Freed: This is Steve Freed with Diabetes In Control and we’re here at AACE 2018 with a special guest, Dr. Aaron Vinik. Dr. Aaron Vinik is on our board because we appreciate what he does. Now, I can go into all the details about his background but it would be a waste of time because it’s just too long. Basically, he is an expert in neuropathy, he is known for it all over the world, not just in the U.S., so it is really an honor to have you here. I got to know Dr. Vinik because back a couple of years when he was doing research and discovered a protein called InGaP, which at the time, we thought might be a cure for different types of diabetes. So maybe we can start off with that. Since then, a lot of things have changed. Where do you stand now with InGaP?
Vinik: Steve, it is a pleasure to be on again with you, I will just have to be careful with what I say because when I hear of it, it comes back again and it gets quoted in so many different ways. The InGaP situation is tricky right now, the issue is being shown in InGaP itself; the small peptide has been shown to stimulate growth and proliferation of stem cells and they differentiate into pancreatic beta cells and they get the whole quandary of the glucagon cells, somatostatin, pancreatic peptide and it becomes a functioning islet and we have shown that that will occur in almost every species we’ve done – all the animal species including monkeys and dogs. We have also shown that it is active in humans, both in type 1 and type 2 diabetes. The only problem we have encountered is what most people encounter when you stimulate regeneration of islets: is that these newly formed islets are attacked as foreign and the body turns against them and causes a lysis of them, autophagy or whatever words you want to use for killing of beta cells. So if we could stop the killing, we’d be a long way. We have now tried a number of different anti-inflammatory agents – all of them supposed to be God’s gift to mankind but none of them have worked so far. We have hopes that there are a couple of new ones around that are, right now, in clinical trials and we will see. It’s not the inability to stimulate the growth, we can do that, and we can regenerate islets, but, we need to stop the killing.
Freed: Well, thank you. Couple of questions I know your expertise in – one of the questions is: Why was the brain the last organ to be implicated in the pathogenesis of diabetes?
Vinik: Everybody has thought of diabetes as an absolute or relative deficiency of insulin. So the whole idea had been in the discovery of the pathogenesis, the development of diabetes, was to look for anything that would affect beta cells that made insulin – anything that would cause a loss of beta cells or beta cell destruction. And then it emerged that the major factors that contributed to that were hormones produced, in the intestine for example, glucagon-like-peptide-1 (GLP-1) – anything that acted on a pancreatic beta cell to stimulate its growth and proliferation, but, in addition, to enhance insulin secretion. It took quite a long time to discover that that wasn’t the only mechanism because if you express or secrete insulin that is what has to be biologically active in many different forms, rather than the native form. A whole new science emerged and that was related to insulin resistance – what turned the body off of insulin. So now we got on the whole quandary of studies and research, all the factors that could affect resistance to the action of insulin. Now we have all the beta cell factors, all the insulin resistance factors and lo and behold, people said, “Oh well it happens in the liver, so they studied the liver; it happens in the muscle, so they studied the muscle; it happens in the GI tract, so they studied the GI tract; it happens in the kidney, so they studied the kidney.” So we’ve got the explosion of factors that can affect diabetes. From my early days where I knew about sulfonylureas and metformin or phenformin in the early days, and insulin and early crude versions of insulin and now, just taken off now, we have 14 different classes of drugs and they act on all those different areas. So, if you take my friend, Ralph DeFronzo, he went from the duet to the triad to the tetret to the pentet to the sextet to the octet and now to the dreadful dectet, and creeping into even his diagram now is the brain.
Freed: When it comes to diabetes, nutrition and metabolism play major roles obviously. We know that the gut plays a role, we know the stomach and the hormones that are released. Maybe you can talk a little bit about the brain – where the brain comes into our metabolism.
Vinik: So, the brain to me is actually the conductor of the autonomic orchestra. The brain controls just about every hormone that is produced in the central nervous system. In the pituitary, there’s growth hormone, there’s HETH, which stimulates cortisol secretion. But more than that, it also controls all the hypothalamic nuclei – the supraventricular, the paraventricular, the nuclei – and those regulate the release of acetylcholine, norepinephrine and epinephrine. So those, we’ll call them hormones, actually regulate all your metabolism. So, if you turn them on like with the sympathetic nervous system activation, you’ll increase the glucose levels and increase liver production of glucose. The glucose itself not only is produced in the liver, but the sympathetic nervous system acts on adipose tissue, adipose tissue causes breakdown of triglycerides, the release of free fatty acids, the free fatty acids then contributing to neoglucogenesis, new glucose formation. All driven by what is happening here, [points to the brain\ in your hypothalamus at the base of the brain. On the other hand, there’s a counterbalancing hormone that is acetylcholine, the parasympathetic nervous system. The parasympathetic nervous system does just the opposite of everything of the sympathetic nervous system. The sympathetic nervous system is “fight or flight,” and the parasympathetic nervous system is quiet and peacefulness – just when you want to drift off. That’s a very nice balance.
