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Stanley Schwartz 2018 Transcript




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Freed: This is Steve Freed and we are here at AACE 2018 in Boston. And we’re here with a special guest, Dr. Stanley Schwartz. [Freed to Schwartz] Maybe you can just start off and just give us a little bit of history of what you do and where you do it.

 

Schwartz: So, I was 32 years at University of Pennsylvania. Now, Emeritus Clinical Associate Professor in Medicine. I was a DCCT Principal Investigator, saw lots and lots of patients. In the past seven and a half years, I’ve had a single solo practice in the Philadelphia area. I’ve actually been more academic since I left the university because now I control my time and not anybody else telling me what to do. And in that regard, I’ve written about 28 papers in seven years, and traveling the world, traveling the U.S., and locally speaking about my new ideas about how we should be organizing and treating — recognizing diabetes and preventing complications.

Freed: We’ve seen a lot of changes over the last years, specially probably the last 10 years. And I was wondering, you know, there used to be two types of diabetes. And now it’s changed, and then there were five, and now we’re talking about 11, but they’re all based upon beta cell issues. Maybe you can talk a little bit about the different types of diabetes.

Schwartz: Well, the current classification: type 1, type 2, LADA, which are the big ones, that have been used in the past 5-10 years, were based on old information. Type 1 was immune destruction of beta cells. Type 2 was insulin resistance. And LADA, they didn’t really know what it is but it suggested immune destruction but in the older patient. When I was asked how do we diagnose diabetes by the ADA, about three years ago now, it took me about three nights before I had the epiphany that says, “The current classification has failed.” And that’s because we’ve — not because they were wrong, but because we’ve learned so much more. And in that regards type 1 patients, 30% to 50% of them now we recognize had insulin resistance. And about 15% of type 2 patients have islet cell antibodies, a sign of immune destruction or inflammation of the beta cell. And LADA turns out to be predominantly type 1 genes. But their expression is delayed, if they surprisingly have type 2 genes. So, we’ve just learned so much more. So, to me, there is only one disease, and that’s hyperglycemia, right. And the real question is what’s causing the damage to the beta cells that results in hyperglycemia? And we’ve recognized 11 mechanisms of hyperglycemia that we gave the story “Egregious Eleven” to. And 6 of these mechanisms are things that damage the beta cell, the muscle liver fat or related to insulin resistance, the brain which results and centrally controls peripheral insulin resistance as well as sympathetic tone. And we know about the gut biome which can damage the beta cell, and by the way, cause insulin resistance. And we also know about inflammation. So, there you have 6 that can damage a beta cell. So, you have 6 mechanisms that damage a beta cell. And then once you have a damaged beta cell, you have 5 results of that damage: reduce insulin, increase glucagon, increase glucagon resistance, reduce amylin which means that the stomach is going to empty faster and raise the sugar. And all those, will cause minor hyperglycemia, results in up-regulation of a protein, SGLT2, in the kidney, which exacerbates hyperglycemia. So, given that logic, it tells us how to take care of patients with diabetes. One, you can implement precision medicine. You can implement Patient-Centric Medicine, in the sense of figure out with appropriate markers, what’s causing the disease in that individual patient, and then use the least number of drugs in combination that treats the most number of mechanisms of hyperglycemia. And that’s the principle surrounding the Egregious Eleven. And the side correlate of that is don’t use drugs that damage the beta cell. So, there’s no logic for sulfonylureas. There’s no logic — even though it’s somewhat less to use with glutamide. And maybe the surprising answer is if you can avoid it, and we’ve written a paper that says, “You should be able to avoid the use of insulin in 90% of your type 2 patients.” So if you can avoid it, don’t use insulin. Because insulin gives you — when you inject it in the periphery, results in obligatory hyperinsulinemia. Hyperinsulinemia means weight gain, which means increased triglycerides and cytocide that damage the beta cell. So, even insulin can damage the beta cell. So, we’re not using sulfonylureas that cause hyperglycemia. We’re not using insulin where both those can damage the beta cells. And we’re using combinations of the newer agents that treat the most number of mechanisms of hyperglycemia.

Freed: You know it used to be that diabetes was a simple disease. We had one oral drug. And the patient goes to a family doc and he knew what to prescribe, sulfonylurea. And now it’s so cheap, the doctors still use it. And then [Ralph] DeFronzo started to look at multiple combination therapies.

Schwartz: Right.

Freed: And he’s very aggressive in using two and three therapies to knock out the diabetes. And what’s the philosophy for doing that? Because some doctors, they say diet and exercise for a couple of years and then they put you on a single drug for a couple of years. And by the time you get to multiple drugs, your cardiovascular risks are way up. And you have all kinds of complications, because it wasn’t treated aggressively. So, what’s the real philosophy for being more aggressive and treating people right at the start with multiple treatments?

