Ethan Weiss, MD A Preventive Cardiology Perspective On Lipid Health 

Dr. Brian Mowll: Hello, and welcome back to the Diabetes Summit 2019. This is Dr. Brian Mowll, the diabetes coach. I'm your host for this event this year, our sixth annual Diabetes Summit. I'm a certified and master-licensed diabetes educator and IFM-certified in functional medicine. My next interview is with a preventive cardiologist from UCSF.

Dr. Brian Mowll: That is the esteemed Dr. Ethan Weiss. Dr. Weiss is a cardiologist specializing in preventive cardiology, coronary artery disease and general cardiology. He's an associate professor of medicine at the University of California San Francisco and a member of the Cardiovascular Research Institute. Dr. Weiss' clinical interest include prevention, lipids and the emerging intersection of endocrinology and cardiology with a specific focus on prediabetes and type II diabetes as risk factors for coronary disease.

Dr. Brian Mowll: Dr. Ethan Weiss is one smart guy and I think you're going to really appreciate his perspective on the connection between type II diabetes and how to prevent cardiovascular problems. Enjoy this interview with Dr. Ethan Weiss. All right, so I'm here with Dr. Ethan Weiss from UCSF out on the West Coast and I'm excited to have a conversation.

Dr. Brian Mowll: Dr. Weiss is a preventive cardiologist and we're going to talk all about lipid health today and diabetes and some new exciting technology that he's working on too so-

Dr. Ethan Weiss: Awesome. Thank you. Thanks for having me.

Dr. Brian Mowll: Absolutely, so I think the first thing I'd love to get into is as a cardiologist, I'm sure that you've had to put a lot of thought into lipid health especially around this particular way of eating that we're going to talk about today which is more of a high carb, low fat type diet. There's just a ton of controversy out there regarding what that does to our lipids and how clinically important that is to cardiovascular health and long term mortality and so forth.

Dr. Brian Mowll: I'd love to get your perspective on how diet just in general relates to lipid health and then again, how you see the connection between lipids and cardiovascular health and longevity and so forth.

Dr. Ethan Weiss: Yeah, sure. There's a lot to unpack there so why don't we start with the… the simple, I'll give you my quickest answer which is when you look at the role of nutrition on cardiovascular health, I think the list of studies that we can point to there. What we would consider to be gold standard like RCT, randomized control trials. It's a short list.

Dr. Ethan Weiss: One of the studies on that list, the Prediments trial was… has its, some questions about how it was done so I think we're all stuck in this world of imperfect information when it comes to what's the impact of nutrition. Any nutritional dimension or change you might make and what's the impact on your risk of having heart attack.

Dr. Ethan Weiss: I think what we're left with is taking the information we have and making as best informed a guess as we can going forward so that's the way I approach things in a general way. I'll also state clearly that I do to subscribe to whatever you want to call the cholesterol or LDL hypothesis. I believe that it's fairly well-established. At least and still in the cardiology world.

Dr. Ethan Weiss: It doesn't mean that we're not going to change our mind someday but as of today, it's established and I am a believer that cholesterol and particularly, some forms of what people might call LDL cholesterol are causative in cardiovascular disease.

Dr. Brian Mowll: Can we dive a little deeper into that because I'm just curious because again, point of controversy, not so much in conventional cardiology certainly but when you get into the more natural health world. You get into paleo, ketogenic diet, low card diet circles. This is debated quite a bit so how does in what you can reveal to us, how does LDL cholesterol relate to cardiovascular disease?

Dr. Ethan Weiss: Well, so you have to go… ask the questions, what are you going to use as your source of information and I think… when I think about these, the risk factors, these circuit markers, you can put them in different categories and I think of it sort of like how well do they fulfill Koch's postulates, right? Which we all learned in medical school so there's definitely been an association between cholesterol.

Dr. Ethan Weiss: Total cholesterol and later, LDL and if you want to get more specific, ApoB containing particles or even LDL particles themselves or even, if you want to get more specific, say small dense LDL particles as opposed to the larger flappier ones, but there's been an association with cholesterol and heart disease forever so that's the etymology.

Dr. Ethan Weiss: That goes back probably hundreds of years but definitely got firmed and formulated during the [Framingham 00:05:45] era in the 1950s. That's the association. There's then, I think… what's the next little evidence? Recently in, let's say, the past 10 years, I think there's been a really abundant amount of information coming from our colleagues who are human geneticists and specifically, the ones doing Mendelian randomization.

Dr. Ethan Weiss: While it's certainly like every other science, is probably imperfect, it's interesting how well it predicts, say, the impact of certain risk factors

and studies that have been done largely at the Broad Institute. It's clear at least from the reading I've done of the literature that LDL is probably the most potent inheritable risk factor.

