You are leaving Medscape Education
Cancel Continue
Log in to save activities Your saved activities will show here so that you can easily access them whenever you're ready. Log in here CME & Education Log in to keep track of your credits.


Updates on Clinical Use of Non-Steroidal Mineralocorticoid Receptor Antagonists in the Management of Chronic Kidney Disease in Patients With Type 2 Diabetes

  • Authors: Matthew R. Weir, MD; Charles P. Vega, MD
  • CME / ABIM MOC Released: 1/4/2023
  • Valid for credit through: 1/4/2024, 11:59 PM EST
Start Activity

  • Credits Available

    Physicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™

    ABIM Diplomates - maximum of 0.25 ABIM MOC points

    You Are Eligible For

    • Letter of Completion
    • ABIM MOC points

Target Audience and Goal Statement

This activity is intended for nephrologists, diabetologists, endocrinologists, cardiologists, primary care physicians, and nurses.

The goal of this activity is for learners to be more knowledgeable about management of the potential side effects of nonsteroidal mineralocorticoid receptor antagonists (MRAs) in the treatment of chronic kidney disease (CKD) in type 2 diabetes (T2D).

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Clinical trial data for new therapies for patients with CKD and T2D
    • Risk mitigation and side effect management for nonsteroidal MRAs for CKD in T2D


Medscape, LLC requires every individual in a position to control educational content to disclose all financial relationships with ineligible companies that have occurred within the past 24 months. Ineligible companies are organizations whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.

All relevant financial relationships for anyone with the ability to control the content of this educational activity are listed below and have been mitigated. Others involved in the planning of this activity have no relevant financial relationships.


  • 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


  • Matthew R. Weir, MD

    Professor of Medicine
    Chief of Nephrology Division
    Department of Medicine
    University of Maryland School of Medicine
    Baltimore, Maryland


    Matthew R. Weir, MD, has the following relevant financial relationships:
    Consultant or advisor for: Akebia Therapeutics; AstraZeneca Pharmaceuticals LP; Bayer; Boehringer Ingelheim Pharmaceuticals, Inc.; FibroGen, Inc.; Janssen; Merck; Novo Nordisk; Vifor Pharma


  • Anne G. Le, PharmD

    Senior Medical Education Director, Medscape, LLC


    Anne G. Le, PharmD, has no relevant financial relationships.

  • Kim Storck, PharmD, RPh

    Senior Director, Medical Writing, Medscape, LLC


    Kim Storck, PharmD, RPh, has no relevant financial relationships.

Compliance Reviewer

  • Susan L. Smith, MN, PhD

    Associate Director, Accreditation and Compliance, Medscape, LLC


    Susan L. Smith, MN, PhD, has no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has no relevant financial relationships.

Accreditation Statements


Interprofessional Continuing Education

In support of improving patient care, Medscape, LLC is jointly accredited with commendation by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

    For Physicians

  • Medscape, LLC designates this enduring material for a maximum of 0.25 AMA PRA Category 1 Credit(s)™ . Physicians should claim only the credit commensurate with the extent of their participation in the activity.

    Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 0.25 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Aggregate participant data will be shared with commercial supporters of this activity.

    Contact This Provider

For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact [email protected]

Instructions for Participation and Credit

There are no fees for participating in or receiving credit for this online educational activity. For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board.

This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period that is noted on the title page. To receive AMA PRA Category 1 Credit™, you must receive a minimum score of 70% on the post-test.

Follow these steps to earn CME/CE credit*:

  1. Read about the target audience, learning objectives, and author disclosures.
  2. Study the educational content online or print it out.
  3. Online, choose the best answer to each test question. To receive a certificate, you must receive a passing score as designated at the top of the test. We encourage you to complete the Activity Evaluation to provide feedback for future programming.

You may now view or print the certificate from your CME/CE Tracker. You may print the certificate, but you cannot alter it. Credits will be tallied in your CME/CE Tracker and archived for 6 years; at any point within this time period, you can print out the tally as well as the certificates from the CME/CE Tracker.

*The credit that you receive is based on your user profile.