The next question you have to ask is, and I’ll ask it for you, is to say: If this control is centralized, in a very small area in the brain, there must be some very powerful substance or substances that act on that area, and they must be defective in obesity and diabetes. Now, we’ve taken everything away from a beta cell, taken it away from the pancreas, taken it away from the liver, from the production of glucose or adipose tissue, production of free fatty acids, and so forth, and we’ve said there is something happening right there. Lo and behold, brain dopamine is deficient in obesity and is deficient in obese diabetics. Just a little molecule, just a few tiny smidgens of this molecule, is required to activate that whole system and we are deficient in it. What is even more interesting about this, is that you will have a circadian rhythm. So, you’ve got a clock that ticks for when the dopamine level must go up and when the dopamine level must go down. So, what goes wrong, is when you’re deficient, your clock is not set properly. As you know, Steve, if you look at your rhythm of glucose, it goes up just before breakfast time, reaches a peak, then goes down, then goes up again, just before lunch, then goes down and then it drops to a nadir between about two and four in the morning. And that clock is regulated but the dopamine clock here (points to brain). Isn’t that cute? So, all we have to know is how we can reset this clock.
Freed: One of the questions I wanted to ask you that goes back probably three years ago and we were sitting there and I asked you what the the most exciting thing coming out of ADA this year. There is a little known drug called cycloset and you had said that it actually reduces the risk for MACE [Major Adverse Cardio Events] or heart attacks by over 50 percent. And, even today, very few physicians even know about it. So my question is: Do you have any information on what is going to be released at ADA that is going to be a breakthrough and exciting?
Vinik: Ok, so I know I told you that at that time because I was very excited with it. I actually was a coauthor of the paper that showed a 50 percent reduction in macrovascular events and I thought that would get the whole world focusing on it, but people keep thinking of cycloset as a drug that you use for the control of prolactin. Endocrinologists think, in particular, that a prolactin-secreting tumor, this is what you needed cycloset for. So that is their focus, not for thinking in that drug that works in diabetes. If you take the whole world of diabetes and say what is it do they think is like the magnum opus of this particular axis area, they will tell you, “We do not think it’s glucose.” All the glucose-centric people say it only produces a fall in hemoglobin A1C of like .6 – .8. We can do very well with all these other drugs that we got and so we don’t get anything out of it. Those are the people that were locked in to thinking that glucose was the center of the world. It’s not by any matter of means. Look what has happened this last year. This last year we’ve come across drugs like empagliflozin with the SGLT2 inhibitors, the incretins, and what are these things doing? They produce a very small effect on glucose levels, but a very large effect on cardiovascular outcomes – major adverse cardiovascular events. So the whole world is now exploding. If you said to me, what is the biggest thing that is going to come out of this meeting, I would say the biggest thing is reinforcing the notion that you’ve got to go outside of glucose centricity to be able to reduce cardiovascular events. It’s now been shown for SGLT2 inhibitors, it’s been shown for at least two incretins, and in that umbrella, cycloset, because cycloset got there first, but people weren’t ready for it. People were shunning it because that is what people do, they shun things they don’t understand and where they haven’t been educated appropriately. The work on cycloset is going great guns, we have just about completed a very significant study. It has profound effects on the autonomic nervous system. So, we like that, and we think that is really terrific. I’ll share with you just some really interesting and easy things. When we went back to look at the data on the 3,300 people who were in a safety trial, to see if we could predict the fall in A1C. Lo and behold, there is a striking positive correlation between the fall in the A1C and the fall in your heart rate. So, that’s provocative, because it’s not saying, I’m measuring your glucose; it’s saying your heart rate is telling me what your A1C will do when I put you on this drug. So, there was no precedent for that until this last year. And then, our paper, [on] gastric bypass surgery, and gastric bypass surgery will restore you to normality. Remember that beautiful paper that came from North Carolina? Who would have believed that surgery would be the cure for diabetes? And surgery is the cure for diabetes when you do the following, when you disturb that axis of the autonomic nervous system and the heart rate falls, and it does. When you do a gastric bypass the heart rate falls. And that heart rate fall is directly related to the improvement in diabetes control or even, the disappearance of diabetes itself – that’s why it cures it. So, we’ve got a very nice example.
