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09-07-2021 | Nephropathy | Ask the expert | Article

DKD treatment update: SGLT2 inhibitors and finerenone

Nephrologist Ian de Boer joins primary care physician Amrit Lamba to discuss how the recent approval of finerenone and extension of the dapagliflozin label is likely to influence the treatment of kidney disease in people with type 2 diabetes.

0:00 Introduction 
1:40 The DAPA-CKD trial: Building on CREDENCE 
5:01 How the trial findings will influence primary care 
7:10 Safety considerations 
12:03 Where does finerenone fit in? 
16:12 Take-home messages

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Transcript

Hello. Welcome to medicine matters diabetes. My name is Amrit Lamba. I'm a GP with a specialist interest in diabetes based in London, UK. And it's my great pleasure to be hosting this ask the expert session where we're hoping to provide an update on SGLT2 inhibitors, and the management of chronic kidney disease. And joining me as our expert today is Doctor Ian de Boer. Ian is a nephrologist and Professor of Medicine based at the University of Washington. Welcome Ian. Great to have you.

Very happy to be here, Amrit. Thanks for having me.

Great. So Ian, I'm just going to start actually by setting a bit of a background to where we are how we've got to where we are in terms of SGLT 2 inhibitors and the management of CKD. So in 2019 after about 20 years almost of no new additions to the toolkit in the management of diabetic kidney disease, we had the results from the Credence trial, which was looking at the SGLT inhibitor canagliflozin. And we saw some positive renal outcomes of using canagliflozin in patients with type 2 diabetes and kidney disease. And that resulted in license changes which many of us I'm sure have all been implementing and utilizing over the last couple of years.

But since then there have been a number of other trials that have been undergoing, and we have some exciting results as well from some of those trials. One in particular that we wanted to discuss today was the DAPA CKD trial. So this is the trial of dapagliflozin, another SGLT inhibitor. Again, looking at a population with kidney disease, interestingly enough, both with and without type 2 diabetes. And Ian I really wanted your thoughts really a bit of an overview of some of the take-home messages from the DAPA CKD trial.

Well I'd say the most important top line information here is that DAPA CKD really confirms the market kidney benefits of SGLT 2 inhibitors for people with type 2 diabetes and chronic kidney disease. And as you noted, this builds on the Credence trial. And in fact, we have 10 high quality randomized controlled trials now of SGLT 2 inhibitors with clinical outcomes that show consistent across the class effects. Those build on the early cardiovascular outcomes trials, like EMPA REG, Canvas, et cetera, that also showed kidney benefits and cardiovascular and heart failure benefits.

And what Credence and DAPA CKD have done is move this particularly into a high risk for kidney progression population, specifically looking at kidney outcomes and confirming those large kidney benefits in those populations. And Credence reported an approximately 30% reduction in risk of CKD progression in type 2 diabetes. In DAPA CKD that estimate was even somewhat larger, closer to 40% reduction in CKD progression.

DAPA CKD also widened the eligibility criteria compared to Credence. It had an albumin to creatinine ratio of 200 milligrams per gram of albumin to 5,000, and an EGFR eligibility criteria of 25 to 75 mLs per minute. So pushing down that EGFR threshold for eligibility beyond the 30 that many of the prior trials have used. And it found benefits for CKD progression, and also for prevention of kidney failure requiring dialysis, a very important outcome for our patients.

And then as you noted 2/3 of the patients had type 2 diabetes in DAPA CKD, but 1/3 did not. What did they have? Had a combination of hypertensive nephrosclerosis, a fair amount of people with IgA nephropathy, and typical to chronic kidney disease, a mishmash of other diseases that are not fully diagnosed. All of them with proteinuria as I noted for the eligibility criteria before.

And interestingly, though the numbers of events in that third of the DAPA CKD population and the incidence rates of kidney disease progression were somewhat lower, the risk reductions of dapagliflozin versus placebo were at least as large as they were in type 2 diabetes, suggesting that dapagliflozin and other SGLT 2 inhibitors may be very effective medications for preventing CKD progression, beyond the setting of type 2 diabetes.

So some really interesting results there. And it's moved the story on from Credence hasn't it? You've identified some areas where it's really expanded our on knowledge and excitement around the use of SGLT2 inhibitors, dapagliflozin in this particular instance. Ian, I'm really interested in terms of how we translate research into practice. And I just wanted your expert opinion on how you feel the combination now of both Credence and DAPA CKD will influence our management of kidney disease in practice. I mean. I'm coming from a primary care perspective, and I know this is still very much within the realms of a primary care clinician isn't it?