Updates on Clinical Use of Non-Steroidal Mineralocorticoid Receptor Antagonists in the Management of Chronic Kidney Disease in Patients With Type 2 Diabetes

Authors: Matthew R. Weir, MD; Charles P. Vega, MDFaculty and Disclosures

CME / ABIM MOC Released: 1/4/2023

Valid for credit through: 1/4/2024, 11:59 PM EST


Activity Transcript

Charles P. Vega, MD: Imagine that there is a game show buzzer in front of you. Maybe on your desk, on your lap, on the forehead of the person sitting next to you. And as soon as you know the answer to the question I'm about to ask, I want you to slap the buzzer. Ready? What is the leading cause of kidney failure requiring transplantation or dialysis? Diabetes. Marcel, you were the first to answer. And you are correct. Diabetes. Diabetes is the leading cause of kidney failure worldwide, followed closely by high blood pressure. As many as 40% of people with diabetes will develop chronic kidney disease in their lifetime. And this includes a significant portion who will progress to kidney failure, dialysis, and transplantation. In fact, half of all new cases of kidney failure are caused by diabetes. And, unfortunately, there's more. CKD increases the risk of atherosclerotic cardiovascular disease, heart failure, and death among patients with diabetes. But stick with me, here. The intent isn't to paint a picture of doom and gloom. Actually, just the opposite. Kidney function can be preserved, and cardiovascular risk can be reduced in patients with diabetes and CKD. It is very possible for these patients to live long and happy lives without needing dialysis or a transplant.

Hello and welcome to our final episode in 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. The estimated prevalence of CKD in the United States is 37 million adults, that's 15% of the population. And CKD is more common in Black or African Americans, Hispanics, and Native Americans. CKD is frequently underdiagnosed. In fact, 9 out of 10 people don't know they have it. In the ADD-CKD study of adults with type 2 diabetes, only 22% of patients with stage 3 to 5 CKD were identified as having CKD by their primary care physician. Awareness increases as CKD severity worsens but by then, there may be little kidney function left to preserve.

In this season's CME-TV series, our eyes have been opened to healthcare disparities in kidney disease and factors contributing to those inequities. We've learned when and how to screen our patients with type 2 diabetes for CKD. How to diagnose CKD. And most importantly, we're learning what to do about CKD if it's detected.

We introduced the novel concept of cardiorenal risk-reducing drugs in this season's first episode. And in this 4th and final episode, we'll travel to Baltimore to meet Dr Matt Weir, professor of medicine and chief of nephrology at the University of Maryland Hospital, where we'll learn how to use these agents shown to slow kidney disease progression and protect the hearts of patients with CKD and type 2 diabetes.

So, how should we get to Baltimore? That seat looks taken. That may be a bit bumpy. Aaah, now there's the ticket. Race ya.

Well, here we are.

Matthew R. Weir, MD: Thanks for the ride. At one point, I thought we were going to take flight.

Dr Vega: I'm saving that trick for the ride home.

So, tell us, how do we lower the risk of cardiorenal events in our patients with type 2 diabetes?

Dr Weir: Well, It's the big 3. Blood pressure control. Glucose control. And proteinuria reduction. We start by using more intensive guideline-based therapeutic approaches to get the systolic blood pressure below 130 mm Hg. Improve glycemic control with an HbA1c less than 7%. And we make sure the patient is on the highest possible tolerated dose of an ACE or an ARB. But here's the thing -- even though you lower the blood pressure, improve the glycemic control and give them an ACE or an ARB, it only provides about a 20% relative risk reduction benefit. So there is still a huge unmet need to slow kidney disease progression and prevent cardiovascular events. This is where the SGLT2 inhibitors and nonsteroidal MRAs come in. Both recently gained regulatory approval for treatment in patients with CKD and type 2 diabetes. And, with their approval, we now have new therapies to actualize cardiorenal disease prevention.

Dr Vega: And you said nonsteroidal MRAs, which is different from the steroidal MRAs we're more familiar with.

