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Updates on Nonsteroidal Mineralocorticoid Receptor Antagonists: Review of Data

  • Authors: George L. Bakris, MD; Charles P. Vega, MD
  • CME / ABIM MOC Released: 9/23/2022
  • Valid for credit through: 9/23/2023
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Target Audience and Goal Statement

This activity is intended for nephrologists, diabetologists/endocrinologists, cardiologists, primary care physicians (PCPs), pharmacists, and nurses.

The goal of this activity is that learners will be better informed about nonsteroidal mineralocorticoid receptor antagonists (MRAs) for the treatment of chronic kidney disease (CKD) in patients with type 2 diabetes (T2D).

Upon completion of this activity, participants will:

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    • Clinical trial data for new therapies for type 2 diabetes in patients with chronic kidney disease


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  • Charles P. Vega, MD

    Clinical Professor, Family Medicine
    University of California Irvine
    Irvine, California


    Charles P. Vega, MD, has the following relevant financial relationships:
    Consultant or advisor for: GlaxoSmithKline; Johnson & Johnson


  • George L. Bakris, MD

    Professor of Medicine
    Director, American Heart Association Comprehensive Hypertension Center
    University of Chicago Medicine
    Chicago, Illinois


    George L. Bakris, MD, has the following relevant financial relationships:
    Consultant or advisor for: Alnylam; AstraZeneca; Bayer; DiaMedica Therapeutics; Horizon; Ionis; KBP Biosciences; Merck; Novo Nordisk; Quantum Genomics
    Research funding from: Bayer


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    Senior Medical Education Director, Medscape, LLC


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  • Kim Storck, PharmD, RPh

    Senior Director, Medical Writing, Medscape, LLC


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  • Susan L. Smith, MN, PhD

    Associate Director, Accreditation and Compliance, Medscape, LLC


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Updates on Nonsteroidal Mineralocorticoid Receptor Antagonists: Review of Data

Authors: George L. Bakris, MD; Charles P. Vega, MDFaculty and Disclosures

CME / ABIM MOC Released: 9/23/2022

Valid for credit through: 9/23/2023


Charles P. Vega, MD: Hello and welcome to season 2 of CME-TV: Chronic Kidney Disease in Type 2 Diabetes. I’m Dr Chuck Vega, clinical professor of family medicine at the University of California at Irvine. Direct your attention to the number on this screen: 35 million. What do you think this number represents? This guy’s bank account? A good guess, but no. There are 35 million people in the United States with type 2 diabetes. What about this percentage? Any ideas on what it represents? Forty percent of people with type 2 diabetes will develop chronic kidney disease or CKD. And this includes a significant portion who will progress to kidney failure, dialysis, and transplantation. And, unfortunately, that’s not the end of it. Along with diabetes and kidney disease comes an increase in cardiovascular risk. An estimated 4 out of 5 patients with type 2 diabetes will be diagnosed with cardiorenal disease or die of cardiovascular causes. How can we slow the progression of kidney disease in our patients with diabetes and CKD? And how can we mitigate their risk for cardiovascular events? We’re here today to find out. This episode isn’t about diabetes or glucose-lowering drugs. And it isn’t about blood pressure-lowering drugs, either. Today, we’ll be talking about a novel concept -- cardiorenal risk-reducing drugs: agents that prevent the progression of kidney disease and reduce the risk of cardiovascular events independent of glycemic and blood pressure control. That’s right -- independent of glycemic and blood pressure control.

So, buckle up as we head to the windy city of Chicago to meet with a world-renowned nephrologist whose research has helped to define the nexus of cardiorenal risk reduction, Dr George Bakris. Dr Bakris is a professor of medicine and Director of the American Heart Association Comprehensive Hypertension Center at the University of Chicago.

It is very nice to be here with you in person.

George L. Bakris, MD: Likewise.

Dr Vega: So, tell us the story behind these cardiorenal risk-reducing agents.

Dr Bakris: The story began somewhat unexpectedly with a "do no harm" mandate by the Food and Drug Administration to test all new glucose-lowering agents for cardiovascular safety. When the antihyperglycemic class of SGLT2 inhibitors were evaluated by these large outcomes trials, they demonstrated cardiorenal protective properties, well beyond their ability to lower glucose. In a meta-analysis of nearly 47,000 patients with type 2 diabetes from 6 clinical outcome trials, the SGLT2 inhibitor class reduced the risk of major adverse cardiovascular events including heart attack, stroke, and cardiovascular death. And specifically, they reduced the risk of hospitalization for heart failure, independent of baseline atherosclerotic disease, prior heart failure, or kidney function. SGLT2 inhibitors also protected the kidney from disease progression -- again, independent of baseline atherosclerotic disease and prior heart failure, and across the spectrum of baseline kidney function. In fact, I've said that these agents should be thought of as cardiorenal protective agents that happen to lower glucose.