Dr. Ethan Weiss: Obviously, smoking is in a class of its own but in terms of inheritable risk factors, if you just look at sort of the heritability of LDL cholesterol so how much does the level of your LDL relate to your genes? That is very strongly associated with your risk of developing a heart attack over years. It turns out that that same line of work was also the beginning of the end of the HDL stories.

Dr. Ethan Weiss: When I was a medical student, we were taught that HDL was good cholesterol and that you want to do what you can to get your HDL up and to some extent, it's true that HDL is associated so high HDL is associated with decreased risk of disease and low HLD is associated with increased risk of disease. The question is can you change that through medicines or lifestyle changes and does that change, impact the effect of risk?

Dr. Ethan Weiss: The bigger question is, is HDL itself causative? It either is a protective if it's… as it goes up and the Mendelian randomization study seems to suggest pretty strongly that HDL has very little causative effect. What's come out of that though is that the third child in this whole family, the one that we were told to ignore when I was a student which is triglycerides.

Dr. Ethan Weiss: We were taught that triglycerides themselves had no impact on our cardiovascular risk and turns out that they have a potent impact on risk in these Mendelian randomization studies. That's the second level of evidence is this Mendelian randomization. The third is the fulfilled Koch's postulates.

Dr. Ethan Weiss: You got to fix it so what are the experiments that we have? Imperfect experiments where we have wealth now over 40 years of drug trials where you modulate cholesterol in some form or another. It's really amazing how well the Mendelian randomization predicts the impact of the three classes or the… of drugs and modulated to these three classes so obviously, LDL cholesterol is significantly modulated by statins and other drugs.

Dr. Ethan Weiss: These newer drugs, [inaudible 00:08:33] inhibitors. I think I'm fond of saying that statins do lower cholesterol. They also absolutely reduce the risk of heart attack. How closely those two things are related is a matter of debate because statins probably do other things besides just lowering cholesterol.

Dr. Ethan Weiss: That's I think powerful, right? We have a long history now of hundreds of thousands of patients randomized to trials and showing that statins do reduce the risk of having a heart attack. Particularly, people who have had a heart attack previously. HDL, we've had now like three or four different classes of drugs that have completely failed, either don't do anything to your risk of heart attack or might even increase it.

Dr. Ethan Weiss: Then lastly, triglycerides, I think, we now have a couple. We have Vascepa, this [Amarin 00:09:16] fish oil story that came out over the summer. It looks as if it has a really potent impact on reducing risk of heart attack. That's how I frame the whole conversation in a long way.

Dr. Brian Mowll: Yeah, I'd love to talk to you more about that, Vascepa. It's that high EPA isolated fish oil. It's interesting. Maybe we can talk about that in just a minute. I would like to ask about the effect of cholesterol. A lot of people have this image that cholesterol is like sludge in a pipe and it blocks up the arteries. Basically is what accumulates as plaques in the arteries. Is that an accurate picture or is something else going on here?

Dr. Ethan Weiss: Well, so any… I don't think we know for sure. I want to be sure to be humble about what we do and don't know. I think if you look at plaques in human arteries specimen, coronary specimens whether they're autopsy specimens or whether they're from… if you get the specimen from an explanted heart or some other... there's definitely LDL cholesterol in them abundantly along with other lipids.

Dr. Ethan Weiss: How LDL itself causes and again, I believe that it does. I know it. There's a controversy about how causative it might be but at least for now, I'm stuck on this idea that it's important. It may not be the only reason but it's certainly a factor. How LDL contributes to that, the growth of that plaque is still something we're learning about.

Dr. Ethan Weiss: I think we're hindered in a large part in this field because it's hard to get a whole tissue, right? Unlike my oncology colleagues who can study the biology of tumors by taking because remember, once the tumor is out, you take the tumor out. You can look at it and profile X, Y or Z metabolator, gene or RNA. We don't get access to tissue very often.

Dr. Ethan Weiss: At least human tissue and the other part of the story is that unfortunately, for reasons that we don't totally understand, there are not great animal models of coronary artery disease. I think we're stuck with a lot of observation. We don't have the best and most refined understanding of how this process happens but there… it's definitely true that you'll find cholesterol in the artery wall in these plaques.

Dr. Ethan Weiss: I think the latest and greatest unifying theory is that that cholesterol my cause its problems by inducing an inflammatory response. In other words, it may trick our immune system into thinking, some people say, it mimics a bacteria and so basically, your turn on this innate immunity and these macrophage is another… inflammatory cells then attack it.

Dr. Ethan Weiss: Then the process of attacking this cholesterol and trying to get rid of it because they think it's a bacteria or something. They create this muck and that's the basis of how this process goes forward. It's definitely not my primary research interest and I wish I was more up to date on it but I will say that that's my latest and simplest way of putting the whole thing together as best I can.

