Written by Christopher Kelly
Aug. 12, 2019
Chris: Dr. McCarter, thank you so much for joining me this morning. I’m very excited to talk to you about the results of your new two-year trial of a novel remote care intervention including nutritional ketosis, so the management of Type 2 Diabetes, a two-year non-randomized clinical trial.
I want to just start by thanking you actually for what you’re doing over at Virta. I know it’s not just you, a bunch of colleagues are doing some really fantastic work to further understanding the importance of -- how can I say it? Non-pharmaceutical based interventions for the treatment of insulin resistance and Type 2 Diabetes.
I think it’s very important work. I think you’ve got a tool that’s possible not optimized for what you’re trying to do which makes your life very difficult. My point is I think it’s very important work. I thank you for doing it. Thank you for joining me this morning to do this interview.
Jim: Thanks, Chris. Glad to be here. You’re right. It’s a big team effort in terms of the researchers and the clinicians and as well as the folks who are doing the software and building the whole intervention.
Chris: Amazing. Talk about the problem. What problem are you setting out to solve and how big of a problem is it?
Jim: Yeah, so the problem of Type 2 Diabetes is enormous and underlying that is just a whole problem of insulin resistance and metabolic disease. But just to put some numbers on it, in terms of Type 2 Diabetes which is the adult onset diabetes with insulin resistance, about 30 million people in the United States, about 400 million worldwide. Economically, it’s about a $300 billion problem in terms of the economic impact in the United States.
Then there’s another 80 million people in the United States who have prediabetes meaning that they’re at risk for progression to diabetes. Every year, a couple million of those folks will, as they get older, eventually have the onset of new Type 2 Diabetes.
Chris: The numbers are absolutely staggering. I wonder what it would be like if you could see it. You know like dogs can small diabetes? Have you seen the studies that they can smell high blood glucose? What would it be like if we could smell high blood glucose? What if diabetes gave you red spots on your skin so you could see everybody that was effected by insulin resistance? I wonder what a different world that would be.
Jim: It is especially in the early stages kind of an invisible disease. But then the reason we care about it so much is the progression of what comes along with it over time.
Retinopathy is the number one cause of blindness in the United States, neuropathy where you’re losing peripheral sensation. It’s the number one cause of amputation in the United States. Nephropathy is the number one cause of kidney familiar, the reason for dialysis and for kidney transplant.
All of those things are the sequelae or the end effects of Type 2 Diabetes, not to mention the obesity that folks are dealing with, the cardiovascular disease, and the cardiovascular disease is actually the number one cause. All those other things, you can survive with to an extent but the cardiovascular disease is the number one cause of death for people with Type 2 Diabetes.
Chris: Why choose clinical trial? Why go down that route? I mean I’m sure most people listening to this podcast have heard about the ketogenic diet and they understand some of the diet and lifestyle interventions that are available that can improve heath and performance outcomes. Why do you need to do a clinical trial in order to demonstrate that your therapy works?
Jim: Yeah. I’d say a couple of things. One in terms of what audiences are you kind of trying to convince. If you were just sort of an N=1 looking to how to improve your own life, you might be willing to move forward without clinical trial level evidence.
But if you’re trying to convince clinicians or you’re trying to convince payers or sort of any sizeable audience that you’re on the right track in terms of your intervention, they’re going to be looking for approved clinical trials that have gone through an institutional review board and are published in the peer review medical literature.
In terms of making something scalable, that’s the standard of proof that you’re looking to achieve.
Chris: Talk about why keto? I think that’s a really interesting question. Obviously, there are a number of interventions that may have therapeutic potential, not least of all vegan or low-fat or maybe a whole-foods based diet. Could you just say to people don’t eat anything that comes out of a crinkly packet? Why is keto special and why did you choose it?
Jim: I think that in the most simplistic terms, you can think of Type 2 Diabetes as a disease of insulin resistance. Another way of saying insulin resistance is carbohydrate intolerance. If you think about it in terms of folks that have insulin resistance, that means that to keep their blood glucose in the normal range, they’re going to have to have a greater insulin spike and response to incoming glucose in order to maintain normal or even elevated levels of blood sugar and prevent it from spiking even further.
The sort of simplistic way of thinking about this is let’s get people off the glucose-insulin roller coaster. Let’s actually take away the incoming carbohydrate or greatly reduce the incoming carbohydrate so that there’s less of a need to respond to it with a big insulin spike.
Incoming carbohydrate or simple starches will cause a big insulin or a big glucose spike followed by a big insulin spike, you’ll see less of that with protein, you see less of that with fat in the meal.
That’s kind of the most simplistic explanation. The more complicated explanation and getting in the more of the mechanism is that you can actually reverse that state of insulin resistance over time with a dietary intervention like a ketogenic diet. We see for instance that the level of resistance will diminish over time by greater than 30%.
Not only is the glucose level coming down but the necessary insulin response to that glucose also comes down. Then there’s other underlying mechanisms that are beneficial in terms of ketogenic diets.
The ketone bodies are in addition to being fuel are hormones or secondary messengers within the body. They’re causing changes to response to oxidative stress and inflammation. They’re anti-inflammatory and if we get into kind of a mechanisms, and we can kind of talk more through that.
There’s multiple mechanism of action but the most simplistic is if you have a disease that is an intolerance to carbohydrate, let’s reduce the carbohydrate.
Chris: How well do you think you understand the process that led to the insulin resistance? My colleague, Tommy, who I think you know. You know Tommy, don’t you?
Chris: Have you looked at any of his systems analysis approach to insulin resistance? The case that Tommy makes in the talks that he’s given is that it’s a complex disease with many interacting factors. Even though a low carbohydrate diet may work well as the treatment, it doesn’t mean that the carbohydrate was the thing that caused the problem in the first place.
Of course, the Nourish Balance Thrive podcast has been an exploration into all of the things that may be contributing to insulin resistance, not least of which are sunlight exposure and circadian rhythm and stress management. It’s a complex problem with many interacting factors and how well do you think Virta and your scientists and health coaches understand the process that led to that insulin resistance?
Jim: Yeah. I think that’s a fair point, Chris, that just because taking the carbohydrate away doesn’t mean that just having too much carbohydrate input was how we got to this place in the first place.
I mean another way of looking at that is you can ask the question of since the 1960s, we’ve seen about a ten-fold increase in Type 2 Diabetes as well as a tripling of obesity in the US population and we’ve seen as kind of world-wide epidemic of diabetes and metabolic disease so what are some of the changes that occurred that underlie that?
