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Yehuda Handelsman Transcript

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Steve: This is Steve Freed with Diabetes in Control and we are here with a very special guest. Dr. Handelsman who is very well known. He’s actually past president of ACE (American College of Endocrinology) and chair of ACE DM with lipids. He has published over 100 papers. So, he is very well known and everybody out there I am sure knows his name. Now you get to meet him in person.  I know you are here to receive an award. What kind of award?


Yehuda: That’s kind of cool. Thank you for even mentioning that. With all the stuff that we are doing, it kind of escaped me for a second until people come and say congratulation. So, this is the Master of the American College of Endocrinology. So American college of endocrinology has won some awards. It recognizes person for its contribution to the field of endocrinology and to ACE, both AACE the association and the college.

Steve: In the title of your talk is “Interpreting Lipid Guidelines: How Low Should We Go?” That’s an interesting topic because ACE’s changes their guidelines many times and it gets a little confusing sometimes. So how low can you go? Maybe you can give us some high points about that. What do you want people to take away from this meeting and from your presentation?

Yehuda: I think that ACE has been quite consistent with early recommendation with ATP3 and CP4, and NIH sponsor accommodation for managing lipids suggesting to go to lower goals of LDL to prevent cardiovascular disease. Some other groups, like American College of Cardiologists few years ago came out and said that goals are not that important. What’s more important is just giving somebody a statin. Now we believed that we need to give statin to the patient. The question is, do all patients act the same? And we used to have several risk categories. The risk category which is low, moderate then high then very high. Very high person could have been somebody who’s got diabetes and couple of risk factors and somebody who once had a heart attack. And may have another one. How should we treat them? We used to recommend to get to goals lower than 70. The American College of Cardiologists came with the guideline. We did not change ours. It says you give them high potency statin, suppose Lipitor 40 or 80mg, or rosuvastatin 40mg. And don’t worry about the goals. Because that’s all you can do. Don’t do combination therapy. And then we were seeing in practice that people get to those goals sometimes or don’t even go to the goals and they keep having events. So, we went ahead and examined the available data. We got a group of experts looking over older guidelines from 2012 looking at other guidelines over there, looking at new data coming in. And data came in to show that really the lower the LDL cholesterol, the better outcome patients had. So, it’s just not a miracle of statin, which we think should be very important, but it’s a fact that we need to get the people to goal. In nearly 50% events, some even less, by other analysis only 30% of patients needs to have an LDL below 70 because they have such a high risk even getting at goal. What we also saw that there were some groups of patients with particular risk. Person with diabetes who already had an event; person with kidney disease who had an event. Somebody with familial hypercholesterolemia who had stroke and couple of other heart events and they may be at a goal of 70 but that may not have been enough. So, we created a new risk category and that’s what’s very new in our guidelines. First time in 14 years there is a new risk group, which is called extreme risk. So, we didn’t want to call it extreme high because there is moderate high, medium high, there is high, very high or extreme risk. And extreme risk are exactly the patient they talked about. People with diabetes, kidney disease or heterozygous familial hypercholesterolemia and these group of people we believe should have more a intense goal, looking at a goal of LDL less than 55. Also looking at ApoB, which is another measurement of risk. We said that could be less than 70. When we can look at goal of non-HDL, we said less than 80. So, all these goals represent a good place for using events in extreme-risk patients. And when we devised that there was one randomized progressive trial, it’s the improvement they showed the patient who got to LDL of 53 had less events than patients with LDL of 69. Not only that, the majority of the events – but that’s a post hoc analysis,  so it’s not as scientific as we would like – but the majority of the people were people with diabetes. Hence, extreme risk group. Various other meta analysis showed very similarly the lower you go, the better it is. So, we went ahead and published our guidelines and it’s still in print this week. And in March, American College of Cardiology there is a trial with a new drug, PCSK9 inhibitors, which is really a 21st century drug. We look at this drug and took patients with high risk for secondary prevention and they reduce LDL down to about 30-32 LDL and reduced heart attacks by 27%. So, you take very high risk people, very well treated they were on stopped statin 80 lipitor, 40 rosuvastatin and they were getting ACE inhibitors and ARBs, beta blockers and top top treatment and even in the treatment group, there was further reduction in MI to say that we really need to focus on people to getting to lower goal especially LDL. And especially in people with diabetes. Because the LDL of a person with diabetes is different than the LDL of people that don’t have insulin resistance and obesity. There are many more particles with this number of 65 compared to someone who doesn’t have it. And I think that’s why people with diabetes are doing better.

Steve: You know it gets a little confusing. We now have a drug called SGLT2, empagliflozin, and that showed a reduction of heart risk by 36-38%. So, do you treat people with an SGLT2? Do you treat people with one of the new hypercholesterolemia drugs? So, you can only….the new drugs are very expensive. You can’t take everybody with diabetes and put them on that because insurance companies would go bankrupt. So, what do you do?

