Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. Narrator - ? 00:11 This podcast is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice, and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk episode 103 I'm your co‑host, Dr. Kane, and I'm Dr. Patel, and the title of today's episode is: how can peeing sugar improve heart failure? No one knows, but we know it works, Dr. Khyati Patel 00:43 yes, and we're going to talk all about it today. P, sugar. Dr. Sean Kane 00:47 And really what we're talking about is a new trial that was published in the New England Journal of Medicine — the DAPA‑HF trial (published Sept 19) — and it was looking at dapagliflozin (brand name Farxiga), which is typically a diabetes drug, and it was actually studied in both diabetics and non‑diabetics for the treatment of systolic heart failure. Dr. Khyati Patel 01:07 And so, kind of a refresher for our audience — what is dapagliflozin and other SGLT2 inhibitors. So we have covered this topic in our previous episodes (16 and 35). The main SGLT2 agents are: Invokana (canagliflozin), Farxiga (dapagliflozin), Jardiance (empagliflozin), and Steglatro (ertugliflozin). Dr. Sean Kane 01:31 And you know the mechanism of this fairly novel drug class. They're called sglt, two inhibitors, and they basically inhibit glucose reuptake in the proximal tubule of the kidney. So normally, what would happen is the kidney, when it sees glucose in the urine, it reabsorbs it back into your blood. This drug prevents that mechanism from happening, so literally, you pee out extra sugar. Dr. Khyati Patel 01:52 And that threshold, I believe it's about somewhere between 70 to 90 milligram per deciliter, correct, exactly. Dr. Sean Kane 01:57 And that's actually one cool thing about the drug — it doesn't make you hypoglycemic because it doesn't work when your glucose gets too low. It only works when your glucose gets above that 70–90 mg/dL threshold in terms of causing glycosuria. Dr. Khyati Patel 02:10 It's kind of like an automatic switch that goes off saying, Oh, I'm detecting too much sugar. Time to pee that off. Dr. Sean Kane 02:15 Yeah. And now, if you just think about it, knowing the mechanism that actually helps inform some of the side effects that we observe. So for example, it causes dehydration, because as you're peeing out that sugar water will also go along with that sugar, and that can lead to dehydration, hyperkalemia, acute kidney injury and very severe cases of dehydration. But again, for a typical patient, as long as they stay hydrated, this is a manageable side Dr. Khyati Patel 02:38 effect, right? And the other side effect, we don't call it a side effect. Maybe it's helpful, especially for our patients with diabetes, is weight loss, and a lot of this weight loss is coming from maybe the water weight, but also caloric weight, because you're not retaining all that sugar. Dr. Sean Kane 02:51 And then, of course, you're going to pee a little bit more with this drug. So increased urination does have kind of a diuretic like effect to it, as we talked about. Dr. Khyati Patel 03:00 And then peeing sugar. Again, that bladder is holding a lot of sugar, so genitourinary infections — such as UTIs or genital mycotic (yeast) infections — are very common in female patients taking these drugs. Dr. Sean Kane 03:13 And as we mentioned, on its own, this drug does not cause hypoglycemia. Now you can get increased risk of hypoglycemia if you normally take a diabetes medication like a sulfonylurea or insulin, you initiate this drug, and you didn't really adjust your initial sulfonylurea well enough. Now that you have a new diabetes agent, of course, your risk of hypoglycemia goes up, but the drug itself is not causing that hypoglycemia. Dr. Khyati Patel 03:37 You're right. And so those were, in summary, more common side effects of this class. Post‑marketing reports have included bone fracture or bone loss and euglycemic DKA. Fournier's gangrene (necrotizing fasciitis of the genital/perineal area) and lower‑limb amputations have also been reported — the latter noted in the CANVAS (Invokana) program. Dr. Sean Kane 04:07 We should be really clear, these are rare but serious side effects measured in like the very small numbers, right? So these are a fraction of the percentage of patients who are taking these drugs. But they're also really scary side effects. Fournier gangrene is extremely severe and can be life threatening as an example. So this is something that we should be aware of, but also should know that it's a rare side effect of these Dr. Khyati Patel 04:27 drugs, correct. So switching gear from safety, let's talk about the efficacy, especially efficacy in heart failure. So where is the idea of running this child for a diabetic drug in patients with heart failure coming from Yeah, yeah. Dr. Sean Kane 04:40 And I'll be honest with you, Dr. Patel, when I saw