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Circulation on the Run


Aug 9, 2022

This week, please join authors John McMurray and David Cherney, editorialist Kausik Umanath, as well as Associate Editors Ian Neeland and Brendan Everett as they discuss the original research articles "Initial Decline (Dip) in Estimated Glomerular Filtration Rate After Initiation of Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction: Insights from DAPA-HF" and "Renal and Vascular Effects of Combined SGLT2 and Angiotensin-Converting Enzyme Inhibition" and editorial ""Dip" in eGFR: Stay the Course With SGLT-2 Inhibition."

Dr. Carolyn Lam:

Welcome to Circulation On the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Centre and Duke National University of Singapore.

Dr. Greg Hundley:

I'm Dr. Greg Hundley, Associate Editor and director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, it's the season of double features. Except this time, we're having a forum discussion of two related articles and an editorial that discusses both. What is it on? SGLT2 inhibitors. In the first paper, an analysis from the DAPA-HF trial, looking specifically at that initial dip in GFR that follows initiation of dapagliflozin in patients with HFrEF. Then we will discuss further, in a mechanistic way, the renal and vascular effects of combining SGLT2 inhibition on top of ACE inhibition. Lots and lots of good learning and insights, but let's go on first to the other papers in today's issue. Shall we?

Dr. Greg Hundley:

You bet, Carolyn, and I'm going to grab a cup of coffee. Carolyn, in this issue, wow, so many exciting original articles. In fact, there are two more articles that were going to pair together, both clinical and pertaining to TAVR procedures. In the first one, it was a group of authors led by Dr. Duk-Woo Park from the Asan Medical Center at the University of Ulsan College of Medicine. They conducted a multicenter, open-label randomized trial comparing edoxaban with dual antiplatelet therapy or DAPT, aspirin plus clopidogrel, in patients who had undergone successful TAVR and did not have an indication for anticoagulation. Now in this study, Carolyn, the primary endpoint was an incidence of leaflet thrombosis on four-dimensional computed tomography, CT, performed at six months after the TAVR procedure. Key secondary endpoints were the number and volume of new cerebral lesions on brain magnetic resonance imaging or MRI and the serial changes of neurological and neurocognitive function between six months and that time immediately post the TAVR procedure.

Dr. Carolyn Lam:

Oh, interesting. What did they find?

Dr. Greg Hundley:

Right, Carolyn. In patients without an indication for long-term anticoagulation after successful TAVR, the incidence of leaflet thrombosis was numerically lower with edoxaban than with dual antiplatelet therapy, but this was not statistically significant. The effect on new cerebral thromboembolism and neurological or neurocognitive function were also not different between the two groups. Now because the study was underpowered, the results should be considered really as hypothesis generating, but do highlight the need for further research.

Dr. Greg Hundley:

Carolyn, there's a second paper pertaining to transcatheter aortic valve prosthesis. It's led by a group directed by Dr. Paul Sorajja from the Minneapolis Heart Institute Foundation and Abbott Northwestern Hospital. Carolyn, these authors prospectively examined 565 patients with cardiac CT screening for HALT, or what we would define as hypoattenuating leaflet thickening, at 30 days following balloon-expandable and self-expanding TAVR. Now, deformation of the TAVR prosthesis, asymmetric prosthesis leaflet expansion, prosthesis sinus volumes, and commissural alignment were analyzed on the post-procedural CT. For descriptive purposes, an index of prosthesis deformation was calculated, with values greater than 1 representing relative midsegment underexpansion. A time-to-event model was also performed to evaluate the association of HALT with the clinical outcomes.

Dr. Carolyn Lam:

Oh, interesting. What did they find?

Dr. Greg Hundley:

Right, Carolyn. Nonuniform expansion of TAVR prosthesis resulting in frame deformation, asymmetric leaflet, and smaller neosinus volume was related to the occurrence of HALT in patients who underwent TAVR. What's the take home here, Carolyn? These data may have implications for both prosthesis valve design and deployment techniques to improve clinical outcomes in these patients. Now, Carolyn, both of these articles are accompanied by an editorial from Dr. Raj Makkar from the Smidt Heart Institute at Cedars-Sinai's Medical Center. It's a very lovely piece entitled Missing Pieces of the TAVR Subclinical Leaflet Thrombosis Puzzle.