You can point to not only increases in sugar and refined starch in the diet but you can look at just greater overall calorie exposure to process foods and inexpensive food. You can look at the way in which people spend their time, so decreased mobility, potentially less sleep, increased stress.
I think you’re right. There could be a number of underlying factors that helped us get to this place as opposed to a single underlying cause. I think that’s right.
Chris: Talk about how the clinical trial is set up. You got this intervention that is very intensive I’m sure working with health coaches. Talk about how well the clinical trial is set up to measure the efficacy of such an intervention.
Jim: Sure. Backing up to the summer of 2015 as Virta Health was just getting started, we were looking at an opportunity to demonstrate a protocol and partnered with Indiana University Health in the clinic that was established by Dr. Sarah Hallberg.
What we did basically was to parachute in seven of us to get the trial underway and then six months recruited nearly 500 people into that clinical trial. It was designed sort of intentionally as a non-randomized trial. Another way of saying that is it’s a patient preference based trial and so the people can select whether they want to opt in to that intervention or not.
By local advertising and word of mouth, we got the news out there that this intervention was possible and found a couple of hundred people who were interested in opting in to the intervention as well as another nearly hundred folks who came on board as part of the usual care arm of the trial where they basically just kept doing what they were doing and allowed us to monitor their health a couple of times along the way.
What we’ve done then is to work closely, I’ll talk a little bit more about the intervention, but to work closely with our patients over the course of several years and now have published nine papers. We have seven on the trial itself as well as two reviews that have come out so far. There’s probably another five papers that are going to result from the trial.
Then we’ve extended it out from the original plan two years out to five years and so we’ll be able to follow the intervention [0:10:23] trial a couple of hundred folks up to five years to look at sustainable.
That’s kind of in terms of getting the trial off the ground and we’ve had a science team in place in Lafayette, Indiana collecting the data from these patients with laboratory values a couple of times a year in clinical findings at a couple of time points along the way. But then the intervention itself really is providing not just saying hey, make these dietary or nutritional changes, but really doing five things with our patients.
First, we are the physician of record so rather than having you relay everything through your primary care physician, we’re making all the medication changes and providing all the instruction directly so it’s Virta or IUH doctor who’s making those changes and recommendations.
Second is 24/7 access to a health coach. You have your own health coach, most of whom are trained as dieticians or nurses.
Third is online nutrition behavior change education. It’s really an advanced course in nutrition science. And then biometric feedback so providing data along the way where people are collecting data points. We can talk about that in more detail but really, the patients and the care team are receiving on a daily basis individualized indications of whether they’re on track or off track.
Then we also established over the course of the first few months of the trial put in place in online community so that people could be talking not just with their care providers but with other folks going through the same thing.
Chris: That’s very interesting. Do you think that was a critical part then having the direct care doctor involved rather than you having to go through somebody else’s doctor saying, “Oh, that keto diet’s going to kill you with all that saturated fat” or something? Do you think that was an important part of the intervention?
Jim: Yeah. I think it’s critically important to have the care team all on the same page. We had an experience actually at Virta back early and getting the company set up in 2014 and in early 2015, there was an attempt to actually do the other model of having Virta provide the software and the health coach and having someone else be the physician.
We ran into exactly that problem of just the patient getting contradictory messages and that cognitive dissonance is just a killer if you’re having the health coach recommend one way of eating and then the physician undermining it. It’s going to lead to the down fall of the intervention.
I think that’s very important. That’s actually one thing on a commercial point that led Virta to make the decision to become a nation-wide medical provider and get license to practice medicine in all 50 states was to establish our own physicians who could do the decision-making around the medical care.
Chris: That’s a huge undertaking. How does it work logistically for the patient? Do they have to come and see someone in person before you could practice medicine remotely?
Jim: Actually, I think all states now allow the initial visit to be a telemedicine visit. That wasn’t the case a few years ago. I think back in 2015, when were first getting started, I think Indiana and Texas and at least a number of states had it set up so the first physician-patient interaction had to be in person and then you could switch over to telemedicine.
But now, that’s changed where a telemedicine doctor-patient interaction can begin remote. Now, the way Virta has delivered, it’s entirely continuous remote care. All the aspects of the intervention are done via internet through video chat with a physician, through text messaging with a health coach, through a hardware that’s delivered to their door step.
When we were first getting started in Indiana, we actually did both. We had two arms to the trial within the intervention, and this is kind of [0:14:07] in the details of the paper because it turned out to not be too important but we actually delivered about half of the folks opted into an in-person care model and half to entirely a remote care model.
We found that both worked equally well. Under one model, they would come in and see the physician and have a class with their health coach on site at the Indiana University Health Clinic and then under the other model, they would use software and interact with the health coach remotely. The outcomes were indistinguishable.
Chris: Okay. How important was the education piece? Did you find the people coming to you, your patients, did they already have the information that they needed or did you need to provide that? Did you need to education them?
Jim: Absolutely critical. We did. It turns out yeah, that there’s so much -- we’re coming out of decades of the predominant model, you think back to the food pyramid of demonization of fat and of teaching people to eat meals where the base of the food pyramid is grains and is a very high carbohydrate approach.
You’re really kind of entirely flipping that and saying okay, we’re going to have dietary patterns that’s outside of the mainstream.
We’re going to have to teach you all the tools to make that work in your own life and to not only provide the foundational education as to the science and the recipes and things like that, but also the behavior change strategies and the individualization of how do you make this work in your life so that it’s not just working when you have full control of your meals but if you’re cooking for a large family or eating out or eating at a cafeteria or whatever your situation is, you have to adapt it to work under those circumstances.
So yeah, there was a great deal of education involved.
Chris: What about the community aspect? I have some insider information from being friends with our mutual friend, Dr. Hilbert, who has done some wonderful talks that I can link to in the show notes for this episode.
Doug was telling me that the community aspect was going really well and sometimes, you would get one of the more senior members of the group answer somebody news question, and it’s like it would all be done and dusted by the time you even got in there to help somebody. Has that been the case from your perspective? Has it been good? The community?
Jim: Yeah. So kudos to Doug for establishing the initial Virta online community and we had a little bit of that going already for the folks who were doing the in-person version of the intervention where they were seeing each other on site at the clinic but for the folks entirely remote, yeah, they were depending on that online community that Doug set up.
