In part 2 of this Exclusive Interview, Dr. Yehuda Handelsman talks with Diabetes in Control Publisher Steve Freed during the AACE 2018 convention in Boston, MA about changing diabetes guidelines and what we’ve learned through studies of new diabetes drugs.
Yehuda Handelsman, MD, FACP, FNLA, MACE is a past president of the American College of Endocrinology and Medical Director of the Metabolic Institute of America in Tarzana, CA.
Transcript of this video segment:
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.