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Steve Freed: This is Steve Freed with Diabetes in Control and we’re here at AACE, the American Association of Clinical Endocrinologists here in Orlando 2016. We have with us Dr. Sloan, Lance Sloan, so we are excited about that and maybe you could start off with and tell us a little bit about who you are, what you do, what kind of practice you have.
Dr. Sloan: I’m an endocrinologist/nephrologist in clinical practice in Lufkin, Texas which is north of Houston, it’s a little bit more rural area. I actively practice in both specialties and I’m going to be talking about SGLT associated DKA so I also see about 200 to 300 patients with DKA each year. They’re not all active patients of mine, in fact almost none of them are. It gives me a pretty good experience as to what is happening in the DKA world and of course being very involved with SGLT-2 inhibitors.
Steve Freed: It’s interesting. You’re here to talk about a drug and DKA. Four years ago you wouldn’t be talking about this because we didn’t even have the drug the SGLT-2s. From your experience what are some of the positives with the SGLT-2 drugs?
Dr. Sloan: Of course, I am talking about a class, not any specific one in the class. Actually, I have a history going back for 25 years with SGLT-2s, with SGLTs became SGLT-2 inhibitors. So I’ve actually talked about it even before 4 years ago but of course we weren’t really talking about this association with DKA that we’re talking about now for safety reasons. It’s a class I’ve been very excited about because again I’m an endocrinologist and a nephrologist and this is a drug that works through a novel renal non-insulin dependent mechanism to help lower blood sugars. Because of the way that it works, I expect that over time as the data is already starting to come out with the EMPA-REG and other trials to follow that this drug has an impact on reducing cardiovascular risk factors and other mechanisms that are particularly favorable to reducing diabetic kidney disease.
Steve Freed: You’ve been favorable towards this drug. First of all it works in a different area that we’ve seen before. From what I’ve read, there’s a lot of concerns about this drug, besides DKA. One of those concerns is, with all that sugar floating around in our urinary system, does it increase our chances for cancer? For urinary issues? We know it does, it increases urinary infections. What are your thoughts about that?
Dr. Sloan: So far we’re much more concerned about cancer. There is a model for this. There are people that have a genetic issue with the SGLT-2 transporter and they don’t either have as many or the ones that they have don’t work very well. Those individuals do have Glycosuria. They don’t develop any type of renal cancer or bladder cancer. They live long healthy lives. They don’t have diabetes and I’m not aware of them having issues with infections for the most part. But certainly with people that have diabetes, when we use this medication, it is a concern, there is an increase of mycotic infections for sure. I always tell my patients that they’re going to peeing out sugar which means they need to drink plenty of fluids so that they can wash out all that sugar. They also have to practice good hygiene care to prevent problems. So that’s part of what we go over with every patient that I talk to about. Most of the time, it really has not been a problem in my practice with my patients. I have a large group of patients, a busy practice, with this issue. Part of it is education. Obviously, if I have a patient who is having problems with mycotic infections or urinary tract infections, I would not start them on this medication until I have that under control. If you start a medication when it’s already a problem, they’re always going blame the medication even of course if the problem was there, and maybe not helped by the medication, but wasn’t the main cause of the issue to begin with. So, certainly it’s something you want to have under control as far as not having infections at the time you consider the medication.
Steve Freed: The issue of DKA with SGLT-2s has just come up, I think within this year, where we noticed an increase in DKA. It’s not the same kind of DKA as somebody that’s a Type 1 whose blood sugars are elevated and they’re not making enough insulin and it goes into DKA. It’s really not the same. How do you differentiate the two?