Dr. Brian Mowll: Now, what about the… the other piece of the equation often is then, what actually causes high LDL? You mentioned obviously, hereditary factors are a big one but when we look at the diet, of course, there's a

lot of disagreement about how much of an impact certain diets that we have is that whether it's a total fat in the diet, saturated fat in the diet, chemically altered fats like hydrogenated fats.

Dr. Brian Mowll: Then some people will argue, sugar and even fructose and so forth leading to fat accumulation in the liver and driving up triglyceride so how do you see the dietary connection to lipid health?

Dr. Ethan Weiss: Yeah, it's a phenomenal question and something I think people ask me all the time whether they're friends or patients or whoever it is. I do have to stop and say I think we, as a world, as a world of medicine so let me just back up and say, I'm a second generation cardiologist. My dad's a cardiologist so I grew up in the 1970s and the '80s in the home of a cardiologist which means, you can imagine that like fat was as demonized a character as you can ever find.

Dr. Ethan Weiss: We had no fat anywhere to be found in our home. We had everything that you could think of to replace fat so skim milk, margarine, any kind of oil. Just anything, but fat, and of course, I'm fond of saying, nutrition is one of these rare things in our world. It's truly a zero sum game so if you keep calorie content or calorie intake the same.

Dr. Ethan Weiss: If you reduce one macronutrient, say you reduce fat, by definition, you're going to increase one of the other two or maybe both of the other two. I think what we've done as a society or what we did in the '70s and '80s by trying to tell people to eat low fat was effectively tell them to eat high carb. I don't want to get down the rat hole of trying to explain what happened with our metabolic health as a society and a world over the past 25 or 30 years.

Dr. Ethan Weiss: It's definitely interesting to me and having lived and watched it is particularly interesting to me. That said, I want to be careful not to make the same mistakes of my father literally so I don't want to prematurely say, I have the answer. I don't have the answer. I think we all have a lot to learn. I'm still learning a ton so if you take the specific intervention of say, low carb and high fat, I think there are observations that it doesn't have impact on circulating blood cholesterol levels.

Dr. Ethan Weiss: I think the question is what does that impact? The best source of information of data that I have probably is that ongoing Virta study and I've been an advisor to them for a couple of years and they published a really nice paper a couple years ago looking at the impact on a bunch of markers, cardiovascular risk markers in their patient population.

Dr. Ethan Weiss: They've got 250, 300 patients who are type II diabetes and they're on this very low carb, high fat diet and they've been following them for now, two years and so what happens to all the markers and I think… I don't remember the exact number but I think they had something like 32 markers of cardiovascular risk and 31 of them moved in what you would call a positive direction, right?

Dr. Ethan Weiss: They moved in a favorable direction whether it was decreasing CRP so they had marker of inflammation or decreasing blood pressure or decreasing triglycerides. Stay away from decreasing fasting insulin. All

these things are moved in the right direction. That one that didn't was LDL cholesterol. LDL went up about 10% but… I'll be honest.

Dr. Ethan Weiss: When I first saw that, it scared me and it bothered me and I think it partly bothered me because I'm trained and conditioned that it bothers me. Luckily, we have a phenomenal group of other advisors over at Virta including my colleague and friend, Ron Krauss and Ron said, "Ethan, let's actually dig a little bit deeper on what this… what's happening with these lipids because if you look at it, yeah, LDL cholesterol does go up.

Dr. Ethan Weiss: "Total cholesterol goes up but what happens to ApoB?" We looked and ApoB didn't change at all. We looked at all the particles and they didn't change and so at that time, I started to become comfortable at the idea especially in that population of patients where you're getting tremendous benefit to them in terms of their diabetes and metabolic health that it was safe from the standpoint of cardiovascular risk.

Dr. Ethan Weiss: That if, at the very worst, it was neutral. At least as a population basis, on a population basis. It's neutral in terms of risk and maybe again, 31 out of 32 markers went the right direction so it also felt good to me and comfortable to me so that's population. The bigger question from my standpoint is what do you do as an individual because if you look as you probably know and other people who take care of patients know that certain individuals have what I would call an extreme response.

Dr. Ethan Weiss: Well, the average change in LDL cholesterol is about 10 milligrams per deciliter in patients on this intervention. Some individuals have a much bigger change. Some have none and some have a decrease. I happen to be one of the lucky people who when I started eating low carb, high fat, my cholesterol numbers improved but that nots true for everybody and you hear these stories of people who go on this diet.

Dr. Ethan Weiss: Their LDL cholesterol goes from 130 to 290 and I hear it all the time so then, the question is what do you do with that? I think that is the most interesting question for us to deal with now going forward. I have my way of thinking about it. I don't know if you have a way of thinking about it if it doesn't bother you at all but I certainly have like developed, I think, over the past years, my approach to dealing with that.