I would also point people, and we can link to this in the show notes, Doug gave a great talk last summer at the Ancestral Health meeting and really went into the behavior change support aspects of the coaching and what it’s like to provide not just the information but that emotional support that people need.
Yeah, I think we found the community is tremendously helpful to people providing thoughts and troubleshooting in a rapid response that somewhat different than the answer you would get from your health coach or your physician, but then also being there for people for each other emotionally.
Chris: Yeah. I was thinking the dream would be, okay, I’m in the supermarket. I’m in Aisle 3 and I’m looking for a mayonnaise that doesn’t have soybean oil in it. Can somebody help me? You know like getting an answer whilst you’re still in the supermarket and I don’t know whether that does happen or whether it will ever happen but yeah, I would love to have that.
Jim: Yeah, I would too. I think that that should be possible through a combination of the machine learning kind of aspects where you have -- Virta doesn’t yet do kind of an automated response to questions like that but something like that could be built along with both community and health coach where you would have more of a response time from the health coach on the order of a few hours as opposed to real-time.
Chris: Talk about the adherence. You now have data on the adherence of the two-year mark which is impressive. Talk about how it’s been going, have people been dropping out?
Jim: One of the things actually I put together, I posted on Medium a blog post today called the Top 10 Keto Myths Debunked After 150,000 Days of Patient Care.
Chris: That’s impressive. Not many people are in a position to write such a blog post.
Jim: Yeah, but number one on the list of myths is this idea that it’s unsustainable and so first, nearly all of the Type 2 Diabetes intervention patients were able to get into nutritional ketosis at least for a while.
We individualized the carbohydrate restriction over time so that not everybody has to stay at high levels of ketosis for years on end but even at two years, the average beta-hydroxybutyrate, one of the ketone bodies that can be measured in the blood was 50% elevated over baseline even out of two years indicating on going restriction of carbohydrate.
So 74% of the patients completed two years of the trial which is very good for an intervention that’s not only asking people to make a major behavioral change but also to do a great deal of follow-up work with us in terms of scans and blood draws and questionnaires.
It’s a big ask to ask people to participate in a clinical trial for two years and see that that many people are still going at two years was very satisfying.
Chris: That’s very impressive. I have some appreciation for what you’ve done. A very tiny, tiny appreciation. We’ve tried to do that small trial where people did blood work. Forget it. You just can’t get people to do blood tests unless they have some problem that they’re dealing with.
People don’t generally do blood tests for fun. Just that alone to get people to comply with the trial is very impressive and then you add on top of that, the intervention, very impressive.
Jim: Well, thanks.
Chris: Talk about the blood level of beta-hydroxybutyrate. You just hinted there that there was a small increase in BHB but when I looked at the data, I couldn’t really see a signal there which I thought was interesting. I wanted you to talk about, is there a therapeutic range that Volek and Phinney have been talking about this 0.5 to 3 millimole per liter for a long time but I’m not exactly sure what that’s based on. Is it based on some health outcome?
Then what do you see in the blood of patients as they go through the trial? I still eat a low carbohydrate diet but I don’t deliberately restrict carbohydrates. The carbohydrates that I’m now eating are whole-food sources of carbohydrates like sweet potatoes and berries.
I still think I wouldn’t look like an outlier in this data. If you measured my blood beta-hydroxybutyrate first thing in the morning, you’ll probably see something around like 0.5, something like that would be -- and my wife definitely would, and she’s certainly not restricting carbohydrates either. Talk about this therapeutic range of beta-hydroxybutyrate and how that changes over time.
Jim: Yeah, excellent. Just a little bit of background for the audience on ketone bodies are formed from the metabolism of fatty acids and there are three beta-hydroxybutyrate, acetoacetate and acetone that are detectable in the blood. Some can also be detected in breath or in urine.
If you were just to go around and kind of on the street, take out the Precision Xtra and start sticking people’s fingers in measuring, you would get a lot of zeroes and a lot of 0.1 millimolar beta-hydroxybutyrate measurements.
Fasting overnight for folks coming off of a high carbohydrate way of eating, you would generally get something in the 0.1 to 0.2 range after a 12-hour overnight fast. For our patients, their baseline levels, I believe, were something like 0.18, and that was similar to what we saw in the usual care arm of the trial.
Then when we go back and look at a year and two years where folks, based not on their daily finger sticks but based on the blood draws that were done by the clinic, they were at 0.36 at a year and 0.27 at two years, so that’s where I’m saying 50% elevated over background.
Now, in terms of that sort of the range that Steve Phinney and Jeff Volek had talked about, about getting above 0.5 to get the full benefits of nutritional ketosis, part of that came from looking at the mechanism of action and animal studies where we know that the beta-hydroxybutyrate is an HDAC inhibitor, histone deacetylase inhibitor. We know that it’s an inhibitor of the NLRP3 inflammasome.
If you look at those studies and say kind of what blood level are needed for you to have those hormonal effects of beta-hydroxybutyrate, that’s where they were saying that becomes very visible above 0.5.
I would recommend that for folks that are following a ketogenic diet for control of epilepsy for instance or other neurologic conditions, the physicians will recommend a more strict ketogenic diet where for those kids with epilepsy, something like 90% of the diet will be derived from fat.
What they’re trying to do in that case is to achieve a higher level of beta-hydroxybutyrate so they would prefer that to be up around 2 or 3 millimolar. Whereas we’re getting a very nice beneficial effect in terms of metabolic change. Our patients had lower levels of beta-hydroxybutyrate.
We did report at the American Diabetes Association this year that there is a correlation between the level of ketosis and the benefit of the outcomes. If you ask the question is higher better in our patients? The answer is yes. It is predictor, at least it correlates with the folks who achieve higher levels of ketones that does correlate with both greater reductions in hemoglobin A1c which is a marker of diabetes status as well as with greater degrees of weight loss.
Chris: You just reminded me that our mutual friend, Ken Ford, has talked about some of these signaling effects. I think I can cite something in the show notes where Ken talked about this. The signaling effects only happen in the millimole concentration. I mean would you expect these patients to still get those same benefits if they’re down at 0.27?
Jim: The degree of the effect does correlate with the level of the ketone. I think that if you’re looking for those effects that you may want to aim higher. But I think that part of what’s exciting about this is the demonstration that the diabetes is reversible at all.