It absolutely is. And of course, diabetes, and chronic kidney disease are extremely prevalent. It is a high risk combination of presentations that requires care, and if it's not done in primary care, people won't be treated. So it is very important for primary care providers to be treating these people, specialists as well.

But I think what DAPA CKD and these other trials have made clear is that SGLT 2 inhibitors really are part of the standard of care now for people who have type 2 diabetes and chronic kidney disease. And by chronic kidney disease, I mean any manifestation, albuminuria, or low EGFR, or both.

Per the KDIGO guidelines that I had the opportunity to co-chair, and also per the American Diabetes Association guidelines, SGLT 2 inhibitors are strongly recommended for those populations. And DAPA CKD really reinforces that, along with lifestyle therapy, goal directed therapy for blood pressure, glycemia, lipids et cetera, RAS inhibition for people who have hypertension and albuminuria. SGLT 2 inhibitors are right there in the base package of what we should be treating all of our patients with type 2 diabetes and CKD with, unless they have a contraindication.

One particular area I suppose which we should still consider the data that we have for adverse events from these trials, but I think that from a practical perspective, that's something that clinicians obviously discuss and consider with the person in front of them. Is there any more data that, and I suppose applications from that data, that we can take from DAPA CKD. I'm particularly interested in patients who did not have diabetes. What were the adverse events in that group? And also there's that age old question about the acute drop in eGFR after initiating an SGLT 2 inhibitor. Anything more that we can glean from this trial?

Well great questions, and most of us are risk averse. We like to avoid adverse events for ourselves and for our patients. And that's appropriate. It can also be a barrier if we're overly reactive to adverse risk. So what are the risks of SGLT 2 inhibitors in these trials. The most common, of course are genital mycotic infections. And those occur on average across trials in about 2% of men and about 5% or 6% of women who have been assigned to an SGLT 2 inhibitor. They tend to be mild. They tend to be treatable, though there are cases of Fournier's gangrene that had been reported as well.

And so when I prescribe SGLT 2 inhibitors, I do absolutely discuss that risk and discuss the importance of general hygiene and presenting to provider if they have symptoms or signs of genital infections. Another category of adverse events are the diabetic ketoacidosis. This is, of course, what is limiting the extension of these drugs to type 1 diabetes at the current time and restricting it to type 2 diabetes.

And those risks have varied across trials. In DAPA CKD, the risk of diabetic ketoacidosis was exceedingly low, in people with type 2 diabetes or without diabetes. And that really emphasizes that in the type 2 diabetes population while there clearly is an increased relative risk of DKA. The absolute risk is low. And that should not be a major barrier for preventing prescription in this population.

I do recommend sick days, for example. So if people are vomiting or awaiting procedures, they should hold their SGLT 2 inhibitors. And I do instruct that for patients as well and recommendations guidelines do do support that. But the risk is quite low on average and should not be a barrier.

The EGFR drop is something also that you bring up that is frequently discussed. And so we do know that there is a hemodynamic reversible drop in eGFR with SGLT 2 inhibition. It tends to be smaller than what we see with Renin angiotensin system inhibitors, though is similar in pathophysiology. And if it drops with initiation, if you discontinue the SGLT 2 inhibitor it will come back up.

There's some suggestion-- this is not randomized data, observational data, but people who do have such a drop may have better, more substantial long term benefits. Perhaps these are patients who have higher glomerular pressure who need a reduction in glomerular pressure for preservation of kidney function long term. So the EGFR drop itself is not necessarily a reason to discontinue and SGLT 2 inhibitor.

And we have a couple of nice studies again exploratory looking at the question how much of a drop is too much. And those come from both Credence and, actually I can't remember the other secondary analysis. I think it was a Canvas secondary analysis. I could be wrong there. Anyway these studies suggests that drops of EGFR in the 10% to 30% range are not associated with increased adverse effects or poor kidney outcomes. When they get to EGFR drops of 30% or more, that's where they may be associated with adverse events. And so there's some suggestion that we should be able to accept an EGFR drop of up to about 30% with the initiation of an SGLT 2 inhibitor.

OK, brilliant. So quite a nice summary there of obviously adverse events to acknowledge, but as you quite nicely put as well, perhaps not to overthink it in that discussion as well that we have with our patients, but to very much be aware of scenarios where it is relevant.