Dr Vega: It’s wild to think how that all evolved. I remember when SGLT2 inhibitors were initially approved, their labeling included warnings against their use in patients with renal dysfunction.

Dr Bakris: That’s true. But keep in mind that those warnings were based exclusively on the attenuation of their glycemic efficacy as kidney function dropped below an eGFR of 45. The warnings were not based on safety concerns. And since then, the SGLT2s have demonstrated cardiorenal benefits across the spectrum of kidney function in patients enrolled in trials to date. Canagliflozin and empagliflozin are labeled for use down to an eGFR as low as 30. And dapagliflozin, down to an eGFR of 25, independent of glucose considerations and based wholly on their cardiovascular and kidney benefits. At this point, even patients with eGFRs as low as 20 have been extensively studied. In fact, the 2022 KDIGO guidelines are currently in review and suggest lowering the recommended threshold for SGLT2 initiation from an eGFR of 30 to an eGFR of 20, particularly for patients with albuminuria or heart failure.

Dr Vega: That’s remarkable. And, more recently, there’s a second class of drugs demonstrating cardiorenal benefits...

Dr. Bakris: Yes, a new class of agents called nonsteroidal mineralocorticoid receptor antagonists.

Dr Vega: That’s a mouthful. Let’s just say nonsteroidal MRAs shall we?

Dr Bakris: Absolutely. Nonsteroidal MRAs. And I emphasize the "nonsteroidal" on purpose because this drug class are not your mother's spironolactone. They’re very different. The steroidal MRAs -- spironolactone and eplerenone -- were first to market and have shown cardiorenal benefits. But their wider use has been limited because of associated complications with hyperkalemia and, for spironolactone, hormonal side effects. The hyperkalemia becomes more severe with declining renal function, which is why steroidal MRAs have been considered problematic in CKD.

Nonsteroidal MRAs are a different class of agents than steroidal MRAs, although both inhibit the mineralocorticoid receptor, albeit in different ways. They have different physicochemical, pharmacodynamic, and pharmacokinetic properties than steroidal agents. The nonsteroidals are more selective for the mineralocorticoid receptor, have a higher potency, and tissue distribution is more evenly balanced between the heart and kidneys.

Dr Vega: Great explanation, but how do these differences net out clinically?

Dr Bakris: Aldosterone levels increase as kidney function declines. Persistently elevated levels of aldosterone will "overactivate" the mineralocorticoid receptors, causing inflammation and subsequent fibrosis of the heart and kidneys. It also causes hypertrophy, or remodeling, of the heart and sodium retention in the kidney. The nonsteroidal MRAs have a high affinity for the mineralocorticoid receptor but a very low affinity for steroid receptors. So, their anti-inflammatory, anti-remodeling, and anti-fibrotic benefits in the kidney and heart are maximized. And the effects on serum potassium and steroid-related side effects are minimized.

Dr Vega: There are several non-steroidal MRAs under development and clinical assessment; of these, only esaxerenone and finerenone are approved for treatment. In Japan, esaxerenone is approved for primary hypertension and has been studied in diabetic nephropathy to reduce albuminuria. Finerenone was recently approved by the US FDA to reduce the risk of cardiorenal events in adult patients with CKD associated with type 2 diabetes. Finerenone’s indications include reducing the risk of sustained eGFR decline, end stage kidney disease, cardiovascular death, non-fatal myocardial infarction, and hospitalization for heart failure. Finerenone was studied in the largest cardiorenal outcomes program in CKD and type 2 diabetes to date. The design was unique. More than 13,000 patients were enrolled in the finerenone program across 2 independent phase 3 trials: FIDELIO DKD and FIGARO DKD. The 2 trials had the same protocol but different inclusion criteria and complementary endpoints. FIDELIO was a primary renal endpoint trial in diabetes and FIGARO was a primary cardiovascular endpoint trial in diabetes. Then a single-patient analysis of both studies was conducted called FIDELITY. Dr Bakris was the primary investigator on FIDELIO.

