, for losing weight, or maybe even treating type 2 diabetes, then maybe the ketone levels don’t matter quite as much. So, I think it’s, although we say the brain and the body are one thing, when it comes to level of ketones, maybe they are a little different?

Do you see it similarly? 

Adam: 
I do. I see it very similarly. And I think that the conclusion here doesn’t necessarily apply to all conditions. But from a very prevalent condition, that’s, great news. 

Bret: 
Yeah. Now, if you Google dietary treatment and prevention of fatty liver or, metabolic-associated steatotic liver disease, you’re going to see Mediterranean diet pop up everywhere.

That is what you’re going to see if you Google it, Mediterranean diet. Why is that? Why do we see that? Why don’t we see keto? Why don’t we see low carb? How do you compare those? 

Adam: 
I think that the literature on Mediterranean diet is mixed. There are some studies showing that it improves or that it reduces the risk of liver disease, and there are others showing that it doesn’t.

I think, honestly, that the literature on these specific diets is really complicated, and many of the larger studies that have driven conclusions are flawed. So, I take that literature with a little bit of a grain of salt, I would say. 

Bret: 
Yeah, I know one study that gets quoted a lot or cited a lot. They just looked at patients coming into the clinic and measured what they term the adherence to a Mediterranean diet, and how much they adhered to those principles, and who was more likely or less likely to end up getting liver disease.

That’s got a ton of healthy user bias, selection bias, et cetera, even more so than your study, for sure. If they’re citing that study and using that as evidence, I would hope they would also notice this study and start talking about this study more as a keto intervention for prevention of liver disease, which makes sense because you’re treating the metabolic dysfunction.

Like you said, it’s a global treatment. So, it sounds like you’re going to have another paper with the financial information on it, and you’re going to have more papers about other disease states as well that are metabolically rated. So, mention those again, the ones that are coming. 

Adam: 
So, in peer review, we have a paper demonstrating the impact of the Virta program on chronic kidney disease, another one on cardiovascular disease and death, and a third on the total cost of care.

And the basic structure of the papers and of the analyses is very similar to the hepatology paper. They just focus on different conditions. 

Bret: 
So, there are a number of primary care doctors, and doctors of all different specialties, out there wanting to improve the health of their patients, but not sure where to start with lifestyle.

It’s so difficult to do. It’s so easy to reach for a prescription instead. What do you want them to take away from this paper and to think about what they can do? 

Adam: 
So, first of all, the very expensive therapeutic treatments that are out there, the big one is Rezdiffra, and then there’s now an indication for semaglutide in patients with obesity and and liver disease.

The indication is reasonably advanced liver disease. So, stage F2 and 3. And I would love to help patients never get there. So, my goal would be for patients and clinicians and health plans to recognize that there is a treatment that will prevent patients from needing these medications to treat a condition that’s avoidable.

Bret: 
And I can see doctors saying, “I don’t have time to sit and talk about diet, and how hard it is to do a keto diet,” especially when they’re unfamiliar with it themselves. So, what’s a step they can take to help take some of that burden off of them? 

Adam: 
I think that first of all, demystifying a well-formulated ketogenic diet and helping people to recognize that it’s easily accessible And that it’s not zero carb. It’s low carb, and you can slide into it over time.

And that content is widely available. It doesn’t require a physician to provide that guidance. It is widely available on the internet. I haven’t tried it, but I can only imagine that ChatGPT would set you up with a great two-week plan to get yourself into nutritional ketosis. Obviously, now 12 million Americans are eligible through their employer or health plan for Virta, and we obviously want to help them.

But this is very accessible, and I hope that this this paper adds to the evidence that it’s a great approach, particularly for patients who have risk factors, like obesity or type 2 diabetes. 

Bret: 
Yeah. Very good. Do you have other thoughts that you wanted to mention about the paper?

And then, of course, to wrap up, where can people find you and learn more about you and about Virta?

Adam: 
No, I appreciate your taking time to talk about the paper with me, Bret. And the work you do at Metabolic Mind is so important for the conditions you focus on, but really, health in general and metabolic disease overall.

Thank you for your work here. I am the Chief Medical Officer at Virta Health. We are at virtahealth.com. And you can find us all over LinkedIn and Instagram. And if anyone has questions or wants to collaborate or reach out or if we can be helpful, you know where to find us. 

Bret: 
Great. thank you so much for joining me.

I really appreciate it. 

Adam: 
Thanks, Bret. 

Bret: 
I really appreciate Dr. Wolfberg joining me and talking about this study. And really, what jumps out to me again is that number needed to treat 65 people to prevent one serious liver complication. And compared to a lot of the drugs we use, that’s pretty small for a preventive intervention.

So, I hope that really gets the attention it deserves because that really jumps out and is really impressive and the cost savings, but more importantly, just the health savings. This, liver disease, is very serious, but it is treatable. And just like Dr. Wolfberg said in the beginning, that we think of maybe metabolic dysfunction as being siloed and being different, but it’s really all together.

And how this started by treating patients with type 2 diabetes and then realizing, hey, their liver function’s getting better, let’s look at that further. And then, to see that this is an effective preventive intervention for liver disease. To me, that’s just dramatic. And I love that sort of progression, how that came to be.

So, hopefully, this was helpful for you to not just to learn about liver disease and the prevention of liver disease and the role of ketogenic interventions. But again, this concept of metabolic dysfunction, metabolic disease being a global in the world and global within humans. The brain, the body, every aspect of the body seems to be touched by our metabolic health.

So, with that, I hope, it helps you be encouraged to improve your metabolic health and make your life healthier. So, thanks for watching. We’ll see you next time at Metabolic Mind. Thanks for listening to the Metabolic Mind Podcast. If you found this episode helpful, please leave a rating and comment as we’d love to hear from you.

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