If you look back to where we were getting started on this in 2015, really, the only recommendation that people could provide for diabetes reversal is bariatric surgery and perhaps severe caloric restriction where you go on one of these shakes that provide 800 or a fewer calories per day and you stay on that for many, many months. Those were really the only ways of achieving Type 2 Diabetes reversal.
I think part of this is just to show that in this outpatient setting where people are not locked in a metabolic ward that they’re actually able to achieve diabetes reversal, eating a whole-foods diet and that’s really the first time that that’s been demonstrated.
Chris: Yeah. You’re completely right that I get lost in the weeds there when really the elephant in the room is that you’ve just reversed what was said to be a chronic and progressive disease.
Jim: Yeah. For your listeners, just to put that in context, there’s a large study out of Kaiser where they looked at the medical records review over a hundred thousand people looking for their diabetes remission rate and it was on the order of 0.1%.
Now, there’s a little bit different definitions for what we call reversal, which is what you call remission. But in general, you’re going to find that if you use our definition of reversal which means that people have a hemoglobin A1c less than 6.5 which is the diabetes threshold and that they do that without any use of medication other than metformin off of all the diabetes specific medications, we’re seeing a 55% reversal rate at two years. Whereas, it’s low single digit in usual care.
Chris: That’s amazing. Absolutely incredible. I wondered if the blood level of beta-hydroxybutyrate was an important self-monitoring input. I mean Ken has talked about this as well that objectively, I know I’m doing it because I see these ketones in the blood and I’m measuring that. If I make a bad decision, I can see that go away.
Now, we’ve got this important feedback mechanism that objectively tells me that I’m doing it right. Is this what you’re finding with --?
Jim: Yeah. What we were measuring on a daily basis was we’re asking people to step on a cell-enabled scale so that they would get a weight that would automatically upload to Virta.
We ask them to do at least one finger stick a day for the first few months to get a beta-hydroxybutyrate level along with the glucose level. And then we ask them four questions. Basically, how is your mood, hunger, energy, and cravings with a check box scale. People could say whether they were up or down at any given day.
That was kind of the daily input as well as people could also list any symptoms or side effects. I think people found the beta-hydroxybutyrate level along with the glucose level very useful in terms of providing guidance. It’s also less intimidating that the daily weight -- because the daily weight, there is sort of the sense of judgment. Are you losing weight or not?
There’s a lot of baggage attached to people’s daily weight as well as it’s extremely noisy just based on daily levels of inflammation or water and you can have a great day in terms of hitting your goals and then finding that your weight is up a couple of pounds so it can be discouraging in that regard. I think the beta-hydroxybutyrate level was a little less judgmental than people feel stepping on the scale.
I would say that it can get a lot better in terms of asking people to do a finger stick. There’s some discomfort involved. It’s also messy and I, for instance, will do finger sticks at my desk but I’m less likely to do it when I travel just because of having to kind of set up the lancet and feed the blood into the meter and the whole rigmarole.
If you could get that same data in an easier way without having to do a finger stick and to get that data not just once a day but get it several times a day, I think that could be very valuable.
Without giving too much away, I’ll say I’m involved in a company that’s working on that called Readout that we’ve gotten underway in the last year, and so look for some announcements in the fall on less invasive ways of measuring metabolic markers.
Chris: Interesting. I wondered if you looked at -- Dan Ariely has done some very interesting and perhaps important work on the compounding loss aversion. As you said, the body weight fluctuates daily and maybe feel the pain of an increased number on the scale a lot more severely than you feel the joy of a lower number.
When you compound that over time, people generally stop using their scales. I wondered whether Virta had looked at any of that and had thought about that.
Dan Ariely had this product where you just step on the scale. I think it’s looking at two-week rolling average or something like that and then it just gives you a green light. Good job. You’re headed in the right direction. I’m not going to tell you what your weight was today. If you poke around in the app far enough, you can see what the actual body weight was but it removes that just because you’re a green light or a red light.
Jim: Yeah. I think it’s a really good point. That’s an interesting idea. We didn’t go as far as actually hiding the daily weight from the patient but we did provide a great deal of education around the interpretation of that number and making sure that people understood what is it that you’re actually getting when you look at daily weight. And then in the app, we are providing a rolling average number, a weekly average, as opposed to just looking at the day-to-day fluctuations.
But I think that the thing to remember in terms of this patient population is that these are folks that have been dealing with not only diabetes but in most cases, obesity for many years including many attempts, prior attempts at weight loss and also both psychologically and socially a great deal of shaming in our culture that’s associated with being overweight or obese.
These are emotionally loaded issues and so we do a lot of work with our patients on how to think about Virta as a diabetes reversal effort as opposed to saying this is all about weight loss because I think that in many cases if you make this all about weight, you’re increasing the likelihood of failure.
Chris: I mean you’ve created a new metric and as soon as I know my number, I want to know okay, what does this mean? How do I compare to everyone else? It’s kind of hard to do that with blood levels beta-hydroxybutyrate if you’re just a human out in the wild whereas body weight like it’s really obvious how to compare that to somebody else and what it means and as you say, that’s a very loaded thing.
Jim: Yeah. It’s one of the things we talked about for instance is what we call non-scale victories or non-scale wins so what else is going right in your life as a result of this effort you’ve put into this intervention as opposed to just looking for a change on the scale?
For instance, we see greater than 70% reduction in diabetes prescriptions, so your 94% reduction in the use of insulin in the first year, reduction or elimination in insulin. If people are taking less medication or saving money because they’re spending less money on their out of pocket deductibles associated with those meds, their hypertension is down, the use of diuretic medications is down.
Then just sort of day-to-day things that people have more energy and improved mood and are more able to do this sort of activities of daily living, talking about being able to get down on the floor and play with grandkids where that wasn’t possible before. There are all these ways in which life is better even if the scale hasn’t moved.
Chris: Yeah, that’s amazing. I’ve recently interviewed a clinical psychologist, Ashley Mason, and she described it as mass quitting of drugs which I love that.
Jim: Oh, I love that too. Yeah. Talking through the prescription, and this is one reason why it’s so important to have a physician who understands this involved is you want to early on get rid of the drugs that put you at any risk of hypoglycemia and low blood sugar. That’s the sulphonylureas as well as insulin.
Actually, in the trial, 100% elimination of sulphonylureas. No patients were on sulphonylureas after the first couple of weeks.