Dr Vega: Can you please walk us through the vision behind FIDELIO, FIGARO, and ultimately, FIDELITY?

Dr Bakris: So, you want to hear an opera oration? Finerenone is a novel nonsteroidal MRA. In a broad stroke, the goal was to evaluate the effect of this novel class of agents on cardiovascular and renal outcomes in patients with type 2 diabetes across the spectrum of kidney disease. But, as you’ve suggested, we need to be familiar with the FIDELIO and FIGARO trials to understand the pooled FIDELITY analysis. FIDELIO was a dedicated kidney outcomes trial with a secondary cardiovascular endpoint that included a little over 5700 patients with severely increased albuminuria and predominantly stages 3 and 4 kidney disease. FIGARO was a dedicated cardiovascular outcomes trial with a secondary renal endpoint that included nearly 7500 patients. The population in FIGARO had a wider range of kidney disease. Participants could have stage 2 to stage 4 CKD and moderately increased albuminuria, or stages 1 to 2 CKD with severely increased albuminuria. Participants in both FIDELIO and FIGARO were on maximally titrated doses of ACE inhibitors or angiotensin receptor blockers.

FIDELIO showed a significant 18% risk reduction vs placebo in its primary composite renal endpoint -- time to dialysis, a reduction in GFR of 40% or more and renal death. The secondary cardiovascular endpoint was significantly reduced by 14%, mainly driven by a reduction in heart failure hospitalization.

Conversely, in FIGARO, the primary outcome of CV death, nonfatal MI, nonfatal stroke, or hospitalization for heart failure was significantly reduced by 13%, again mainly driven by a reduction in hospitalization for heart failure. Secondary renal composite outcomes just missed statistical significance -- one of which was defined by a sustained eGFR reduction of 40% or more. But, recall, FIGARO enrolled a much healthier kidney group than did FIDELIO. And though FIGARO just missed its secondary renal endpoint, guess what happened when we looked at a more rigorous endpoint for kidney outcomes, a greater than 57% reduction in eGFR or the doubling of creatinine -- there was a 23% risk reduction, which was statistically significant.

Dr Vega: So very powerful news for clinicians -- including those in primary care and cardiology -- who should now be checking albuminuria and thinking about interventions for their patients with type 2 diabetes in stage 2 or early stage 3 CKD.

As a prespecified analysis, FIDELITY pooled the data from the complementary FIDELIO and FIGARO studies with their similar study designs and overlapping research sites. The aim of FIDELITY was to confirm the safety and efficacy of finerenone over 3 years, with the advantage of being able to use individual patient-level data from the 13,000 plus patients enrolled in the 2 phase 3 trials. The study investigators sought to answer 2 key questions: Could a nonsteroidal MRA added to standard of care reduce cardiorenal risk across this spectrum of patients with CKD and T2D? And could it do so without the same safety issues plaguing the steroidal MRAs, spironolactone and eplerenone?

Let’s head back to Chicago to find out.

Dr Bakris: Wow. Amazing, amazing. Listen, I'm glad you could join us, but how can you be in two places at once?

Dr Vega: It saves me a lot in airline travel. So, FIDELITY assessed cardiorenal risk reduction in patients with type 2 diabetes across a substantial part of the CKD spectrum. What can you tell us about the range of eGFR reported among the study’s population?

Dr Bakris: Coming from FIDELIO and FIGARO, patients in FIDELITY had kidney disease that ranged from microalbuminuria and an eGFR in the 80s to very heavy albuminuria and an eGFR down to 25. The mean GFR in FIDELITY was 57.6. And the median albumin-to-creatinine ratio in the urine was 515.

Dr Vega: Very high. What were some of the key findings from FIDELITY?

Dr Bakris: Treatment with finerenone reduced cardiorenal outcomes in a statistically significant way in FIDELITY. The composite cardiovascular outcome was reduced by 14%. This included time to cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for heart failure. Hospitalization for heart failure was the main driver of the cardiovascular benefit in FIDELITY. Risk of hospitalization for heart failure was reduced by 22% with finerenone added to maximally dosed RAS blockade use, minimally, of SGLT2 inhibitors that were not part of the protocol, but they were added ad lib by investigators. The benefit of finerenone on cardiovascular events was independent of baseline eGFR or albuminuria. The number needed to treat after 3 years was 46. There was also a significant 23% reduction in the composite kidney outcome that used a doubling of serum creatinine, a sustained 57% reduction in eGFR as part of the outcome. The number needed to treat after 3 years was 60 for the kidney outcome. Essentially, each component of the composite kidney outcome was reduced, including kidney failure, end-stage kidney disease, eGFR of less than 15, and a doubling, or a 57% decrease in eGFR. FIDELITY showed a 20% reduction in dialysis.