Dr Weir: Yes, that's correct. Steroidal MRAs have been around a long time – like spironolactone and eplerenone – and have been used for decades to treat hypertension, primary aldosteronism, and systolic heart failure. However, steroidal MRAs are associated with hyperkalemia, gynecomastia, and female menstrual disorders, which limits their clinical utility in some patients. The newer nonsteroidal MRAs have no significant affinity or activity at androgen, progesterone, and glucocorticoid receptors. They're selective for the mineralocorticoid receptor, so they have a more manageable side effect profile. There's also less influence on serum potassium levels at the doses studied for cardiorenal protection. This makes the nonsteroidal MRAs much more facile to use in clinical practice because of their safety.

Dr Vega: And what is their safety profile, exactly?

Dr Weir: Well, there are 2 nonsteroidal MRAs approved for treatment – esaxerenone and finerenone. In Japan, esaxerenone is approved for primary hypertension and has been studied in diabetic nephropathy to reduce albuminuria. Finerenone is the first nonsteroidal MRA approved by the FDA in the US to reduce cardiorenal events, specifically in patients with CKD and type 2 diabetes. From a clinical standpoint, nonsteroidal MRAs have various advantages over steroidal MRAs with proven benefit in patients with type 2 diabetes and CKD and an improved safety profile. The most notable side effect is a slight change in serum potassium – around 0.2 milliequivalents per liter with finerenone. So, if you start with a potassium level of 4.8 -- on average -- it can increase to 5.0, which is manageable. But you still need to routinely monitor potassium as you would in any clinical situation.

Dr Vega: And that's what they did in finerenone's FIDELIO trial, right?

Dr Weir: Yes, the enrollment criteria required a potassium level of less than 4.8 during screening and run-in. The phase 3 trials also implemented strict potassium monitoring and hyperkalemia risk mitigation strategies that were carried over into the prescribing information. In a nutshell, if serum potassium is above 5, do not start finerenone. If between 4.8 and 5, you can consider starting finerenone but need to frequently measure potassium during the first 4 weeks. If less than or equal to 4.8, you can start finerenone and measure it after 4 weeks. Finerenone's starting dose is based on the patient's estimated GFR: if their estimated GFR is greater than or equal to 60, then 20 mg daily is the recommended starting dose. If their eGFR is greater than or equal to 25 and less than 60, a starting dose of 10 mg daily is recommended. Measure potassium 4 weeks after starting finerenone, 4 weeks after a dose adjustment, and throughout treatment -- adjusting the dose as necessary. Finerenone treatment should not be initiated in patients with an eGFR less than 25.

Dr Vega: Is there guidance on how to adjust the dose?

Dr Weir: Yes, based on serum potassium. The guidance in this table is taken straight from the package insert. If the patient is on 10 mg, and serum potassium is less than or equal to 4.8, increase the dose to 20 mg. If potassium is greater than 4.8 but less than 5.5, maintain the 10 mg dose. If serum potassium is greater than 5.5, withhold finerenone. And then consider restarting at the 10 mg dose when potassium levels are less than or equal to 5. If the patient is on 20 mg, and potassium levels are between 4.8 and 5.5, maintain the 20 mg dose. If potassium levels rise above 5.5, withhold finerenone. And consider restarting at the 10 mg dose when potassium levels are less than or equal to 5. Withholding finerenone can effectively manage hyperkalemia because it has a short half-life of about 2 to 3 hours, and there are no active metabolites. Whereas spironolactone has a long half-life and multiple active metabolites. Finerenone is also equally distributed between the heart and kidneys, whereas, spironolactone and eplerenone accumulate in higher concentrations in the kidney. And this may contribute to their higher risk for hyperkalemia.

Dr Vega: Are there certain patient groups at higher risk for hyperkalemia?

Dr Weir: Yes, certainly there are. Risk increases in patients with worsening kidney function, diabetes, higher baseline serum potassium, and of course, ACE, ARB, and/or beta-blocker use.

Dr Vega: So similar to the population studied in finerenone's FIDELIO trial?

Dr Weir: Yes. Patients in FIDELIO-DKD had a high intrinsic risk of hyperkalemia because of their advanced CKD, type 2 diabetes, and treatment with optimized doses of an angiotensin-converting enzyme (ACE inhibitors) or an angiotensin receptor blocker (ARB). But, routine potassium monitoring and management reduced hyperkalemia's clinical impact. In a post-hoc safety analysis of FIDELIO-DKD study, the benefits of finerenone outweighed the risk for hyperkalemia over a median period of 2.6 years of follow-up.