Dr. Sloan: I think that’s something that has kind of gotten out there because Ann Peters wrote an article in Diabetes Care and her article was talking about euglycemic DKA, which is not a term that I agree with. I don’t think it’s real world. As somebody who takes care of a lot of DKAs, I’ve said before, I don’t sit there and focus on the blood sugar. When an individual comes in with the signs and symptoms of DKA who is a diabetic and generally their blood sugars are elevated, I don’t care how elevated they are. Your next step is to check for ketones and to check to see if they have an anion gap acidosis. If they do, they have diabetic ketoacidosis, regardless of what the blood sugar is. I think what this focus which somewhat comes from a publication from the ADA, saying that people with DKA have a blood sugar above 250, well it just isn’t true. At least 20% have blood sugars below that and that’s what the data says. The focus should not be on a particular number but more for somebody in the right clinical setting, where the right individual has diabetes and an elevated blood sugar and of course the other things that I just talked about. That is still the most common scenario that we see with these medications is actually people that have high blood sugars. The patients that are taking it that meet the package insert indications, in other words, they have Type 2 diabetes. We see more of this euglycemic DKA in people with Type 1 diabetes, which again the drug doesn’t have a current indication for. It’s being used off label by individuals, endocrinologists, and maybe even some primary cares, we certainly can do that, we want to do it safely. It’s really necessary, that’s what Ann Peters was focused on in her article. I think there’s been some confusion about that. The majority of patients are not euglycemic. The majority of patients that I’ve reviewed and seen the blood sugars are actually quite high.
Steve Freed: How do you define DKA? At a particular blood sugar level? There’s got to be other indications?
Dr. Sloan: I think this is something that’s very important that needs to be updated. It shouldn’t be based on a particular blood sugar level. That just isn’t accurate. There are up to 1/5th of the people that develop DKA have blood sugar levels below 250. I’m not talking about people on SGLT-2 inhibitors. I’m talking about DKA in general. The diagnosis ought to be somebody comes in with the signs and symptoms of DKA which is nausea, vomiting, and abdominal pain, shortness of breath, who has an elevated blood sugar and of course may or may not have a history of diabetes. Because sometimes we make the diagnosis of diabetes on presentation of DKA. But then, particularly in a patient who is diabetic, who we then check to see if they have ketones, preferably serum ketones, and has an anion gap acidosis, and that should only be a gap of greater than 16.
Steve Freed: I had a question from a diabetic patient just the other day. He’s on a low carbohydrate diet, which causes ketosis. He asked about a urine strip, there’s a range of different colors. What would you consider in that situation, where they’re in ketosis, where it could become dangerous for Type 2s on a low carbohydrate diet?
Dr. Sloan: So, very low carbohydrate diet is basically, particularly if it’s high fat too, which generally it is, is a ketosis diet. That would be a potential contributing factor to somebody developing DKA. The other point is just because somebody measure their ketones in their urine and they’re positive, does not mean they’re in DKA. The two don’t go together. People with DKA usually do have ketones in their urine. Many people have ketosis or ketones in their urine for being on that type a diet or not being on an adequate diet, or frankly starving can have ketones in their urine, but they don’t have an anion gap acidosis. They don’t meet the criteria that I talked about a minute ago for having DKA.
Steve Freed: So, someone checks their urine and as you said, they’re not eating properly. If they don’t have nausea, they’re not vomiting, dizzy, et cetera, can you say that being in ketosis for that type of situation is not dangerous at all?
Dr. Sloan: In general, particularly for diabetic patients, we don’t particularly want them in ketosis. I’m not really wild about any diets that cause ketosis in particular but I particularly wouldn’t use such a diet in somebody who has diabetes. Again, I want to make sure that people understand that there is a difference between a low-carb, low-fat diet, which is what I prefer and an extremely low-carb, particularly if it’s a high fat diet, like an Adkin’s diet that can be a ketogenic diet. I don’t think that’s a good diet for somebody who has diabetes and maybe even a worse diet for somebody who has diabetes who is on an SGLT-2 inhibitor, particularly if their blood sugars are very high.
Steve Freed: Would you say to somebody that goes on an SGLT-2 not to be on a diet that causes ketosis, because it’s a little more dangerous because you’re on a SGLT-2 drug?
Dr. Sloan: I think, in general, I don’t like to see any diabetic on it. But yes, that would probably put them in a little more risk for diabetic ketoacidosis if you’re on an SGLT-2 inhibitor if you were on such a diet. Particularly, I would not encourage such a diet in somebody who’s on an SGLT-2 inhibitor.
Steve Freed: Let’s look at some of the benefits of the SGLT-2s. Number one, weight loss. What kind of weight loss have you seen in the patients with SGLT-2s?
