In this exclusive interview transcript, Dr. Handelsman discusses the relationship between diabetes and cardiovascular disease, and the impact new diabetes drugs are having on management of both conditions.
Freed: This is Steve Freed and we are here at AACE in Boston. We have the luxury of having some great endocrinologists to talk to. One of my favorite to talk to is Yehuda Handelsman. [Freed to Handelsman] I was going to read all the stuff about you –
Handelsman: (Laughs) Don’t!
Freed: – but, that was going to take too long.
Freed: Can you give us a 30 second overview of what you do?
Handelsman: Yes. I am an endocrinologist in a solo private practice – I am one of 17 percent of soloists still left around. I take care of endocrine-related diseases with a big focus on the metabolic aspect and cardiovascular disease. I am involved in the Metabolic Institute of America where we are doing educational activities as well as research – I am involved in quite a bit of clinical research on a different level. In my professional life, I am also the Chair of the Diabetes and Lipid Scientific Committees for the American Association of Clinical Endocrinologists. I publish quite a bit and I do education for a couple important conferences that I am involved in. One is the Heart in Diabetes physician [conference] in July in Philadelphia; we’re looking at everything heart in people with diabetes and how we incorporate a lot of the new information we have today in diabetes and cardiovascular disease. The other meeting that we’ve done for about 15 to 16 years is called the World Congress on Insulin Resistance – Diabetes and Cardiovascular Disease. We are looking at everything from basic signs to clinical signs of obesity, fatty liver, and diabetes; again, looking at everything which we call Tomorrow’s Clinical Science Today. So, kind of two educational laboratories were made where I can take the expertise of my people and see how we can apply it to medicine. I think that is plenty on myself.
Freed: (Laughs) That’s great! You have already done a presentation here and I believe the title was, “A Contemporary Approach to the Management of Diabetes as a Cardiovascular Disease.” If we go back 50 years, we had one drug for diabetes – it was Sulfonylurea which we do not even recommend anymore. It took us 50 years just to get one other drug. But now, we have so many other possible alternatives, especially in the cardiovascular area. We never had a drug before that could prevent cardiovascular disease, which most people with diabetes die from, and now, we have that. So, when you look at a patient, what do you look at? Blood sugar levels? Cardiovascular risk?
Handelsman: We think that a person with diabetes, specifically coming from the insulin resistance background, has too much fat in the body and free fatty acid, already has changes in their vascular bed and already has changes in target organ such as the kidney and heart. And so, they are already at the very high risk even before they get diabetes – higher risk for cardiovascular disease. Once a person has diabetes, they typically also have hypertension. So, the rate of people with diabetes and hypertension is about 85-90 percent. So, the majority of people with hypertension have diabetes and the majority of people with diabetes have hypertension. Not all, but the majority. Also, lipid disorders. We have the dyslipidemia of diabetes which is dyslipidemia of insulin resistance – it’s high triglycerides, low HDL, and many particles of low-dense LDL. So, the number may not look very high for the LDL but they have issues with cholesterol that we need to treat. We have blood pressure to deal with, cholesterol to deal with, high glucose – there’s an increased coagulation in people who have diabetes. Due to that increase of coagulation, we are then seeing that we may need to give [patients] medication to reduce Pi 1 (which is one of the coagulation) or reduce platelet aggregation so that they don’t get blood clot(s) or heart attacks and, of course, lifestyle and exercise and smoking – all of these factors are part of it. In 1998, I created, for the first time, a slide to one of my first lectures and I said, “Diabetes is a cardiovascular disease; treat all risk factors.” And that was actually done in Denmark in a small clinic called Steno, it’s in the Steno village, where they took 160 people and they just said we’ll treat you to three goals: blood pressure less than 150/80, LDL less than 100, and A1C less than 7. So, simple goals, not crazy goals. They showed that when they controlled all three, there was reduction in events of near 50 percent by 8 years and by 13 years, reduction in mortality by 53 percent. So, what you were seeing in addressing all of this was that it was working. Even though many of them did not even get to the goals, just addressing that [worked]. From that moment on, we were promoting this combination approach. So, when you ask me how to treat, and since I oversee the guidelines, I changed the name from “Diabetes Guidelines” into “Creating a Comprehensive Healthcare Plan for People with Diabetes.” I made this change in 2012. We also have an algorithm, a comprehensive approach to that management of people with diabetes. And so, what does that mean? Treat the obesity, treat the blood pressure, treat the lipid, and treat the glucose. We had a session this morning and I was asked about that. I was asked in which of these areas do I treat the patient and I said I treat them in all of those areas. This is my responsibility for “John,” who is my patient. I do not treat my patients’ glucose and send them somewhere else to treat their blood pressure. I do not know if someone is able to treat those things for my patient, so for me, I believe you need to treat the whole patient.
