Nonsteroidal MRAs: Latest Evidence of Cardiorenal Protection in CKD and T2D

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Welcome to CME on ReachMD. This activity, entitled “Nonsteroidal MRAs: Latest Evidence of Cardiorenal Protection in CKD and T2D” is provided by Medtelligence.

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[CHAPTER 1]

Dr. Wright:
Welcome to the Cardiorenal Educational Series. In the first chapter, we’ll set the stage for the series in its entirety.

This is CME on Reach MD, and I’m Dr. Eugene Wright.

Dr. Małyszko:
And I’m Dr. Jolanta Małyszko.

Dr. Soler:
And I’m Dr. María José Soler.

Dr. Wright:
Let’s get started. Dr. Małyszko, can you give us a brief overview of the finerenone and the FIDELIO-DKD trial?

Dr. Małyszko:
Good morning, Eugene. I’m Dr. Małyszko, and I would like to share my knowledge concerning finerenone’s mode of action at first. This is not our mother MRA [mineralocorticoid receptor antagonist] because it was developed as a potent and selective mineralocorticoid receptor. What is really amazing is that it has no relevant affinity for androgen, progesterone, estrogen, and glucocorticoid receptors, which makes this very, very special.

The first trial which examined the role of finerenone in kidney and heart protection was FIDELIO. And diabetes and chronic kidney disease [CKD] were used as a cardiovascular disease risk accelerator, and as a marker, the study shows urinary albumin excretion ratio. What is really important is that all the patients were on the maximum tolerated dose of ACEI [angiotensin-converting enzyme inhibitor] or ARBs [angiotensin receptor blockers], and also the inclusion criteria was good kidney function. The efficacy and the safety results were the following: We found that finerenone reduced the composite outcomes for kidney failure, which was defined as more than 40% decrease in EGFR over a 4-week period or death from renal causes. The secondary composite outcomes were death from cardiovascular causes or hospitalizations for any cause. And what we found out was that finerenone slowed the progression of chronic kidney disease and reduced the cardiovascular mortality in patients with type 2 diabetes.

What was really important, when we’ve learned from our previous mineralocorticoid receptors, like spironolactone or eplerenone, in general the problem is hyperkalemia. In the FIDELIO trial, when the patients used finerenone, the rate of hyperkalemia was significantly lower, and also it was really more important to monitor the potassium levels to enable appropriate dosing. For the practicing nephrologists, what is really important from the clinical point of view, that finerenone appeared to be a new drug on the horizon to slow the progression of chronic kidney disease in patients with type 2 diabetes. It also should be stressed that it reduced cardiovascular mortality. Why is it important? Because with artificial kidneys, our patients are not dying of renal causes. They are dying of cardiovascular reasons.

Dr. Wright:
Thanks, Dr. Małyszko. One of the things that you mentioned that is extremely interesting to me is that having type 2 diabetes and chronic kidney disease is a risk accelerator for cardiovascular disease and cardiovascular death. Can you talk about that a little more?

Dr. Małyszko:
It’s like a double trouble. Unfortunately, we have more comorbidities or even multi-morbidities. And for nephrologists, right now the leading cause of end-stage kidney failure is diabetic kidney disease. That’s why we try to put all the efforts not only to slow the progression of the CKD, but also to lower the proteinuria and albuminuria, which are a surrogate point for a progression of a CKD. And paradoxically, only the people in dialysis are the happy survivors, because vast majority of them, when they reach the stage 4 or even 5 of chronic kidney disease, they are dying of cardiovascular reasons.

Dr. Wright:
This has been great. Before we wrap up, Dr. Małyszko, can you provide us with one key takeaway from this chapter?

Dr. Małyszko:
We have a new drug which is effective in slowing the progression of CKD and reducing cardiovascular mortality with acceptable side effects, and it was generally safe, and we can use it in, generally, in the population of type 2 diabetes and patients with chronic kidney disease.

Dr. Wright:
Thank you. In Chapter 2, we’ll be discussing the follow-up FIGARO-DKD trial and the FIDELITY Analysis. Stay tuned.

[CHAPTER 2]

Dr. Wright:
Welcome back. In the first chapter, we discussed the novel nonsteroidal MRA finerenone in the FIDELIO-DKD trial. We also discussed safety and how to manage hyperkalemia in patients with CKD and type 2 diabetes. In Chapter 2, we’re going to look at the follow-up trial, FIGARO-DKD, and the subsequent FIDELITY Analysis.

Dr. Soler, can you give us a brief overview of the FIGARO-DKD trial and how it compared to its predecessor?

Dr. Soler:
Thank you for your nice introduction and question. Actually, the FIGARO study is different in 2 important points. The estimated GFR [glomerular filtration rate] in this study, in the FIGARO, is from 25 mL/min, and the albuminuria that here we start albuminuria degree 1, that is higher than 30 mg/g. So the very important thing of this study is this means that these patients are healthier than the patients from the FIDELIO study in terms of kidney disease or diabetic kidney disease. Another important thing of this study is the change of the primary outcome. This is a study more of designed for cardiovascular, with the primary cardiovascular composite endpoint of cardiovascular event, as you already know, nonfatal myocardial infarction, and nonfatal stroke or heart failure. And in that study, the secondary endpoint was kidney failure.

What do we know of the safety and the efficacy of this study? This study, the adverse events were the same – the similar incidence than in the placebo group, with finerenone. And on top of all optimizers, renin-angiotensin system blockade, finerenone significantly reduced the risk of the primary cardiovascular outcome by 13% as compared to placebo. Another step important here, and another question that we have is worse danger from the potassium levels, and the results were similar – were tested at 1 month from 4 months with the study and then every 4 months. And the results were similar than in the FIDELIO study. They had a hyperkalemia of 10.8%, but only 1.2% of the patients included in the study needed discontinuation. That is very low as compared with the other mineralocorticoid agent.