Dr. Sloan: Well, it varies from patient to patient. In general, we see around 10 pounds of weight loss. Some people do better and some people do worse. In my practice, I’m lucky enough that I actually have a professor of nutrition who works in the practice. We’ve always been very focused on nutrition. Anybody can out-eat any drug on the market. That includes the SGLT-2 inhibitor. If you can’t get your patients to at some level, buy into a more healthy diet and trying to have adequate exercise, it’s kind of a long-term losing scenario. So in our practice we actually think we do a little bit better than what’s been seen in some of the registrational trials because we’re very actively involved in diet and exercise with our patients. In general, we’d like to have them on drugs that aren’t going to discourage by causing weight gain or make it more difficult to lose weight. We prefer to have them on medications that are either weight neutral or actually help them lose weight. Obviously all the studies show that this class of medication does that.
Steve Freed: Then, let’s take a look at A1C. What kind of positive results have you seen in using the A1Cs as a tool to see how well they’re doing controlling their blood sugars? Obviously it makes a difference whether you’re starting at 12 or you’re starting at 6.5. But in general?
Dr. Sloan: Like you say, it does make a difference where you start. The higher the A1C the greater reduction you’re going to see with A1C with really any medication on the market, but particularly this one that is very true, because it probably has a greater reduction A1C at the higher A1Cs than other drugs do because the way it works. I’m big on combination therapy. I combine the drugs a lot to get the effects that I want to get. But, the main thing we want to see is this reduction of blood sugar and hopefully the improvement in weight that we tend to see with the clients.
Steve Freed: Have you ever seen an SGLT-2 being the first drug of choice instead of Metformin, because it provides weight loss, lowers blood sugar, it certainly provides more weight loss than Metformin does. You can almost see this being a drug of first choice, possibly.
Dr. Sloan: I think it should be, based on the all the things that you just said. The main reason I think Metformin is at the top of the list has to do with cost. It’s been around for a long period of time, but up to 30% of people can’t tolerate it due to gastrointestinal side effects. I find it kind of humorous that we put it up there. In fact in some guidelines, it keeps showing it as Metformin plus this drug, Metformin plus this drug and this drug. What if the patient can’t take Metformin? There are many patients that can’t. Some of course has to do with kidney function. If your kidney function is low enough that you can’t take Metformin, then the SGLT-2 inhibitor may not be a good choice for you either. Nevertheless we don’t have the diarrhea, the nausea and vomiting that sometimes is seen with Metformin that limits its use. For the most part, there’s not one drug that’s good for everybody. We need to individualize therapy and we keep talking about individualizing and then we write guidelines out there that seem to not restrict the doctor in the individualizing. The FDA comes up with things that restrict individualization. Luckily just the other day, the FDA just approved a combination of an SGLT-2 and Metformin together for initial use to improve blood sugar control. I think everybody should be on combination therapy. For me, it’s not a choice most of the time of which one drug I’m going to start off with. It’s which two drugs in combination. In people who can tolerate Metformin then I think Metformin and SGLT-2 inhibitors is a great choice. For somebody who can’t tolerate Metformin then it would be SGLT-2 and another drug. Maybe a GLP-1. I’m not believer that the Metformin should be the first choice for everybody. I think that’s crazy. We actually work with the Texas Diabetes Council. We write guidelines and have been doing it longer than anyone. We actually give people choices. We don’t say that everybody has to start with Metformin.
Steve Freed: What about the other benefit. That’s a reduction of blood pressure. What have you seen there?
Dr. Sloan: The studies I think people miss out on this, is that they were done on people that have normal blood pressures and we’re seeing about a 5 mm reduction of systolic blood pressure and 1 to 2 with the diastolic. That’s similar to what you see with an ACE inhibitor in somebody who has normal blood pressure. When I start these medications, if the blood pressure’s up and the blood sugars are up, I start this medication and wait to see how they do, before I start adding other blood pressure medications. We’ve seen a very good effect in blood pressure lowering in patients and sometimes that means that I don’t have to add other medications on to get their blood pressure and their blood sugars under control.