Freed: That is interesting. How has this changed the clinical recommendations for diabetes, with all these new things and changes? It took 50 years to make one change but now it changes every 30 days.
Handelsman: So, what if it did not require a lot of change? How to manage hypertension, we always knew – we have all the drugs and all the recommendations and ACE [inhibitors] and ARBs – these are just to make sure when you do one thing, you also do another thing. How to manage lipids becomes very easy with statins; maybe statins, some newer drugs, some PSDK9. But, it is easy, you are right – how to manage the hyperglycemia, we have seen an acceleration from the one drug and then the second drug, all of a sudden the past ten years another 10-12 classes of drugs. So, people need to know how to use them, and on top of it, which you alluded to, some of those drugs showed that in people who already have heart disease, giving those drugs reduced heart disease.
Freed: We have all these studies and we have all this great new information. Have they all been able to go into the guidelines or are we still working on that?
Handelsman: Some did, some did not, and others, we do not know all. These are questions we need to be able to ask and be able to respond to, for example, with a study called EMPA-REG. First of all, we had to prove to the ADA that all of these diabetes drugs are safe because some cardiologists, 10 years ago, said that this drug is bad and that drug is bad. We thought that TZDs were good for cardiovascular disease but now they were killing patients, supposedly. It turns out, however, that they were not killing patients. So, in the meantime, we had to do studies. The first wave of studies was on DPP-4s and all of the studies on them showed that they are very safe. Then, they carried out studies on GLP-1s, a couple of them; very safe. All of a sudden, an SGLT2 (Empagliflozin) from a study called EMPA-REG shows reduction in MACE (major adverse cardiovascular events) 14 percent and reduction in CV (cardiovascular) death by 37 percent – this is huge now! Now, how they do it is a different question but that was the result of the study.
So, all of a sudden, the benchmark has changed. It’s old enough now to see that our drugs for managing hyperglycemia are safe. Now, we actually want them also to do other stuff. How much they are related, we don’t know. There can be some properties in those drugs that are beyond the hyperglycemia properties, which are important. Now, these drugs like SGLT2, and the other one in the family, canagliflozin (Invokana), had a study called CANVAS and was very similar – did not show the mortality data but it did show reduction in all three MACE: non-fatal MI (myocardial infarction), non-fatal stroke and CV death. It showed statistically significant reduction of 14 percent. It was not as striking as the other one but it was similar. Most of them showed reduction of hospitalization for congestive heart failure. In fact, they both were positive in reduction of CHF and mortality. That’s incredible.