this published in the table of contents of New England Journal of Medicine, I was flabbergasted. I had no clue that they were even studying diabetic drugs and non diabetic patients with heart failure. And basically, this came from the fact that in these phase three trials for all of these sglt Two inhibitors, they. They did look at heart failure hospitalization. So they looked at a heart failure endpoint, and only about 10% of the patients in many of these phase three trials for sglt, two inhibitors, only about 10% of the time they had heart failure patients. So 90% of these patients did not have heart failure. And yet we did see improvements in heart failure hospitalization — typically about a 30% relative reduction. So we're looking at EMPA‑REG, CANVAS, and DECLARE‑TIMI 58 — the landmark trials for the major SGLT2 inhibitors — and in the case of empagliflozin (EMPA‑REG) there was an all‑cause mortality benefit as well, presumably from cardiovascular effects including heart‑failure benefit. Dr. Khyati Patel 05:41 yeah, and that's what's been speculated in the world of diabetes too, is how do these drug help? And you know, that's probably that diuretic mechanism that's coming into play. So I guess on the basis of this reduction in heart failure, the next logical step for the companies were to see what's the benefit in patients who have heart failure. Yeah. Dr. Sean Kane 06:00 I mean, and if you think about it, if I was an executive designing this clinical trial, I would say, Okay, let's find some diabetic patients who have heart failure, and then let's see if we can prevent heart failure hospitalization, like we saw as a primary prevention strategy in these original trials, except plot twist. They didn't just include diabetics, but they included non diabetic patients as well. And I think this is a really major pivotal point for this drug class, because now this isn't just restricted to diabetic patients anymore, right? Dr. Khyati Patel 06:27 So when we again talk about SGLT2 inhibitors in patients with heart failure but without diabetes, where are we getting the benefits from? So again, we talked about the diuretic effect, correct? Dr. Kane, yeah. Dr. Sean Kane 06:40 So you know, as you waste any glucose, and again, the threshold is around 70 to 90 milligrams per deciliter. So any glucose above that, you will start peeing out some sugar and water. So if you have heart failure, maybe you get some diuretic effect out of that. With that said, though, if you don't have diabetes, the degree of diuretic effect probably won't be very substantial, because you're not wasting that much glucose in your urine, so presumably it can help with your blood pressure, your edema, if you have heart failure, but really, if you don't have diabetes, you wouldn't expect this to be a profound effect versus, let's say, Lasix, which does have a profound effect with edema, right? Dr. Khyati Patel 07:19 So this might be just a little bit of augmentation of that diuretic effect that your loop diuretics are already giving it Dr. Sean Kane 07:26 to you right now, if you look at the DAPA HF trial in the manuscript, they do go through some other proposed mechanisms, including effects on, quote, myocardial metabolism, ion transporters, fibrosis, adipokines and vascular function, and I'll be honest with you, yes, they have citations. Usually, when a paper goes through a multitude of different proposed mechanisms, it usually means we have no clue exactly what the mechanism is. There's a lot of proposed mechanisms, but this kind of goes back to like the pleiotropic effects of statins, right, right? So LDL reduction may be a component of it, but there's probably other stuff going on that we don't even really appreciate. And to be fair, it might not even matter, as long as we know it's helpful, right? Dr. Khyati Patel 08:10 So let's talk about the DAPA HF trial. So again, like Dr. Kane said, it was published in September 2019, so it's just off the press. It included patients with systolic heart failure. They were looking at ejection fraction of less than 40% less than or equal to 40% and symptomatic heart failure. NYHA class two, three and four patients. So these were patients who had symptoms, you know, at some exertion or a symptom at rest, which is what the class four means Dr. Sean Kane 08:41 they also mandated that patients had to have elevated NT pro BNP levels, this is a serum biomarker of heart failure, and the threshold depended on some different factors that honestly aren't that relevant to this discussion. And then finally, all of these patients had to be receiving standard CHF drug therapy. So we're talking about ace ARB or Arni. Arni would be like ENTRESTO, a beta blocker, and they didn't mandate it as part of their inclusion criteria, but they did highly encourage the use of an aldosterone antagonist for the systolic heart