There was another study that pooled the data together from the FIDELIO-DKD and the FIGARO-DKD, and I think that this is really important because this enlarge a lot the sample size. And this was named the FIDELITY study. It’s important to know they think that the majority of the patients of both the studies have microalbuminuria, and the mean estimated GFR was 57.6 mL/min. And from both results, from both the studies together, the results were that finerenone significantly reduced the risk of composite cardiovascular outcome by 14%, and very important that the primary reduction was driven by the reduction of heart failures or hospitalization secondary to heart failure.

Dr. Wright:
This is great. And one of the things that you’ve highlighted, because these are patients that were at relatively low risk in the FIGARO trial, that we now have the ability to change the conversation. One of the things that both we as clinicians and our patients are most concerned about with type 2 diabetes and CKD are death and dialysis. And now we have a study that has a favorable impact on both.

For those of you just tuning in, you’re listening to CME on ReachMD. I’m Dr. Eugene Wright, and here with me today are Dr. Marias Jose Soler, and Dr. Jolanta Malyszko. We’re discussing the latest evidence for cardiorenal protection from nonsteroidal MRAs in CKD and Type 2 diabetes.

This has been great. Before we wrap up, Dr. Soler, can you provide us with one key takeaway from this chapter?

Dr. Soler:
So in my opinion, the implications for clinical care from the 2 studies that I commented are finerenone is an effective treatment option for cardiovascular and kidney protection in patients with mild to severe chronic kidney disease and type 2 diabetes. So albuminuria measurement in patients with type 2 diabetes is important for the identification of patients who can benefit from treatment with finerenone, independent of the estimated GFR.

Dr. Wright:
Thank you again. In Chapter 3, we’ll be discussing a patient case and the clinical implications of initiating MRAs in patients with late-stage kidney disease and type 2 diabetes. Stay tuned.

[CHAPTER 3]

Dr. Wright:
Welcome back. In Chapter 2, we discussed the FIGARO-DKD trial and how it compared to its predecessor, the FIDELIO-DKD trial, along with the follow-up FIDELITY Analysis of both trials. Now in Chapter 3, we’re discussing a patient case.
So let’s get started.

Drs. Małyszko and Soler, we’ve discussed some of the distinctions of finerenone in the clinical trials and what sets finerenone apart from earlier MRAs. What are the clinical implications of initiating MRAs in a patient with late-stage kidney disease and type 2 diabetes?

Dr. Małyszko:
For the practicing nephrologists, the most important part is to underline the urinary albumin excretion ratio over a 300 mg/g as a time to initiate, to introduce, finerenone treatment. What is really important, and this is kind of a message not only to nephrologists, but to the general practitioners, internists, and endocrinologists, that we have to bear in mind that urinalysis is a very easy, very cheap, and noninvasive method to assess kidney function. And if we do find the albuminuria or proteinuria, we have to think about the kidney protection and try to start as early as possible, because with the earlier start, we can gain as much as we can. With the later, there are also some gains, but not so significant. And what is also really important, that urinary albumin excretion ratio is seen at 4 months with these new nonsteroidal mineralocorticoid receptor antagonists. It is of utmost importance as this is the marker of slowing the progression of chronic kidney disease and giving a chance for a patient not to reach end-stage kidney failure and not to end up on the dialysis and also to lower the risk of cardiovascular mortality.

Dr. Soler:
If you ask me how finerenone may improve cardiorenal outcomes across the spectrum of current kidney disease, together the results of FIGARO-DKD and FIDELIO-DKD suggest that finerenone provides kidney and cardiovascular benefits across all of the spectrum of patients with chronic kidney disease and type 2 diabetes.

To overcome the clinical inertia in my daily clinical practice, I used to do a checklist. For years, in my checklist, the more important drug for patients with chronic kidney disease and type 2 diabetes was the renin-angiotensin system blockade. We are happy because we have more therapies for this type of patient, so currently in my daily clinical practice, in my checklist, there are SGLT2 [sodium-glucose transport protein 2] inhibitors, GLP-1 [glucagon-like peptide 1] agonists, and finerenone. And I think that they should be included, and we should decide which patient will need each one of them to improve their renal and cardiovascular prognosis.

Dr. Wright:
So that’s great. Thank you both. What I take away from this as a primary care clinician is that we need to, one, have early awareness and recognition of the possibility or potential of chronic kidney disease as well as early and aggressive treatment of all the targets that we can identify to significantly slow down the progression of chronic kidney disease and cardiovascular disease. And now we have a therapy that starts to address these issues.

This has been great. Before we wrap up, Dr. Małyszko and Soler, can each of you provide us with one key takeaway from this chapter?

Dr. Małyszko:
Think about your patients and look whom you treat. Medicine makes enormous progress and enables us to live longer, and now we would like to live better, not only longer, with a good quality of life, not to end up on dialysis. And this is kind of a new milestone in the therapy of diabetic kidney disease.

Dr. Soler:
And I would like to say that after years in the darkness, nephrologists that take care of patients with chronic kidney disease and diabetic kidney disease – patients that we already told are at high risk for dialysis and cardiovascular mortality – finally, I’m happy because I have new tools for treating this type of patient.

Dr. Wright:
Unfortunately, that’s all the time we have today. So I want to thank our audience for listening in and thank you, Dr. Jolanta Małyszko and Dr. María José Soler, for joining me and sharing all of your valuable insights. It was great speaking with you today.

Dr. Małyszko:
Thank you, and good-bye.

Dr. Soler:
Thank you, and good-bye.

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