Yehuda: I think we are looking here at two different aspects. One aspect says people that have lipid disorders that propel their cardiovascular disease, we put them on astatin and they don’t go to goals. We can put them further on goal and put them on drugs like ezetimibe, which would probably go first before we put them on PSCK9. And there could be group of people we could get to goal with a lesser expensive drug. If I see a person and they keep having atherosclerosis-related MIs or strokes, I will give them a lipid lowering drug. This is true whether they have diabetes or not. Somebody with kidney disease not necessarily with diabetes can also be extreme risk. It does not have to be just diabetes. The SGLT2 inhibitors are terrific drugs for people with diabetes. In fact ACE recommends them as first therapy after metformin even before this very nice study EMPA-REG. In the EMPA-REG study, there was a reduction in CV mortality starting the first 3 months corresponding to a reduction in congestive heart failure hospitalization. So, we don’t know yet why people did not die because of that, but they have to have diabetes and when you have to control glucose and they already have an established disease, yeah, that is a drug of choice.  And we don’t know. A month from now, American Diabetes Association and other trials, CANVAS, CANVAS-R, looking cardiovascular outcome with the drug canagliflozin may also show the same thing. We don’t know yet. We have to see. So yes, the SGLT2s are important but we also have GLP1 receptor agonist drug like liraglutide, Victoza. They have a reduction in CV mortality and we’re waiting to see if FDA will give them that indication. So now we are in better conversation with diabetes drug. Remember until two years ago we said they kill patients. Don’t give diabetes drugs! Avandia kills patients. Actos give cancer, you know? Januvia gives pancreatitis or this or that. All of this became bogus. It was a very hard place to discuss. All of a sudden in the last two years we are seeing the drugs trial after trial after trial to show how safe the drugs of diabetes are and now trials to show not only safe but to also reduce cardiovascular mortality. And I think that will obviously make us that we will need to take into account these drugs you know it’s a big problem now. Insurance companies say I only chose metformin and sulfonylurea because they are cheap. I don’t blame them. It’s cheap. They save money. But guess what? You give SGLT2 and you reduce mortality. That’s expensive. Why? It’s expensive because they live longer. It cost more to insurance. I think people will have to evaluate what is the cost of life again.

Steve: So, you say the new guidelines will say that a person with diabetes, they should try to get their LDL…

Yehuda: What we are saying is this: the lower the LDL the better. The different risk groups that we have, let’s say somebody has diabetes and has a couple of risk factors. We would say LDL less than 70 would be okay. Somebody who doesn’t have diabetes who had a heart attack, we would say LDL less than 70. But if somebody has diabetes and a heart attack or somebody had kidney disease and heart attack or heterozygous FH and heart attack, to these groups we say even lower, even 55. So, the lower the risk group, the higher the LDL can be. We also address triglycerides and other stuff in the guidelines, but this is like the new stuff. New stuff is extreme risk group with much lower and the fact that we now have evidence to support combination therapy to get patients to goal. That’s very important. So it’s not statin alone anymore. We have got two keys to the market: ezetimibe and now the PCSK9 in addition to a statin. That can get us to the lower goals and to the better outcomes.

Steve: So, for someone who is at a high risk who has had a heart attack, and you want to get them to a at least 55 or below…

Yehuda: That depends. If somebody had a heart attack, their goal should be around less than 70. But let’s say they are at 67 and they keep having events, then I want them below 55.

Steve: Can you do that with the standard lipids that are available today without the new ?

Yehuda: I don’t know. Some yes, some not. All the PSCK9 are revolutionary. Here is the point, if they would cost $5 a month, there’s no question there. They’re going to give it. Very nice drugs, seemingly very safe, we have four years of data to show safety and that’s really starting to accumulate. They can get our patients to very low goals and they can reduce heart attacks by now by at least 25%. Somebody will need to evaluate events in life. I am not there you know. I recognize it’s a big burden. I also don’t think everybody needs to have that. And the other ways to mitigate risk that we can work with. But there will be patients that need to have this drug and they are expensive but you know what? Drugs for rheumatoid arthritis are very expensive. Drugs for mental disorders are very expensive. Drugs for hepatitis C are very expensive. You know metformin used to be expensive, actos used to be expensive and then they become generic. Sooner or later these new drugs will be less expensive. We need to take them into account and there always will be a time that any insurance company, any person, any government needs to say what is the value of the life of the person across from me? And this is a big question. How do you answer it? If you know that you can reduce the chances of getting heart attacks and stop it from going on. I have a musician patient. Not musician, he actually big music producer for movies, you know I am from Los Angeles, so in Beverly hills in Hollywood actually. And the guy has diabetes and guy had a stroke and some how got out of stroke…mentally okay and physically not as good and then his LDL with statins. He was on rosuvastatin and he was also tried ezetimibe and he was okay with it to a point. LDL was in low 70’s and then he get an acute coronary syndrome. So the fear is not another acute coronary syndrome, it’s another stroke that takes him out of business at all. So we started him on medication and so his LDL now is down to less than 40. And in the past year, he did not have any event. Did we do that? Did life do that? I don’t know. But at least we tried to stop the down spiral road that he was on.