Then another trial from another drug class, GLP-1, we already saw two of them to be safe. This one was Liraglutide, known as Victoza. All of a sudden, we see reduction of MACE again of 14 percent – all three MACEs I just counted plus CV death by 23-24 percent. Suddenly, we start asking what is it related to? One could say all these drugs improve kidney function. Maybe that’s a reason. One could say all these drugs, even though they were not supposed to have a difference in glucose control vs. the placebo group, the whole idea was to keep equi-glucose so we can see the cardiovascular aspect, all of them had a significant reduction in glucose. All of them had a significant blood pressure reduction and all of them had a significant weight reduction. A fourth one called Semaglutide (Ozempic), just got on the market, but this was before that. They just did a safety trial they didn’t try to make it equivocal. They had a one percent—one and a half– A1C, big weight loss, big blood pressure reduction, and reduction in death and strokes, in their case it was strokes. So, look at all of this and ask what is going on. Are all of these aspects what is causing it or is it something else? So, people on the SGLT2 said, “Well it reduces volumes, maybe it changes the histologic dysfunction, or maybe it’s good for congestive heart failure.” On the GLP-1, maybe it does have some effect on ….vasculature. We don’t exactly know, so we do have them in the guidelines. Now the ACCE guidelines do not need to change much because we already recommend metformin, which we all recommend as first line because all the studies were done on metformin, but on top of metformin, we give a GLP-1 and then an SGLT2 – that is how we recommend anyone how to do it. For many patients, we actually give them a combination. So, this is very early on. We have another SGLT2 inhibitor which is called dapagliflozin, it’s Farxiga, and they looked in observation studies in millions of people that were on different drugs – they did what’s called propensity matching and they showed that in those studies, there was reduction in CHF and mortalities, both in people that had established disease and in people that did not yet have cardiovascular disease. So, we are saying at AACE we do not need to change our guidelines; we’re already suggesting to you to use these drugs early on. But the American Diabetes Association in 2017 said, “If your patient has established cardiovascular disease then you need to manage glucose, please think of empagliflozin and liraglutide.” In 2018 they said, “and also think of canagliflozin.” The Canadian [guidelines] were the first one to come in and they said, “You need to think first about what drug shows cardiovascular benefit.” But now, they’re also naming them: same three drugs empagliflozin, canagliflozin, and liraglutide. Now both empagliflozin (Jaridance) and liraglutide (Victoza) got approved by the FDA. Jardiance was to reduce mortality – reduce CV death – and Victoza was for the MACE: MI, strokes and mortality all together – which is a very difficult concept, by the way, to put together. So what drug will we use? Canagliflozin still did not get indication but the trial was very clear that they have a good MACE reduction. So we incorporated this and recommended. In the AACE drug attribute, we say specifically, “If your patient has cardiovascular disease, look at these drugs.” They don’t have to have a high A1C for that – they were not restricted for that – they can use it early on.
So, it made it into guidelines in the European Cardiology Society. In 2016 they already said, “People that have diabetes and CHF should take empagliflozin.” Is that correct statement? I do not know but it is in the guidelines. Therefore, there are a lot of trials going on looking at two types of CHF; there’s reduce ejection fraction, which is what we know, but the big epidemic now is what we call preserve function. This is going from people with normal ejection fraction, which is 55 and 60 percent, and we think that in two years, in 2020, 65 percent of all CHF will be preserved CHF. This is a huge epidemic and these drugs help this population. So, these are some of the studies that are going on right now.
Freed: Well, recently ACP, the American College of Physicians, came out with their own guidelines that said A1Cs should be 7-8 percent and that, that is O.K. Where did that come from?
Handelsman: You know it’s a good question. I am a member of ACP (American College of Physicians) and they know that I am an endocrinologist. In fact, many of my colleagues are not only members of ACP but ACP have been utilizing them to teach diabetes. Yet, they did not contact any of us. They did not really develop a correct guideline. This is really a travesty to a point. What they did, they took 5-6 guidelines AACE, ADA, and others and said that when they look at those guidelines, they are not convinced that what is being said is correct, and therefore, they are O.K. with 7-8 [A1C] because there were studies that when you treated the patients to goals at less than 7 there were hypoglycemia and death and we do not want that; 7-8 is O.K. They were not convinced. But, did the [ACP] look at the studies of the last 5-8 years? They said they did not. So, we looked at them and asked them if they were regressive or something. We do not want to treat to hypoglycemia; we say, we treat safely. It’s not just the goal, it’s how you get there. When you get there by causing hypoglycemia, yes say higher, but then your patients will die from other complications, or will have retinopathy, or will have more kidney disease. I mean, that’s not important? Well, you know, many of my patients wouldn’t mind an MI that maybe won’t see as much with an A1C of 7.7 but definitely will see a lot of blindness with that. So, this is kind of very regressive, they are not the true guidelines. It’s a reflection on our guideline. I was interviewed about that and I got an email from England by very well-known epidemiologist in the field of diabetes and in practice. He said, “Dr. Handelsman, why are you so against the ACP? What we do in England is very similar and we have great results and we show that if we don’t go below 7, mortality will increase.” Then he showed me all the studies that he based on it. All of them were done with either Sulfonylurea or older types of insulin with a lot of hypoglycemia just underscoring what we are saying – when we are using the newer drugs we can get people not just to reduce heart disease like we saw with empagliflozin or with liraglutide, but we know that they are very safe. I can take a person with an A1C of 10, I give them triple therapy with a once-a-week GLP-1 and a once-a-day combination of metformin/SGLT2 and I will get them to 6.5 A1C with no side effects for 75 percent of them. I’ve got them to go and I’ve got no issues with them – they won’t get hypoglycemia and who knows now, based on the studies, maybe they’ll get very good cardiovascular benefit, they’ll lose some weight, they’ll get their blood pressure better. I do not think we should be blind to new science. Sometimes ignorance is bliss and sadly enough, that is what graced the ACP with their new guidelines.