Now, if you let me ramble a bit more, I will tell you that you don’t have to do a complete gastric bypass. We’ve now done close to 100 patients with a sleeve, just a gastric sleeve. A gastric sleeve doesn’t cut anything out like bypass does and you get exactly the same result. So, guess what the news is? The news is, in your jejunum or maybe a little further down, there are hormones that are talking to the brain. That is going to take you into another arena and that is, we know you’ve got GIP there, we know that you’ve got other incretins there, we know you’ve got ghrelin there, we know that adipose tissue makes leptin and adiponectin, but we don’t know which hormone is coming from here (stomach) and talking to the brain and resetting its clock. With the reset of the clock, it turns the sympathetic nervous system off and allowing the parasympathetic to balance out. That way, we’ve reset that whole metabolic profile. But, we learn something good and the second big thing that is going to break out because my friend, Tony (Antony) Sincarta, they’ve got I think seven presentations on at the ADA to show that it does not only involve this clock over here (points to brain) but it involves resistance to the action of insulin.
Freed: So, did you say the gastric sleeve gives the same end result?
Vinik: Same end result. Much less risk of mortality and much less morbidity.
Freed: Now when is that information going to be released?
Vinik: When I can get Carolina Casellini to finish the paper then we’ll get it, but it’s being presented at the ADA. I’ll tell you a funny story. We submitted it to two places, ADA doesn’t allow you to present at a second place. So, we submitted it to the ADA and to AACE. AACE put it on as a poster. ADA gave it first place for the presentation at the National Meeting. So, we took it off here and it’s being presented at the ADA by Carolina Casellini . We’re working with one of the fellows to get the paper done and it’s not been published but it will be presented at ADA and that will be a public announcement.
Freed: Changing the subject a little bit, you’ve talked about the resting heart rate and what we can determine and how important it is and yet it is such a simple number to get to. What does the resting heart rate show us? How important is that information?
Vinik: You know what is going to happen to all of us soon? (pulls out Smartphone) This is going to be a very important new index of metabolic control. Because what I’ve told you is, not only is it affecting the clock here (brain), this clock is determining what is happening in your liver, in your adipose tissue and what happens in your pancreas and your pancreatic beta cells and glucagon. All of that in one number! So, you’d like to say, is this going to be a risk calculator? Yes, it is and a very simple one. So, if you’ve got a heart rate that’s over 78 beats per minute, you’re in trouble. You want your heart rate to be 58 beats per minute, if you can get there. If you’ve got a good heart rate like 58 and then something happens to you and you slow down and you don’t stop your exercising, and your heart rate goes from 58 to 78, now your mortality increases dramatically by one number – that’s going to be an easy world.
Freed: How important is the time it takes to go from exercising strenuously to get to a resting heart rate, the time it takes whether it takes 30 seconds or a minute, how important is that?
Vinik: I don’t think that they’ve based it quite like that. They’ve indirectly measured it. There is a really good paper that came from Israel. They put people on a treadmill. They looked [at], not so much how [much] time to get to that level, but whether you could get to the number. I got on one of those to see what it meant, and you have to work damn hard to get your heart rate above that 78 number. But you have to get above that number, so that is number one; to get your maximum heart rate above 78. Second thing is, most people think about your cardiac maximum by 220 minus your age and to be healthy you have to have a value above 75 percent. So, what does that work out to be? I am not going to tell you how old I am, but what does that work out to be in a person like me? I’ve got to get my heart rate above 120 otherwise I am failing that test. And then there is a third measure which is a simple measure: how long, not to get there but how long it takes you to get down. So, when you’ve got up to that 75 percent of max., you want to be back to normal in about 18 seconds.
Freed: And that’s pretty tough to do.
Vinik: Yes, it’s tough to do. I have new numbers in my head. I think that I am an endocrinologist and I have these cardiac numbers in my head now and I’ll carry one of these. (Smartphone)
Freed: So, what do we need to be able to measure the balance status, in a given individual?