Steve: So, for patient who has diabetes and one coronary situation, you are still satisfied with around 70 LDL?

Yehuda: If they had an event, then no. if they have severe risk, then 70 is fine. If somebody had diabetes with high blood pressure and some lipid disorders and they did not have a heart attack or any kind of an event, then I am okay with less than 70.

Steve: So the next big question that I have is, I know the ADA says if you have diabetes, your A1C should be below 7%. And the ACE says it should be below 6.5%. Who do we believe?

Yehuda: You believe the patient. I think the ADA says less than 7.0%, that’s 6.9 and ACE says 6.5% and below so we are very close. But Steve, last week, a very elegant study from Denmark looking at 28,000 patients and Denmark is a very controlled place. They looked at the patients started on metformin from year 2000 to 2012-2014, around there. They looked at several aspects of that. One, they looked to see to which goal they got to the metformin. The people that were at 6.5% or less had less events and it was gradual then 7, then 7.5, then 7.5 to less than 8, then less than 8.5. To the 6.5 then less than 7. That is the study in Denmark. I know in United States, we are not as the Danish. We have different body composition, if you will, but in that particular group less than 6.5 was better than less than 7. But get me to patient to 6.8. I am not going to fight over it and that’s not the issue. Even people at ADA will agree with you that if you can get them to a good goal safely without hypoglycemia, sure, of course it’s better. Another trial. In older people, comparing A1c less than 6.5 vs above 8 in people 55 to 80 years old. Less death, less heart attack and less stroke…6.5% vs 8%. In the older population, what does it tell us? It tells us that there was a time where we had to be more careful about the goals. Because to get to 6.5%, would give hypoglycemia. Remember, sulfonylurea that’s what we had and insulin and we put them back both together and you reduce them down. We just published an editorial in Diabetes Care. Because there was a publication in Diabetes Care saying that people that are older should not have too low or too high goals because it can cause a lot damage if it’s too low or too night whatever it is. And we don’t think that’s correct. It’s not the age that determines. It’s the comorbidities that create an issue and if you cause them damage giving hypoglycemia with metformin, GLP1 and SGLT2, I can get the majority of patients from 9.5% even 10% A1c with down to 6.5% with no hypoglycemia. By the way, that study in Denmark also showed that the faster you reduce the glucose, the better outcome you had. It also showed that those people with very high glucose reduced by far more had better outcomes. Sometimes people say don’t do it too fast, it may cause damage. No, it doesn’t. if you don’t cause hypoglycemia, if you don’t take somebody with DKA and take 500 or 600 of glucose down to 120 in 12 hours, which can be risky because of osmotic changes, you can control glucose fast into goal. My issue is not the 6.9% vs 6.5%. We are close enough. My issue is to get there safely. My issue is to make sure if you don’t do sulfonylurea the people can get hypoglycemia, the number one cost in emergency room in hospital is hypoglycemia. We have to prevent it. I manage people with type 1 diabetes. They come to me with 5.8% diabetes, 6.2% A1C and how much hypoglycemia do you have? That’s part of their life. Not in my book. When I manage, you don’t have hypoglycemia. Every type 1 will eventually have hypoglycemia but if you teach them to first prevent hypoglycemia then working on higher number they are good to go. Everybody should be that way.

Steve: But don’t you find that a person who has A1C of 9 or 10 and you try to get them rapidly safely down to as low as possible in 6 range that they can’t deal with it because they feel the side effects of hypoglycemia at 8.

