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CE: Nonsteroidal Mineralcorticoid Receptor Antagonists in Diabetic Kidney Disease

06 Apr 2022 11:17 AM | Anonymous

Authors: Stephanie Chau PharmD and Sarah Billings PharmD, BCACP, CDCES

Program Number: 2202-02-03
Approved Dates:  April 1, 2022 - October 1, 2022
Approved Contact Hours:  One Hour(s) (1) CE(s) per session

Objectives

  1. Compare the difference between the nonsteroidal mineralcorticoid receptor antagonist finerenone to steroidal mineralocorticoid receptor antagonists
  2. Assess literature on cardiovascular and renal effects of finerenone in type 2 diabetics with diabetic kidney disease
  3. Review other medications with cardiovascular and renal benefits used in type 2 diabetics

Background

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD) and is associated with an increase in mortality in diabetics1. Chronic kidney disease (CKD) and diabetes mellitus lead to an additive effect that increases the cardiovascular mortality rate. The current mainstay of therapy used to reduce the progression of DKD are angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Sodium-glucose co-transporter-2 (SGLT2) inhibitors further decrease the progression of DKD, incidence of major adverse cardiovascular events, and heart failure hospitalizations.

Mineralocorticoid receptor antagonists (MRA) have been shown to reduce albuminuria in patients with CKD when given alone or with renin-angiotensin system (RAS) blockers and reduce overall mortality in patients with heart failure. Albuminuria reduction is a main factor of improving renal outcomes in patients with CKD. A 30% or greater reduction in albumin that is sustained for at least 2 years is considered to be a validated surrogate for slowing down CKD progression1. The addition of spironolactone or eplerenone to RAS blockers to improve renal outcomes is unclear in patients with DKD since there is limited renal outcome data. An issue with steroidal MRAs such as spironolactone and eplerenone is they are associated with an increase in serum potassium. The potential benefits and adverse events of steroidal and non-steroidal MRAs in DKD patients will be compared.

Non-steroidal vs Steroidal Mineralocorticoid Receptor Antagonists

While both non-steroidal and steroidal MRAs block aldosterone activity, the effects on potassium levels are different. Spironolactone is a potent steroidal MRA, has a long half-life, and relatively low selectivity since it also acts on progesterone and androgen receptors as well. One of the most important side effects of spironolactone is hyperkalemia. Eplerenone is another steroidal MRA with higher receptor specificity, but is still associated with hyperkalemia especially at a higher dose of 200 mg1. Both spironolactone and eplerenone are associated with a three-to-eight-fold increased risk of hyperkalemia in stage 3 CKD or higher patients1.

Non-steroidal MRAs include the agents apararenone, esaxerenone, and finerenone. Finerenone has a high potency and selectivity for mineralocorticoid receptors and acts as an inverse agonist. It has a greater receptor selectivity compared to spironolactone. Finerenone has stronger mineralocorticoid receptor binding affinity compared to eplerenone and a lower affinity for androgen, progesterone, and glucocorticoid receptors similar to eplerenone. Compared to steroidal MRAs, finerenone has a reduced blood pressure lowering effect since it is unable to cross the blood-brain barrier and does not inhibit central mineralocorticoid receptors. However, finerenone is expected to have a lower risk of hyperkalemia compared to steroidal MRAs. This is thought to be due to a balanced kidney and heart distribution of finerenone while spironolactone and eplerenone are mostly distributed in the kidney compared to the heart. Also finerenone has no active metabolites and a shorter half-life of 2 hours compared to spironolactone which has a half-life of 14-16 hours with active metabolites. Eplerenone has no active metabolites, but has a slightly longer half-life of 4-6 hours2. However, finerenone is still dosed based potassium levels, which requires routine monitoring.