failure. Example would be Spironolactone. Dr. Khyati Patel 09:15 And so those were inclusion criteria. Looking at the exclusion criteria, they kind of excluded people who had unacceptable side effects of sglt, two inhibitors. So we're looking at, you know, having history of genital Mycotic infection, yeast infection, or UTIs. And this will probably help with the, you know, the side effect profile in this study, which we're going to talk about it in little bit Dr. Sean Kane 09:38 for sure. Yeah, you know, another exclusion was you could not have type one diabetes, and it's really important that they did not mandate that you did or did not have type two diabetes. They basically included you regardless of your type two diabetes status. And as we'll talk about, about 40% of the trial had type two diabetes. 60% did not have diabetes at all. But they did exclude type one diabetes. Dr. Khyati Patel 10:00 And I think this is for a reason, because the post marketing data showing the EU glycemic DKA risk and patients with type one diabetes might be at a higher risk Dr. Sean Kane 10:10 and really consistent with the packaging you were excluded from the trial. If you had hypotension, these drugs cause a diuretic effect, and they can make you more hypotensive. So that makes sense, and also, if you had an eGFR less than 30, again these can cause acute kidney injury and dehydration. You're at higher risk for getting worsening AKI if you already have some degree of renal impairment. So they also excluded those patients as well. Dr. Khyati Patel 10:35 So looking at how the treatment groups were divided, they put patients on standard‑of‑care heart‑failure therapy. One group received dapagliflozin 10 mg once daily, and the other group received placebo. If they had AKI, dehydration, or signs of low blood pressure, the dose of Farxiga (dapagliflozin) could be reduced to 5 mg per day. Dr. Sean Kane 11:03 Dr. Patel, when I look at a trial that uses especially Diabetes drugs, and we've seen this with weight loss for the GLP‑1 agonist, I always like to compare the dose that they're using for diabetes versus the dose that they're using for this non diabetes indication. So 10 milligrams of far siga, how does that compare to a patient who is starting that for type two diabetes? Dr. Khyati Patel 11:24 Normally, we start out with five milligrams a day for a diabetes patient, and then looking at their glucose control, A and C, will increase it to 10 milligrams per day as necessary. So it's kind of interesting to see this trial put them on 10 milligrams to begin with, Dr. Sean Kane 11:36 yeah, and again, if we look at the weight‑loss data — that's a different topic — they also picked higher doses. With GLP‑1s, for example, higher doses produce more nausea as a side effect, so it makes sense they sometimes pick larger doses. Kind of interesting here that they chose 10 mg even though non‑diabetics might have been expected to respond at 5 mg. Dr. Khyati Patel 12:01 So let's look at who was included in the study. This study enrolled about 4,744 patients at 410 centers in 20 countries. Seventy‑five percent of these patients were men. That is relevant because fewer women were included — UTIs and yeast infections are more common in women. Dr. Sean Kane 12:27 we saw, you know, the majority were Caucasian or white, 70% they only had 5% black and 24% Asian. So Asians were actually disproportionately higher than what you would see in the US patient population. Now, in this case, that 5% African American cohort is interesting because we do have drugs that treat heart failure, like vasodilators, isosorbide and nitrate with hydralazine, that do tend to work better in African Americans versus non African Americans. So there may be some implication there. It's something to be noted that is a potential weakness of the trial, but isn't also a deal breaker either. Dr. Khyati Patel 13:01 And then looking at the New York Heart Association (NYHA) classes: two‑thirds of the patients were in class II (slight limitation in physical activity); one‑third were class III (marked limitation in physical activity); and the remainder were class IV (symptoms at rest). Dr. Sean Kane 13:23 and it's really difficult to study class four patients. If they include them as part of their inclusion criteria, that's fine, but almost always they're, like, less than 5% or less than 1% of the study population, because, honestly, their mortality is so high and they're really difficult to study. So typically, for any of these symptomatic heart failure trials, we do see class two and three, and that's just kind of how it's always been. Dr. Khyati Patel 13:44 And we discussed earlier that type one patients were absolutely excluded from the trial, but they didn't have any pick or choose between. They had type two or not. So 40% of the study population ended up having type two diabetes. So 60% of the