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SGLT-2s and Evidence-Based Medicine

Part 2 of an exclusive interview from AACE 2016. Click here for Part 1 | Click here for video

Steve Freed: So, let’s change the topic. I consider you a very aggressive physician. What I mean by that is you’re not afraid to use new therapies if they’ve been proven safe and efficacious. We had talked about your thoughts on SGLT-2. Most physicians think it’s a whole new paradigm because it also prevents cardiovascular issues. But recently in the news, we’ve seen that all of a sudden DKA is more prevalent in people that take SGLT-2s even with close to normal blood sugars for Type 2s and the other thing that just came out within a matter of a week ago, that it increases the risk for losing your toes. What do those issues have to do with your using it with patients? If anything?

Dr. Schwartz:  So, I’m going to get there in a second. But you touch on a rant that I have to give. I’m aggressive with logic, I don’t believe that evidence-based medicine, the way it’s applied– it says if you don’t have the evidence, keep doing the same lousy thing you’ve been doing for 20 years, that’s sulfonylureas use, early insulin use with its weight gain, hypoglycemia. People say they don’t see hypoglycemia with it, but guess what, we know that people who wear continuous glucose monitors, sulfonylurea insulin, half the time they don’t even recognize the low sugars. It’s always underestimated. You see the same mistake all over. Everybody says no hypoglycemia, but guess what, they have it because they are not measuring it. So I believe in what’s now called, I learned it 40 years ago, but it’s now called “Evidence Based Practice”. If there’s evidence, certainly I’m going to use it, but a lot of times the patient in front of you doesn’t fit the patient that was in the studies. So I’ll use the evidence that exists. If it doesn’t exist, I was taught how to ‘think diabetes’ by Dr. Rubenstein, University of Chicago- what he told me is understand pathophysiology, read the primary data that comes out, get early experience, and if it makes sense, go out and teach. That’s my approach, so specifically with SGLT-2 inhibitors, the DKA story was just reviewed here today at AACE and it comes down to the same principle. If you use on label, the risk of DKA in Type 2 diabetes which is on label, is .05%. Five in 10,000, compared to a benefit of 38% reduction across the board in reducing cardiovascular mortality, 35% reduction in heart failure. It’s an easy decision. We’ve learned who are the people that are more likely to get it. They’re having an acute situation, a heart attack, a stroke, or another major stress, which increases glucagon, which by the way SGLT-2s can decrease, and by the way, we’ve learned that some physicians were reducing the insulin too much as they start the SGLT-2. So we’re reducing the insulin a little bit to avoid hypoglycemia, we’re not reducing it a lot. We’ve learned, basically, that you have the same common precipitants. You have people that are more susceptible, eg: some of the Type 2s have islet antibodies. We know how to assess that, we know how to pick the patients and follow to reduce the risk of ketoacidosis. The toe amputation story, nobody has come out with a theory, as scientists, I can understand where they’re living. On the other hand, I’m a clinician, I have to understand it in my own head, why I think they saw increased toe amputations. We know that this class of drugs has an osmotic diuresis and a potentially sudden reduction in intravascular volume, it can lower blood pressure. We’ve taught all along since the beginning, advise a patient that you hand them the script, drink more liquids, if you’re on diuretic, maybe I’ll get rid of the hydrochlorothiazide, if you’re on a loop diuretic, I might cut back on the furosemide, if you’re on two antihypertensives, I might get rid of one of them. If you’re on just an ACE inhibitor, I might stop it and start this, because it reduces pressure and reduces microalbumin. So we know about the volume issues. My interpretation of the toe amputation, it’s a volume issue. You take people, all these people have prior toe amputations, so we know they have reduced arterial blood flow to their limbs. They’re losing volume. So if you have a sudden reduce in volume, in an arterial compromised limb, maybe they haven’t had the surrogates affected, there’s your increase in toe amputation. So typically in this regard the media has overextended the importance of that finding, and guess what, it’s preventable given the logic that I’ve just given you.