Table Finerenone vs Traditional Steroidal Mineralocorticoid Receptors Antagonists1


Table 2 Dosing of Finerenone3

Finerenone Tolerability

The ARTS studies looked at the tolerability of MRAs in heart failure in DKD. The study included patients with chronic systolic heart failure and stage 3 CKD who received finerenone, placebo, or open-label spironolactone. Finerenone was associated with smaller increases in serum potassium levels compared to spironolactone and a reduced incidence of hyperkalemia. The ARTS-DN trial and ARTS-HF trial looked at tolerability of finerenone in DKD and heart failure, which showed that finerenone was safe and efficacious.

The ARTS-DN study was a randomized, double-blind, parallel-group placebo-controlled trial that compared efficacy and safety of different once-daily doses of finerenone compared to placebo for 90 days in patients with type 2 diabetes who had high or very high albuminuria. High albuminuria is defined as a urine to albumin creatinine ratio (UACR) 30 mg/g and very high albuminuria is defined as UACR 300 mg/g. This study had all patients receive an ACE inhibitor or ARB, have albuminuria (UACR 30 mg/g), have an estimated glomerular filtration rate (eGFR) greater than 30 mL/min/1.73 m2 with serum potassium levels less than or equal to 4.8 mmol/L. The doses of finerenone varied from 1.25, 2.5, 5, 7.5, 10, 15, and 20 mg daily. The primary outcome of the study was the ratio of UACR at day 90 vs at baseline. Finerenone doses of 7.5-20 mg daily showed a dose-dependent reduction in the UACR with the largest reduction in the 20 mg daily group at day 904. The study observed a mean change in serum potassium of 0.2-0.25 mmol/L in the 20 mg daily finerenone group4. Hyperkalemia and discontinuation of finerenone was observed in 1.8% of patients who received 7.5-20 mg daily compared to zero patients in the placebo group4. There were two cases of serum potassium levels greater than 6 mmol/L in the finerenone 1.25 mg group, and 1 in the 15 mg group only4. There was not a difference in the incidence of an eGFR decrease of at least 30% between finerenone and placebo4. There was also no difference in the overall difference in the incidence of adverse events between both groups4.

The ARTS-HF study evaluated the effectiveness and safety of finerenone in heart failure with reduced ejection fraction (HFrEF) and type 2 diabetes and/or CKD stage 3 or higher patients compared to eplerenone. The patients also had to require hospitalization and treatment with emergency intravenous diuretics. In this study patients received finerenone 2.5 to 20 mg daily and eplerenone 25 to 50 mg daily. The primary outcome of this study was the percent of patients who had a decrease in N-terminal pro-B-type natriuretic peptide (NT-proBNP) level of >30% from baseline to day 90. About 30.9% to 38.8% of patients in the finerenone group compared to 37.2% of patients in the eplerenone group had a >30% decrease in NT-proBNP levels from baseline to day 905. Finerenone had a greater benefit in the composite endpoint of cardiovascular hospitalization, death from any cause, and emergency presentation for worsening heart failure at day 90. The most benefit was seen with a finerenone dose of 10-20 mg daily (HR: 0.56, 95% CI: 0.35-0.90, P=0.02) mostly due to a reduction in cardiovascular hospitalization5. Overall there were a total of 44 patients with hyperkalemia ( 5.6 mmol/L) and these were balanced between the finerenone and eplerenone group5. There were 5 patients in the eplerenone group and 4 in the finerenone group who had potassium concentrations >6.0 mmol/L at any point after baseline. The mean change in potassium from baseline to day 90 was greater in the epelerenone group (0.262 mmol/L) compared to the finerenone groups (0.119-0.202 mmol/L)5.

