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Chronic kidney disease causes and symptoms:

Chronic kidney disease (CKD) is a gradual loss of kidney function leading to renal failure. The disease is often associated with type 2 diabetes (T2D) and around 40% of the T2D patients develop CKD. [1]

The condition develops when the kidneys are damaged and become unable to filter blood normally. Patients may experience problems associated with fluid, electrolytes, and waste build-up due to improper filtration, and the disease can increase the risk of developing heart disease.

CKD can shorten the life expectancy of patients with diabetes by up to 16 years, relative to the general population with neither disease. [2]

The current standard of care leaves patients open to the risks of inflammation and fibrosis, a largely unaddressed driver of CKD progression. [3-5]

 

Heart failure causes and symptoms:

Globally more than 60 million people are living with heart failure (HF), with approximately half of these people characterized by a mildly reduced (HFmrEF) or preserved left ventricular ejection fraction (HFpEF). [6,7]

HFpEF is the leading cause of hospitalizations in elderly and associated with considerable mortality. Importantly, the prevalence of heart failure is expected to increase drastically over the next decades. An estimated 160 million patients globally are living with chronic kidney disease and Type 2 Diabetes. They are at high risk of experiencing cardiovascular events, as well as progressing to end-stage renal disease. [8]

HF with left ventricular ejection fraction (LVEF) ≥40% is often accompanied by multimorbidity, including obesity, chronic kidney disease and diabetes mellitus, making the management of patients challenging and aggravating outcomes.
It often manifests as the first cardiovascular (CV) event. Symptoms are often overlooked and diagnosis is made too late, resulting in delayed implementation of treatment as well. [9,10]

 

Finerenone mechanism of action:

Finerenone is a selective antagonist of the mineralocorticoid receptor (MR). Activated by aldosterone and cortisol, the nonsteroidal MRA regulates gene transcription. The overexpression of the MR is believed to contribute to fibrosis and inflammation [11,12].

The drug inhibits MR-mediated sodium reabsorption as well as MR overexpression in both epithelial (kidney) and nonepithelial (heart and blood vessel) tissues.

Finerenone has a high potency and selectivity for the MR but no significant affinity for androgen, progesterone, oestrogen, or glucocorticoid receptors.

 

Clinical trials on finerenone:

Two large studies (see below) investigated the effects of finerenone on clinical outcomes in patients with type 2 diabetes and chronic kidney disease. The first study (FIDELIO-DKD) examined kidney disease outcomes, and the second study (FIGARO-DKD) examined cardiovascular outcomes [13,14].

The finerenone clinical trial program enrolled 13,000 patients with a wide spectrum of disease severity, including those with early kidney impairment and those in more advanced stages of kidney disease.

FIDELITY, a comprehensive analysis of the FIDELIO-DKD and FIGARO-DKD trials focusing on the interplay between CKD and heart failure, showed that the cardiovascular benefits of finerenone were consistent across eGFR and UACR categories, indicating that treatment should be initiated in the early stages of kidney disease. [15]

The Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure (FINEARTS-HF) was designed to test the hypothesis that finerenone, in addition to usual therapy, would reduce the rate of total worsening heart failure events and death from cardiovascular causes among patients with heart failure and mildly reduced or preserved ejection. Finerenone resulted in a significantly lower rate of a composite of total worsening heart failure events and death from cardiovascular causes (the primary outcome) than placebo. It was associated with better patient-reported health status as well as an increased risk of hyperkalemia but a decreased risk of hypokalemia. [16]

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FIDELIO-DKD - [Clinical Trial Information]

Finerenone vs Placebo for CKD Outcomes in Patients with T2D and CKD, NEJM 2020 - [PubMed Abstract]


Findings:
In patients with CKD and T2D, treatment with finerenone resulted in lower risks of CKD progression
and cardiovascular events than placebo.

Primary outcome:
Composite of kidney failure, a sustained decrease of at least 40% in the eGFR from
baseline over a period of at least 4 weeks, or death from renal causes

Outcome

Finerenone

Placebo

HR (95 % CI), p-value

Primary composite outcome

17.8%

21.1%

0.82 (0.73 - 0.93), p=0.001

Kidney failure

7.3%

8.3%

0.87 (0.72 - 1.05)

GFR decrease ≥ 40%

16.9%

20.3%

0.81 (0.72 - 0.92)

Death from renal causes

<0.1%

<0.1%

N/A

Overall mortality

7.7%

8.6%

HR 0.90, 95%CI [0.75 - 1.07]

Hyperkalemia

18.3%

9%

N/A

Serious hyperkalemia

1.6%

0.4%

N/A

 

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FIGARO-DKD - [Clinical Trial Information]

Finerenone vs Placebo for CVD Outcomes in Patients with T2D and CKD, NEJM 2021 - [PubMed Abstract]


Findings:
Among patients with T2D and stage 2 to 4 CKD with moderately elevated albuminuria or stage 1 or 2 CKD with
severely elevated albuminuria, finerenone therapy improved cardiovascular outcomes as compared with placebo.

Primary outcome:
Composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke,
or hospitalization for heart failure

Outcome

Finerenone

Placebo

HR (95 % CI), p-value

Primary composite outcome

12.4%

14.2%

0.87 (0.76 - 0.98), p=0.03

Death from CV causes

5.3%

5.8%

0.90 (0.74 - 1.09]

Nonfatal myocardial infarction

2.8%

2.8%

0.99 (0.76 - 1.31)

Nonfatal stroke

2.9%

3.0%

0.97 (0.74 - 1.26)

Hospitalization for heart failure

3.2%

4.4%

0.71 (0.56 - 0.90)

Overall mortality

9.0%

10.1%

0.89 (0.77 - 1.04)

Hyperkalemia

10.8%

5.3%

N/A

Serious hyperkalemia

0.7%

0.1%

N/A

 

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CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; HR, hazard ratio; MR, mineralocorticoid receptor; MRA, mineralocorticoid receptor antagonist; T2D, type 2 diabetes

 

References: 1. Alicic RZ, et al. Clin J Am Soc Nephrol. 2017;12(12):2032–2045. 2. Wen CP, et al. Kidney Int. 2017;92(2):388–396. 3. Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. Kidney Int. 2020;98(4S):S1–S115. 4. Cosentino F, et al; ESC Scientific Document Group. Eur Heart J. 2020;41(2):255–323. 5. Tuttle KR, et al. Am J Kidney Dis. 2021;77(1):94–109. 6. Shahim B, et al. Card Fail Rev. 2023 Jul 27;9:e11. 7. Savarese G, et al. Cardiovascular Research, Volume 118, Issue 17, December 2022. 8. Bozkurz B, et al. J Card Fail. 2024 Sep 14:S1071-9164(24)00232-X. 9. House AA, et al. Kidney Int. 2019 Jun;95(6):1304-1317. 10. Abdin A, et al. ESC Heart Fail. 2021 Oct 16;8(6):4444–4453. 11. Bärfacker L, et al. ChemMedChem. 2012;7(8):1385-403. 12. Kolkhof P, et al. Cardiovasc Pharmacol. 2014;64(1):69-78. 13. Bakris GL, et al. N Engl J Med 2020;383:2219–2229 14. Pitt B, et al. N Engl J Med 2021;10.105. 15. Agarwal R, et al. Eur Heart J. 2022 Feb 10;43(6):474-484. 16. Solomon SD, et al. N Engl J Med . 2024 Oct 24;391(16):1475-1485.