Well, how about we check what else is in this issue? My goodness, this was a packed issue. First, Carolyn, there are three letters to the editor from Professors Ennezat, Dweck, and then a response from Dr. Banovic pertaining to a follow-up from a previously published study, the AVATAR study, in evaluating valve replacement in asymptomatic aortic stenosis. There's also a Perspective piece from Dr. Wells entitled “Treatment of Chronic Hypertension in Pregnancy: Is It Time For A Change?” There's a Global Rounds piece from Professor Berwanger entitled “Cardiovascular Care in Brazil: Current Status, Challenges, and Opportunities.” Then there's also a Research Letter from Professor Eikelboom entitled “Rivaroxaban 2.5 mg Twice Daily Plus Aspirin Reduces Venous Thromboembolism in Patients With Chronic Atherosclerosis.”

Dr. Carolyn Lam:

There's another Research letter by Dr. Borlaug on longitudinal evolution of cardiac dysfunction in heart failure with normal natriuretic peptide levels. There's also a beautiful Cardiology News piece by Bridget Kuehn on the post-COVID return to play guidelines and how they're evolving. Well, that was a great summary of today's issue. Let's hop on to our feature forum. Shall we?

Dr. Greg Hundley:

You bet, Carolyn. Can't wait.

Dr. Carolyn Lam:

Today's feature discussion is actually a forum because we have two feature papers in today's issue. They all surround the cardiorenal interaction, should I say, of the SGLT2 inhibitors. For the first paper, discussing that initial decline or that dip in the GFR following initiation of dapagliflozin would be Dr. John McMurray, who's the corresponding author of this paper from DAPA-HF. Dr. John McMurray's from the University of Glasgow. Now next, we have also the corresponding author of another paper, really going into the mechanistic insights of the renal and vascular effects of combined SGLT2 and ACE inhibition. Dr. David Cherney is from Toronto General Hospital, University of Toronto.

Dr. Carolyn Lam:

We have the editorial list of these two wonderful papers, Dr. Kausik Umanath from Henry Ford Health in Michigan. Finally, our beloved associate editors, Dr. Ian Neeland from Case Western Reserve and Dr. Brendan Everett from Brigham and Women's Hospital, Harvard Medical School. Thank you, gentlemen. Now with all of that, what an exciting forum we have in front of us. Could I start by asking, of course, the respective authors to talk a little bit about your papers? I think a good place to start would be with Dr. McMurray. John, please.

Dr. John McMurray:

Thanks, Carolyn. I think our paper had three key messages. The early dip in eGFR that we saw was, on average, very small in patients with heart failure, about 3 mLs/min or about 5%. Very few patients had a large reduction in the eGFR. It was around 3%. Dapagliflozin-treated patients had a 30% or greater decline compared to about 1% of placebo patients. Finally, very few of those patients had a decline in the eGFR below a critical threshold, which for cardiologists might be around 20 mLs/min. We saw that in only five patients; that's 0.2% of the dapagliflozin-treated patients. Second message was that that early decline partially reverses. The nadir in our study was about 14 days. But by 60 days, on average, eGFR had increased again. Hold your nerve if you see an early decline in eGFR.

 

Dr. John McMurray:

Maybe the most important message was that that decline in the eGFR is not associated with worse cardiovascular or renal outcomes. In fact, if anything, the opposite. If you look at the patients in the dapagliflozin group with a 10% or greater decline in eGFR, then compare it to patients who didn't have that decline, these individuals were about 27% less likely to experience the primary composite outcome of worsening heart failure and cardiovascular death. If you look at the placebo group, we saw exactly the opposite. Amongst those who had a greater than 10% decline in eGFR compared to those who didn't, those people with the early decline in eGFR were 45% more likely to experience the primary composite endpoint. The same is true for other cardiovascular outcomes for worsening kidney function. In the dapagliflozin group, decline in eGFR was not associated with more adverse events, not associated with more treatment discontinuation. That small decline in the eGFR is not a bad prognostic sign. If anything, it might be the opposite.

Dr. Carolyn Lam:

Thank you so much. That was really clear. David, are you going to tell us why this decline occurs?

Dr. David Cherney:

Yeah. Perhaps the paper that we published gives some insights into the mechanisms that are responsible for some of those changes in GFR that are thought to be acute hemodynamic effects. In the between trial, which is the trial that we published examining the effect of ACE inhibition followed by SGLT2 inhibition in patients with type 1 diabetes, we also saw that there was an expected effect of adding SGLT2 inhibition on top of an ACE inhibitor in people with uncomplicated type 1 diabetes. This acute dip in GFR was seen in this cohort of patients. We included only 30 patients in this small mechanistic study. At the same time, along with that dip in GFR, we also saw an increase in measures of proximal natriuresis. That proximal sodium loss is linked with changes in sodium handling in the kidney, which then causes changes in both probably afferent and efferent tone, which causes this dip in GFR primarily through natriuresis in this phenomenon called tubuloglomerular feedback. That was one major observation that gives insight into what we see in larger trials around the dip in GFR.

