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Cardiorenal Benefits of Finerenone in the Treatment of Diabetic Kidney Disease

Allyson Ellsworth, PharmD Candidate, Class of 2023, 

Ben and Maytee Fisch College of Pharmacy

Lourdes Cross, PharmD, BCACP, CDCES,

Sullivan University College of Pharmacy & Health Sciences

Both type 2 diabetes (T2D) and chronic kidney disease (CKD) are becoming increasingly prevalent within the United States. Currently, over twenty million adults have T2D, and 20-40% of these patients are expected to develop some form of CKD.1 Further, kidney disease development plays a role in increased cardiovascular (CV) disease. 

Finerenone is a novel nonsteroidal, selective mineralocorticoid receptor antagonist (MRA) that has shown positive renal and CV outcomes in patients with kidney disease and T2D. This medication works by antagonizing mineralocorticoid receptors in both the nonepithelial cells of the heart and blood vessels and in the epithelial cells of the kidney. In turn, sodium reabsorption is hindered, and fibrosis and inflammation are reduced. Unlike other MRAs such as spironolactone, finerenone has little affinity for estrogen, progesterone, androgen, and glucocorticoid receptors. Another major difference is that steroidal MRAs act primarily on the kidneys, while nonsteroidal MRAs act equally on the kidneys and heart.2 Historically, MRA medications have not been used in CKD because of the high risk of hyperkalemia. However, this effect is lower with nonsteroidal MRAs.

In July 2021, the FDA approved finerenone (brand name: Kerendia) for the treatment of adult patients with CKD associated with T2D. It is specifically indicated to decrease decline in kidney function and failure, nonfatal atherosclerotic events, CV death, and hospitalization for heart failure.3 Initial support for this indication was based on results from the FIDELIO-DKD trial. The FIGARO-DKD trial provided additional support for the use of finerenone in patients with T2D and CKD.

FIDELIO-DKD

FIDELIO-DKD was a randomized, placebo-controlled, double-blind trial designed to determine the cardiorenal outcomes associated with the use of finerenone in those with T2D and associated CKD.4 5674 patients were randomized to receive either placebo or oral finerenone at a 1:1 ratio in addition to maximum tolerated renin-angiotensin system (RAS) blockers. For the purposes of inclusion, the study defined CKD with two differing criteria. The first criteria set included an estimated glomerular filtration rate (eGFR) between 25 to 60 mL/minute/1.73 m2, diabetic retinopathy, and a moderate elevation in urinary albumin-to-creatinine ratio (UACR) of 30 to 300 mg/g. The second set of inclusion criteria consisted of a UACR of 300 to 5000 mg/g with an eGFR between 25 to 75 mL/minute/1.73 m2. Finerenone was administered at a starting dose of 10 or 20 mg based on initial eGFR and titrated up or down as needed based on potassium levels. The primary composite outcome was time to renal mortality, kidney failure, or overall decline of ≥40% in eGFR from baseline over a period of at least 4 weeks. The key secondary composite outcome included time to CV mortality, nonfatal myocardial infarction (MI), nonfatal stroke, and heart failure hospitalization. Follow up for patients was an average of 2.6 years. 

Baseline characteristics

• Age: 65.6 years
• Sex: 70.2% male
• Diabetes duration: 16.6 years
• Mean eGFR: 44.3 ml/min/1.73 m2
• Median UACR: 852 mg/g
• Medications:
• ACE-inhibitor: 34.2%
• Angiotensin-receptor blocker: 65.7%
• Diuretic: 56.6%
• Statin: 74.3%
• Potassium-lowering agent: 2.4%
• Glucose-lowering agent: 97.4%
• SGLT2 inhibitor: 4.6%

The primary composite outcome of decline in eGFR, kidney failure, or death from renal causes occurred less in the finerenone group compared to the placebo group, 17.8% versus 21.2%, respectively (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.73 to 0.93; P= 0.001). The key secondary composite outcome was also lower in the treatment arm compared to the placebo, 13.0% versus 14.8%, respectively (HR, 0.86; CI, 0.75 to 0.99; P= 0.03). Investigator-reported hyperkalemia was higher in the finerenone group compared to placebo (18.3 versus 9.0%), with a maximal difference of 0.23 mmol/liter observed at month 4. Treatment discontinuation due to hyperkalemia was 2.3% with finerenone and 0.9% with placebo.