Steve Freed:  So, why is it that you don’t think that most physicians write a prescription but they don’t tell their patients that they should be increasing their volume of fluids?

Dr. Schwartz: You have another one of my biases, and I’ll put my neck out, is because A) the companies haven’t really taught it, they should, but the common answer that I get from the companies is unless you study every single statement you put in a patient education piece, the FDA doesn’t let them put that statement in the patient education. So they’re not allowed to put a statement “you must drink more”. They’re not allowed to put in the statement “have fastidious bathroom habits” because they haven’t studied it.  If the company was permitted to put in the literature to drink more liquids, then the risk of the vast majority of the side effects of this drug class could be addressed.

Steve Freed: Drinking more fluids also is going to help prevent DKA, won’t it?

Dr. Schwartz: Potentially yes.

Steve Freed:  My last question is: you’re here at AACE. I presume you’ll be at ADA. What are you looking forward to as far as some exciting news coming out, either at this event or the one at the ADA?

Dr. Schwartz:  This event is overall education. So if you’ve missed some loose stuff in various aspects of endocrinology, let alone in diabetes, this a good place to get it and hear it from the experts. ADA is a little more new science based. What I’m looking forward to there, the most prominent thing is the results of the Leader Study, that’s the randomized perspective controlled trial in using liraglutide in cardiovascular outcomes. It’s been announced publicly, it reduces cardiovascular outcomes. Now we want to see the data and be convinced completely. That’s going to be the most exciting thing in that regard. Then there’s another GLP-1 study, cardiovascular outcomes are said to be positive, that will be announced at the EASD, in September in Munich. That’s semaglutide, not released yet, but to have a cardiovascular benefit potentially with new release of a drug, or approval of a drug will be even more exciting. We’re always learning things, these are the biggest things that I’m looking forward to.

Steve Freed: It’s kind of strange that over the last five years we’ve found these other drugs that can reduce cardiovascular events.

Dr. Schwartz:  Well, Dr. Nissen, reminded us that he was one of the key people who encouraged the FDA, not only to study a drug for its glycemic benefit but by cardiovascular. So, by his push and the FDAs push, let’s look at the cardiovascular benefits or risk of new drugs for diabetes, the surprise was, not only do we find some drugs that we’ve now thrown away that had risk, the surprise is we now have drugs that have benefit. Boy is that wonderful. We have pioglitazone, prospecively, reducing stroke and MI in people with insulin resistance and prediabetes; we have the EMPA-REG study last year; we have the Leader coming up, the semaglutide. We have the bromocriptine-quick release study. That was randomized perspective, you just need another one to confirm it, but within one year, a 50% reduction of cardiovascular outcomes. By the fact that the FDA put into place,rules to make sure new DM do no harm, and guess what, we found now diabetic drugs can be the cardiologist’s best friend. We now have classes that can reduce cardiovascular outcomes.

Steve Freed:  So, with Dr. Nissen, we have to ridicule him for the Avandia, getting that taken off the market, by misinformation.

Dr. Schwartz:  Well, actually I disagree with that.

Steve Freed:  But in the same tone we have to thank him because of the cardiovascular risk, we’re finding these benefits.

Dr. Schwartz:  I stopped using rosiglitazone right after pioglitazone came out, because there was such a clear difference that worried me. Rosi had adverse lipid profile, pioglitazone had a positive lipid profile. I had a heart attack about the same time. I didn’t want to use the Rosi in myself or anybody else. I actually think he did us a service.  A greater service, even if there’s a debate there. He did us a greater service because he got the FDA to say let’s evaluate cardiovascular outcomes in patients with diabetes.

Steve Freed: I want to thank you for your time. It was very interesting conversation. Looking forward to seeing you at ADA. Enjoy the rest of your time.

Dr. Schwartz:  Thank you so much for having me.