Schwartz: It has to do — and I’ve written a paper on this, that the same mechanisms that damage the beta cell are responsible for your risk of diabetic complications. So, genetic mechanism information, insulin  resistance and environmental factors, diet, exercise, so forth are the things that put somebody at risk for complications of diabetes. And so, you have a damaged beta cell, raises the sugar, that means it also raises lipids, so there’s your glucolipotoxicity. Those go to the peripheral tissues. I get away from using this, the sense that there’s micro- or macrovessels, these are the same pathophysiologic process. I get away from using type 1 and type 2 having different complications. It’s all the same complications, depending on which cells are being affected and how susceptible you are to them. And the logic then becomes let’s — by these markers, identify which things are going on in any individual patient. And we’ve learned usually multiple things are going on and they’ll be different in different individuals. And that gives you a logic. Not an arbitrary, “Oh, use three or four drugs,” but a logic for combining drugs. Again, most number of drugs that treats the most number of mechanisms of hyperglycemia. But by the way, use the appropriate drugs that would prevent or treat the complications that this person is at risk for depending on their level of inflammation or insulin resistance, and other things like reactive oxygen species and so forth. So, there’s truly now a pathophysiologic basis for combination therapy for diabetes and its complications.

Freed: So, give me a description of a patient that comes to you that you diagnosed with Type 2 diabetes that you would put on combination therapy day 1.

Schwartz: Well, I was part of the committee that — from AACE 2009 we were the first that then said, “Well, if your sugar is 6.5 to 7.5 use one drug, 7.5 to 9 two drugs, and over 9 use three drugs from the get-go.” And so, I feel proud I was on that committee that helped define that. So, I have no hesitations. Somebody comes to me the first time, they’re 7.6, I have no hesitation starting them on two drugs at the same time.

Freed: And how long, from your experience, to get that patient to goal on two or three drugs?

Schwartz: You have to understand the pharmacokinetics and the pharmacology of each of the drugs you’re using. So, two — actually there’s three drug classes — well, two drug classes; Incretins and SGLT2s, and Incretins have DPP-4s and GLP-1s. Those classes work in 24 hours. So, I can have no hesitation in saying, “Decide in one month,”  because they’re working in 24 hours full effect of it. One month, are they having an effect or not? And the standard approach is wait three months and see what the glycohemoglobin [is], because glycohemoglobin represents three months of the lifespan of the hemoglobin molecule. But I use fructosamine which is glucose attached to all the protein in the serum. And that’s one month halfway. So, in one month, I can figure out if they’re working. If not, I have no hesitation one month later adding the third drug. And the third drug will depend on the patient. Again, ideally depending on what other things are going on if I can figure it out. You know, inflammation, resistance, so forth, as well as the nature of that specific drug. So, pioglitazone, let’s say, half effect in six weeks and full effect in three months, so I would wait three months for that. Metformin takes you two to four weeks to titrate it up, so I’ll probably wait three months for that. So, the second batch of agents works slower. You have to tie trade from an encrypting quick release, works slower. So, the first agents will be GLP-1, SGLT2, or SGLT2 and DPP-4, they work right away. One month later make a decision about adding third — three months later you can add the fourth. So, I can get people under control very quickly as opposed to the old habits of “clinical inertia,” where, “Oh, we’ll wait three months. Oh, we’ll see, I know you weren’t right and neither did I, so we’ll wait another few months.” And that’s how people got delayed therapy and increased the risk of complication.

Freed: What is the logic of precision medicine?

Schwartz: It’s to find out the specific cause of the beta cell destruction. For that matter, other things, the specific risk they have of complications of diabetes. And that would be to identify markers in each individual patient that tell you then which drugs. Guess what? We’re doing that today in breast cancer, right. They have a genomic ChIP, put a drop, tells which genes are involved, and the readout tells them, “This is the drug you should be using.” We should use the same process of care for patients with diabetes; the genomic ChIP, a metabolomic ChIP, a proteomic ChIP. What are the markers in that individual patient that identify the processes of pathophysiology of destroying beta cells, putting at risk for complications, and figure out the right drugs that treat those complications, and treat the mechanisms that are damaging the beta cells.

Freed: So, what is the value of recognizing the same mechanisms that damage beta cells that are responsible for complication risk?