Dr. Brian Mowll: Yeah, and no. I'd love to hear your thoughts on it. Those are people often called hyperresponders that will get, like you said, will have a negative reflection in their lipid values from eating high fat so for me, what we're typically doing is working on figuring out what's causing that and usually, it's certain fats or it's the combination of foods they're eating.

Dr. Brian Mowll: Sometimes, not everybody does well in a high fat diet so sometimes, we have to adjust that and focus more on allowing more carbs. Just making sure they're really good whole food, real carbs and try to keep it low in the glycemic index and so forth but yeah, but I'd love to hear your thoughts on it as a scientist.

Dr. Ethan Weiss: Yeah, sure so I take four… I think you have four so let's just say you're this hypothetical person and you go on low carb diet. You have an awesome response. You lose a bunch of weight. All your metabolic numbers look good. You're feeling great. Your LDL cholesterol skyrockets so what do you do with that? I think you risk by four choices.

Dr. Ethan Weiss: One choice is to say, "Well, I'm going to ignore it. I don't believe the cholesterol's causative in cardiovascular disease. I think it's much more important that my metabolic health is optimized so I'm going to ignore it." I think a version of that, maybe like option 1B is to say, "I'm not going to do anything about it but I'm going to keep an eye on things in a different way like I'm going to do a calcium scan now.

Dr. Ethan Weiss: "I'll follow that every five years or something and if it looks like my calcium score is zero, I'm going to feel more comfortable about this number that scares everybody else." That's one approach. It's not my favorite approach but it's an approach and I don't think it's… I think the ignoring thing is probably… to me, it just is risky but I think the approach of following calcium scans over a period of time is reasonable, so that's option one.

Dr. Ethan Weiss: Option two is like you said, keto is not for me, right? Maybe I got to try a different diet or add more carbs or do something else. I think that's option two. Option three is look, I love this. I don't care about taking medicines that much and statins are generally pretty safe. They may be tolerated but if I can take a statin and tolerate it.

Dr. Ethan Weiss: It doesn't bother me. It doesn't give me aches or anything, then maybe to stay on this diet, I'll take a statin so that's option three. I think those three options are all imperfect and so my favorite option is the last one which is what you described which is I think right now, it looks like and it's super anecdotal and most of us just have small numbers of patients we've done this with but it does look like what you pointed to that the big driver of this change is probably not as much the total fat, the dietary fat content.

Dr. Ethan Weiss: It's really the saturated fat content in your diet and so I've had some luck in switching the ratio of saturated fats, more on saturated fats and so replacing, not completely like if somebody wants to have a stake once a week or once every couple… of course, do it but instead of emphasizing eating stake X number of nights a week and burgers and all this super high fat, saturated fat.

Dr. Ethan Weiss: Maybe to emphasize the plant-based fats like avocado and nuts, certain walnuts and Macadamia nuts. Fish like salmon. Fatty fish like salmon and things like that and to switch that ratio, saturated by non-saturated. That's the thing that I've been the most excited about especially in primary prevention so for people who've never had a heart attack.

Dr. Ethan Weiss: They're just trying to optimize their health. They don't want to take medicines. That seems like it's the optimal way to deal. I think it's important that people who've had heart attacks because I listen to a lot of podcasts and I've heard different things come up. Somebody will call

in or they'll write in and say, "I had a heart attack and I got statins and my doctor, I've been on a statin and my LDL cholesterol went crazy when I was on it.

Dr. Ethan Weiss: "They want me to stay on the statin but I don't want to stay on it." I think if you had heart attack that it's important to treat things differently. That I think respect that that is a different animal so I'm not yet comfortable recommending diet as a mechanism to treat people who've had heart attacks alone. It certainly can be a part of the program. It should be.

Dr. Brian Mowll: Yeah. Yeah, I think that sounds very responsible, makes total sense. You talked about statins and their clinical use. Are there and we mentioned earlier the fish oil product, Vascepa. Are there other natural things that you found and I don't know how comfortable you are talking about that or if you've done any exploration into that area but are there other things that you've found that helped to improve lipid health other than statin therapy or maybe in addition to statin therapy?

Dr. Ethan Weiss: Yeah, so red… I can never say this but make red rice yeast extract. I think it basically is that. I think it ends up being on the chemistry level but I think it basically ends up being basically statin but some people like the idea of it being a more natural product. I have a lot of patients out here and that they are who are averse to taking chemicals or averse to taking manmade chemicals and don't like taking drugs.

Dr. Ethan Weiss: This conversation comes up a lot. Again, it really depends on the context. It depends on the risk and the patient, what they've been through. I met patients of mine who were violently, not violently, but it's a really strong anti-statin that had a heart attack and were less anti-statin after the heart attack. I think there are all different ways to do things. I don't have a ton of experience with the other supplements or other non-medical ways to modulate cholesterol per se.