patients did not have diabetes. Dr. Sean Kane 14:00 And again, if I was to design this trial, if I was the executive of the company that owned this drug, I probably would have done a diabetes only trial first, basically because it seems like a layup shot. This seems like a longer shot. Maybe they had other data that we're not aware of, but the fact that they went out out the gate and said, We don't care how many type two diabetics we get, or how few we get, we're still going to go along with the trial. I think that's notable. In terms of the heart failure regimen, as we said, the protocol mandated to be included, you had to be on ace Arbor Arni and a beta blocker. And actually, the vast majority, even though it wasn't mandated, the vast majority, were on aldosterone antagonists. Now with that, said the manuscript, and even the supplement only talks about yes, no, were they on these drugs or not? They don't talk at all about whether they were at Target doses or near target doses or the mean doses of these agents. And we know, based on heart failure literature, that you do have to titrate up these agents. You can't stay on Coreg 3.125 mg and expect the same benefit. For heart failure, patients are often titrated up to 25 mg BID of Coreg, right? So that is one limitation of the trial — we don't know how optimized the baseline CHF regimen was, and if it wasn't optimized whether we'd still see an additional benefit from dapagliflozin. Dr. Khyati Patel 15:17 And that's that's a good point to notice. But then I'm looking at more of the clinical picture too, and how many patients in clinical life are titrated optimally on on those heart failure medication the way they're supposed to, or the way the these drugs were studied in the clinical trial. So perhaps maybe we're looking at the real world application when we say maybe they were titrated, or maybe they were not titrated. Dr. Sean Kane 15:40 That's a great point. Dr. Patel in terms of the results of the study. So the trial ran for a median of 18 months. In terms of efficacy, the primary endpoint was worsening heart failure, which meant that you were hospitalized for heart failure, or you had an urgent visit for IV drug therapy for your heart failure, which typically is going to mean an emergency department visit, and you just don't make it as an admitted patient. So we're saying "worsening HF" — we'll just call it heart failure hospitalization or ER visit, or cardiovascular death. So you die of a cardiovascular reason. And with this primary endpoint, it was 16.3% with dapagliflozin versus 21.2% with placebo. So roughly a 25% reduction with the number needed to treat of 21 for this primary composite endpoint. Dr. Khyati Patel 16:24 Heart‑failure–related hospitalization was 9.7% in the dapagliflozin group versus 13.4% in the placebo group (NNT 27; p < 0.05). Cardiovascular death was 9.6% with dapagliflozin versus 11.5% with placebo (NNT 53). All‑cause mortality also favored dapagliflozin (NNT 42). Overall, the results favored dapagliflozin. Dr. Sean Kane 17:05 So both the composite and the independent end points were all in favor, right? They also did a CHF symptom questionnaire where they basically asked patients how their heart failure symptoms were and not to get too much into the weeds, but globally, it appears that there is some symptom improvement. You can kind of argue back and forth based on what endpoint you select, whether it's a did you have a clinically meaningful change? Yes or no, and that in that case, there was a significant difference, but the mean points between the two groups was actually not clinically significant, so they did meet the p value for significance, but the numerical difference in terms of their point value improvement was not clinically different because the threshold was five points, and it was only about three points of difference in terms of their symptoms as a mean change over time. Dr. Khyati Patel 17:51 And maybe this data did not differ between the two groups, and it's fine, but it's kind of interesting to see a clinical trial include sort of that humanistic outcome of how patients actually felt after taking the drug or placebo, for that matter. Dr. Sean Kane 18:06 And you could even argue it doesn't matter, right? So if you live longer, unless your quality of life is getting worse, it probably doesn't matter if it improves your quality of life or not. But it is really nice to see that you can talk to a patient about not only will this drug make you live longer, but you'll even feel better by taking this drug. And that's a huge Dr. Khyati Patel 18:24 deal, right? That you will be able to do some chores. You'll be able to meet some life goals if you have, such as, I don't know, run a marathon, which is actually a little bit of a stretch, Dr. Sean Kane 18:33 but yeah, or even play with your grandchildren, right? Exactly. More