FIGARO-DKD

The FIGARO-DKD trial sought to further investigate the potential risks and CV benefits of finerenone in patients with T2D and a wider range of CKD.5 Specifically, the FIGARO-DKD trial included 7437 patients with an eGFR between 25 and 90 mL/min/1.73m2 and moderately elevated albuminuria (UACR 30 to 300 mg/g) or those with an eGFR >60 mL/min/1.72m2 and severely elevated albuminuria (UACR 300 to 5000 mg/g). All the patients were treated with RAS blockade. Participants in the finerenone group received a starting dose of 10 or 20 mg based on initial eGFR. Titration to the 20 mg dose was encouraged if the serum potassium level was ≤4.8 mmol/L. The primary composite outcome was time to CV mortality, nonfatal MI, nonfatal stroke, or hospitalization for heart failure. The median follow-up was 3.4 years.

Baseline characteristics

• Age: 64.1 years
• Sex: 69.4% male
• A1C: 7.7±1.4%
• Mean eGFR: 67.8 ml/min/1.73 m2
• Median UACR: 308 mg/g
• Medications:
• Renin-angiotensin system inhibitor: 99.9%
• Diuretic: 47.6%
• Statin: 70.5%
• Glucose-lowering agent: 97.9%
• SGLT2 inhibitor: 8.4%

This trial demonstrated clinically significant improvement in CV outcomes with finerenone compared to placebo. The primary outcome occurred in 12.4% patients in the finerenone group and in 14.2% patients in the placebo group (HR, 0.87; 95% CI, 0.76-0.98; P=0.03). This outcome was primarily driven by the lower incidence of heart failure hospitalizations. There was not a statistically significant difference in the secondary composite outcome of kidney failure, a sustained decrease in eGFR of ≥40% from baseline, or renal death with finerenone compared to placebo (9.5% vs 10.5%, respectively; HR, 0.87; 95% CI, 0.76-1.01). More patients in the finerenone group discontinued treatment due to hyperkalemia (1.2%) compared to placebo (0.4%). 

Discussion

Ultimately, both studies demonstrated that finerenone can improve CV and renal outcomes across a wide range of CKD in patients with T2D who are receiving maximum tolerated RAS blockade. The most common adverse effect was hyperkalemia, though this rarely led to permanent discontinuation of finerenone. Of the currently FDA-approved MRAs, finerenone is the first MRA to receive an indication for CKD associated with T2D. It is unknown how finerenone compares to SGLT2 inhibitors, if one should be preferred over the other for cardiorenal protection, or if both classes should be used together. In the FIDELIO-DKD and FIGARO-DKD trials, 4.6% and 8.4% of patients, respectively, were on an SGLT2 inhibitor at baseline.

Per the 2022 American Diabetes Association Standards of Care, SGLT2 inhibitors are a preferred class in patients with T2D and CKD.6  Finerenone is recommended in those with T2D and CKD who are at increased risk for disease progression and CV-related events and in those who are unable to use SGLT2 inhibitors. It is likely that there will be greater use of SGLT2 inhibitors in this patient population because of their expanding indications (i.e., heart failure, CKD), inclusion in national clinical guidelines, and glucose-lowering effects. However, there is a possibility that the use of finerenone with RAS blockade and SGLT2 inhibitors may offer additional cardiorenal benefits in those with T2D and CKD. Further, finerenone may be an option if a patient is unable to tolerate these classes.

References

1. Lytvyn Y, Godoy LC, Scholtes RA, van Raalte DH, Cherney DZ. Mineralocorticoid antagonism and diabetic kidney disease. Curr Diab Rep. 2019;19(1):4.
2. Agarwal R, Kolkhof P, Bakris G, et al. Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine. Eur Heart J. 2021;42(2):152-161. 
3. Bayer HealthCare Pharmaceuticals Inc. Kerendia. 2021.
4. 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.
5. Pitt B, Filippatos G, Agarwal R, et al. Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N Engl J Med. 2021;385(24):2252-2263. 
6. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes - 2022. Diabetes Care. 2022;45:Suppl 1):S125-S143.