Dr. Ethan Weiss: Obviously, fish oil has been around for a long time in a lot of different flavors and formats. It's been shown to modulate lipids, both triglycerides and cholesterol. I think there was a lot of excitement over this trial that was published recently with the Vascepa drug, the REDUCE-IT trial. We could probably take an entire podcast to talk about that trial but-

Dr. Brian Mowll: Sure, sure. I think the general gist is that they're having some sides to show that DHA can actually raise LDL, I think and that the EPA fatty acid component of fish oil seems to have the most profound impact on lowering triglycerides and so they've isolated this and it's a high EPA product, pharmaceutical grade product so that trial seemed pretty impressive so-

Dr. Ethan Weiss: It did. Absolutely, it did and I should say I'm not an advisor to that. In fact, I think they would prefer to not have me around. It was exciting is that somebody who pays attention to all this stuff like it was super exciting when they announced the results because to me like it was the validation of the triglyceride hypothesis which was this thing that we

were all told didn't exist and so the problem is like the devils in the details.

Dr. Ethan Weiss: When you peel back and look at the details of this trial, unfortunately, there didn't seem to be a strong relationship between triglyceride, either baseline triglyceride or the degree or amount of triglyceride lowering. There's this unanswered story of like how is Vascepa? Vascepa clearly seems to be reducing risk of heart disease.

Dr. Ethan Weiss: There's no doubt. It has a huge robust impact but I think we're all left puzzled as to how that works and I was disappointed. I'll be just totally honest. I was disappointed that the triglyceride impact wasn't greater because I think because that validates this whole hypothesis and that opens up the idea of using nutrition to modulate triglycerides as a mechanism, as a treatment.

Dr. Ethan Weiss: Then, I'm stuck. Well, gosh, if it's not triglyceride, then what is it? Anyway, it's a… like everything else in science, we don't have the answer now.

Dr. Brian Mowll: More questions.

Dr. Ethan Weiss: Yeah, lots more questions. Lots more questions.

Dr. Brian Mowll: Well, let's talk diabetes specific recently. You mentioned that you worked with Virta Health a little bit and they're obviously doing some trials. You talked about one of them's been published. I think they're still in their two-year trial right now so it's exciting information and they, of course, used this ketogenic, ultra-low carb ketogenic diet as the main mechanism of treatment there.

Dr. Brian Mowll: Then health coaching, doctor supervised health coaching and it seems to be pretty impressive so what are your thoughts on the ketogenic diet for diabetes that you've gathered or from your own personal and equals one trials on yourself?

Dr. Ethan Weiss: Yeah. Yeah, I would say, awesome question so I was introduced to them so I'm an advisor. I'm a financial stake, I guess, although I don't think it's a lot but I get that out there in terms of conflicts of interest so I was introduced to them probably two and a half or three years ago by one of their investors and when he told me about them, the story was he said, "Look, Ethan, this intervention they have is spectacular."

Dr. Ethan Weiss: I think he described it as being next to bariatric surgery, the most impressive data that he'd ever seen. I have to say, I think that description is relatively apt. I think it actually… I'm not a diabetologist. I happen to spend a lot of time in the lab thinking about diabetes, insulin resistance, and I treat a lot of patients with type II diabetes but I'm not an endocrinologist and not a diabetologist.

Dr. Ethan Weiss: That said, it's really… you don't often see people coming in to the office with fewer and fewer drugs. It's usually the other way around, right? People come back to you and you're adding more and more so I think the fact that they're coming off of all these diabetes medications and not

just their diabetes medications are coming off of their blood pressure medications.

Dr. Ethan Weiss: They're losing weight and they're sticking with this program. It's definitely impressive. Again, from the outside. When I got involved with them, I did a deep dive because I had not really paid attention since the whole Atkins thing. I hadn't paid attention in a detailed way and I went back and looked and I found publications of using low carb, high fat diets to treat diabetes.

Dr. Ethan Weiss: They didn't call it type I or type II back then. Dating back to 1795 so this is by no means, a new discovery. I think doctors in the old days had to be more creative when it came to treatment of patients because they didn't have a medicine cabinet full of options or surgery or whatever it is, procedure to do so it's interesting.

Dr. Ethan Weiss: If you go back and look through the literature of the 18th to 19th century, you'll find lots of examples of doctors publishing results of using these diets to treat patients with diabetes. They were really successful.

Dr. Brian Mowll: Yeah, it's really interesting. You're right. I've looked at some of that same… some of those old texts where they really were just feeding patients meat and maybe a few vegetables and that was the gist of the diet with some coffee, tea and sometimes, some whiskey thrown in there for good measure.

Dr. Ethan Weiss: Yeah. It sounded, it sounded… well, the way they would describe it, it didn't sound super appetizing but maybe modern version of that, better.