Dr Vega: Finerenone was studied in the largest cardiorenal outcomes program to date across the spectrum of CKD in type 2 diabetes. It was specifically designed to investigate the occurrence of cardiovascular events and kidney disease progression. More than 13,000 patients were enrolled into 2 independent phase 3 trials, FIDELIO DKD and FIGARO DKD. FIDELIO had a primary renal endpoint and FIGARO had a primary cardiovascular endpoint. Then a pre-specified single-patient analysis of both studies was conducted – and called FIDELITY. In the FIDELITY dataset, treatment with finerenone led to a significant 23% reduction in the composite kidney outcome and a 14% reduction in the combined cardiovascular disease endpoint. This netted out to a 1.6% absolute reduction in adverse kidney events and a 1.7% absolute reduction in cardiovascular events over 3 years of treatment.

Alright, now that we have that straight, let's get back before Dr Weir notices that we're gone.

So, FIDELITY was a prespecified analysis and pooled the data for more than 13,000 patients from FIDELIO and FIGARO. What can we glean about the safety of finerenone from FIDELITY?

Dr Weir: Well, I think this large data set provided a very important opportunity to evaluate finerenone's therapeutic index – its benefit-to-risk ratio. FIDELITY encompassed the full range of kidney disease severity -- from an estimated glomerular filtration rate (GFR) of 25 up to 90. And overall, safety outcomes were similar between finerenone and placebo over 3 years follow up. Finerenone improved cardiorenal outcomes but was associated with twice as many hyperkalemia-related adverse events -- 14% of patients vs 6.9% of placebo-treated patients. No hyperkalemia-related adverse events were fatal, although they led to permanent treatment discontinuation for 1.7% of patients on finerenone and 0.6% of patients on placebo. Hospitalization rates due to hyperkalemia were less than 1% -- 0.9% with finerenone vs 0.2% with placebo to be exact.

Dr Vega: Was potassium intake restricted during the trials?

Dr Weir: No, but whether you're using an ACE, an ARB, or a nonsteroidal MRA, patients should be counseled on dietary potassium intake. Outside of diet, nonsteroidal anti-inflammatory drugs can raise serum potassium, as can many over-the-counter vitamin supplements that contain potassium or potassium-sparing diuretics. And as clinicians, we need to learn how to carefully adjust the dosing of RAS inhibitors and nonsteroidal MRAs and use them safely. RAS inhibitors are guideline-recommended, disease-modifying therapies. But they are widely underprescribed. Often because of concern over changes in creatinine and potassium.

And the data from large clinical studies with finerenone basically show that if you have a potassium level of 4.8 or less before you start patients on finerenone, there's a less than 2% chance that you're going to have an increase in serum potassium, and an even lower percentage of patients who would actually have to stop the drug because potassium was a concern, which means 98% of patients are going to benefit in a safe and effective manner.

Dr Vega: In October 2022, the American Diabetes Association and KDIGO -- which is an international panel of experts in nephrology -- published a consensus report addressing how to optimize slowing the progression of CKD while also applying best practices for controlling glycemia and minimizing other diabetes complications. Go ahead. Check it out. A major thrust of the consensus is guidance on the use of newer cardiorenal risk-reducing drugs – specifically sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, and nonsteroidal MRAs.

We've talked about clinical trial data, risk mitigation, and side effect management for the nonsteroidal MRAs. But what about the SGLT2 inhibitors? Let's head back to Baltimore and see what Dr Weir has to say.

That might take too long.

That's better. I'll see you there.

Can you tell us how SGLT2 inhibitors have transformed the management of diabetic kidney disease from a cardiorenal perspective?

Dr Weir: SGLT2 inhibitors were originally developed to treat hyperglycemia in patients with diabetes; that was all. And they were shown in clinical trials to be effective at lowering serum glucose. But glucose-lowering therapies cannot receive FDA approval until it's proven that they don't increase the risk of major adverse cardiovascular events. This evidence is typically generated through cardiovascular safety outcomes trials. When the antihyperglycemic class of SGLT2 inhibitors were evaluated by these large, randomized outcomes trials, they demonstrated cardiorenal protective properties, well beyond their ability to lower glucose.