I'm going to move the story on a little bit because although SGLT 2 inhibitors have stolen much of the headlines over the last few years, we have other agents as well that had been investigated for their kidney benefits. And one of those agents is finerenone, for which we had some results last year in the Fidelio DKD trial, which again was quite exciting. And from which I understand we've had some license change-- well a new license approved by the FDA very recently as well. Ian, again top lines from the Fidelio DKD trial to share with everyone?

Right, so Fidelio DKD studied finerenone, which is a nonsteroidal, mineralocorticoid receptor antagonist, similar in many ways to spironolactone and eplerenone. There are some differences in tissue specificity, half-life, and other pharmacokinetic aspects that may be relevant. However, spironolactone and eplerenone, while studied for blood pressure, have not really been studied for clinical kidney outcomes. And finerenone was studied in the Fidelio DKD trial as an adjunct to reduce chronic kidney disease progression.

So what did Fidelio DKD study? It had people with type 2 diabetes, again, who had micro albuminuria, or macro albuminuria. The eligibility criteria are a little bit less easy to summarize. They were at high risk of progressive chronic kidney disease. They added Finerenone or placebo to a background of standard care, including an ACE inhibitor or an ARB-- so this is on top of background RAS inhibition, and examined a primary kidney outcome of progressive chronic kidney disease. And that was reduced by 18% with finerenone compared with placebo.

So it's actually quite exciting, as you said in the introduction. 20 years ago in 2001, we had evidence showing that RAS inhibition and ACE or an ARB can prevent kidney disease progression, and really nothing for many years after that. Now SGLT 2 inhibitors have been added to that foundation, and we have another option with mineralocorticoid receptor antagonist, finerenone. We also have other options like GLP 1 receptor agonist, which I don't think we'll be able to discuss today, that may be layered on top here.

And so we're in the enviable position, finally of having choices to offer our patients. And it becomes then hard to know how do we package these together? And I would say based on accumulated evidence and. All of this SGLT 2 inhibitor evidence that still RAS inhibitors and SGLT 2 inhibitors are the starting place for type 2 diabetes and chronic kidney disease.

And we're still learning, I think, how to add something like finerenone, which was recently approved by the FDA as you noted, on top of that. I am hopeful that it will be another option that's useful for some patients, particularly patients who are heavily pro-anuric and showing progression in their chronic kidney disease who are at high risk of continued progression. I suspect that's where we'll be using additions like finerenone, but we need a little bit more data to figure out how to incorporate that into our packages just now.

Yeah, when you mentioned the lack of options, perhaps additional new options for quite a while, and then now we've got a few on the go, it's almost like London buses. You wait for an hour there's no bus, and then you have three or four coming together. It feels like that. But a very exciting time. I was interested in how you perhaps place the different therapeutic options there. And I suppose as you mentioned in the coming year or two, we will start to see our guidelines, both internationally and nationally, incorporating these different treatment options.

Well, I think we've covered quite a lot. I'm sure we could have spoken for a lot longer actually, Ian. We've just scratched the surface, but I really appreciated your insights there today. I suppose from my perspective as the person asking the questions to the expert, I think I've really got a better understanding of the therapeutic options that are now available to us on top of standard of care as you mentioned with the lifestyle measures or ACE blockade in the past. We now have the SGLT 2 inhibitor trials that have resulted in license changes and some other exciting options as well, perhaps just starting to become available and in the future.

Obviously many other trials also ongoing, as well, at the moment, and we look forward to the results of those trials, too. But one thing that I did pick up from what you were saying, Ian, is that very much the onus is on the clinician to identify patients at the appropriate early stage to ensure that they can gain maximum benefit from these agents that have done so well in the trials. But in the real world, it's a case of identifying perhaps being very proactive with urine ACR measurement and reviews of patients on a regular basis.

But lots of options and exciting times I think in this part of diabetes and kidney medicine as well. So thank you very much, Ian, for all your wonderful insights. It's been great chatting to you. And thank you everyone who's joined us today. We hope you've enjoyed this video.

More videos in the "diabetic kidney disease" series

About the speakers

Ian de Boer

Dr. de Boer is a Nephrologist, Professor of Medicine, and Adjunct Professor of Epidemiology at the University of Washington. His research focuses on the metabolic causes and consequences of chronic kidney disease.
 

Full biography

Amrit Lamba

Amrit Lamba is a GP Partner at Colindale Medical Centre in North Central London CCG. He is a Diabetes clinical lead for Barnet Federated GPs and serves on the operational board for the Community Diabetes Service.

Full biography

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