Schwartz: Well, to go back to when I was in medical school the original thought was, “Are the complications of diabetes a given?” You know, an independent genetic factor that is inherited and completely different from diabetes per se. And there was a gentleman, Marvin Siperstein, quality guy, but he believed that they were two separate diseases; diabetes and the complications of diabetes, and they were completely different. And then, what happened was a gentleman out of Britain, Harry Keen, came up with something that was proven to be more logical. He says, “Diabetes has an abnormal metabolic environment,” right, creates an abnormal metabolic environment; high sugar, high lipids. And you wanted to explain why did some people with the same degree of abnormal metabolic environment, some get complications and some don’t. So, he said, “Well, guess what? Some people are more or less susceptible to damage by the metabolic environment,” so there’s your genetic component. But by the way, some people have other confounding issues; hypertension, hyperlipidemia. Maybe some environmental issues; diet, exercise. And so, your risk of actually getting a complication depends on which genes you have and which comorbidities you have. And then, at some point you’ll get complications, some of them are reversible. And at some point, there may be enough damage to a tissue that it’s irreversible. And that’s the value of recognizing which pathophysiological mechanisms of both diabetes and its complications are going on in a specific way in any individual. So, you can define precise care, there’s where the word precision medicine comes from, for each individual patient.

Freed: Recently, in fact, this morning, I read an article that diabetes increases your risk for liver cancer. We know it basically increases your risk for every disease known to man; dry skin, wrinkles, hearing, eyes, circulation. I can’t think of a disease that somehow is not affected indirectly or directly by elevated blood sugars. And so, maybe you can kind of explain what’s the value of recognizing the mechanisms that damage beta cells that are responsible for malignancy risk and why certain meds can actually treat cancer.

Schwartz: So, this was another 3 AM epiphany I had. (Laughs) And I’m in the process of writing the article. I was asked to review an article. There had been other articles before, so I’m not violating any issues. But the basic principle was there was a clear association of diabetes with malignancy, especially in those patients who were obese and had insulin resistance, and by definition hyperinsulinemia. And you could correlate this increased risk, especially in pancreatic cancer, liver cancer, and endometrial cancer to the greatest degree, and then some other cancers to a lesser degree. And they were the same cancers in “type 1, type 2,” that’s why we should get away from using those designations. And it seems to be related to insulin resistance. And the reason I want to emphasize the type 1 story here, because people say, “Oh, we just said obesity has resistance and so forth,” but guess what, 30% to 50% of type 1 patients have insulin resistance. So, they’re at the same epidemiologic now proven risk of cancer as the type 2s. And not for all cancers, but especially for the three that I mentioned. And it seems to be related to hyperinsulinemia, and the inflammation that can result from it, and over-nutrition, high nutrient states. Because it turns out high nutrient states will lead to biologic pathways that increase the risk of developing cancer and progression of cancer. So, think about it, the same pathophysiological mechanisms that are involved with damaging beta cells, its resistance, inflammation genes, and viral factors put you at risk for complication — could put you at risk for damaged beta cells, put you at risk for complications. And now, seem to put you at risk for developing at least some malignancies. And the correlate not only for stimulating more research but the valuable clinician correlate is it says, “Well, guess what? There are some medicines that we use for diabetes, treating the hyperglycemia that might, in fact, help cardiovascular disease.” I didn’t make that connection before. But guess what? Now, we have the SGLT2s. We have the GLP-1s. We have the bromocriptine quick release, that seem to reduce cardiovascular outcomes. Metformin, 20 years later has that effect, right. And guess what? Now, they’re seeing articles — remember, the same pathophysiological processes are involved and diabetes complications are now involved or been associated with, not proven, with cancer. Guess what? There’s data that now that says, “Metformin might prevent cancer, might treat cancer.” And now, there’s early data suggesting that may be the case with GLP-1s and with SGLT2s. And maybe surprise, turns out that statins might have a benefit that would affect the inflammation story. Turns out some tea leaves. Certain kinds of tea leaves. I don’t know what it’s called. Maybe it’s a fruit, bitter lemon. Both of those, the teas, the bitter lemon, treat sugar and they may be ways to prevent or treat diabetes — treat the cancer related to diabetes. So, it all fits together. But you want to be precision medicine, so you find out the factors affecting each of these issues in each individual patient and then define the right pharmacologic therapy for each of these patients.

Freed: Recently, the American College of Physicians came out with the statement saying that the A1C is okay if it’s between 7% and 8%. After AACE and how many years American Diabetes — even American Diabetes Association is learning that normal is good. That having an A1C, that is not considered in the diabetic range for a normal person who doesn’t have diabetes, is a good thing. And yet this organization, I don’t know, they took it upon themselves to come out with this statement that really doesn’t make any sense. At least from the studies that have come — in the hundreds of thousands of studies that have come saying that normal is good. And they come out and say that 7% – 8% is okay.