Steve Freed: Because of the weight loss and the way you lose weight on the SGLT-2s, you’re basically peeing away some of the sugars that’s causing your body to add weight, et cetera. If a person doesn’t have truly elevated blood sugars. Just slightly, maybe their A1C is 5.7, 5.8, will you see a weight loss in those people? Do they have to exceed their glucose threshold?
Dr. Sloan: It lowers the glucose threshold. We get this question a lot, what about a non-diabetic using these medications as weight loss medications, which of course would be off label. It’s not just off label. I don’t think that would be something that would make sense to me physiologically. Yes you will lose some sugar, they’re certainly not going to cause weight gain. I don’t think they’re going to end up causing much weight loss. Most of the time, we use a medication for weight loss, we like to see at least a 5% or greater reduction in weight. I think with somebody that has relatively normal blood sugars you’re not going to get that kind of weight loss because the amount of sugar they’re going to be excreting is not going to be as much as what you see in the diabetic situation. It’s not going to be enough to cause a tremendous amount of weight loss.
Steve Freed: One of the other questions that they have when it comes to the SGLT-2s is for Type 1s, it’s off label use. I have a personal friend who’s a Type 1 who’s about 34 years of age and he’s seen great results. It reduces insulin intake dramatically, which again if you take less insulin you have better control, because insulin is not an exact science. Where do you think it’s going for an indication for Type 1s? Is that not even being looked at? Is it being looked at? Where do you think that’s going?
Dr. Sloan: Well, what is being looked at, every single company that has a drug on the market now is doing studies in that area and even some companies that have drugs that aren’t on the market are doing studies. It’s obviously an area of interest particularly in the endocrine world, because most patients with Type 1 we hope are being taken care of by an endocrinologist. I’m a big believer it’s a very malignant, difficult to care for disease, really I don’t believe should be in the domain of primary care. So really it should be more of a specialty type thing too. The problem is that using these drugs in Type 1 are kind of tricky. You have to pick the patients because in certain patients it can lower the insulin level to below the ketogenic threshold and somebody could go in DKA like we were talking about before, this, I don’t like the term, euglycemic DKA because they’re not euglycemic when their blood sugar is 240. I think it makes people miss the diagnosis of DKA by using that terminology. But nevertheless in Type 1 diabetics that are on a significant amount of insulin and because they develop visceral obesity, I have this thing I call the VIRAS syndrome, which stands for visceral insulin resistant adiposity syndrome, which is the virus that’s killing most people in the world, not the hantavirus or the Ebola virus or things of that sort. But Type 1 diabetics can now develop this metabolic VIRAS syndrome that I just mentioned, just like Type 2s and have insulin resistance from them. Those type of Type 1s is where I see the SGLT-2 inhibitors potentially being used because they’re on a lot of insulin. The main reason that we’re using these drugs in people with Type 1 isn’t necessarily to lower the insulin levels, it’s to prevent weight gain or maybe even get some weight loss and get them to lose the weight. A classic Type 1 who’s not obese to begin with, maybe fairly lean, doesn’t need a drug that is going to help them lose weight because they don’t need to lose weight and all this drug can do is end up lowering the insulin level and putting them at increased risk for DKA so that would not be a good patient to use. It’s more the Type 1 who has that extra visceral fat that they need to not be putting more on and hopefully losing that I think is the right person to be using. Obviously there are other potential effects to using an SGLT-2 in this group. There’s talk about reducing glucose variability, which you kind of mentioned, which would be helpful and of course we have touched a little bit upon how this class of medications may end up with better long-term cardio-renal outcomes. That might be a reason in the future to consider it too as we get more data.
Steve Freed: Is there a type of patient that is more prone to, Type 2, DKA if put on an SGLT-2?