Chris: A pharmaceutical company’s not coming after you saying, “This isn’t great for business, Jim. Is there something you could do?”
Jim: They haven’t yet. We’ll see as it really gets bigger and is treating millions of people as opposed to thousands of people. They might start to care a little bit more, not so much about sulphonylureas which are generic but about some of the actual more expensive medications, they may eventually care about those things. You want to get rid of early on, of those drugs that can cause side effects like hypoglycemia.
Chris: Were there any pitfalls that you saw lots of patients fall into? Is there a checklist so you get somebody on board like okay, this is what’s going to happen in the first few days. You’re going to do this thing and it’s not what we want you to do and so just mind out for that. Were there any things like that with every single patient?
Jim: Absolutely. The sort of number one mistake that people make in terms of -- and this goes not for just folks with Type 2 Diabetes, but this goes for anyone who is experimenting with a ketogenic diet, is that it changes the way in which your body handles electrolytes.
It turns out that there’s actually signaling, insulin does a lot in terms of it’s not just signaling to maintain blood glucose in the normal range. It’s signaling for fast storage. It also signals the kidneys in terms of the way that it handles sodium. You’ve heard for instance that sort of early in the implementation of a low carbohydrate diet, people will see a bunch of weight fall off the scale in the first few days and that’s generally water.
The reason for that is that insulin is signaling the kidneys for retention of sodium, for reabsorption of sodium. You take away that insulin signal as you reduce the carbohydrates, as you enter ketosis, and all of the sudden, your kidneys are secreting a lot more sodium and not reabsorbing it. The water follows that sodium. People become what’s called hyponatremic as well as volume depleted. Well, what does that lead to? Headache and fatigue.
You’ve heard of keto flu, Atkins flu, all these things. This basically, you’re not replenishing your salt. Virta provides a lot of education around using broth or bouillon, you can just heavily salt your food. I actually have gone to just for convenience, taking a salt tablet. I’ve been in a ketogenic diet for six and a half years. I don’t want to take the time to make broth for myself. I’ll just have a salt tablet.
But you end up actually increasing your sodium beyond the recommended range, dietary range. But the reason you’re doing that is not because you want more sodium in your blood, it’s that you need to replenish what you’re losing.
Chris: Have you ever thought about sending patients this stuff? I think you’ve already picked up on the fact that this is just enough friction for me to not do it. What the heck’s a bouillon?
Jim: Yeah, right. What Virta’s done and there’s a number of ways that you could do this, but what Virta does is to ship everyone a starter kit and in that starter kit is the glucometer/ketone meter. It’s a cell-enabled scale. It’s actually a food scale so that people can weigh out food in the kitchen because we provide a lot of guidance around portion sizes.
And then included in there are bouillon cubes as well as magnesium. Another side effect that you get in terms of the way that your body handles electrolytes as you restrict carbohydrates is that -- it turns out many Americans are already low in terms of their blood levels of magnesium. That can be replenished. We provide what’s called Mag64, Slow-Mag, as a magnesium supplement. It’s included in that starter kit.
One other side effect that people will see when they start a ketogenic diet are muscle cramps particularly calf cramps at night and that can be most easily addressed through magnesium supplementation or just getting more magnesium in a diet.
Chris: And so you’re not seeing any adverse events as people transition into the diet now?
Jim: We’re not in terms of -- most of the stuff is stuff that can be handled in terms of working and that’s why it’s so helpful to work with a knowledgeable health coach is that the vast majority of these kind of issues that people run into and complain about early in a transition to a ketogenic diet, if you’re working with somebody who’s knowledgeable, you can troubleshoot through them.
We tracked all aversive events in the trial. Number two actually on my list of myth busters is this idea that ketogenic diets will cause diabetic ketoacidosis or DKA. We saw no DKA events in the trial at all. There’s no evidence of metabolic acidosis or anion gaps in our patients.
This whole idea that somehow nutritional ketosis is similar to diabetic ketoacidosis or DKA is patently false.
Chris: Do you see any change in the anion gap at all? You’d expect, if you’re putting more ketones which is an organic acid, you would expect a slight acidification of the blood.
Jim: We don’t. We don’t see that at all. I think the body has splendid regulatory mechanisms in terms of maintaining metabolic acidosis or alkalosis and so this is just somewhat a change in the composition of the food. This is a whole-foods approach so it’s pretty easy for the body to adapt to that change.
Chris: Talk about some of the most impressive and objective markers, changes that you did see in the blood. You’ve already talked about increased quality of life, mass quitting of drugs. I mean those are probably the two most important things, right? But if we could see some nice changes in the blood too, that would be cool. Is there anything in particular that impressed you?
Jim: Yeah. I think particularly, the cardiovascular risk markers. We actually published among those papers that we published so far, one of them was looking at the one-year data and rather than doing a deep dive on the diabetes status, doing a deep dive on the cardiovascular status.
That showed if you take what’s called ASCVD ten-year risks score which is commonly used in cardiology as a way of monitoring the risk status of patients for cardiac events, we see I believe it was 12% improvement at the one-year mark in terms of their ASCVD ten-year risks score.
There’s a number of kind of markers that go into deriving that number. As you break it up by individual markers, we looked at 26 different markers of cardiovascular risk and we saw statistically significant improvement in 22 out of 26 in our intervention folks versus zero out of 26 improved in the usual care folks.
That includes things from the lipid profile for instance looking at things like triglyceride and HDL and the subfractions of LDL to now also looking at the systolic and diastolic blood pressure as well as sort of the whole -- probably the most important -- impressive, if you look across all of them, there was I think it was a 37% reduction at one year and a 35% reduction at two years in the High-sensitivity C-reactive Protein, HSCRP.
You see this dramatic decline in inflammation which is increasingly seen as a major risk factor for cardiovascular disease other than just the lipid profile.
Chris: One thing I found confusing about -- I don’t know how you describe it. Maybe public relations or something. I mean it’s in the paper. For sure, you’ve got these improvements in metabolic health which is super important for cardiovascular disease risk and then you’ve got this kind of weird inconsistent thing where you say LDLC increase is sometimes observed like that means anything.
I think most people listening to this podcast will be agreed on the fact that blood levels of LDL have basically no effect on cardiovascular disease and you really do need to look somewhere else to know your risk. Why is it that kind of your -- just placating the --
Jim: I would say mainstream medicine is obsessed with --
Chris: Yeah, mainstream medicine. That’s the right --
Jim: Mainstream medicine is obsessed with LDL. If you look at it, the sort of kind of decade by decade version of this is sort of this finding your keys under the street lamp because that’s where the light is as opposed to where else do you look.