Dr. Brian Mowll: Yeah, yeah. Sometimes, you see described gluten red. I had to look up what gluten red was. I guess it's basically just high protein bread, high gluten protein bread which-

Dr. Ethan Weiss: I didn't know that.

Dr. Brian Mowll: I don't know how well that would go over today but anyway.

Dr. Ethan Weiss: Yeah.

Dr. Brian Mowll: No. Yeah, it's super interesting. I'd love to talk to you about what you're doing now with the tech side. I know that you're a researcher, a physician, treating patients and then you have a startup where you're interested in bringing this model to people in a new way. Would you mind sharing a little bit about that?

Dr. Ethan Weiss: Of course. Yeah, so I have been… I guess I should just tell you a little bit more about my background because it's unusual so I actually… I came to UCSF 20 years ago. Now, almost 21 years ago to do my cardiology, do my training in cardiology, but I also came here to do training in science. At that time, my scientific interest was in blood clotting and mechanisms, biological mechanisms underlying blood clotting.

Dr. Ethan Weiss: That made sense as a cardiologist, right? Like we knew the blood clots where that's their final common pathway of heart attacks and strokes

and so I thought it would be great to get involved and try to understand how that happens. Particularly, I was really interested in like why would somebody… I think if you go back and look at the pathology literature, you can see that they can… if somebody dies from a heart attack, they can go and look at the artery.

Dr. Ethan Weiss: They can see how many times that plaque is ruptured over the life of that patient, much like you can look at rings on a tree. I think there were studies published by this British pathologist, Michael Davis back in the '70s and '80s and from the average number of times that plaques ruptured was like seven or eight before somebody died from a heart attack.

Dr. Ethan Weiss: That left me wondering. Well, why didn't somebody die on the first one? It's still, I think, a fascinating question we don't have an answer to so that's what I got interested in. I'll make a very long story short which is that I started my own lab 15, 16 years ago with the interest of trying to understand the mechanisms of blood clothing and got sidetracked by what was really interesting biology story which is how men and women or males and females are different.

Dr. Ethan Weiss: This, what we call sexual dimorphism so I was interested in the sex dimorphism blood clothing so why are there differences in the way men and women might cloth and why are there differences clinically in bleeding or risk of bleeding when you put them on blood thinners. That led me to this whole fascinating story of the biology of growth hormone, human growth hormone.

Dr. Ethan Weiss: It turns out that a lot of the sex differences in mammals are driven by a difference in the way males and females secrete growth hormone from the pituitary gland so I spent the last 10 plus years of my life trying to understand how growth hormone impacts metabolism. Sorry, I left out the most important part which was we did an experiment back in like 2008.

Dr. Ethan Weiss: We did a mouse experiment where we made a genetically engineered mouse that was not able to respond to growth hormone and we did that with the expressed… we were trying to understand the effect that it would have on blood clothing and particularly, if it would make the sex differences go away. It did but what was fascinating was that that mouse also developed fatty liver.

Dr. Ethan Weiss: That, what we call now NAFLD. It had like the most profound fat accumulate… triglyceride accumulation in the liver that I'd ever seen. That was something I was not familiar with so that was how my science interest began to shift and over the period of a few years, let's say 2007 to 2010. My lab focus changed almost 100% from thinking about blood clotting to thinking about metabolism.

Dr. Ethan Weiss: For the past 10, 15 years, we've focused in the lab on the biology of growth hormone, how it interacts with insulin and how that regulates the insulin, glucose homeostasis and metabolism in a whole animal and so that was what I'd been doing. I woke up probably five or six years ago

and thought, gosh, this is super interesting work to me and all of my lab people and probably to 25 or 30 other people in the world.

Dr. Ethan Weiss: It's hard to imagine a day where this is going to impact anyone else like is this really going to have an impact on a patient. Around that time, I was introduced to Omada Health which uses the DPP. Actually, I looked at a job there. I didn't end up taking the job but I was struck by what they were doing and I thought, gosh, it's really amazing how you can use technology to influence human behavior and that seemed like something that you can scale and that would have a huge impact.

Dr. Ethan Weiss: It was around the same time that it also became clear that from an economic standpoint, developing new drugs or devices or other things within cardiovascular medicine or metabolic medicine was going to get harder and harder to do that it was getting expensive and harder to justify. We had this crisis and so I started to think about, gosh, how could this be something?

Dr. Ethan Weiss: This is fascinating to me. I would love to be able to find a way to explore this further. Then I met Virta and saw what they were doing and again, I'm [inaudible 00:34:17] that might love those guys. What they do is still, even though it's a tech solution, it still has a lot of human interaction so they're still interfacing with human beings whether they are physicians like us or they're health coaches.