Dr. Sloan: From my review of the information that we have out there which is looking at case studies. Case studies are hard to come by. I had one case myself and I’ve reviewed a number of cases that have been presented at this meeting last year and this year as well as other cases. What I see consistently for people, who again are not Type 1s, that are clearly Type 2s and don’t have other precipitating or contributing factors is that their A1Cs tend to be very high. They tend to be higher than 12.5. That’s part of the reason that the DKA really was not seen to any great extent in the registrational trials, because they didn’t allow patients with A1Cs that high to be in the studies. These were people that had high blood sugars, they were started on an SGLT-2 inhibitor without insulin and there may be some cases where they are started on just a little bit of insulin, but generally it’s without insulin and then went into DKA. I had such a patient. Again, it wasn’t my patient that I started on an SGLT-2, it was someone else. But I ended up taking care of it because I see 200 to 300 patients with DKA in the hospital. I’m actually one of the endos that still goes to the hospital and does critical care medicine. The main point is every time I look at a case where DKA has occurred, usually it’s an exercise in bad medical practice. Someone with an A1C that high, above 12.5, needs to be on insulin. They should have been started on long-acting insulin either prior to being started on an SGLT-2 inhibitor or at the same time. In my practice we strongly consider long-term insulin therapy in combination with oral therapy for anyone who has an A1C up above 9 to 10, depending on the situation. Certainly above 12.5 we would start long acting insulin. We wouldn’t be starting them on anything else without an adequate amount of long-acting insulin. So if you’re practicing good clinical medicine, consistent with the guidelines that are out there, I don’t think we would see this as an issue at all. The problem is, out in the real world, we do have doctors that are doing things that aren’t always the best practice in medicine and that’s where we seeing the issue.
Steve Freed: You said how many cases of DKA do you see?
Dr. Sloan: I see about 200 – 300 a year, in that range. I’ve been doing this for 29 years now. Considering that these days most endocrinologists go into the hospital, I doubt there’s very many endos out there that see as many DKAs as I do, year in and year out. I’ve only seen one where I consider true episode of SGLT-2 associated DKA since the drugs have been on the market.
Steve Freed: How many since then?
Dr. Sloan: Just one.
Steve Freed: Just one. All this talk is really a lot of talk about something that there’s more important things to look at because it doesn’t happen that often. Would you consider it rare?
Dr. Sloan: Yeah, I would say, again there’s Type 2 and there’s Type 1, and we’ve talked a little bit about what I consider the appropriate use in Type 1. We look at where the drug, if prescribed appropriately, that is it has an indication in the Type 2 market right now, it’s pretty rare. For somebody who actually has Type 2. Now there are people that are getting the drug that have been misdiagnosed as Type 2 when they’re really Type 1. In general, this is a fairly uncommon problem from what I’ve seen from looking at the data that is out there.
Steve Freed: And yet there has been so much written about it, especially just recently.
Dr. Sloan: We do want to encourage good clinical care and good clinical care would be starting insulin at the appropriate time and good clinical care would be if somebody comes into the hospital who is, which is the other group, the group that has Type 2 with contributing factors, somebody comes into the hospital and they’re septic or have pancreatitis, they may be on a vent or they may not be on a vent, they’re not eating or they’re unstable, they need to be on IV insulin. It’s not putting them on oral medications like an SGLT-2 inhibitor. Again this is just another exercise in bad clinical practice. So, in some ways it’s good that we talk about that, because we talk about things and educate doctors, hopefully not necessarily the ones that are coming to this meeting that we think are all hopefully good practicing endocrinologists, but a lot of the primary care out there or doctors that are coming to the hospital and seeing patients. What is good clinical care? So that these patients can get recognized and they have DKA and get treated appropriately. We have better outcomes.
Steve Freed: You haven’t seen a patient with Type 2 on SGLT-2s that blood sugar, it wasn’t euglycemic, basically it’s going to be higher than the over 200 range?
Dr. Sloan: I have not. Again, I’ve only seen that in one case, this person’s blood sugars were in the 300s when they presented. They were more like what you would expect to see with the classical DKA. Most of the cases that I’ve reviewed that others have seen is, it’s the same way. I think it’s more the Type 1 are that you see this euglycemic type of picture. Again, I’d like to say that all the Type 1s where I’m at are being seen by me, but an awful lot are. I’m very selective if I were going to go off label and use this medication. I have not had any of my patients that were Type 1 develop DKA based upon using the drug the way I talked about before which would be off label. It’s just really been that one case in the Type 2 that I got called to see in the ICU when they were admitted with DKA.
