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Nihar R. Desai, MD, MPH: Hello. I'm Dr Nihar Desai from the Yale School of Medicine. Welcome to season 1 of the Medscape InDiscussion: Cardiorenal Metabolic Syndrome podcast series. Today we're discussing novel therapies and we're going to focus on the sodium-glucose cotransporter-2 (SGLT2) inhibitors. I'm delighted to have as my expert guest Dr Jacob Udell. Dr Udell is a cardiologist within the Department of Medicine at Women's College Hospital and the University Health Network, and a clinician scientist at the Women's College Research Institute and University of Toronto, Faculty of Medicine. Dr Udell's research focus is on cardiovascular outcome studies.
He has been a leader in this field, a close friend of mine, and we had similar training paths and overlap for some time at the TIMI study group. I'm delighted to have Jay with us. Jay, welcome to the Medscape InDiscussion podcast.
Jacob A. Udell, MD, MPH: Thanks for having me.
Desai: There's been a lot of interest and focus on cardiorenal metabolic topics in general. In this podcast series, we talked about epidemiology, social determinants of health, and how they overlap with the rise and prevalence of cardiorenal metabolic conditions.
We're going to switch gears and go deep on the SGLT2 inhibitors. I'd love to get your sense of the history and talk about how these therapies even came onto the cardiorenal metabolic landscape. I think it's a very interesting part of their development.
And then we'll dive into some of the clinical trials and the recent work that you led, which was presented at the American College of Cardiology meeting.
Udell: If I remember, the -flozin story dates back to the mid-1800s. It was originally isolated from the bark of the apple tree. "The bark of the apple tree a day keeps the doctor away" was a tongue-in-cheek saying. You'd go to your apothecary in the Middle Ages, and if you had a touch of the sugar diabetes, they would shave off a little bit of the bark of the apple tree. That would be your therapy. Eventually, hundreds of years later, they isolated the molecule, the flozin molecule. Eventually, it became a drug that was in the development pathway around the 1960s and '70s in experimental models for diabetes.
SGLT2 inhibitors work by inhibiting this enzyme in the renal tubule that resorbs sodium and glucose, which, again, in hunter-gatherer days was very important for us so that we could retain these essential nutrients when we had a fight-or-flight and feast-or-famine environment. But in the scourge of the 21st-century Western lifestyle, we know that we now have an overabundance of these nutrients that leads to adverse outcomes, including obesity and diabetes.
When these inhibitors started to come out, they were being tested because it seemed most obvious that we would now have this first-time therapy that excretes glucose and causes glucosylurea, so urination of the glucose molecule by inhibiting the retention of the glucose in the renal tubule. It became a natural therapy to develop for the treatment of diabetes.
As it came down through phase 2, and when we were at the precipice of one of the phase 3 studies in DECLARE, it became obvious as we were even discussing the outcomes, as you remember, and it wasn't initially on the radar to study it as a therapy that could reduce the risk for heart failure because its subtle co-transport inhibitor was the sodium.
We've thought about this. We know very well that excessive sodium in patients who are at risk for heart failure can tip somebody over the edge and can lead to decompensated heart failure. And so natriuresis, excretion of the sodium, became intriguing to look at, even before there was a signal that we had heard about in any of the other diabetes outcome trials that were testing in SGLT2s to think about it as a potential therapy or prevention for heart failure.
I remember Dr Sabatini coming to my office and asking if we were studying this in the other therapeutic classes of diabetes drug outcome studies that we were looking at; we really thought that there was something that we might see here and we had a hunch. And so again, it was the excretion of glucose, which we thought would be good for diabetes. And in that era, it was very much a hot topic to look at any diabetes therapy in a cardiovascular outcome study. A generation earlier, we had seen the story of thiazolidinediones increasing the risk for potential cardiovascular (CV) adverse outcomes, particularly heart failure.
So all of these CV outcome studies were initially designed or thought of as noninferiority studies. Many of us had pushed them to become superiority studies for CV benefits. The focus was on the major adverse cardiovascular events (MACE) signal and not necessarily on the heart failure signal.