In the ‘70s, people could measure cholesterol so they looked at cholesterol. In the ‘80s, they could look at LDL and HDL cholesterol, so they looked at those two fractions. Then it’s kind of gone on from there.
But you know, the whole development of the statins and the whole mainstream medicine view of lipids is sort of stuck in the ‘80s in terms of looking not at particle number, not looking at particle subfractions and not looking at all the other risk factors that play into cardiovascular disease but just looking at this one number, this calculated low density lipoprotein cholesterol fraction.
Because there is more dietary fat in these diets, you do see that it’s correlated with the rise in LDLC. We kind of addressed that head on as opposed to ignoring it. We said yes, we do see a rise in calculated LDL in our patients, yet, at the same time, the number of particles of LDL particles, both by NMR LipoProfile as well as by looking at the apoB levels which are the actual proteins that are part of the LDL particle that the particle number’s unchanged.
And then the subfraction is shifting from a small dense to a large buoyant LDL which multiple studies have shown is a less atherogenic subfraction. We think it’s favorable but we have to kind of walk the medical community through our thinking.
Chris: You have to keep that LDL please. Malcolm Kendrick talked about this. You’ve got this jigsaw puzzle and it doesn’t really go together because you’ve got this cholesterol piece in the middle and it’s upside down and none of the other pieces will fit. But if you don’t have that piece in the middle, then the rest of the medical community is going to write you off as a quack and so you have to kind of placate them. What I really what you just say is, oh, LDLC is sometimes increased but that has stuff all to do with cardiovascular disease risk. But maybe that’s too much friction.
Jim: It’s complicated, all right? We’ve tried our best to walk people through it as opposed to sweeping it under the rug.
I think that it usually comes up as Virta’s commercialized and is now treating patients in all 50 states and is working with dozens of self-insured employers and health plans and we recently rolled out with the Veterans Administration as well as Blue Cross Blue Shield of California that invariably in those discussions with those major employers and health plans, there will be sessions where we kind of go deep into the science with their physicians.
That’s why it’s important to publish detail papers on that as well as give detail talks about the lipid response.
Chris: Right. Yeah. I would encourage anybody listening to this to look at Dave Feldman’s work. He recently did an interview with Ivor Cummins. Dave was presenting the NHANES data. We helped him put that together. What you find is that you stratify by age. Obviously, your age is the greatest risk factor for dying.
Once you get to 50 years old, you find the higher level of LDLC, the longer you live. That is the less risk of dying. The data is there. It’s in the NHANES data. It’s just kind of tricky to put it together.
I mean it’s good news to Virta. So you sometimes see a small increase in LDL, that’s a good thing. It’s consistent with your other findings. I wonder why you don’t just do a coronary artery calcium scan. Just look at the disease directly.
Have you ever thought about doing that? I mean it’s not something you’re going to do every day like you do with the blood levels of beta-hydroxybutyrate but you could’ve done it before they start the clinical trial and then again at the one or two-year mark.
Jim: Yeah. What we did instead, in retrospect, knowing what we know now in 2019, we might’ve chosen something different than we chose to do in 2015. We did a carotid ultrasound looking for a carotid intima-media thickness.
What we basically found so far is that at one year, there was no change at all and we’re waiting on the crunching of the two-year data on that outcome. That is something where carotid intima-media thickness, you could see regression or change overtime versus with the calcium score, generally, once that calcium is there, it won’t regress. It’s kind of permanently in place.
If you want to see progression, you could detect that with the calcium scan but you wouldn’t necessarily be able to monitor regression. I’ve had a number of people point that out to say, “Why didn’t you do the calcium scan?” That was kind of the thinking behind it in 2015.
Since then, there have been a couple of publications around the carotid ultrasound in diabetes showing that it’s not predictive of coronary or cardiac outcomes. It’s perhaps less important than we thought it was at the time.
Chris: I think you’re right. We have had some clients that have documented decreases in their scores though.
Jim: You have in their calcium scores? Okay.
Chris: Yeah, definitely. It is possible. I think you’re right. I think it’ll be hard for me to find that in the literature but we’ve definitely seen it.
Jim: Yeah. It’s interesting because you think about kind of once those plaques are calcified, you would expect to kind of, you know, other than rupturing, there’s no other way to get rid of that calcium but perhaps that’s an overly simplistic way of thinking about it.
Chris: Do you think at the two-year mark, these patients are healthy now? I look at some of the objective markers, although I see huge improvement as you said with High-sensitivity C-reactive protein, fasting glucose, fasting insulin, pretty much everything you proved across the board but still, you’ve got people with a fasting glucose over 134 and a fasting insulin of 16 and a C-reactive protein of 5 milligrams per deciliter. I would be kind of scared still if they were still my numbers.
It’s a big question but you think these people are healthy now, do you think you’ll ever get them to a point where you might consider them to be optimal where optimal is blood level of said thing with respect to mortality?
Jim: Yeah. In terms of the idea of sort of diabetes reversal, it’s not as if you’re returning to the health that you might’ve enjoyed as a teenager. These folks are not entirely out of the woods. Some still have metabolic syndrome. Some still have diabetes.
Even the folks that no longer meet the diagnostic criteria of diabetes, many of them would meet the criteria of prediabetes. I would say that they are much healthier. I wouldn’t say that they’ve returned to necessarily to optimal health. There’s a lot of variety across the population as well. Some folks are doing better than others.
One of the questions I sometimes get is okay, you’ve got 55% who’ve reversed their diabetes two years but what about the folks who -- the other 45% who haven’t reversed their diabetes? It’s important to point out that basically, well over 90% of the folks in the trial got substantially better.
For those who don’t reverse their diabetes, their A1c is still down 1.2%. They still eliminated 45% of their medications. They’ve eliminated 81% of their insulin. They’ve lost 23 pounds and they’ve shown a 17% improvement in their ASCVD risks score.
Even their “failures” are not failures. They’re a lot healthier than they were when they began.
Chris: What’s next for Virta? Are you going to do more clinical trials?
