Finerenone is now available on the Pharmaceutical Benefits Scheme (PBS) for the treatment of chronic kidney disease (CKD) with type II diabetes.
Finerenone is a mineralocorticoid receptor antagonist. The mineralocorticoid receptor plays an important role in the regulation of blood pressure and fluid and electrolyte balance. The main ligand for this receptor is aldosterone, a hormone produced in the adrenal glands. Aldosterone acts on mineralocorticoid receptors in epithelial tissues (e.g. kidney and colon) as well as nonepithelial tissues (e.g. heart and vasculature). Activation of mineralocorticoid receptors in the kidney increases sodium and water reabsorption, resulting in increased blood pressure.
Aldosterone may also contribute to structural changes as a result of hypertrophy and tissue remodelling. Its stimulation of cell proliferation in the kidneys may be an important contributory factor in the progression of CKD. Excessive activation of mineralocorticoid receptors may also result in tissue injury, such as myocardial and vascular fibrosis.
Mineralocorticoid receptor antagonists
Other mineralocorticoid receptor antagonists on the market are spironolactone and eplerenone. These agents may also reduce fibrosis, inflammation, and adverse remodelling in the kidneys and cardiovascular system. However, their use may be limited by the risk of hyperkalaemia. Spironolactone may also be associated with endocrine adverse effects, such as gynaecomastia and menstrual changes.
Of the three mineralocorticoid antagonists currently available, finerenone is the only non-steroidal agent. Compared to steroidal mineralocorticoid antagonists, finerenone is more potent and distributes more evenly between the kidneys and the heart. A comparison of mineralocorticoid receptor antagonists can be seen in Table 1.
Table 1. Comparison of mineralocorticoid receptor antagonists
|Indications||CKD with type II diabetes||Hypertension, oedema, primary hyperaldosteronism, hirsutism||Heart failure|
|Distribution||Equal between heart and kidney||Higher concentrations in renal tissue compared to heart|
|Half maximal inhibitory concentration (IC50)|
The IC50 values in Table 1 provide an indication of the potency of these agents at different receptor types. These figures signify how much of the drug (in nanomoles) is required to inhibit the receptors by 50% in vitro, i.e. higher values indicate weaker inhibition.
The IC50 values demonstrate that finerenone may overcome some of the selectivity issues associated with spironolactone and the low potency associated with eplerenone. Finerenone has high selectivity for the mineralocorticoid receptor, which is responsible for the desired pharmacological action. Affinity at androgen, progesterone, estrogen, and glucocorticoid receptors is considered insignificant. This higher selectivity avoids some of the adverse effects associated with spironolactone.
The FIDELIO-DKD study investigated the effect of finerenone on kidney and cardiovascular outcomes in patients with CKD and type II diabetes. Patients treated with the maximally tolerated dose of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) were randomly assigned to receive finerenone or placebo. Finerenone was initiated at 20mg daily, or 10mg daily for patients with an estimated glomerular filtration rate (eGFR) of less than 60 ml/minute/1.73 m2. The lower doses could be increased after one month if renal function and serum potassium remained stable.
The primary composite outcome in this study was kidney failure, a sustained reduction in the eGFR of at least 40% from baseline, or death from renal causes. The key secondary composite outcome was death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, or hospitalisation for heart failure. The median follow-up period was 2.6 years.
The incidence of the primary composite outcome was significantly lower in the finerenone group compared to the placebo group (17.8% vs 21.1%), as was the incidence of key secondary outcomes (13.0% vs 14.8%). While the incidence of non-fatal stroke was similar between the groups, all other components of the key secondary outcome were lower for finerenone.
Most of the patients in the FIDELIO-DKD study had advanced CKD, which may limit the generalisability of the results. The more recently published FIGARO-DKD trial sought to address this issue by including patients with a wider range of kidney impairment (stages 1-4 CKD). Patients treated with maximal tolerated doses of an ACE inhibitor or ARB were randomly assigned to receive finerenone or placebo.
The primary outcome in this study was a composite of death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, or hospitalisation for heart failure. A secondary outcome was a composite of the first occurrence of kidney failure, sustained reduction in eGFR of at least 40%, or death from renal causes. The median follow-up period was longer at 3.4 years.
The incidence of the primary composite outcome was significantly lower in the finerenone group than in the placebo group (12.4% vs 14.2%). This difference was primarily driven by a reduction in hospitalisation for heart failure in the finerenone group. Interestingly, patients with symptomatic chronic heart failure with a reduced ejection fraction were excluded from this trial. As heart failure (new-onset or preexisting) confers a very high risk for hospitalisation and death in patients with CKD and type II diabetes, finerenone may offer benefits in the management of heart failure in this population.
The incidence of the first secondary composite outcome was also lower in the finerenone group compared to placebo (9.5% vs 10.8%), although this did not reach significance.
A comparison of the two trials can be seen in Table 2.