Dr. David Cherney:

In our mechanistic study, we also saw an additive effect on blood pressure. Blood pressure went down further with the addition of empagliflozin on top of an ACE inhibitor. In terms of the mechanisms that are responsible for the reduction in blood pressure, natriuresis certainly may be in part responsible, but we also saw a novel observation whereby there was a reduction in peripheral vascular resistance using noninvasive measures. There are likely several mechanisms that are responsible for the reduction in blood pressure. Then finally, we also saw reductions in markers of oxidative stress, which may also account for some of the effects that we see in blood pressure, as well as potentially some of the anti-inflammatory and anti-fibrotic effects that we see at least in experimental models that may have some clinical translatability to humans as well around the clinical benefits. I think the blood pressure, the renal hemodynamic effects, and some of the neurohormonal mechanisms are the major observations that we saw that may in part explain some of the really nice changes that were seen in Dr. McMurray's study.

Dr. Carolyn Lam:

Right. Thanks, David. But these were patients with type 1 diabetes and no heart failure. John, do you have any reflections or questions about how that may apply? By the way, what a beautiful study. Thank you, David.

Dr. David Cherney:

Pleasure. Thank you.

Dr. John McMurray:

Yes, David. I really enjoyed your study. In fact, I think, Carolyn, it does shed some insights perhaps to what's going on. As David pointed out, the reduction in peripheral arterial resistance, reduction in blood pressure, that may play some role in that early dip in eGFR as well as autoregulation in the kidney. Then the other interesting thing is that the distal nephron seems to adapt to that effect in the proximal tubule. Again, that may account for some of that recovery in eGFR, that reversal in the early dip that I spoke about, and which I think is very clinically important because, of course, physicians should make sure that they recheck eGFR if they see that early dip. Because they may find that few weeks later that that dip is much smaller and of much less concern.

Dr. Carolyn Lam:

Thank you, John. In fact, you're saying, stay the course, right-

Dr. John McMurray:

I have.

Dr. Carolyn Lam:

... with the SGLT2 inhibitors. I'm actually stealing the words of the title of the editorial, a beautiful editorial by Kausik. I love that. Stay the course. Kausik, please, could you frame both papers and then with an important clinical take home message for our audience?

Dr. Kausik Umanath:

Sure. I think the analysis by John and his group was really relevant with the large sample size. What's impressive? Similar to a lot of these other SGLT2 studies that have come out, both in heart failure and in kidney disease progression and so on, it's remarkable how the other analysis, like the analysis of EMPA-REG and CREDENCE and so on, of similar dips. All show more or less the same magnitude, the same relative proportions of this GFR trajectory. I think the mechanistic study only highlights that though it's working with a slightly different population of type 1 patients and much earlier in their course in terms of where their GFRs are.

Dr. Kausik Umanath:

The other piece is that ultimately we need to understand this dip and know to monitor for it and so on. But I think the general clinician should really understand that a dip of greater than 10% really occurs in less than half the population that takes these agents. That dip, if it occurs, certainly doesn't do any harm. That said, if they see a bigger dip in the 30% range, monitor more closely and consider making sure that there aren't any other renal issues out there for that patient because they are a much smaller proportion of patients in these large trials that generate that level of dip. They should be monitored.

Dr. Kausik Umanath:

The other thought that we had, and thinking through this in a practical sense, is because you expect this dip, many of our cardiologists or even the nephrologists when we titrate these drugs, they're on a suite of other drugs. It's probably best to not adjust their Lasix or their loop diuretic, or their RAAS inhibitor at the same time as you're adjusting the SGLT2 inhibitor or starting it because then you may just introduce more noise into the GFR changes that you see over the next several weeks. It may be a sequential piece or at least holding those other agents constant while this gets titrated and introduced is a prudent course of action, so you don't misattribute changes.

Dr. Carolyn Lam:

Thanks so much. What clinically relevant points. In fact, that point about the diuretic especially applies in our heart failure world. You see the dip. Well, first, make sure the patient's not overdiuresed. Remember, there's more that the patient's taking. Thank you. That was a really great point. Brendan and Ian, I have to get you guys to share your views and questions right now. But before that, can I take a pause with you and just say, aren't you just so proud to be AEs of Circulation when we see papers like these and we just realize how incredible the data are and the clinical implications are? I just really had to say that. All right. But with that, please, what are your thoughts, Brendan?