Schwartz: So, simple statement is it’s the most horrible recommendation I have seen come from a traditional medical organization through my 40 years of medicine. Just horrible. Historically, I know — I believe I know where it came from. And let’s start with the fact that even though they question it, there should be no doubt that the higher the sugar the greater the risk of damage to tissues. We know what normal is. We know what abnormal is. And that damages tissues in many patients, not every single one. And we even have — and by the way, the final clinical thing there were the old Pirart studies out of Belgium, who, no ifs, ands, or buts, that was the marker that actually was the best argument for Keen’s issue about diabetes and complications. So, there should be no doubt about the fact that the high sugars markedly increase sources of diabetic complications. And then, now I’m giving you the high level historical approach– then you had, you’ll excuse the expression and I’ll apologize to the viewers out there, this horrible thing called evidence-based medicine. Evidence-based medicine as it’s used in the US and really across the world in the past 50 years, I think has destroyed medicine. Because it says if there’s no evidence, my translation is, keep doing the lousy thing you’ve been doing for so many years. My personal bias is, you should be using evidence-based practice. Evidence-based practice, I learned when I went to medical school. It’s if there’s evidence, I’m going to use it. And maybe that’s what they were trying to say with evidence-based medicine. But evidence-based practice says, “We use it as, if there’s evidence, we’ll use it. If there’s no evidence, I’ll understand the disease. I’ll read the primary data, around drugs, around conditions, and then make a logical decision.” So, what American College of Physician said was the evidence may not be as precise as a pure scientist working with mice and tissues might like about the relationship of sugar to complications. I think it’s good enough they said, “Oh, it’s not quite precise.” And by the way, when we tested that, ACCORD, VADT, ADVANCE trials, we saw no benefit. So, there must be something wrong. Now, their interpretation was, “Well, let’s ignore how it happened,” but there was really no good benefit, right, but that’s a misstatement for multiple reasons. The single most important reason is those studies had high risk of hypoglycemia and they had high risk of weight gain. And no surprise then that there were adverse cardiovascular events with those elements in those three studies. So, that’s what they saw and said, “Well, we’re in an evidenced-based medical construct, not perfectly sure that sugar is related, and by the way, you had complications. So, we’ll accept seven to eight.” So, I think they had the wrong clinical approach to the data that they had available to them. So, my interpretation is that the data is more than sufficient: sugar is related to complications. The problem with the studies was that they didn’t have the right tools to try to bring the patient down, so they got into trouble with the hyperglycemia weight gain. Guess what? My approach which I gave you earlier was, “I’m not using sulfonylureas, I’m avoiding Insulin in 90% of my patients,” so I should be able to get wonderful control and reduce complications if you use the right drugs, right. And don’t engender the hypoglycemia. So, they were so worried about the hypoglycemic risk that they’re making the wrong clinical decisions overall. What is needed is not what’s being now done by the NIH. There’s a study. I actually forget the name of the study. They’re comparing individual agents and say, “This one might be a little better than that one,” point one or point two. But the right study is a process of care, sort of what they use in ACCORD but without sulfonylureas at all, and insulin as a last alternative. And if they did three or four drugs, right, non-hypoglycemic, no weight gain, and use that as a way to take care of diabetes, I submit to you that you’re going to see clear benefit. And we have the inference from separate studies with GLP-1s, separate studies with SGLT2 inhibitors, separate studies with bromocriptine. Guess what? If you use those in combinations, right, you might get a supra- or additional effect with each and to enable to show a reduction of cardiovascular outcomes, reduction with even complications. If you did that kind of study, instead of the one they’re using now and instead of the ACCORD study [in which you] use your own drugs, hypoglycemic agents, and we could easily prove that there’s value. But ACP just misinterpreted the data they had and were not thinking in evidence-based practice mode. They were using the old and, to me, illogical evidence-based — I mean, if the patient sitting in front of you doesn’t fit the patients that were in the studies, then what do you do? So, you need a process of care now. And the process of care says, “Use the evidence that’s available and then be logical based on interpretation of all the other data and come out with the conclusion that I’ve given you.” Don’t use hypoglycemic agents, avoid weight gain, and the current medicines will be more sufficient. And you will be able to prove as my logical conclusion, my evidence-based practice approach to care patients with diabetes.

Freed: I want to thank you for your time. It’s very interesting, educational. And looking forward to talking to you again at ADA coming up next month.

Schwartz: Wonderful! Thank you so much for having me.