Jim: Yeah. In terms of Virta, what we’re doing, and this part around my departure from the company, and going off and looking for what’s next for me is that Virta is focused around commercialization. We’re in this position now and I think the real critical breakthrough, and you could put it down to one thing, was the change in the status of recommendations from the American Diabetes Association.
We’ve had a banner year in terms of 2019 where they’ve changed both their standard of care in January as well as their nutrition consensus in April to include individualized carbohydrate restriction citing our trial.
What Virta does and the overall utilization of ketogenic nutrition for the treatment of Type 2 Diabetes has suddenly shifted from an outlier to mainstream.
Chris: Wow. That’s huge. Let’s pause for a moment and congratulate you there. That’s incredible.
Jim: Yeah. We’ve come a long way. It’s not been just the Virta trial. There’ve been other trials that have been done by academic investigators that have been published in the last couple of years. Several of these recited in those two important publications in diabetes care.
I think what Virta has decided to do based on that is to just put all our resources into commercialization, so sales and marketing and clinical care and roll out -- we’ve got the VA roll out, the Blue Cross Blue Shield California roll out but other major employers across the country and get to the point where we’re treating hundreds and thousands and eventually millions of people as fast as we can.
I think there is a tremendous amount still to be done on the research front. Whether that eventually comes out of Virta or comes out of other groups is to be determined. But I’ve got my own kind of long list of researches that I think needs to be done.
Chris: What’s the business model then? You just mentioned an insurance company. That’s one model and then there’s selling into businesses, self-insured businesses as well. Is that correct?
Jim: What Virta decided to do really was to work with the payer. Let’s just say okay, you’ve got the opportunity to improve the health of the patient but in terms of paying for the intervention, who pays the salary of the health coach and that physician and the software team and how do you pay for all of that that you’ve got to address whoever is the payer that’s “suffering” in terms of the financial hit.
The average care for a person with Type 2 Diabetes in the United States even before they get very sick is about $16,000 a year. If you can move that person back to a healthier range, reduce their medication use and just get them overall healthier, there’s the opportunity to save thousands of dollars a year and that more than pays for the cost of the intervention.
What Virta decided to do last year interestingly was to put the entire cost of the intervention at risk so to say don’t pay us anything upfront. Wait and see can we enroll and retain your patients and then can we make that healthy and you pay for results.
The entire sales model of Virta is value-based level. You slowly see health care moving in this way, moving from a fee-for-service to a value-based model. Virta just jumped entirely into value-based model and said, pay for results. Don’t pay for what we do.
Chris: Wow. You call it value-based results. I call it skin in the game.
Jim: Yeah, and what we found was that especially the health plans are looking for ROI or return on investment in less than a year. They want to be cash flow positive at least by the one year mark if not sooner in terms of they want to not just make people healthier, they really want to save money.
Chris: Have there been any big corporate client announcements? You’re doing this for Walmart?
Jim: Among the bigger players that we’ve announced are US Foods, Nielsen Analytics, we’re working with Activision Blizzard. We’ve got a number of big ones that are in the pipeline to be announced. I think one of the most interesting ones, you know, US Foods is interesting because we’re working with truck drivers and so we’re working with folks that have to figure out how to get these meals on the road.
And then one of my favorite examples is the Chickasaw Nation which is a Native American tribe that runs a number of casinos in Oklahoma. So in that case, you’re dealing with a Native American population as well as folks that are living in what people call a food desert meaning that there aren’t a lot of nearby grocery stores with fresh produce and nearby food options.
We actually brought in a team, our clinical operations team and spent some time on the ground in Oklahoma to figure out how do you help people navigate that food environment?
Chris: How do you navigate? Start from scratch.
Jim: Yeah, so first in terms of outcomes, both in terms of US Foods for their truck drivers and warehouse workers as well as with the casino employees and families in Oklahoma with Chickasaw Nation, we’ve seen results that are comparable or better than our clinical trial.
We see for instance rather than I think in the clinical trial we are 83% one-year retention, 74% two-year retention, we actually see greater than 90% retention at a year in our commercial populations. We make it easier for people in terms of providing everything remote. They never need to come into the clinic like they did in the clinical trial. They don’t have to do all the extra bells and whistles of clinical testing.
The outcomes are great. In terms of how do people navigate the food environment, it’s basically figuring out how do you implement a ketogenic diet when you know if you are forced to go into a fast food restaurant, what do you order? If you’re eating at the casino cafeteria, what do you order?
You can almost always find something on that menu that will work. That’s kind of the sort of grounded day-to-day tactics of implementation is that you don’t always have a large food budget and gourmet dining choices at your disposal.
Chris: You don’t always have my wife is what you’re saying.
Jim: Or my wife too is a wonderful cook and one of the things for instance that I get the fun of benefiting from not only having a wife who’s a wonderful cook but having a farm where my wife runs a farm and so I have fresh eggs almost every day. But not everybody gets those kind of benefits for foods at their disposal.
Chris: We’ve had our mutual friends, Robb Wolf, talk about the Chickasaw Nation and the the changes that might be happening there. Do you think that the way that food is produced might change as a result of this new finding because they’re a tightly-knit community and they probably do have the ability to all do the same thing and therefore change the way that if everybody’s eating the same thing in the cafeteria then what’s all these other stuff for, right?
Jim: Oh, absolutely. We’ve seen this with a number of employers. I think one example for instance I think is in Lafayette, Indiana. So for those who aren’t familiar with that area, it’s a mid-sized city of about I think 100,000 people in the entire metro area, about an hour’s drive north of Indianapolis, two hours’ drive south of Chicago. In addition to having an Indiana University Health hospital and clinic there, West Lafayette is the home of Purdue University.
As we’ve had hundreds of people in our clinical trial under our care, the community has gotten very familiar with this approach to eating. We’ve brought on board both the city and county as clients and then also importantly Purdue University as a client.
We have hundreds of people at Purdue University under our care. That, we’ve seen changes to cafeteria offerings. People have gotten active and said, hey, there are hundreds of doing this. Let’s work with the decision-makers who control the food that’s in the cafeteria and actually implement changes.
And then you see it across the grocery stores and the restaurants in the region. Walmart stocks Kerrygold grass-fed butter and Walmart stocks pre-shredded cauliflower and these other sort of staples that are useful if you’re implementing this way of eating or the discount of olive oil.
And then the pizza places have a crust list version or a version of pizza without the -- they make the crust out of something else. I forgot. The set of cheeses or cauliflower or something but it’s a non-starchy crust as an alternative.