Dr. Brendan Everett:

Yeah, sure. Thank you, Carolyn. Hats off to all three of our authors today for doing some amazing science. Thank you for sending it to Circulation. I think, in particular, I handled David's paper. I'm not a nephrologist and I'm probably the furthest thing from a nephrologist. Had to do my best to try and understand these concepts that I'm not sure I ever even was exposed to in medical school many years ago. I think it shows the breadth of the interest in our readership. The fact that these changes in eGFR have become a primary focus for our cardiovascular patients and that the clinical implications are really important. I guess my question, David, is... In your paper, you talked a little bit about this hypothesis of hyperfiltration and the role that hyperfiltration plays in setting patients with diabetes up for kidney disease. Is that playing a role in John's observation or not? Again, as a non-nephrologist, I have trouble connecting the dots in terms of that hypothesis and John's observation of the clinical benefit for patients that have a reduction in eGFR as opposed to no change.

Dr. David Cherney:

Yeah. It's a great question. It's very difficult to know with certainty in a human cohort because we can't measure the critical parameter, which is intraglomerular pressure, which we think these changes in GFR are a surrogate for. But if we go along with that train of thought, along reductions in glomerular hypertension, it very much makes sense that the patients who dip are those who have the... They're taking their medication, number one. Number two, they respond physiologically in the way that you expect them to, which is that their GFR dips at least transiently and then goes back up again through some of the compensatory mechanisms that John mentioned earlier. As was mentioned not only in this paper, but also in previous analyses from CREDENCE and previous analyses from VERTIS CV and others have shown that indeed that dip in GFR is linked with longer term renal benefits, at least. That is reflected in a reduction in the loss of kidney function over time.

Dr. David Cherney:

The patients who are on an SGLT2 inhibitor and those who dip by around 10% or less, those patients tend to do the best over time in terms of preserving GFR, not losing kidney function compared to patients who are on an SGLT2 inhibitor but do not dip, or those patients who actually have an increase in GFR. That is consistent with this idea that there may be a reduction in glomerular pressure, which is protective over the long term. That ties back into your question around hyperfiltration that this may indeed be due to a reduction in glomerular pressure, which is linked with risk over the long term.

Dr. Carolyn Lam:

Ian?

Dr. Ian Neeland:

I wanted to echo Brendan's comments about the excellent science. When I read these papers, it really speaks to the existential struggle that cardiologists have between kidney function and these medications that we know have cardiovascular benefits. How do we manage that practically? It's so clinically relevant, both the observation that John's paper made about the dip in the DAPA-HF trial as well as, David, your mechanistic insights.

Dr. Ian Neeland:

I wanted to ask John potentially about the most fascinating aspect to me of this paper was that patients with a dip of 10% or more actually ended up doing better in terms of cardiovascular outcomes, specifically hospital heart failure and hospitalizations than people on placebo with a greater than 10% dip. It speaks to the fact that... Is the physiology going on here different between those individuals whose GFR went down on placebo versus those who are on SGLT2 inhibitors? All the mechanistic insight that David's paper had in terms of blood pressure and intraglomerular pressure, how does that feedback and speak to why heart failure is strongly linked to this mechanism? We see this not just with SGLT2 inhibitors, but there are other medications now coming out showing that there's a relationship between this dip in GFR and heart failure. Can you speak to why this heart failure-kidney connection is so important and becoming greater and greater in terms of our understanding?

Dr. John McMurray:

Well, thank you for asking me the hardest question and one that I truly don't think I have a good answer to. I think it's obvious to all of us that the kidney is central in heart failure and perhaps cardiologists have neglected that fact, focusing more on the other organ. But by definition, almost the fluid retention that characterizes heart failure in terms of signs, and probably is the primary cause of symptoms, that clearly is a renally-mediated phenomenon. The kidney must be central to all of this. I think David right. I think the decline in eGFR that you see with this drug is simply a marker that the drug is having its physiological effect or effects. Whatever those are, they're beneficial. Clearly, patients who have an eGFR decline on placebo are different and they reflect, again, the patients that we see all the time. As our patients with heart failure deteriorate, one of the things that we commonly see, in fact becomes one of the biggest problems that we have to deal with, is that their kidney function declines. As their symptoms get worse, as their cardiac function gets worse, their kidney function also declines.