Yehuda: That’s correct. You do gradually if you start, let’s say at 10, by two month you are at 8. It’s not true hypoglycemia, you get little shaky and you get used to it. You take 3 to 6 months to get them to goal but I will tell you I had often those patients. It’s not true hypoglycemia; it’s not that they got huge amount of insulin in very little hypoglycemia is 40. Their sugar is relatively because of their pituitary, the set point, they changed it and they think that 140 is too low. Nothing will happen to them. They will not even have a car accident. I think we shouldn’t be afraid to get them to goal. I think they show that often and often again. Also remember that metformin, lots of side effects, so I titrate my patients. It takes a month to get them to goal. Some of the GLP1 works immediately, again actos.  They will be generic and they are going to be inexpensive. You will see more actos coming now into the mix of managing diabetes. So you can give actos, but it takes 6 to 8 to 10 weeks to work. So, this SGLT2 works immediately. So even if you start it takes a month for them to start coming down. Put them on a diet. The sugar starts coming down. I can get people sometimes in 48 hours from a sugar which is as high as 320 down to 120 just with very intensive diet. It can be done. It’s done before.  Their A1c will time to show it but glucose can come down. We live in a time right now we have such wonderful tools. I just wish that a lot people would know how to use it and, as you mention, get access to them. Some of them are expensive.

Steve: So what do you think is the greatest discovery over the last couple of years? looking to the future that’s gonna make a huge impact on diabetes because they say that every other person in the United States either has diabetes or prediabetes.

Yehuda: Yes and above age 65, 50% have prediabetes and 25% have diabetes. That’s ¾ above age 65. I really am very excited on the direction of the CGM, the continuous glucose monitoring, are going. I mean I have said it all the 8 -9 -10 years ago. It’s a game changer. It wasn’t a game changer initially because expense and not so accurate. When we are looking at modern accuracy right now with CGM, you know you slap a CGM on a type 2 diabetes and they can watch what they eat and they can see the reaction of the food and see what it is. To me, it’s getting less and less and less expensive. So you don’t need anymore special unit CGM. It can be on iPhone. Now it goes to clouds and parents can watch kids at kindergarten at school and watch to see if they are okay. Parent can see that maybe a kid was going to go down to hypo, can call the school. CGM is going to revolutionize, and I believe CGM is going to be inexpensive in a few years….I see a disposable kind of a unit….$35-40 a month. You know Libre is going to come from Europe and you can put on your arm and for two weeks you can watch what you eat. In Israel, they actually use that Libre as helping people do diets. So, it’s crazy but they are doing that. You know everything can create a diet but people will buy it. I think it’s such a powerful tool to prevent hypoglycemia (which is very important) and to just for you to know should I eat this or not? Should I stop it in middle of the pasta? Or this pasta doesn’t get my sugar up. Is my fruit watermelon, melon, apple, berry? That would be incredible. So, I see the CGM and with it the closed loop, the hybrid closed loop that is coming to market. I think that will be very helpful to many people. I think in 3-4 years we will have total closed loop also dealing with boluses. And with it there will be one that is bihormonal, like a bionic pancreatic, whichever will be, I think that we will see CGM trials to see them implantable. You may have full closed loop system implantable. People will live practically normal life and I think that next 5-10 years probably and I mean there are some other things like islet coming back and some way to do that. Still this is further away. So, I see the technology is what’s really going to lead. I can have another great drug and another great drug and I can identify gaps in what we need and still they said let me see people use what they have right now. And I would be very happy to get more drugs.

Steve: So, I don’t want to keep you to keep you too much longer, but I love sitting here talking to you. I don’t get opportunity to talk to someone as infamous as you are. (laughter) you know so. Couple of years ago, Dr. Nisan started this thing with avandia and it caused heart attacks.

Yehuda:  Yeah, I told you avandia killed people for few years. It stopped, FDA said it doesn’t kill anymore. You cannot even buy it anymore, but it doesn’t kill anymore.              

Steve: Yeah, but because of that though, the FDA requires all new diabetes drugs to go through cardiovascular trials. And that’s the reason why we found that SGLT2. If it wasn’t for Dr. Nisan, we would have never done that.

Yehuda: Yes, so Steve, for wrong reasons we have got the best credit. We all love those trials. I will tell you, even the companies that were faced with this huge investment, and those trials were very expensive, even those companies are now really appreciative of a lot of data. Seeing the effect on kidney, seeing true side effect profile, there are lot of things that are going on. FDA get some report and they slapped them with one warning after another warning. There are some long-term trials. CANVAS has up to 7 years of data, that’s great. GLP1 coming out end of this year or beginning next year. We will see lots of data so the data we will see it’s not only on the mortality, not only on cardiac event but you’re looking at the looking at kidneys. We need to see what happened with eyes, we need to understand neuropathy, we need to understand the bones, liver. So many stuff that we want to understand.

Steve: One quick last question, are you looking forward to any news coming out of ADA next month?

Yehuda: Well, CANVAS. I think CANVAS is a big thing. There was some other interesting stuff but CANVAS is probably biggest thing. We are all waiting to see what’s going to happen.

Steve: I want to thank you for your time. Very interesting and I am sure we have all learned something new today. Thank you

Yehuda:  Thank you, Steve.

Steve: Enjoy the rest of your stay here.

Yehuda: Thanks.