If you’re looking for the sort of oasis of these food choices, surprisingly, it’s actually in West Lafayette, Indiana.
Chris: Wow. Where’d you go from here, Jim? You’ve finished changing the world. What’s next for you? Surely, you could only go down from here. [0:58:12] [Indiscernible].
Jim: What we’ve done over the last four years might be kind of a once in a lifetime opportunity to have an impact in terms of how often do you run a clinical trial that changes the standard of care.
But I think it is the tip of the iceberg in terms of not just the implementation of ketogenic diets but really the recognition that so much of the chronic disease burden in our country and nation-wide is dependent on nutrition and behavior change or the underlying nutrition and behavior.
I think so much over the last couple of decades, people have seen chronic diseases from not only diabetes but cardiovascular disease and cancer and Alzheimer’s disease, seeing these as sort of inevitable. This idea that as we get older, we’re going to get these diseases and the best we can do is throw pharmaceuticals at them.
I think we’re seeing the sea change in realizing that these diseases are not necessarily an innate part of the human condition. They can be changed through nutrition and behavior.
I think there are other opportunities to do that in terms of clinical trials around cardiovascular disease, around cancer, around neurological conditions that could have as big an impact on those conditions as we had with diabetes.
Chris: Is that your interest you’re looking for positions where you could do that sort of research?
Jim: Yeah, either research or implementation of clinical protocols and whether that’s across startups or growth stage companies or more mature payers or providers or I think there’s a number of different ways to have that impact. That’s kind of the type of thing that I’m looking to do next. I’m kind of in the exploration phase of figuring out what that will be.
Chris: If you could have your dream study funded, what would it be?
Jim: I’ll mention two. I would say that if you look at what we did and what we were able to do in the Virta, Indiana University Health study, we had to do that as a non-randomized study in terms of the way we recruited those patients.
To recruit 378 people to the intervention arm of the trial, 262 with Type 2 Diabetes, 116 with prediabetes to recruit those people at a single site in less than six months required telling what the intervention would be.
Whereas if you’re going to randomize people and say, “Hey, sign up for two years.” You don’t know what you’re getting into. You’re going to have a lot harder time recruiting that trial so it’s going to need to be multi-center. You’re going to need to look at many more incoming candidates who will, when you explain to them the description of the trial, many more will say no.
I will say somebody needs to do a randomized trial, multi-site, separating the care team from the research team, blinding portions of the trial and basically doing all the things that we couldn’t afford to do in the IUH trial and then ideally taking it out to morbidity and mortality endpoints.
If the National Institute of Health was to throw many millions of dollars at this and look at a trial in the thousands of patients and following those folks out for five years in a randomized study, that would be the ideal thing for somebody to do. That’s what the pharmaceutical companies have been able to afford to do.
If you look at the positive results that have come out in terms of cardiovascular effects of GLP-1 and SGLT2 inhibitor drugs in the last couple of years, those studies have involved on the order of 2,000 to 5,000 patients.
They are randomized multi-year trials where the pharmaceutical companies had I don’t know the exact budget but hundred million dollar budgets to do these kind of trials. In a Type 2 Diabetes realm, that would be something that somebody needs to do.
Chris: But who’s going to fund it? You’re reminding me -- I just published a podcast with Simon who’s an expert on behavior change and at the end of that interview, he said -- well, I talked about how cheap his training course was and he said to me, “Well, Chris, you know that nobody gets into behavior change with money.”
Jim: Right, right. Yeah.
Chris: Who’s going to fund that trial?
Jim: Right. Virta has figured out one way to kind of go to marketing strategy to fund behavior change but it doesn’t provide pharmaceutical level deep dollars at its disposal so it doesn’t have a multi-billion dollar research budget.
One of the only groups that has a research budget like that is the National Institute of Health. So far, they have ignored nutritional ketosis, low carbohydrate approaches. They’ve, in general, downplayed nutritional or dietary interventions as something that should be studied but really, outside of the pharmaceutical company, that’s really where the dollars are for clinical trials like that.
Chris: What are the chances of that happening? I think I saw a picture the other day of McDonald’s being delivered to the White House. I’m sure whether it is fake news, somebody photoshopped that but I’m pretty sure it was legit.
Jim: Yeah. I think that irrespective of political party and power, this kind of long standing avoidance of nutritional approaches for diabetes with NIH, it was there kind of before any kind of changes in political power and were probably there after changes in various parties in political power. I think it’s sort of a separate issue.
Chris: Okay. That’s good.
Jim: I think that’s of interest. I think there’s an interesting study underway or actually proposed to be funded in New York looking at cancer therapeutics around combining nutritional ketosis as an adjunct therapy together with pharmaceuticals for cancer together with chemotherapy and where you may see a synergistic effect between the chemotherapy and the nutritional changes. I think stay tuned for kind of some progress on the cancer front.
Chris: Is there anything else that I should’ve asked you?
Jim: Yeah. I’m really glad that we got around to talking about the changes to American Diabetes Association. That was kind of the number one thing on my list to make sure.
Then the other thing would be just to sort of say that I think we’ve kind of put to rest this issue of can nutritional ketosis for Type 2 Diabetes be achieved and maintained safely and sustainably? I think we’ve clearly answered yes to that.
That was the main thing about the trial that I wanted to make sure that we didn’t miss.
Chris: Excellent. Well, where can people find you online?
Jim: The best place is on Twitter, @JPMcCarter. You can find me tweeting there and reach out to me directly and happy to get in touch that way. Also, I’m on Medium and LinkedIn.
Chris: That’s excellent. I will of course link to all of those resources in the show notes for this episode that you can find over at nourishbalancethrive.com/podcast or if you poke around inside of your podcast that you’ll probably see a little info button and you find clickable links just inside your phone there.
Well, Jim, thank you so much. We really appreciate you’re changing the world, doing some amazing things. It’s very exciting. Congratulations and thank you.
Jim: Thanks so much, Chris, for the opportunity to talk about it and thanks for all that you’re achieving with Nourish Balance Thrive both in terms of your clinical practice but also in terms of using your podcast and other ways of reaching a larger audience.
Chris: Well, thank you. I mean it’s a position of privilege and something that I would do even if -- well, it’s questionable whether it does [1:05:46] [Indiscernible] or anything useful but with me, it’s just a labor of love that I would do it even if I could do anything. So yeah, thanks and I appreciate that.
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