Freed: Maybe we should put that combination into my drinking water.
Handelsman: Well, no, only if you have diabetes and you are not controlled.
Freed: You have a couple of conferences coming up. Can you give us a little bit of information about them?
Handelsman: Because of all this new information that you are asking me about regarding the new drugs, cardiologists now, all of a sudden, woke up saying. “Oh yeah, people with diabetes are at risk and we need to treat them!” So, it’s not only glucose. You did not treat them because it is only glucose. It is very clear now that people with diabetes have very high risk for cardiovascular disease and we need to understand the information of the new drugs. Should we give them SGLT2, should we give them GLP-1, should we give a TZD, when is it ok to give an insulin, for example, when is metformin as part of the combination O.K., when is it related to arrhythmia possibly? We do not know any of that. We have learned a lot. How much is it related to the kidney? So, we developed a program; it’s called, “The Heart in Diabetes.” It’s going to be in Philadelphia at the Loews Hotel from July 13-15, I believe. The program is going to be two days and is going to be to examine all these questions. We partner, for example, with Circulation which is the Journal of The American Heart Association, looking at many of the aspects of diabetes that came to the journal. We are also looking to see the world of inflammation in relationship with diabetes and the heart and having some people look at the newer data on inflammation. Then we are going to look at your question exactly: How did these new studies impact guidelines? We are going to have a lecture on what are guidelines or recommendations for practice. We are going to have Sanjay Kaul who the FDA has been using to evaluate data to check those guidelines. Then somebody will talk about the AACE guidelines and the president of the ADA will talk about the ADA guidelines and somebody from ACC will talk about the American College of Cardiology’s guidelines. How is all this information impacting guidelines? Then, we are going to have a session on, based on all this information, how should we choose drugs. Should we use metformin first line or not? Should we use SGLT2 or GLP-1? So, we are going to have a head to head. We will also question whether blood pressure goals should be higher or lower. Should we have people like George Bakris who says it should be lower. We’ll have someone like Paul Wellman …. who says higher. All of this will be head to head and we’ll be looking at PCSK9 and the lipids – all of these for people with diabetes. Everything heart and diabetes – everything clinical. In November, from the 29th to December 1st, we have the World Congress on Insulin Resistance – Diabetes and Cardiovascular Disease. This is going on its 16th year. This is now a much different program – it’s Tomorrow’s Clinical Science Today. We are looking at basic research, at obesity, and at the liver and heart, and how they interact and how the different drugs affect different organ statues. It’s a 3-day’s full impact which, this here, we are dedicating and honoring Gerald Reaven who passed away a few months ago. So, we are going to have a symposium in his memory and we renamed the award that we give after his name and there are lots of stuff that will we look at on insulin resistance, and obliviously then, on cardiovascular disease.
Freed: So, if you look into the future, you’re involved in a lot of studies… do you see any kind of breakthroughs in science for diabetes?
Handelsman: I do not think in science. What I am seeing is that we have glucose monitors – we now are going to get an implantable glucose monitor approved most likely. If you are going to have an implantable monitor for three months, this is a (brain to put a closed loop that we call and we’re allowed to have an independent system implanted. I can see that happening in three to five years. I think that would be a huge breakthrough. Another interesting breakthrough is to look at creating some cell lines that will transfer from STEM lines into beta cells and we are seeing at least two independent slides. It is still a bit too early but right now, I am seeing that happen in front of my own eyes. Until now, we needed to get it from a lot of pancreases to get beta cells to be good for a couple of years. Once we get limitless beta cells and everyone works to protect them from the immune system, it is another breakthrough.
Freed: Well, I want to thank you for your time. Enjoy the rest of your time here in Boston and I thank you once again for all of this great information.
Handelsman: Thank you for having me!