But the first drug to come out of that initial trial was empagliflozin, in the EMPA-REG outcome study. And you remember that caught everyone off guard. It was designed for a noninferiority study. It was only powered for a noninferiority study, but it hit on superiority, and it hit on that primary endpoint, which was that triple composite of myocardial infarction (MI), stroke, and CV death.
However, it was pushed predominantly by CV death reduction, and it became evident that the secondary endpoint that it had a substantial impact on was that reduction in heart failure. We didn't understand how many patients were actually at risk for heart failure. We never captured left ventricular ejection fraction in any of our patients and we didn't have a good grasp of whether this was heart failure with reduced ejection fraction or heart failure with preserved ejection fraction. That evolved and we learned more over the course of several other subsequent diabetes–CV outcomes studies. That pattern kept showing up, that there was a reduction in heart failure. And then it was sometimes hit, sometimes miss on CV, and even in EMPA-REG's case, all-cause mortality. By the time four CV outcome trials of SGLT2 inhibitors came out — and if you include SGLT1 and SGLT2 inhibitors — in sotagliflozin, there was this consistent signal. It became self-evident that we should move away from its effect on glucosylurea, which wasn't even that effective as a diabetic therapy.
It has this beautiful, self-regulating off switch in turning off the glucosylurea so you don't see hypoglycemia. You see a reduction in that excretion, but you still see that consistent natriuretic effect. It was then evident that we should move the field toward treatment of heart failure.
We saw many very impressive outcomes, I think even more impressive than many of us were expecting in the dapagliflozin and empagliflozin studies of heart failure. It was also evident that we don't exactly know the mechanism, but we feel that great pathobiology and mechanistic studies are showing that there is this deep compression reduction in intraglomerular hypertension, and we presume also in improvement in myocardial handling. It was evident as well, especially its effects in the nephron, that it should be studied as a renal preservation therapy. And then we saw many other chronic kidney disease (CKD) studies that showed this impressive reduction and progression to end-stage renal disease or dying from renal disease.
You see this beautiful arc of cardio, endocrine, and renal risk reduction. And to your point, then we thought, Oh, if this stuff works after the disease sets in, perhaps we should even step back and ask the question at the time of a large insult, like MI; perhaps it could work as well for reduction in prevention of the incident to heart failure in those patients.
Desai: It's interesting to recall those early days, and it was a US Food and Drug Administration (FDA) mandate for any new "diabetes medicine" to be evaluated for cardiovascular safety, just like you said, given what the experience had been with the thiazolidinediones and rosiglitazone, and kind of on the cardiovascular side.
From that FDA mandate, if you will, come these therapies that not only show safety but become some of the first therapies on the diabetes side that show cardiovascular benefit.
I want to double-click a little bit on that for our audience. Give us your sense of where we are in terms of the SGLT2 inhibitors, which seem, as rightfully pointed out, almost the poster child for cardiorenal metabolic disease and cardiorenal metabolic syndrome.
Udell: They're the angiotensin-converting enzyme (ACE) inhibitors of the 21st century, hard stop. Drilling down into the pathobiology, the pathomechanism, in the nephron and how it affects vasodilation vs afferent vasoconstriction, it acts as the reciprocal effect of what we see with ACE and angiotensin II receptor blocker (ARB) inhibition in the nephron.
It has that same counterbalance and allows for that decongestion and decompression at the kidney — at the nephron level — that leads to those benefits, we think in the kidney. We think then either directly or indirectly the same off-target mechanism allows a decompression or a decongestion at the cardiac level.
It's been this impressive, consistent signal of effect that has settled down in the heart failure space in terms of its ability to prevent incident and recurrent heart failure. Its effects on other events are less consistent. It's certainly a different story than we see with other metabolic therapies, like the glucagon-like peptide (GLP)-1s right now, and then likely different from what we're probably going to see with the gastric inhibitory polypeptide (GIP) and GLP-1 combination therapies.
