Cardioprotective Treatment Options for Diabetes - Episode 9
Keith C. Ferdinand, MD, FACC, FAHA, FASH, FNLA: One of the questions that we look at is that most of these studies were done in patients who were very high risk or had documented atherosclerotic cardiovascular disease.Suppose the person hasn’t had a heart attack, doesn’t have carotid disease, doesn’t have peripheral arterial disease but is just a higher-risk patient. Now, this is maybe outside the true label because the label is for persons who have atherosclerotic cardiovascular disease to show these benefits. Do you think the other patients would benefit? Melissa, what do you think?
Melissa L. Magwire, RN, MSN, CDE: I do, just because of some of the other effects that we’ve talked to, that the main reasons these drugs were developed were for the change in glucose levels. But we do see weight loss with most of these medications, especially with the GLP-1 [glucagon-like peptide-1] receptor agonists. And we all know that that belly fat and that insulin resistance and adiposity is a huge risk factor in and of itself, so I think not only getting the glucose down but the weight down as well. And those 2 classes, the SGLT-2 [sodium-glucose cotransporter 2] inhibitors and GLP-1s, as you know, are very low risk for hypoglycemia, which is something we do worry about in our cardiac patients.
Keith C. Ferdinand, MD, FACC, FAHA, FASH, FNLA: That’s a good point with the hypoglycemia, and I’m going to come right back at you on that. But let me revisit what I asked. So the person hasn’t had a heart attack, a stent, peripheral arterial disease, or a stroke. Do you still consider these medications?
Melissa L. Magwire, RN, MSN, CDE: I would still consider it. I know it’s not in the label specifically for that, but both of these medications are in the ADA [American Diabetes Association] and AACE [American Association of Clinical Endocrinologists] algorithms for the treatment of type 2 diabetes. And we know that our patients are at risk, and we know that these are effective classes of medications that will do what we want them to do as far as maintaining glycemic control, and a little bit of weight loss, and a little bit of blood pressure. So I don’t see a reason for not using them.
Keith C. Ferdinand, MD, FACC, FAHA, FASH, FNLA: Now we’ll go back. You said there was no risk of hypo, h-y-p-o, low glucose?
Melissa L. Magwire, RN, MSN, CDE: Exactly. Unless it’s in combination with a secretagogue or insulin, both GLP-1 receptor agonists and SGLT-2 inhibitors don’t inherently drop the glucose on their own to a hypoglycemic level. Certainly, if you’re adding it in addition to a sulfonylurea on board or someone with basal insulin on board, you need to cut that back. But I know that you can prescribe a GLP-1 to a patient and have a very, fairly low risk of hypoglycemia as long as there’s no secretagogue on board.
Keith C. Ferdinand, MD, FACC, FAHA, FASH, FNLA: All drugs have adverse effects, so SGLT-2s—and we’re going to go into the GLP-1s next, but let’s stick with the SGLT-2. What kind of adverse effects do you tell your patients about?
Melissa L. Magwire, RN, MSN, CDE: So we talk about really watching for orthostatic blood pressure changes, really making sure patients know the symptomatology of that—that if you stand up too quickly, are you getting too busy or are you getting weak or fatigued—to make sure they report that to avoid dehydration. And then of course there’s the genital mycotic infections, and we talk about making sure that you pay special attention to hygiene, especially if you’re a female patient who is prone to UTIs [urinary tract infections] or yeast infections or uncircumcised males as well. So we do have to touch on that just to make sure the patients are aware of those things.
Keith C. Ferdinand, MD, FACC, FAHA, FASH, FNLA: Peter, you would think we probably—despite its benefit for heart failure, benefit for protection against progression of CKD [chronic kidney disease]—need to be careful with over diuresis of the persons on high-dose loop diuretics. And you add the SGLT-2, and you may get some of the complications that Melissa just mentioned.
Peter McCullough, MD, MPH, FACC, FACP, FAHA, FCCP, FNKF: You know, that’s been my experience. I’m almost to the point of just automatically cutting the existing diuretic regimen down when I start 1 of these drugs because there’s such a predictable diuresis. And I do agree that there’s kind of an initial adjustment phase that patients go through on these drugs, and it’s about 3 months in which—this is isn’t the type of drug one can prescribe and say, “Oh, see me in 6 months.” I really think patients need to be followed up, and invariably one will see some volume contraction and a slight increase in BUN [blood urea nitrogen] and creatinine, one can see a slight increase in hematocrit with this. And we have to make some adjustments to baseline diuretics. There are some patients who actually come off their thiazide diuretic when they go on this class of drugs.