Vinik: It’s actually complex and simple. So, you know that I am going to meet the Professor Sessions today? And they are talking about balance. So, I picked a case, well I picked a few, but I picked one long case. Just to take these endocrinologists through their ropes and to say to them, “I am going to show you a person that has everything wrong, that’s all fallen apart.” And then we will go through all the complex measures because they need to learn that now, but then I will show you the simple ones. The new EKG machine vomits out a couple of numbers, when you see it, it vomits out your heart rate, so that was the first number I told you. But it also vomits out the interval between the Q wave, the first deflection, the negative deflection, and the T wave is the recovery, the Q-T interval, and is corrected for right Q-T-C; that is the number it gives you. If your number if over 440, you’re in trouble. You want it to be under 440, and the heart rate I told you must be under 78. So, I’ve given you two numbers and you don’t have to do any work for it, you’re on the EKG, it’s there. The EKG these days also gives you two more measures. It gives you the RMSSD, the root mean square of the standard deviation of the RR interval or the SDN, that’s the standard deviation of the normal intervals. The SDN tells you how your whole body nervous system is functioning. The sympathetic, the parasympathetic, what’s happening in the brain, the hypothalamus, all that – just one number, SDN on that EKG. The RMSSD very nicely tells you what the parasympathetic nervous system is doing. So now you know all of those, one look at the EKG and you make your diagnosis of where you are.
Now I’ll take you back to your question, who’s being educated on this? Very few people. And who is going to prescribe cycloset? Only when they understand these numbers. So, the title of my presentation is, “Demystifying the Autonomic Nervous System.” Let’s get all you people in the same room and talk to you and start educating you about the numbers you need to know.
Freed: How does that information filter down to the practicing physician.
Vinik: Well, I mean the mission of AACE is to educate the practicing physician. Up until now, they’ve wanted to educate endocrinologists. Now they think they must turn Primary Care Doctors into endocrinologists. And so, they are going to have a very big drive to educate those people and I think that, that is the right thing to do. You have to get out there and educate the people who apply this but who, for this most part in this area, are ignorant.
Freed: Are there simple measures that can be made at the bedside as prognosticators of risk?
Vinik: The strange thing is the following: We’ve worked with a group of 200 Romanian physicians and we have information on 26,000 people with diabetes. We didn’t do a lot of work on them, we just got them to fill out a questionnaire. The questionnaire is the quality of life, a diabetic neuropathy questionnaire. It has been translated into 56 different languages and it is used worldwide as an endpoint for diagnosing neuropathy. With the Romanians, we had such a large quantity of people, so we could ask a lot of people the questions and then see what it told us. So, the first thing it told us that of the 26,000 people, 6,600 people had neuropathy by the definition of the tool and they didn’t know, nor did the doctors know. So, that is just an interesting discovery phenomenon.
So, at the ADA, you will see another nice paper and it says that if we take a section of questions out of that tool, just a small section of questions, we have now a new mortality of risk calculation. And it is done just with a few questions.
Freed: Getting back to cardiovascular risk, if you go back, it was always about A1C blood sugars and that was because we didn’t have anything to treat the cardiovascular except for hypertension. But for MACE, we didn’t have any drugs. Now we have the SGLT2 inhibitors that are playing a major role. How do you use those when it comes into your practice? What type of patient do you provide SGLT2 that you think is absolutely important?
Vinik: I think that patients who have high risk. But remember now, everybody was using the wrong risk calculator. Wilson’s paper actually, that came out & that we spoke about a year ago, showed that their calculations of risk using standardized measures was fallacious so you needed new risk calculation. If you go and look at the numbers that I just gave you, in terms of exercise, all Wilson’s calculations relate to one thing: heart rate. So if you put that into your new calculation, and then say, can I identify the person at risk that I should give an SGLT2 inhibitor or an incretin, it’s very easy; any one of my patients have a resting heart rate above 78 beats per minute who’s going to do poorly in terms of control is going to be a candidate for me to put either on a SGLT2 inhibitor or an incretin or a cycloset. So, that’s my choice. Now is there anything we should be learning from the results? Yes. What is the percent reduction in macrovascular events if I put you on a SGLT2 inhibitor, I can get 38 percent? With the EMPA-REG study. But, if I take you across the line and I give you an incretin like liraglutide with which I can get 13 percent. Do you know what the difference between those two is? Empa and Cana will drop your blood pressure and they will not increase your heart rate, no increase in heart rate. Lira will drop your blood pressure and increase your heart rate. So, there are swings and roundabouts. Lira would have it all if they could stop that increase. And then I’ll tell you next year because we’ll be finishing our study in September. It’s that exact question. So, I know I am naughty to start speculating [on] the differences in the autonomic nervous system between those drugs but I have no doubt. There’s another paper out right now that Lira can actually affect the autonomic nervous system negatively.
Freed: So, the chances of that drug getting approval?
Vinik: I think that drug will get approved. If there is a 13 percent change, people will grab it. Do you want to know what the number is for cycloset? Fifty percent. But nobody wants to believe that.
Freed: It’s amazing that the information, for whatever reason, isn’t getting out there and I guess it has a lot to do with the FDA and how they are allowed to market the drug.