It seems to be that there's something, particularly with the natriuretic effect, that is the reason we see that effect in the heart failure space. There are other physiologic benefits, a slight reduction in blood pressure, a slight weight reduction, and a slight reduction in circulating glucose levels, all of which likely contribute to the pleiotropic benefits ultimately. That said, the signal is predominantly heart failure, and then plus or minus the effect on CV death, which is likely all driven from its reduction downstream from heart failure. That signal hasn't been as consistent, but when you meta-analyze the studies, again, it's a modest reduction: about 10% and CV death, all of which points in the right direction.
And it's an elegantly simple drug to use. It's not as complicated as many of our other heart failure therapies or many of our other cardiovascular therapies. There is a broad therapeutic safety window. It's a fixed-dose therapy with minimal side effects — things that we can very simply treat in the outpatient center. It's easy to use for the routine clinician. We both have cardiometabolic clinics at Toronto General Hospital and Women's College Hospital. We have trainees from a spectrum of family medicine to anesthesiology, nephrology, endocrinology, and cardiology. Everyone feels very comfortable.
Desai: It has been such an interesting story there. As we think about our cardiorenal metabolic syndrome patients, and we think about the SGLT2 inhibitors, yes, they're important as glucose-lowering and diabetes medicines, and as you very nicely laid out for us, there are important cardiovascular benefits in terms of atherosclerotic cardiovascular disease (ASCVD) and heart failure. So maybe we'll sort of round that out. Can you take us inside a little bit on the renal-protective story? What do we know about the SGLT2 inhibitors for that set of patients?
Udell: Initially the therapies were tested in the most mild CKD outcomes, and then we pushed the envelope. Initially there were restrictions on how low you could go in the glomerular filtration rate (GFR). I remember when we were studying these in the diabetes outcome studies, the GFR cutoff where you can even implement these therapies was in the 45-50 range. Then we pushed the envelope down into the 35-40 range, and then we pushed the envelope all the way down into the 15-20 range.
In the trials, if you develop progressive renal disease, there was no mandate to stop therapies, even down to whether the patient was on dialysis. We have really good safety data in implementing and initiating the therapies such that the labels now have reduced the GFR exclusion far down.
That's not a safety reason. It turns out that that's a concern about effectiveness and efficacy; when the GFR is that low, it's really hard to get the drug into the renal tubule to do its job. It never has shown in any trial of CKD patients to be a safety issue of implementing these therapies at a very low GFR. That's why the protocols have not mandated you to stop those therapies when you cross over and get into a very low GFR. And it has shown a consistent benefit.
Each trial has done a slightly different composite of the renal outcome. There's been an attempt to kind of harmonize the analysis across trials of a consistent composite renal endpoint. And no matter how you slice it, whether it's a reduction in GFR, whether it's GFR slope, whether it's a progression to the next stage of kidney disease, whether it's progression to dialysis, whether it's a transplant or dying from kidney-related causes, which again has a slight variation in its definition… All of those have been consistently reduced across the different GFRs, across the different spectrums of albuminuria from macroalbuminuria to microalbuminuria.
And again, that simplifies the effect and the plan in the clinic, right? After evaluating hundreds of thousands of patients across the spectrum of cardiorenal metabolic disease, and tens of thousands of investigators and clinic support staff, we really can simplify the message in clinic.
Desai: Yes, and I think that that's a point we probably can't overstate and overemphasize enough. There are clear benefits for patients with diabetes, clear benefits for patients who then have concomitant ASCVD and heart failure, regardless of having diabetes.
Udell: Absolutely. In these trials, many didn't mandate that patients who have diabetes enroll. And that's the beautiful thing. It unlocks the potential. I agree.
Desai: These therapies and the SGLT2 inhibitors seem like a part or maybe a magic bullet of sorts, whether your patient has diabetes, whether they have heart failure, whether they have CKD. Or, like too many of the patients that we see now, they have many of these things that are all coming together and interacting with each other. I think that illuminates and highlights the power of a therapy and a class of medicines like this one, and it's why we're so excited about them.