Dr. Ethan Weiss: For that reason, it's more expensive and I think it's really geared towards people who require that level of intervention, that is people with type II diabetes. What about just a run-of-the-mill person out there who wants to optimize their metabolism or they want to lose some weight or they want to even get beyond that? How can we begin to offer something like this to them without the cost and the burden of having all this human interaction?

Dr. Ethan Weiss: That was how this whole thing started and I won't drag you to the whole thing but basically, I was introduced to the two people who were now co-founders of this company that we started. They are both much younger than I am and their background was interesting so one of them had been an MDA student and then left before he practiced medicine to go work at [McKenzie 00:35:19] as a consultant and decided that he wanted to start a company.

Dr. Ethan Weiss: He applied to this incubator out here called [Y Combinator 00:35:25]. Ended up starting a company and this is probably five years ago and that company in its first iteration was basically a social network for weight loss. It was basically like an Instagram feed for weight loss. His cofounder in that company and his chief technology officer who's our cofounder of our company is this spectacular software engineer.

Dr. Ethan Weiss: They ended up selling their company to Weight Watchers a few years ago and then went to work at Weight Watchers and were basically the team that launched what's become Weight Watchers Connect because Weight Watchers at that time didn't have… it didn't really have a mobile platform and was weak on the social things.

Dr. Ethan Weiss: That was very successful. I think very successful for Weight Watchers and successful for these guys and so then they were looking for something to do. We got together, introduced by mutual friends and had a lot of shared interest and started thinking basically, well, what's different about keto than like other diets independent of all the other noise that people get sucked into arguing about?

Dr. Ethan Weiss: Like forget the energy expenditure stuff, all that. It's all interesting biology and science and stuff but what's really different is that keto or low carb, high fat diets offer something that other diets don't offer which is they offer you the ability to track a biomarker which basically gives you a sense as an individual of how you're doing.

Dr. Ethan Weiss: It allows you to track your own adherence or compliance or whatever it is and it changes the focus from the other biomarker which is stepping on your skill everyday which I think is a terrible way of assessing how you're doing. It gets you distracted from that and focused on just trying to adhere to this diet which in large part… again, forget all the craziness but it means you're eating more whole foods and less processed foods, less refined carbohydrates, less added sugar, less.

Dr. Ethan Weiss: What you're doing basically is getting people to try to adhere to this diet. We started to think, all right, well, how do people do that now? People use blood. They measure ketones in blood. They use, they measure in urine strips. It turns out that their publication is going back 100 years so you can do this by measuring acetone in the breath.

Dr. Ethan Weiss: We thought that sounds great, right? Like people don't like pricking themselves. They don't like peeing on themselves. Both those options are imperfect and potentially expensive with consumable so what about a breath option? There are lots out there. There are many different flavors of it but we decided, we'd build something that would be based on this breath sensor that we were going to develop.

Dr. Ethan Weiss: The feedback that it gives you in terms of how you're doing and basically build an entire program around that, so that was something that we decided to do relatively recently just this past fall in September. We've launched this thing and so it's been a great adventure for me. A completely different experience to anything I've ever had in my entire life.

Dr. Brian Mowll: Very cool. Yeah, it's an app-based program, right? Is the-

Dr. Ethan Weiss: It is, yeah.

Dr. Brian Mowll: Okay. Is it launched at this point? Is this something that people can buy and check out?

Dr. Ethan Weiss: Yeah, it's store launched. We did a crowd funding campaign. Not so much for the financial reasons but we thought it would be a good way to gauge interest and demand and to test some messaging and marketing so we did an Indiegogo campaign. I think you can actually still buy it on Indiegogo. We closed the campaign a couple days ago.

Dr. Ethan Weiss: We're starting to shift devices this week. The app will go live in the app store, I believe, either Monday or sometime next week. Sometime really soon so we're basically at the point of like soft launching as of today. We're about to have like real paying customers on our app and using the device for the first time. We've had a bunch of alpha testers who've been testing it for us for the past couple months.

Dr. Ethan Weiss: The first like real paying customers are going to come online in a couple of… in the next week.

Dr. Brian Mowll: What's it called for people who want to search and see the-

Dr. Ethan Weiss: Yeah, yeah. It's an ingenious name. We called ourselves Keyto but we spelled it K-E-Y-T-O and we did that for a variety of reasons but we thought it'd be fun because you can have a double on top of it being key to, whatever.

Dr. Brian Mowll: Nice. Yeah, I like that.

Dr. Ethan Weiss: Yeah. It's called Keyto.

Dr. Brian Mowll: Keyto. That's great. Then I guess there's probably some instructions on how to get the breath analyzer that would help you track ketones?

Dr. Ethan Weiss: Yeah. The breath sensor comes with… it remains to be determined at how linked those two things are going to be in the future but I think right now, it's all one product. It's pretty optimized at least as best as we can and for being as young as we are, free optimized for people who don't know what they're doing so we've tried to build in as much resources for people who've never heard of keto or never heard of low carb diets or what should I be eating?