realistic. Now, for me, the number one subgroup I was interested in was, was this benefit driven by the patients with diabetes? And how did the patients who did not have diabetes fair in terms of, did they get benefit from dapagliflozin or not? That's the number one question that I have in my brain, and you're going to talk about subgroups now. Dr. Kane, of course. So in this case, again, 60% of the trial was non diabetic patients that presumably would not have that robust of a benefit from dapagliflozin, but it turns out that in subgroup analysis, they benefited basically the same amount as the diabetic patients did as well. So there was no clear difference in terms of the degree of benefit for the primary endpoint, which was heart failure, hospitalization or death. There was no big difference in terms of the benefit between diabetics and non diabetics in this trial, which is fascinating to me, that the diabetics didn't receive more benefit in some way, it was pretty much equal between the two groups. Dr. Khyati Patel 19:32 And bingo like this probably is the blockbuster finding that you could consider for a diabetes drug that could be applicable for non diabetic patients like heart failure patients. Dr. Sean Kane 19:44 This was the slam dunk that those executives at the committee probably high fived each other with and said, Wow, we finally did it. We have a diabetes drug that we don't even have to give to diabetics, we can market to everyone, in this case, with heart failure. Dr. Khyati Patel 19:56 And soon enough, we're going to see that change in the guidelines. We'll see. I think so. Dr. Sean Kane 20:00 Okay, and I feel obligated to just mention that there were some other parameters that are interesting to talk about. So blood pressure was slightly lower (≈1.5 mmHg systolic), and body weight was slightly lower with dapagliflozin by about 1 kg — neither of which would plausibly explain the mortality benefit on their own. So clearly, in my opinion, at least the benefit observed was not simply due to lower blood pressure and a slightly lower body weight. Dr. Khyati Patel 20:32 So we kind of alluded that the safety outcomes were a little bit interesting to talk about. So let's dive into on the safety in terms of things. So we talked about the tolerability of the drug and tolerability of the drug, again to our listener, it's about how many patients really stick to the study drug versus how many actually exit the study because of the untolerable side effect, right? So looking at the tolerability, it was pretty similar to the placebo. About 10% for both the drug and placebo taking patient had stopped the therapy or stopped the study, and Dr. Sean Kane 21:05 roughly about 5% of the patients stopped because they experienced the side effect. So some patients are going to stop it just because they don't want to take it. About half the time patients stopped it because they experienced the side effect. But there was no difference in either stopping globally or stopping because you had a side effect between the two groups. Dr. Khyati Patel 21:21 And so looking at some of the common and uncommon side effects we talked about — dehydration leading to AKI, fracture, amputation, major hypoglycemia, DKA, or Fournier's gangrene — there was no significant difference between the two groups. Dr. Sean Kane 21:39 So, Dr. Patel, what you're telling me is that this drug has an awesome efficacy profile and causes zero side effects. Dr. Khyati Patel 21:47 I guess we should wait and talk a little bit more about some of the common ones. Dr. Sean Kane 21:51 So again, 60% of the patients were non diabetic. So you could say, well, you know, if they aren't peeing out that much sugar, maybe you wouldn't expect to see that much of a side effect profile like Mycotic infections and UTIs, if you're really not putting that much sugar in the urine, because many of these patients did not have diabetes, Dr. Khyati Patel 22:09 and remember, we said if they had issues with these drugs before had common side effect like the mycological infection or UTIs, they were excluded from the trial. Dr. Sean Kane 22:19 And in addition to that, the study follow up period was 18 months. So if you look at the phase three trials for these sglt, two inhibitors, which got Invokana, for example, its box warning for amputations, that was a roughly four year study as opposed to an 18 month study. So perhaps we didn't follow these patients long enough to really observe some of these rare but serious side effects that have come to light, mostly actually in Phase four trials as well, right? Dr. Khyati Patel 22:45 So we are talking about amputation or bone loss, fractures and such, right? Dr. Sean Kane 22:50 And then probably my biggest pet peeve of what the authors did was, in my opinion, kind of sneaky. So the number one side effect that I think about with sglt Two