Udell: Well, let me ask you a question. I know you have one for me. But is it provocative, then, to ask the question, when we do drug development, perhaps we shouldn't be so myopic and think about these therapies by disease state? Perhaps we should be testing more broadly across the spectrum. For instance, look at the GLP-1 signal as well. It's not necessarily restricted to patients with diabetes. And so perhaps we're unlocking even an approach to the development of these therapies, that they should be earlier tested more broadly across the spectrum. Perhaps it has nothing to do with the tip of the iceberg, overt disease — that the sugar level happens to be over a certain threshold. Perhaps there are metabolic effects that are irrelevant to whether or not you need other therapies to control your glucose.
Desai: That dovetails to exactly where I want to go. You have seen all of this being involved in many of the clinical trials for the SGLT2 inhibitors. You were looking at the frontier and saying, hey, we're seeing these important benefits. Look at what we've discovered about heart failure, CKD, ASCVD, and diabetes.
To your point, that's really what drove some of the work, the ambition, and the aspirations, I should say, of EMPACT-MI. Can you tell us quickly about what the hypothesis of that study was and how it came into existence, and then take us through some of the key findings?
Udell: It had been a while since a new therapy was affecting or was being tested for acute MI that wasn't focused on somewhere along the spectrum of the platelet or the thrombin, and that spectrum of where the insult was along that thromboembolic pathway. If you harken back to the early days of acute MI care, even before we had antithrombotic, the effects were focused on these large MIs. Before we even had reperfusion therapies, there was this huge scourge of myocardial injury resulting in heart failure. And so therapies that can modulate that spectrum along the neurohormonal pathway, or myocardial handling, have always seemed to both cross the threshold of benefit for chronic heart failure and then earlier on an acute MI.
There have been some clear wins. There have been some that were mixed results, but it seemed obvious to me, at least after EMPA-REG OUTCOME came out, that there was an immediate rush to go treat heart failure.
I thought treating MI and preventing heart failure in that patient population might be a very interesting space to go to with this very safe and usually very tolerable therapy. The caveat, of course, is that we've had a huge improvement with reperfusion in reducing the overall background risk of large MIs leading to chronic heart failure. We were threading a needle a bit to find MIs of a certain size that indicated sick-enough patients who would be the right patients to potentially benefit, similar to our current therapy of using, let's say, a mineralocorticoid receptor antagonist, a spironolactone or eplerenone, in those large MIs that will result in LV dysfunction or congestion in subsequent heart failure.
And so that's what we set out to do. We partnered with the manufacturer of empagliflozin and we did this large trial. We initially had humble expectations and a small size, but we decided to scale this up and test this properly across multiple countries. It was an international study of 6500 patients, where we asked a simple question: What happens when there is early SGLT2 inhibitor initiation, after you stabilize the patient with a large acute MI with either congestion at presentation or significant LV dysfunction? Early initiation could be anywhere along the time that they presented, within the first 14 days. This was compared with placebo.
We saw mixed results. The overall trial, which was powered for the primary endpoint of all-cause mortality or acute — actually, incident — heart failure hospitalization, had a modest effect that was nonsignificant — about a 10% risk reduction, where the action predominantly was incident heart failure hospitalization. Again, in retrospect, that is the consistent signal across all the other trials.
When you look at the totality of data, which we didn't focus on as our primary endpoint, we look at other heart failure events that occurred, especially as the timing of when we did this trial was during the height of the COVID-19 pandemic. There was a lot of shift in a further acceleration of treatment of acute heart failure decompensation at the outpatient setting. We found that when you capture those events as well, the totality of the data showed a positive reduction in all-cause mortality and the totality of those incident heart failure events. We're digging deeper into the data. We're looking at different particular subgroups of interest. We're looking at the consistency of those results and for any kind of effect modulation, maybe by risk. And we think that this again may serve a role, particularly in those who have the most severe MIs when they present themselves.