Finerenone Trials on Progression of Diabetic Kidney Disease

The FIDELIO-DKD trial evaluated the efficacy and safety of finerenone, in addition to the standard of care, on the progression of CKD in type 2 diabetics and advanced CKD. The study included patients who were at least 18 years old or older with type 2 diabetes with an established clinical diagnosis of CKD who were already being treated with maximally tolerated RAS blocker therapy. Patients with heart failure with reduced ejection fraction were excluded. Patients received finerenone 10 mg daily if they had an eGFR of 25-59 mL/min/1.73 m2 and 20 mg daily for an eGFR greater or equal to 60 mL/min/1.73 m2 or placebo. Patients had a serum potassium of 4.8 mmol/L or less upon study entry. Either finerenone or placebo were held if potassium concentration exceeded 5.5 mmol/L. Finerenone or placebo were restarted when potassium levels fell to 5.0 mmol/L or less. The average dose of finerenone was 15.1 mg daily. The primary composite outcome was kidney failure, a sustained decrease of at least 40% in the eGFR from baseline over at least 4 weeks, or death from renal causes. The main secondary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. The median follow-up time was 2.6 years and the primary outcome event occurred in 504 (17.8%) patients in the finerenone group and 600 (21.1%) in the placebo group (HR: 0.82; 95% CI: 0.73-0.93; P=0.001)6. This benefit was mostly due to a reduction in the sustained decrease of at least 40% in eGFR from baseline (HR: 0.81, 95% CI: 0.72-0.92). There was not a statistically significant difference in the incidence of kidney failure or death from renal causes. However a total of 4.6% of patients were on a SGLT2 inhibitor, which have been shown to have renal benefits as well. The secondary outcome occurred in 367 (13.0%) patients in the finerenone group and 420 (14.8%) in the placebo group (HR: 0.86; 95% CI: 0.75-0.99; P=0.03)6. Finerenone was associated with a 31% greater reduction in the UACR from baseline to month four compared to placebo (ratio of least-squares mean change from baseline: 0.69; 95% CI: 0.66-0.71)6. A total of 252 (8.9%) of finerenone patients compared to 326 (11.5%) of placebo patients had a secondary composite kidney outcome event which included kidney failure, a sustained decrease of 57% or greater in the eGFR from baseline, or death from renal causes (HR: 0.76; 95% CI: 0.65-0.90)6. The incidence of hyperkalemia-related adverse events was more frequent in the finerenone group compared to placebo (18.3% and 9.0% respectively)6. The incidence of hyperkalemia-related discontinuation was higher in the finerenone group compared to placebo (2.3% and 0.9% respectively), but no fatal hyperkalemia adverse events were reported6. This study showed a statistically significant benefit in kidney outcomes and cardiovascular benefit with finerenone with the main adverse event being hyperkalemia.