inhibitors is going to be Mycotic infections, so yeast infections or urinary tract infections. The problem, though, is, if you look at the supplement, it is really buried in there. And they, they were clever, in my opinion, a negative way to kind of hide the fact of whether they did or did not see UTIs. And what I mean by that is they had multiple different categories. So in the ADR table, they had UTI that was defined as urosepsis, a separate entry for infection, a separate entry for pyelonephritis, acute a separate entry for localized infection, pylocystitis. Pyelonephritis is an acute cystitis, renal abscess, urinary tract infection that was staphylococcal. Basically, these are all side effects that are similar, and they're not grouped together. So when you kind of dilute out a given side effect into multiple different categories, you're not going to be able to see a difference, because now you have 10 different categories that may constitute UTI as opposed to one single urinary tract infection category. And on top of that, keep in mind that this was a 75% male trial, and most of these UTIs and Mycotic infections are seen in women. So between enrolling mostly men, excluding people that have had side effects to sglt, two inhibitors in the past, and then diluting out how you report this, just to give you an example, it took 18 pages in the supplement to go through every side effect, because they had such specific side effects that were listed there, it's really not possible to kind of aggregate those with your eye visually and say whether or not the side effect profile observed is what you would actually see in clinical practice or not. 18 pages. 18 pages, wow, literally hundreds of side effects or ADRs that were reported in the supplement. Dr. Khyati Patel 24:44 And if we take that back, keeping all those caveats in mind — not a lot of women were included in the trial, and 60% of the patients were non‑diabetic — so the mycotic/UTI signal may be attenuated here compared with prior diabetes trials. Dr. Sean Kane 25:11 dilute that effect. And not to beat up on New England Journal of Medicine too much, but in my opinion, I think that they could have forced the authors to aggregate this in a more readable format that also is more clinically relevant, right? You can't go through 18 pages and come up with a realistic side effect profile of a given drug like that. Dr. Khyati Patel 25:29 Yeah, absolutely right. So really, where do we go from here? This is one trial for dapagliflozin, and we talked about other agents. Is this a class effect — are we seeing similar effects across the pipeline? Dr. Sean Kane 25:45 So in terms of the cardiovascular benefit, if I had a crystal ball, I would predict that probably we're going to see similar effects from all of the other sglt Two inhibitors. The reason I say that is with dapagliflozin (DAPA‑HF) and the earlier dapagliflozin/empagliflozin/canagliflozin programs, these drugs showed cardiovascular and, in some cases, mortality benefit — suggesting a potential class effect. So I absolutely would expect to see a class effect from these drugs, but we should still prove it right. Just because we expect it doesn't mean we shouldn't study it absolutely. Dr. Khyati Patel 26:14 So I think it sounds like EMPEROR‑Reduced and EMPEROR‑Preserved — and there are empagliflozin‑program studies looking at heart‑failure outcomes. The results are still pending, and we hope for similar findings in those trials as well. Dr. Sean Kane 26:31 And I'm actually really excited about the EMPEROR‑Preserved trial, and the reason for that is that they're specifically studying preserved ejection fraction or diastolic heart failure patients, and especially because we have no clue how these SG, LT, two inhibitors, are working to help with heart failure, it would be incredibly exciting to have a drug category that could have a mortality benefit in this preserved ejection fraction patient population, because we have zero drugs that help with diastolic heart failure long term outcomes like mortality. Dr. Khyati Patel 26:59 Yeah, you're absolutely right. So if that proves the mortality or benefit, then it will be definitely a blockbuster. Dr. Sean Kane 27:06 And I should mention, just because I teach heart failure, 50% of heart failure is diastolic heart failure, so that means half of all patients with heart failure don't have a drug regimen that improves their mortality, and the other half have a handful of drugs that improve mortality. So it's crazy that we haven't been able to really find able to really find that awesome drug to help with that preserved ejection fraction, which is why I'm so excited Dr. Khyati Patel 27:27 about it. Yeah, no, your excitement is completely justified Dr. Sean Kane 27:31 in terms of the side effect profile. I think that's the other question that I really have. So I'm not happy with how