Dr. Ethan Weiss: What should I not be eating so we have databases of food that they can search. We do not recommend and don't ask them to track their macros or to count their calories. We think that that's unsustainable and going to be hard. Then the last thing I think and this may end up being the most important thing is that we believe strongly that having support from other people is going to be important.

Dr. Ethan Weiss: While some models are… that support comes from a health coach. We think that there are plenty of peers out there who can be supportive and so we have a big social group chat thing and some friendly competition where you get into one of these things and it helps motivate you and do it with friends. That's the last component is to have this social component.

Dr. Brian Mowll: Very cool, so definitely check that out. Keyto, K-E-Y-T-O. All right, so we are getting close to wrapping up here and there's a few questions that I'd like to ask all my guests so I'll do that now. Before I do that, just, I guess, other than the Keyto app which we mentioned, is there anything else that you have out there that you want to recommend?

Dr. Brian Mowll: Is there anything that you are associated with? Any place that you write articles or publish articles, anything where people can follow you?

Dr. Ethan Weiss: Yes, so before I got super busy trying to have a full-time job and a family and this startup that I'm involved with. I spend a lot of time on Twitter. That was my main social thing and I loved being on Twitter. I think it's a phenomenal resource for medicine and science. If you can weed out the politics, it's even better. I want to spend more time there.

Dr. Ethan Weiss: I haven't been around as much because I've been so busy but I definitely spend a lot of time over on Twitter and my handle is Ethan J. Weiss. Basically my name with my middle initial. I have an Instagram account but I hardly ever go in there and I have a blog and I used to blog but I basically found myself just doing everything on Twitter so I stopped doing that.

Dr. Ethan Weiss: We will be blogging and I'll be blogging on the Keyto website when that goes live but that hasn't happened yet. In terms of other stuff, we're doing… in my academic world, I'm doing… we're doing clinical trial now to look at time restricted eating, to look at some intermittent fasting stuff that's not commercial. It's just an academic pursuit that I think we'll be interested.

Dr. Ethan Weiss: I think people will be interested in the results when we get those out. Otherwise, no, I'm basically just pouring.

Dr. Brian Mowll: Okay, cool. Twitter at Ethan J. Weiss and that's probably the best place to find him. Questions.

Dr. Ethan Weiss: Yeah.

Dr. Brian Mowll: What statement or quote or idea would you most like people to hear or leave this podcast with today? What's one thing that you really want to get across or share with people listening?

Dr. Ethan Weiss: I would say that my journey has been one of consistent and continued humility. I embrace being wrong. I think a lot of the things that we believe today to be statements of fact or truth end up being neither in the future so I would just maybe hope everyone keeps an open mind that things they may be very attached to today as truth may not be truth in the future.

Dr. Ethan Weiss: I'll just would love us all to keep an open and inquisitive scientific mind about finding truth as opposed to being attached to any one theory or another.

Dr. Brian Mowll: Really refreshing to hear that in medicine especially, so fantastic. Is there a book that you feel significantly changed your life or helped shape your current views around some of the things we talked about today?

Dr. Ethan Weiss: 100%, yeah. I read Thinking, Fast and Slow by Daniel Kahneman who won the Nobel Prize in economics and that changed everything. I've had that great fortune of having a fun email exchange with him. I called, emailed him a few months ago because I thought he'd be interested in some of the work we we're doing because of the behavioral science.

Dr. Ethan Weiss: He responded and we had a fun exchange so yeah. His book is the one that really changed my life.

Dr. Brian Mowll: All right. Cool. Lastly, if a friend or family member… I know you have patients obviously who do this but friend or family member came to you and was recently diagnosed with type II diabetes and you just had a minute or two to give them some good advice, what would you share with them? What would you tell them to do?

Dr. Ethan Weiss: Well, today, I'd say find somebody out there who can help you take on low carb, high fat diet because I think it's the best intervention you're going to find. Again, I'm open to that being wrong in the future but as of today, it's phenomenal and amazing way to take control of your own health in a way that people love.

Dr. Ethan Weiss: They love to be able to do it on their own. Again, or with the help of other people but it's a really powerful thing so that's what I would say.

Dr. Brian Mowll: Very, very good. Dr. Ethan Weiss, a great conversation. I enjoyed having you on.

Dr. Ethan Weiss: Thank you. Thanks so much for having me.

Dr. Brian Mowll: All right, that was Dr. Ethan Weiss, preventive cardiologist. I know this interview was not without some controversy so go ahead and make some comments below and let's get a great conversation going. I hope you really enjoyed the interview and thank you for being part of the Diabetes Summit 2019. This is Dr. Brian Mowll, the diabetes coach and I'll see you back next time with another expert interview.