Dr Vega: Can you summarize those trials for us?

Dr Weir: To date, 3 clinical trials with primary kidney disease outcomes have been published. The CREDENCE trial using canagliflozin in patients with CKD and type 2 diabetes, DAPA-CKD using dapagliflozin in patients with CKD with or without type 2 diabetes, and EMPA-KIDNEY using empagliflozin, also in patients with CKD with or without diabetes. These trials demonstrated significant benefit for composite outcomes including endpoints of substantial estimated GFR decline, kidney failure, and death. These trials enrolled participants with albuminuria; therefore, current evidence is strongest in this population. But evidence from combined major SGLT2 inhibitor trials suggests cardiorenal benefits regardless of baseline albumin excretion.

Dr Vega: And is it correct that the lower limit of eGFR for which initiation of SGLT2 inhibitor is recommended has recently changed?

Dr Weir: Yes it has. It was lowered to 20 mL/min in the KDIGO 2022 guidelines and by the ADA in its living Standards of Care. So, the guidance is now for patients with T2D, CKD, and estimated GFR greater than or equal to 20 to be treated with an SGLT2 inhibitor that has demonstrated cardiorenal benefit.

Dr Vega: And what about side effects with SGLT2 inhibitors? How can we mitigate risk?

Dr Weir: There's an increased risk of genital mycotic infections and urinary tract infections. But the risk for UTIs is "questionable" because it wasn't supported in larger clinical trials. Most of the time, these infections can be managed with topical antifungal medications. And maintaining personal hygiene lowers risk of infection. An initial increase in diuresis at the start of SGLT2 inhibitor therapy should be anticipated, but absolute risks are low. Adjustment of background therapies is generally not required but it may be prudent in some patients -- like those on loop diuretics -- to follow-up to reassess volume status and glycemia during treatment.

The risk of serious adverse events with SGLT2 inhibitors is low. Euglycemic diabetic ketoacidosis may occur, particularly in patients with type 2 diabetes requiring insulin, those with restricted carbohydrate intake, or history of alcohol abuse. But otherwise it's rare, occurring in less than 1 per 1000 patient years. In CREDENCE, the rate of DKA with canagliflozin was 2.2 per 1000 patient years vs 0.2 with placebo, but in DAPA-CKD, there were no cases of DKA reported with dapagliflozin.

In the last 20 years, ACEs and ARBs have been the only classes of agents recommended for patients with CKD and hypertension, with or without type 2 diabetes. Although these drugs reduce CKD progression to about a 4 to 5 mL/min/year loss, we still didn't have a way to normalize the rate of decline to 0.8 mL/min/year -- the rate associated with normal aging. But ACE inhibitors and ARBs, SGLT2 inhibitors, and finerenone work by complementary mechanisms to protect the kidneys and heart. So now, it seems that we can finally celebrate the availability of new agents that slow CKD progression in diabetes from the 10 to 12 mL per year loss we saw in the 1980s to the approximate 3 mL/min/year loss that we see today.

Dr Vega: Fantastic. You ready to get out of here.

Dr Weir: You bet. I'm ready to rock and roll. Let's go do it.

Dr Vega: Alright.

Ladies and gentlemen, this has been one heck of a ride. On behalf of everyone who has participated in this series -- Dr Weir and his patient Valdez, Dr Bakris and his patient Jerry, and myself, we've enjoyed spending this time with you. Please continue on to answer the questions that follow this episode and complete the evaluation for your CME credit. And if you missed any of the first 3 episodes, we encourage you to check them out. I'm Chuck Vega, signing off for the last time from season 2 of CME-TV: Chronic Kidney Disease in Type 2 Diabetes. 3...2...1.

This transcript has not been copyedited.

« Return to: Updates on Clinical Use of Non-Steroidal Mineralocorticoid Receptor Antagonists in the Management of Chronic Kidney Disease in Patients With Type 2 Diabetes
  • Print