Vinik: Well, with the FDA, but also, the history. The history of this drug is it came from trying to shut down pituitary tumors. And that’s what people think. Endocrinologists only think about that.
Freed: So, can we restore balance with readily available medications because there are so many medications now.
Vinik: Oh, it’s a piece of cake. The cases I’ve put together for my little two sessions today were straightforward. I picked people that had parasympathetic excess and parasympathetic deficiency and sympathetic excess and sympathetic deficiency, and we’ll be showing them the clinical syndromes. Then we’ll say if you’ve got a parasympathetic excess, I can block it. I can take a drug that people take for their nerves and block it. Piece of cake. One pill at night. If you’ve got the opposite, it’s a parasympathetic deficiency, I have tons of drugs, I have a little patch that I can stick on and turn on your parasympathetic nervous system. If sympathetic blockers, they’re a dime a dozen, beta blockers of all variety are available to me. If you are deficient, I have every form of agonist possible. It’s like a delicacy that’s available with all these condiments that I could add to and then rebalance you very easily.
Freed: I don’t want to take any more of your time, I know you are a busy guy and you have things happening but there is one thing that I would like to just briefly mention to you and get your opinion on. I am working with a physician, you may even be aware of this, and a computer guy, and they basically put together a software program where you take the patients’ information such as blood pressure and A1C, put it into a program and it goes through 5 million possible combinations. Then, it spits out 6 possible combinations that you might consider, and it rates them and tells you how much the A1C should drop according to the studies. You put their insurance in and it will also tell you which drugs are going to cost the most so you can ask the patient if he or she is willing to spend 20 dollars more a month to help with your neuropathy or whatever the case may be. It also puts the drug coupons in there too to help lower the cost. What do you think of that particular idea?
Vinik: I must tell you where I think the problem is. The problem right now is, who is supposed to be using that? The patient or the physician?
Freed: No this is the physician and it’s not meant to put like in the Bible, “This is what you need to do.” It gives you 6 possible combinations and the physician has to decide which one he or she thinks is going to be the best one for that individual patient. That’s why they don’t even need FDA approval.
Vinik: I’ll give you my closing remark. The catastrophe that is occurring with healthcare, not only in this country but globally, is that decision is not being made by the physician. The physician is no longer Dr. So and So, he or she is a healthcare provider, an HCP. He or she is a unit of service. Ninety percent or more of the decision-making he or she makes is made by the third-party payer. So that is what your problem is. So, you can have the best tool in the world and you can’t lead the horse to water, it won’t drink.
Freed: There’s 5 million possible combinations, how do you determine the one –
Vinik: – that’s going to work and that the physician can apply? It’s the same question you asked me earlier when you asked why aren’t people on cycloset doing this? Why aren’t they using it? Why aren’t they reading this? It’s because they take on a mindset that they’ve lived with for years, donkey’s years. That’s why I started off by talking about glucose centricity. So, I think glucose centricity has to go away. And until we change the way healthcare, I mean Donald Trump told you he’s going to change it right, and he’s going to get them out of the equation. But, if you today are on insulin and say for example, you are taking 40 units a day and so you are taking about 1200 units a month, a pharmacist gives you maybe 1,150 units. So, you’re 50 units short and you’re a kid with type 1 diabetes and you end up in ketoacidosis – do you believe that’s happening today?
Freed: Oh, of course.
Vinik: Every day. And then you go and have a fight with them. And that means you spend hours as a physician saying, “Why the hell did you do that?” And they say, “Well it’s specific, we are held at the point of a gun.”
I am not decrying this [software]. I think it’s fantastic. What I do, it’s just the opposite, that’s why I told you about the QUAL questionnaire. It boils down to six questions. Six. That’s all. And I can predict your mortality.
Freed: Endocrinologists have it a little bit easier because they have a much better understanding and they are more focused on diabetes. When you go to the family practitioner, I think it’s just overwhelming all the possible combinations.
Vinik: They don’t even want to try it.
Freed: They stay with what they know – sulfonylureas, it’s cheap, metformin, it’s expensive.
Vinik: That’s exactly right. We had all the primary care doctors, very nice, and they came to say, “We just want to hear what is happening, that doesn’t mean we’re going to do that.”
Freed: It’s just mindboggling that we keep coming out with these new drugs that have unbelievable benefits in so many different ways, and yet, it’s not being used properly.
Vinik: Oh yes, but we still haven’t had the experience that we need. One that is going to have, ultimately, and you must not forget that when we started looking at risk calculation for heart attacks and strokes and death, we only account for 24 percent of the total risk. So, 76 percent of the time we’re ignorant. Now we get these new drugs that we apply them to the same endpoint.