Table 2. Comparison of the FIDELIO-DKD and FIGARO-DKD trials (adapted from KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease)
|Number of participants||5734||7437|
|Proportion with CVD||45.4%||44.7|
|eGFR and ACR at enrolment||25–<60 ml/min/1.73 m2 and ACR 30–<300 mg/g
OR 25–<75 ml/min/1.73 m2
and ACR 300-5000 mg/g
|25–90 ml/min/1.73 m2 and ACR 30–<300 mg/g
OR ≥60 ml/min/1.73 m2
and ACR 300–5000 mg/g
|Mean eGFR at enrolment||44||68|
|Proportion with eGFR <60 ml/min/1.73 m2||88.4%||38.2%|
|Median ACR at enrolment||850mg/g||309mg/g|
|Proportion with ACR ≥300mg/g||87.5%||50.7%|
|Median follow-up||2.6 years||3.4 years|
|Primary outcome||Kidney composite: kidney failure, a sustained decrease ≥40% in GFR, renal death||CV composite: death from CV causes, nonfatal MI, nonfatal stroke, or hospitalisation for HF|
|Main secondary outcome||CV composite: death from CV causes, nonfatal MI, nonfatal stroke, or hospitalisation for HF||Kidney composite: kidney failure, a sustained decrease ≥40% in GFR, renal death|
|Kidney composite outcome result||HR: 0.82; 95% CI: 0.73–0.93||HR: 0.87; 95% CI: 0.76–1.01|
|Cardiovascular composite outcome result||HR: 0.86; 95% CI: 0.75–0.99||HR: 0.87; 95% CI: 0.76–0.98|
In the FIDELIO-DKD study, the incidence of adverse effects was similar in the finerenone and placebo groups. Serious adverse events were reported in 31.9% of the patients in the finerenone group and 34.3% of the placebo group. Hyperkalaemia occurred in almost twice as many patients in the finerenone group compared to the placebo group (15.8% vs 7.8%), although this was only considered serious in 1.6% of the study group (compared to 0.4% in the placebo group). Other commonly reported adverse reactions include hyponatraemia, hypotension, and reduced GFR.
The incidence of adverse effects was similar in the FIGARO-DKD study. Hyperkalaemia was less commonly reported (10.8% for finerenone and 5.2% for placebo), with serious hyperkalaemia occurring in only 0.7% of patients receiving finerenone. This may reflect the higher mean eGFR in this trial.
Hyperkalaemia can occur in advanced CKD and type II diabetes. It may also be exacerbated by medications such as ACE inhibitors, ARBs, and mineralocorticoid receptor antagonists. The Mineralocorticoid Receptor Antagonist Tolerability Study helps put the risk of hyperkalaemia in perspective. The incidence of hyperkalaemia in patients taking finerenone (10mg daily) was compared to patients taking spironolactone (25-50mg daily). Finerenone was associated with a significantly lower risk of hyperkalaemia (4.5% vs 11.1%).
Place in therapy
Diabetes is a significant cause of CKD. The KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease provides recommendations for the care of patients with type II diabetes and CKD, including:
- Lifestyle measures (diet, exercise, weight control, smoking cessation);
- First-line medication options (metformin, ACE inhibitor or ARB, sodium-glucose cotransporter 2 (SGLT2) inhibitor, statin); and
- Additional drugs with heart and kidney protection (non-steroidal mineralocorticoid receptor antagonists).
Finerenone is the only non-steroidal mineralocorticoid receptor antagonist currently approved for use in Australia. It is indicated to delay the progressive decline in kidney function in patients with CKD associated with type II diabetes.
Patients with CKD and type II diabetes may qualify for PBS-subsidised finerenone therapy if they meet the following criteria:
- No known significant non-diabetic renal disease prior to initiating treatment;
- eGFR of at least 25 mL/min/1.73 m2 prior to initiating treatment;
- Urinary albumin-to-creatinine ratio of at least 200 mg/g (22.6 mg/mmol) prior to initiating treatment;
- Stabilised for at least four weeks prior to initiation of finerenone on either an ACE inhibitor or ARB, unless medically contraindicated;
- The treatment must be in combination with an SGLT2 inhibitor unless medically contraindicated or intolerant;
- Treatment must not be in combination with another selective non-steroidal mineralocorticoid receptor antagonist, a renin inhibitor, or a potassium-sparing diuretic;
- The patient must not have established heart failure with reduced ejection fraction with an indication for treatment with a mineralocorticoid receptor antagonist; and
- Finerenone treatment must be discontinued prior to initiating renal replacement therapy (i.e. dialysis or kidney transplant).
- Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 2020; 383: 2219-29.
- Dymala K. How finerenone compares to other mineralocorticoid receptor antagonists. Pharmacy Times; 2022.
- Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int. 2022; 102(5S): S1–S127.
- Pandey AK, Bhatt DL, Cosentino F, Marx N, Rotstein O, Pitt B, et al. Non-steroidal mineralocorticoid receptor antagonists in cardiorenal disease. Eur Heart J. 2022; 43(31): 2931-45.
- Pitt B, Filippatos G, Agarwal R, Anker SD, Bakris GL, Rossing P, et al. Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N Engl J Med. 2021; 385: 2252-63.
- Pitt B, Kober L, Ponikowski P, Gheorghiade M, Filippatos G, Krum H, et al. Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial. Eur Heart J. 2012; 34(31), 2453-63.
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