The FIGARO-DKD trial evaluated the effectiveness of finerenone in reducing major cardiovascular event and death from cardiovascular cause in type 2 diabetics with CKD. The study included patients who were at least 18 years old or older with type 2 diabetes and CKD stage 2 to 4 with moderately elevated albuminuria or stage 1 or 2 CKD with severely elevated albuminuria who were receiving a RAS inhibitor. Patients with symptomatic chronic heart failure with reduced ejection fraction and patients highly represented in the FIDELIO-DKD trial (UACR of 300-5000 mcg/mg and eGFR of 25 to less than 60 mL/min/1.73 m2) were excluded. Patients received finerenone 10 mg once daily if eGFR was 25 to less than 60 mL/min/1.73 m2 and 20 mg once daily if eGFR was at least 60 mL/min/1.73 m2 or placebo. Patients had a serum potassium of 4.8 mmol/L or less upon study entry and finerenone or placebo were held if potassium concentration exceeded 5.5 mmol/L. Finerenone or placebo were restarted when potassium levels fell to 5.0 mmol/L or less. The average dose of finerenone received was 17.5 mg daily. The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. The main secondary outcome was a composite of the first occurrence of kidney failure, a sustained decrease from baseline of at least 40% in the eGFR for a period of at least 4 weeks, or death from renal causes. The median follow up time was 3.4 years and the primary outcome event occurred in 458 (12.4%) in the finerenone group compared to 519 (14.2%) in the placebo group (HR: 0.87; 95% CI: 0.76-0.98; P=0.03)7. The number needed to treat to prevent one primary outcome event was 47 based on a between group difference of 2.1% after 3.5 years7. More specifically, there was a lower incidence of hospitalization for heart failure in the finerenone group compared to placebo (HR: 0.71; 95% CI: 0.56-0.90)7. However 8.4% of patients were also on SGLT2 inhibitors, which have also been shown to have cardiovascular and heart failure benefits. The secondary composite outcome occurred in 350 (9.5%) in the finerenone group compared to 395 (10.8%) in the placebo group (HR: 0.87; 95% CI: 0.76-1.01)7. The reduction in the UACR from baseline to month 4 was 32% greater in the finerenone group compared to the placebo group (ratio of the least-squares mean change from baseline: 0.68; 95% CI: 0.65-0.70)7. The incidence of hyperkalemia was higher in the finerenone group compared to placebo (10.8% and 5.3%), but no adverse events resulted in death7. Hyperkalemia led to discontinuation in 1.2% in the finerenone group compared to 0.4% of placebo patients7. The incidence the composite outcome of kidney failure occurred in 108 (2.9%) patients in the finerenone group compared to 139 (3.8%) in the placebo group (HR: 0.77; 95% CI: 0.60-0.99)7. This study showed a statistically significant benefit in cardiovascular events mostly due to a reduction in heart failure hospitalizations, but the benefit in kidney outcomes was not statistically significant. 

Table 3 FIDELIO-DKD vs FIGARO-DKD Trials6,7

Esaxerenone Trial on the Progression Diabetic Kidney Disease

The ESAX-DN investigated the effects of esaxerenone on microalbuminuria defined as a UACR 45 to <300 mg/g creatinine in type 2 diabetes patients receiving RAS inhibitors. The primary outcome was UACR remission defined as a <30 mg/g creatinine and a  30% reduction from baseline on two consecutive occasions. The study included 455 type 2 diabetes patients with microalbuminuria who received esaxerenone 1.25 mg and titrated to 2.5 mg daily or placebo. After 52 weeks, the esaxerenone showed a significantly increased incidence of UACR remission (22%) compared to the placebo group (4%) with an absolute difference of 18% (95% CI: 12%-25%; P<0.001)8. The change in UACR from baseline was a 58% decrease in the esaxerenone group compared to 8% in the placebo group8. Furthermore there was a significant improvement in time to first remission and time to first UACR 300 mg/g creatinine. Hyperkalemia was observed in 9% in the esaxerenone group compared to 2% in the placebo group, but the events were asymptomatic8. Hyperkalemia was resolved after dosage reduction or treatment discontinuation. Esaxerenone in addition to a RAS inhibitor in patients with type 2 diabetes and microalbuminuria increased the incidence albuminuria returning to normal and reduced the progression of albuminuria to higher levels. However, esaxerenone has only been approved in Japan for the treatment of hypertension since January 2019.

Other Agents with Cardiorenal Benefits

Newer antihyperglycemic agents, which include SGLT2 inhibitors and GLP-1 receptor agonists have also been shown to have cardiorenal benefits. The SGLT-2 inhibitors that have shown cardiovascular benfit include empagliflozin and canagliflozin9. In addition, dapagliflozin and empagliflozin have shown a benefit in heart failure as well9. The SGLT-2 inhibitors that have shown renal benefits as the primary outcome include dapagliflozin and canagliflozin9. The GLP-1 receptor agonists that have shown cardiovascular benefit include albiglutide, dulaglutide, liraglutide and semaglutide (injection)9. The cardiovascular and renal benefits of these SGLT-2 inhibitors and GLP-1 receptor agonists have become the preferred agents used in type 2 diabetics.