Dr Vega: I’m also concerned about safety in these trials. Did finerenone -- as a nonsteroidal MRA -- fare differently than the steroidal MRAs we’ve used in the past?

Dr Bakris: There was a low incidence of hyperkalemia compared with what’s usually seen with the steroidal MRAs. Finerenone produced a 14% incidence of any hyperkalemia compared with 7% among placebo-treated patients, and the rate of patients stopping their treatment because of hyperkalemia was 1.7% of the approximate 6500 patients that were taking finerenone vs 0.6% of the approximate 6500 patients on placebo. To lend some context, 23% of patients had to stop spironolactone in the AMBER trial because of hyperkalemia. Even with a potassium binder, 6% had to stop it. In FIDELITY, yes, there is a risk for hyperkalemia with finerenone by its mechanism, but it's dramatically less.

Dr Vega: I find that withdrawal from clinical trials is always such an important statistic to follow, because that really has clinical implications with my patients.

So, with that, finerenone was shown to safely and effectively reduce kidney disease progression and cardiovascular events in patients with T2D. And the first-in-class nonsteroidal MRA joined the ranks of SGLT2 inhibitors as a cardiorenal risk-reducing agent. Since these two classes have different mechanisms of action, what about using them in combination? Let’s pay another visit to Dr Bakris.

Can you tell us what’s known about using SGLT2 inhibitors and nonsteroidal MRAs in combination?

Dr Bakris: That's an excellent question that you asked, so let me see if I can shed some light on it. Participants in FIDELITY were on an ACE inhibitor or ARB at maximal tolerated doses. That’s standard of care. There were a relatively small number of patients taking an SGLT2 inhibitor -- around 7% -- and the cardiorenal benefits of finerenone were shown to be independent of the SGLT2 inhibitor use, because SGLT2s were not part of the protocol. Ideally, patients with T2D and CKD and an eGFR below 60 regardless of albuminuria should be on a RAS inhibitor, an SGLT2 inhibitor, and finerenone, the so-called 3 pillars of treatment now in nephrology approaching the same model as heart failure cardiologists. Otherwise, we’re not maximizing the benefit to the patient.

Dr Vega: It’s great to have these options. How should the drugs be sequenced?

Dr Bakris: Keep in mind that all 3 of these drugs – the RAS inhibitor, SGLT2 inhibitor, and finerenone -- can cause an initial drop in eGFR. I suggest the following: start with a maximally tolerated dose of an ACE inhibitor or ARB. Once they’re stable on that, in about 1 to 2 weeks, you can start either an SGLT2 inhibitor, especially if glucose is an issue and their GFR will tolerate it, or finerenone if glucose is not an issue or their GFR is low. Either one is fine. Keep in mind that it's not an either or, it's an and.

If the patient is on a diuretic, I would say you may want to hold the diuretic for a week to alleviate any further fall in eGFR, because the diuretic will potentially make it worse, especially if the volume is depleted. Finerenone does have some small diuretic properties in people with reasonable kidney function, eGFR above 60 -- the equivalent of about 5 mg of hydrochlorothiazide, so very minimal effects, but nevertheless, something to be considered in the treatment plan.

Dr Vega: Sage advice from Dr Bakris. And a fascinating look at the history of successful interventions to protect patients with type 2 diabetes and CKD from renal decline and cardiovascular events. The treatment approach for type 2 diabetes and kidney disease has evolved and, as clinicians, we need to reframe the way that we think about risk factor reduction. We need to expand our focus beyond blood glucose lowering, beyond blood pressure lowering, and think of drugs that reduce cardiorenal risk independent of these traditional risk factors.

On behalf of Dr Bakris and myself, we have enjoyed spending this time with you. This concludes Episode 1 of this season’s CME-TV: Chronic Kidney Disease in Type 2 Diabetes. We hope you found it informative and helpful to your practice. Please continue on to answer the questions that follow and complete the evaluation for your CME credit. And now, for the last time, be sure to check back next month for Episode 2 – a special CME-TV patient case presentation, “To Screen or Not to Screen for Chronic Kidney Disease.”

This transcript has been edited for style and clarity.

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