And then the question, of course, for our general community and the guidelines is, is a reduction in heart failure substantial enough, even though the all-cause mortality signal wasn't there to consider this as part of routine practice?
Desai: I have to say that the adoption and implementation of the SGLT2 inhibitors have been far too slow and too variable. I want to get your thoughts on that. What do you think some of the barriers are?
Udell: You're speaking to both a Canadian-practicing and American-trained cardiologist. You may not be aware that dapagliflozin is now generic in Canada, as it may potentially be in many, many countries. It's starting to become generic. We're already seeing that that barrier is being reduced.
I'll honestly admit that I think there's a gap, potentially, in the generation that you trained. When I asked my senior colleagues about this, that was the generation of the HOPE study and the ACE inhibitor and ARB trials.
Those were the really hot stuff, and the practitioners and clinicians a generation above them thought that was a step too far; those were therapies that they weren't comfortable with. They would recommend it to the primary care provider but they wouldn't implement it.
The onus is on us and our generation to implement these ourselves. I mean, you can't find a broader, safer, more efficacious therapy class. I think we're going to see it in our training arc in our generation, and so I think it's on us to own this space.
Kudos to Medscape and yourself for having this discussion. Hopefully, there'll be other opportunities so that we adapt, adopt, and continue to talk about these treatments. I think this will be our huge, generational impact on the outcomes of care. And when we look back 20-30 years from now, I think this will be a huge step in the direction of reduction of hospitalization events, end-organ damage, and mortality in this patient population over the next 30 years.
Desai: Incredibly well said, Jay. For our audience, we're going to have an entire session on implementation to take us inside that story around what we can do and where we're heading. My final question is, what are you most excited about?
Udell: We are excited about using novel approaches to risk stratification before it is self-evident that you have a cardiorenal metabolic condition — at the earlier stages; and initiating and implementing a therapy like an SGLT2 inhibitor that can reduce the incidence of developing cardiac conditions in the first place, or developing renal disease in the first place.
The FDA is having, as I understand it, I've never been in the middle of a conversation… But from what I understand, there's historically been a hesitation to allow for a therapy that treats diabetes to be studied to reduce the incidence of diabetes because you can imagine that it's a self-fulfilling prophecy.
You're taking a diabetes drug, so do you or don't you already have diabetes, even if you prevent diabetes? But preventing a cardiac event — incident heart failure, for instance — if this signal has been consistent for all of these other spectrums of illness, why don't we go for even lower-risk patients?
Now, you're going to have to study maybe a larger contingent of patients and find a way again to risk-stratify them to find the highest-risk patients as a proof of concept. I think that's where we're going, and I think that would be a really exciting development as well. That would round out the SGLT2 inhibitor story.
Suppose we're now talking about primary prevention of disease. We hinted at some of these. There's that Venn diagram in cardiorenal metabolic syndrome, because it impacts several systems and the vast majority of the population. For instance, people take statins for primary prevention; hypertension, I think, is probably the other real domain of primary prevention therapies. And this could be the next frontier. But it probably will take public funding to do that, and so that's where we're heading. Hopefully, we'll have an update in a few years.
Desai: Wow. Really exciting stuff, Jay. I mean, think about the true public health population impact. I will just tell the audience to take a moment to download the Medscape app to listen and subscribe to this podcast series.
Thank you again for joining us. This is Nihar Desai for the Medscape InDiscussion: Cardiorenal Metabolic Syndrome podcast.
Resources
Effects of SGLT2 Inhibitors on Kidney and Cardiovascular Function
The Bark Giving Diabetes Therapy Some Bite: The SGLT Inhibitors
Thiazolidinediones and Heart Failure: A Teleo-Analysis
Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes
Sotagliflozin in Patients With Diabetes and Recent Worsening Heart Failure
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Cite this: SGLT2 Inhibitors: A Future in Cardiorenal Metabolic Syndrome - Medscape - Jul 18, 2024.
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