Table 4 Agents with Cardiorenal Benefits in Type 2 Diabetics

Application to Practice

The FIDELIO-DKD study showed renal benefits and the FIGARO-DKD study showed cardiovascular benefits with finerenone in type 2 diabetics with CKD in addition to guideline recommended RAS blockers, cardiovascular medications, and well-controlled hemoglobin A1c levels and blood pressure levels. In addition, both trials covered a wide spectrum of CKD stage 2 to stage 4 with moderately elevated albuminuria or stage 1 to stage 4 CKD with severely elevated albuminuria. The FIDELIO-DKD trial showed a statistically significant decrease from baseline of at least 40% in the eGFR, but the FIGARO-DKD trial showed a decrease that was not statistically significant difference as a secondary outcome. The FIGARO-DKD did show a significant cardiovascular benefit, but it was mostly due to a reduction in heart failure hospitalizations. There is a need for more data to determine whether combination therapy with finerenone will result in greater cardiorenal protection in patients with DKD. In addition, the ESAX-DN trial also showed that esaxerenone is beneficial in returning albuminuria to normal and reducing the progression of albuminuria in type 2 diabetes patients with microalbuminuria. However esaxerenone is not available in the United States. One of the major concerns with use of MRAs is the increase serum potassium, but finerenone has been showed to have a lower incidence of hyperkalemia compared to spironolactone making it a better option for patients with DKD. Dosing for finerenone is adjusted based on serum potassium levels which requires frequent potassium monitoring especially during initaition. Currently finerenone is only available under the brand name Kerendia with an estimated cash price of $680 for a 30 day supply. There are savings programs available for patients who qualify, but cost is still a major concern for this medication. Overall, finerenone is another agent that provides cardiorenal benefits for patients with DKD.

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References

  1. Al Dhaybi O, Bakris GL. Non-steroidal mineralocorticoid antagonists: Prospects for renoprotection in diabetic kidney disease. Diabetes Obes Metab. 2020;22(Suppl.1):69-76. doi:10.1111/dom.13983
  2. Kawanami D, Takashi Y, Muta Y, et al. Mineralocorticoid receptor antagonists in diabetic kidney disease. Front Pharmacol. 2021;12. doi:10.3389/fphar.2021.754239
  3. AHFS DI. Lexicomp. UpToDate, Inc,; 2021. Updated periodically. Accessed December 2021. http://online.lexi.com
  4. Bakris GL, Agarwal R, Chan JC, et al. Effect of Finerenone on Albuminuria in Patients With Diabetic Nephropathy: A Randomized Clinical Trial. JAMA. 2015;314(9):884–894. doi:10.1001/jama.2015.10081
  5. Filippatos G, Anker SD, Böhm M, et al. A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease. Eur Heart J. 2016;37(27):2105-2114. doi:10.1093/eurheartj/ehw132
  6. Bakris GL, Agarwal R, Anker SD, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 2020;383(23):2219-2229. doi:10.1056/nejmoa2025845
  7. Pitt B, Filippatos G, Agarwal R, et al. Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N Engl J Med. August 2021. doi:10.1056/nejmoa2110956
  8. Ito S, Kashihara N, Shikata K, et al. Esaxerenone (CS-3150) in Patients with Type 2 Diabetes and Microalbuminuria (ESAX-DN): Phase 3 Randomized Controlled Clinical Trial. Clin J Am Soc Nephrol. 2020;15(12):1715-1727. doi:10.2215/CJN.06870520
  9. Rangaswami J, Bhalla V, de Boer IH, Staruschenko A, Sharp JA, Singh RR, Lo KB, Tuttle K, Vaduganathan M, Ventura H, McCullough PA; on behalf of the American Heart Association Council on the Kidney in Cardiovascular Disease; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; and Council on Lifestyle and Cardiometabolic Health. Cardiorenal protection with the newer antidiabetic agents in patients with diabetes and chronic kidney disease: a scientific statement from the American Heart Association. Circulation. 2020;142:e265–e286. doi:10.1161/CIR.0000000000000920

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