Dr. John McMurray:

I think you're seeing two contrasting effects here. One is the background change in eGFR, which is the placebo patients, and we've always known that that's a bad thing. Then we're seeing that early within 14 days marker of the pharmacological or physiological action of the drug. I hope you don't ask me how SGLT2 inhibitors work in heart failure. That's the other most difficult question I can think of, but I think this is just a marker of the fact that they are working.

Dr. David Cherney:

Yeah. Just to add to that briefly, there is this difficulty in sorting out the mechanisms that are relevant around the acute effects in the kidney that the dip in GFR reflects natriuresis that could keep patients out of heart failure; that the reduction in glomerular pressure reduces albuminuria. Albuminuria reduction is linked with kidney protection. It's linked with heart failure and ASCVD protection. Then there's also this concept of if you dip and then you stay stable afterwards, your GFR stays stable afterwards, those patients with stable kidney function that's not declining, the dippers in other words, those patients are probably able to maintain salt and water homeostasis better than someone who's declining more rapidly. All these things probably tie together in order to reflect, of course, there's a renal protective effect, but that some of those mechanisms may also tie into the heart failure mechanisms that John was mentioning.

Dr. John McMurray:

But, David, it's hard to imagine if we don't protect the kidney, we won't protect patients with heart failure given how fundamental, as I said, the kidney is, and how fundamentally important worsening kidney function is. Not only because it is a marker of things going badly, but also because it often results in discontinuation or reduction in dose of other life-saving treatments. To Kausik's point, it was very important about the risk of changing background life-saving disease modifying therapy. Actually, we didn't see that in DAPA-HF, which was very intriguing. There was no reduction in use of renin-angiotensin system blockers or mineralocorticoid receptor antagonists.

Dr. Carolyn Lam:

Thank you so much, gentlemen. Unfortunately, we are running out of time, but I would really like to ask one last question to the guests, if possible. Where do you think the field is heading? What next? What's the next most important thing we need to know? David, do you want to start? Then John, then Kausik.

Dr. David Cherney:

I think one of the aspects that we need to know in the future is where else can we extend these therapies into novel indications and extend the boundaries of where we currently work with these therapies. People with type 1 diabetes, for example, with either heart failure or with significant kidney disease, patients with kidney transplantation, is there a renal or cardiovascular protective effect? Then another high risk cohorts who have not been included in trials, those on immunosuppressants, for example, who were excluded from the trials. I think those are some of the areas that we need to extend into now that we understand how these therapies work in even very sick patients and that we also know that they likely have at least some benefit through suppressing inflammation, and possibly reducing infectious risks. That would provide a rationale for extending into some of these new areas. I think that's certainly, hopefully on the horizon for us.

Dr. Carolyn Lam:

John?

Dr. John McMurray:

Carolyn, obviously I think looking at post myocardial infarction population, that's an obvious place to go. There are a couple of trials there. I suppose the trial that I would love to see, and which I think would address the core question that we've been discussing today, which is: Is this all about the effect in the kidney and how important is the diuretic and natriuretic action of these drugs in heart failure? I think the key study that would address this would be doing a study in patients on dialysis. Because in those patients we could, I think, separate the issue of natriuresis, diuresis, and maybe even the dip in EGR that we've been talking about. If these drugs prove to be effective in end-stage kidney disease, patients on dialysis, that would be really fascinating.

Dr. Carolyn Lam:

Kausik?

Dr. Kausik Umanath:

That is a very interesting point. I don't know that we know necessarily outcomes, but I think from working with the DAPA-CKD, we do have a little bit of the safety data because we did continue it. I was the US MLI for that study and we did continue the SGLT2 passed into renal failure. There is a little bit of safety data there. But I don't think once you've declared an outcome, you're not collecting outcomes data after that point. That's a very interesting area to look into.

Dr. Kausik Umanath:

I also think the other place where this field's heading is trying to better tier and layer the multitude of agents. I think we've been waiting for about 20 to 30 years, at least in the kidney field, for something new to affect the progression of kidney disease after the ACE/ARB trials and so on. This one we've got SGLT2 inhibitors. We've got the new MRA, finerenone, and so on, which also have very beneficial cardiovascular effects. The question becomes: How do we layer these therapies? Which sequence to go in? Some of the others that are in pipeline as well that are out there that have very beneficial cardiovascular effects that may indeed also help kidney function and diabetes control, which do you go with first and so on?

Dr. Carolyn Lam:

Wow! Thank you so much. We really could go on forever on this topic, but it has been tremendous. Thank you once again. On behalf of Brendan, Ian, Greg, thank you so much for joining us today in the audience. You've been listening to Circulation On the Run. Don't forget to tune in again next week.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.