Keith C. Ferdinand, MD, FACC, FAHA, FASH, FNLA: We have empagliflozin, canagliflozin, dapagliflozin. The dapagliflozin was a mixed bag. I don’t think it had the same great outcomes that we saw with the first 2. Now, I’m not saying that the medication was inherently different, but the study, DECLARE-[TIMI58], did not really show the same level of outcomes. Why would that be, Chris?
Christopher P. Cannon, MD: Well, they did move in a big way to include many patients without prior atherosclerotic cardiovascular disease. So they did have sizable number, of roughly 7000 with disease, but 10,000 without. And the MACE [major adverse cardiovascular event] effect was that there was no reduction in cardiovascular death, MI [myocardial infarction], or stroke in those without prior disease of the primary prevention group, and that probably led to some of the lack of big benefit. But all the trends were the same. In those with known disease, it wasn’t statistically significant but the same idea in the meta-analysis of reduction, about 15% or so. There’s another—ertugliflozin is the fourth agent, and that trial is still ongoing to finish up at the end of the year. So we’ll get even more data coming to understand this class. Then a series of trials in these other areas. In kidney disease, CREDENCE will be out later, in a month or so. But then other agents have kidney-dedicated diseases and then a series of trials in patients with heart failure. So the benefits that we’re seeing now are being formally studied in nice trials, so that we’ll get much more understanding of how to use these properly and safely.
Peter McCullough, MD, MPH, FACC, FACP, FAHA, FCCP, FNKF: I wanted to point out, though, in the DECLARE-[TIMI58] trial with dapagliflozin, that the event rates in the placebo group, when compared with the placebo group in empagliflozin or canagliflozin trials, the events were about half. And I think a big factor that played into this was renal function at baseline. With dapagliflozin, they were following the current prescribing information at the time, in which patients with estimated GFR [glomerular filtration rate] below 60 mL/min weren’t entered into the DAPA trial, where some patients lower than that.
Christopher P. Cannon, MD: Yeah.
Peter McCullough, MD, MPH, FACC, FACP, FAHA, FCCP, FNKF: And as things have changed now, we’re realizing that the renal risk is a risk, not only just for progression of kidney disease but…cardiovascular risk. So at lower levels of renal function, then these cardiovascular risks amplify, and the effects of the drugs can be seen.
Keith C. Ferdinand, MD, FACC, FAHA, FASH, FNLA: Chris, I’m going to ask you now to go over the GLP-1 agonist outcomes. But before I do that, I’m going to ask Seth and Melissa: SGLT-2s, you want to give us 2 take-home points in how you feel these drugs will be used going forward?
Seth J. Baum, MD, FACC, FACPM, FAHA, FNLA, FASPC: Well, yeah, I think the drugs should be used very, very frequently. I agree with Melissa that there’s no reason to have to restrict oneself to the PI [protease inhibitor] for established cardiovascular disease because they’re already approved diabetic medications. So I think we need to embrace them. I was concerned about Fournier’s gangrene, just in terms of frightening people. It’s so incredibly rare, yet I thought people would be so frightened that they would stay away from the SGLT-2 inhibitors. And I wanted to ask you, in your practice actually, if you don’t mind, have you seen that?
Melissa L. Magwire, RN, MSN, CDE: We really haven’t, and I think we’ve also seen fewer UTIs and yeast infections because I think we were aware from the onset to start educating patients and not wait for that patient to come back to us and say, “Hey, I’ve got a really bad UTI.” I also think we’re a little bit choosy. If I have a female patient whose blood sugar levels are 3 or 400 mg/dL, and I know they’re really going to be having a lot of glucose in the urine, I might pull their blood sugar down before adding an SGLT-2 inhibitor to it. I think just really having that forethought of where to start the drug and when can mitigate some of the adverse effects. But as you said, I think a really good class of medication is when you get kind of a double bang for your buck; that’s how I see it. You get really good glycemic response, weight loss, and then that cardioprotective effect.
Transcript edited for clarity.