Steve Freed: If you were talking to a group of family practitioners that have a lot of diabetic patients, and they’re concern was using a new drug. We don’t know what the 30 year results are or the 20 year results or even the 8 year results. It may take 5 years before doctors get comfortable prescribing an SGLT-2. And then we get these headlines, DKA, major problems. Now they’ve backed off a little bit more. I always find that, in the same way, I don’t know if you remember Resulin? It was pulled off the market for reasons that were actually not true because the doctors weren’t following the protocols in taking the certain diagnostic test. It was a good drug. At least I think so, if you follow the protocols. I think this is kind of in that same area where, except the government’s not going to take it off because we’ve seen some great, positive results. I think it’s a damage to the medical community that scares doctors from writing this prescription. I can’t tell you how many times I’ve seen on television, if you’re on these certain drugs, Invokana, SGLT-2s, call us we have a great lawsuit for you. You’re telling us that you don’t see that many of them. In your experience you’ve only seen one case. What would you tell the family practitioner to make them feel more comfortable that this is something that you should consider in that category of drugs?
Dr. Sloan: First of all, I think the Resulin thing was a completely different scenario. I would tell them that these drugs have just tremendous advantages in reducing cardiovascular risk factors. They lower blood sugars, they lower weight, they lower blood pressure, and they do a number of other things I won’t go into. They’re also inhibiting sugar from getting into the renal interstitium, which is where it can stick to proteins and result in advanced glycosylation end products and develop inflammation interstitial fibrosis and lowering kidney disease. The main point is that it’s keeping the sugar out of the kidney and making it go into the toilet bowl, where it can’t do any harm to the body. So in general these are safe drugs, they’re not for everybody. Not everybody has the kidney function, there are some problems with mycotic infections and UTIs, potentially. For the overwhelming majority of patients these are wonderful drugs that I think we’re going to continue to see just incredible data come out over the next few years, which is my prediction, mechanistically. If they’re practicing good clinical medicine, starting insulin particularly when people’s A1C’s are above 9 to 10 and certainly above 12.5, and doing everything else on label, which is again not starting a person on a drug when they’re dehydrated. They need to not be intravascularly depleted. Then the risk to the patient is very low for DKA. It’s really very low for other things too. There is, like anything in medicine, there is an art to using these drugs, as there is an art to taking care of diabetic patients. I think this is a very exciting and important class of medications.
Steve Freed: We talked about Type 1s and SGLT-2s. We talked about Type 2s and SGLT-2s. I think that’s where it’s really exciting, you haven’t mentioned it yet. That’s cardiovascular disease. It used to be we only looked at A1C and blood sugar levels. That’s how you treat a diabetic. If you want to prevent the complications from diabetes, you really need to lower their A1C to a level that’s individualized for all the patients. Now, we’ve found out, here’s a drug that not only lowers your blood sugar, lowers your blood pressure, reduces your weight, and on top of that it lowers your risk from dying from the disease that most people die from with diabetes. I think they should be putting SGLT-2 in the water. It would be too expensive. So, it’s kind of like shifting paradigms. It was always about blood sugar, number 1, but now if you have a drug that could prevent death, that’s more important I think than controlling blood sugars almost, certainly you have to look at both. It’s an exciting paradigm shift that we should be looking at the end result. What are your thoughts on that?
Dr. Sloan: I agree, I like the enthusiasm. I’m not so sure with putting it in the water yet. Again, I think it’s a very exciting area and as we get more data, I hope that we will see new indications for this medication, which maybe will be for cardiovascular risk reduction and renal protection. I think that there may even be a group whose estimated GFR is below, I’m talking about the 30 to 45 area where the blood sugar lowering is not that much but nevertheless the drug’s actually maybe renal protective and cardiovascular protective. Down the road, just like with ACE inhibitors we consider them for people over the age of 50, even with good blood pressures, to reduce cardiovascular outcomes, again not using the drug for blood pressure but for cardiovascular wellness. There might be even a group in here that we might consider these drugs for reducing certain outcomes in the future, besides just lowering blood sugar. I think it’s a very exciting area that we’re all looking forward to the new studies coming out.
Steve Freed: I want to thank you for your time I know you have a busy schedule. Certainly enjoy the rest of your time here. I want to thank you again for taking some of your time to talk to us and educate other medical professionals. Thank you.