the authors reported their side effects, and I think that I still don't have a good feel for. If you don't have diabetes, what is the realistic side effect profile, given that you're not going to have the same degree of glycosyuria, which drives many of the side effects that we see when we use this drug class in diabetic patients? We don't know. Dr. Khyati Patel 27:54 Yeah, absolutely right. And so should then we start giving this drug to patients with heart failure, or, I should say, reduce ejection fraction heart Dr. Sean Kane 28:04 failure, right? Well, I think that my answer, if I had heart failure, would be yes, as long as you've maximized the CHF regimen. That is the bread and butter of CHF regimen. So we're talking about ace Arbor Arni, beta blocker, spironolactone, at the maximally tolerated target doses for these agents. Once you've done that, and if you're still New York Heart Association, class two or worse, then I think that this is the trial that informs our clinical practice and tells us that we should be doing that regardless of what the guidelines say, because the guidelines aren't going to be up to date with a trial that came out a month ago, right? Dr. Khyati Patel 28:37 Oh, yeah. Not not the guidelines, not the insurance company, let's be honest, they're going to look for what the FDA approval of the indication, and so that takes a little bit longer on the FDA side to approve it, based on the study results, though, Dr. Sean Kane 28:50 and we probably are due for more updates of the heart failure guidelines, at a minimum, for this, if not for other reasons as well. So once that takes effect, once the FDA, I'm sure they're going to submit this to the FDA for approval and heart failure and diabetics and non diabetics. So once those things happen from an insurance standpoint, it's going to be way easier. But until that time, I think really the difficult part is going to be cost, in terms of getting it paid for by someone, Dr. Khyati Patel 29:17 right, right? And I mean, compared to some of the other standard of care drugs for heart failure, which are available in generic form. So again, cheaper regimen altogether. This is only a brand of available drug, right? So we'll have to see how much added cost this causes to patients with heart Dr. Sean Kane 29:35 failure to be determined. Yes. So to kind of wrap the show up, you know, a couple key take home points from today's episode. So dapagliflozin (Farxiga). We've talked about that extensively today. That's part of the drug class that we call SGLT2 inhibitors. Now, classically, these are approved for type 2 diabetes, and they work by making you excrete glucose in your urine when your serum glucose levels exceed around 70–90 mg/dL. Dr. Khyati Patel 30:01 And this drug was recently studied in patients with reduced‑ejection‑fraction heart failure (systolic HF). The study included patients with or without diabetes, and it showed a benefit in mortality as well as heart‑failure–associated hospitalization in patients taking dapagliflozin over placebo. Dr. Sean Kane 30:22 And as we mentioned, the side effect profile was probably not as well represented as it could have been. And it's kind of a big question mark in terms of how bad are the side effects, not whether side effects happen or not. So among non diabetic patients, we just don't have a good feel for the side effect profile because of how they reported the 18 pages worth of side effects and their supplement right? Dr. Khyati Patel 30:44 And so we're hoping that heart‑failure guidelines will take these results from the DAPA‑HF trial into consideration, as well as results from ongoing trials of other SGLT2 inhibitors. It's likely that SGLT2 inhibitors will be recommended as part of the standard systolic heart‑failure regimen. Dr. Sean Kane 31:04 Yeah, we should note that we're recording this in mid October of 2019, by the time listeners listen to this stuff can change, right? Especially if you're listening to older episodes. So of course, take a look at something like the heart failure guidelines to see if they've updated, or even the package insert for any of these drugs, if you're listening in the future to see kind of what the update has come about from the DAPA HF trial. Yeah, that's right. So with that, we love the five star reviews and iTunes. We love followers on Twitter, so if you have any episode suggestions or you just want to reach out to us, you can either do that on Twitter, we're at HelixTalk, or go to our website, HelixTalk.com to go through older episodes and our contact information as well. So with that, I'm Dr. Kane and Dr. Khyati Patel 31:47 I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 31:50 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. Search for HelixTalk and place your review there Narrator - ? 32:01 to suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.