12th July 2023, Dr Chee L Khoo
It’s almost a year since we foreshadowed the arrival of finerenone and it’s finally on the PBS, albeit with the usual and expected very restricted criteria. We discussed finerenone’s impressive cardiovascular and renal outcomes in patients with heart failure and chronic kidney disease. We further discussed why finerenone is a better mineralo-corticosteroid receptor antagonist (MRA) than what we have at the moment, spironolactone and eplenerone. Elsewhere in the world, finerenone is the preferred MRA in patients with HF. It is worthwhile revising what finerenone is all about.
Remember, there are two different mineralo-corticosteroid agonists – aldosterone and cortisol. Activation of the mineralo-cortisone receptors (MR) by aldosterone leads to the expression of protein transporters (mainly the Na+/K+ pump) regulating ionic and water transports and maintains sodium and potassium homeostasis. The problem is overactivation of the MR leads to inflammation and fibrosis in the heart, kidneys and elsewhere where the MR is extensively expressed. This can drive CKD and CV progression and fibrosis in lungs and blood vessels (1).
MRAs can either be steroidal MRAs (SMRA) (e.g. spironolactone, eplenerone) or non-steroidal MRAs (e.g. finerenone). The SMRAs have medium to long half-life and have sexual side-effects (e.g. gynaecomastia) although eplerenone has reduced affinity for the androgen and progesterone receptors compared with spironolactone and hence, have less gynaecomastia.
Finerenone is a novel, selective, nonsteroidal MRA that blocks MR mediated sodium reabsorption and MR overactivation and has demonstrated anti-inflammatory and anti-fibrotic effects in preclinical kidney and CV disease models (1,2). Finerenone has no or few sexual side effects, very short half-life and very selective in its binding. It also has no CNS penetration and no active metabolites. The SMRAs are indicated for HFrEF only while finerenone has indication for HFrEF as well as CKD.
Because finerenone have cardiovascular and renal benefits, two parallel studies were conducted to test the efficacy and safety of finerenone in reducing cardiovascular as well as renal complications. The Finerenone in reducing kidney failure and disease progression in Diabetic Kidney Disease (FIDELIO-DKD) looked at kidney complications while the Finerenone in reducing cardiovascular mortality and morbidity in Diabetic Kidney Disease (FIGARO-DKD) looked at cardiac complications (3,4).
In the FIDELIO-DKD trial, 5734 patients with CKD and type 2 diabetes (T2D) and uACR of 30-300 mg/g, eGFR 25-60 ml per minute per 1.73 m2 of body surface area and diabetic retinopathy or uACR 300-5000 mg/g and eGFR 25-75 ml per minute per 1.73 m2 of body surface area were randomised to either finerenone or placebo. The primary composite outcome, assessed in a time-to-event analysis, was kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes. Over a median follow up of 2.6 years, treatment with finerenone resulted in 18% lower risks of CKD progression and cardiovascular events than placebo.
In the FIGARO-DKD trial, the subjects were pretty similar to the FIDELIO-DKD trial but this time they looked more at cardiovascular outcomes. The primary outcome, assessed in a time-to-event analysis, was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Over a median follow up of 3.4 years, treatment with finerenone resulted in 13% reduction in cardiovascular outcomes compared with placebo.
Despite finerenone theoretically being less likely to cause hypokalaemia, the incidence of hyperkalaemia-related discontinuation of the trial regimen was higher with finerenone than with placebo although the numbers were low overall (2.3% vs 0.9% and 1.2% vs 0.4% in the finerenone vs placebo in the FIDELIO-DKD and FIGARO-DKD respectively).
We have spironolactone and eplerenone in Australia for treatment of heart failure with reduced ejection fraction (HFrEF) but their use comes with significant incidence of hyperkalaemia and gynaecomastia which limits our use in patients with HFrEF. Further, eplerenone must be initiated in patients within 14 days of a myocardial infarction.
While spironolactone is efficacious in improving cardiovascular outcomes, finerenone improves both cardiovascular and renal outcomes. This is important since most patients with cardiovascular complications also have renal complications.
Now comes the catch: PBS Authority restrictions.
PBS/RPBS Authority required (Streamlined)
Restriction: Chronic kidney disease with Type 2 diabetes
Patients must have diabetic kidney disease AND
* Patient must have an eGFR of ≥ 25 mL/min/1.73 m2 AND
* Patient must have a uACR of ≥ 200 mg/g (22.6 mg/mmol) AND
* Patient must be stabilised, for at least 4 weeks, on either: (i) an ACE inhibitor or (ii) an angiotensin II receptor antagonist, unless medically contraindicated, AND
* The treatment must be in combination with an SGLT2i unless medically contraindicated or intolerant, AND
* Patient must not be receiving treatment with another selective nonsteroidal mineralocorticoid receptor antagonist, a renin inhibitor or a potassium-sparing diuretic, AND
* Patient must not have established heart failure with reduced ejection fraction with an indication for treatment with a mineralocorticoid receptor antagonist.
The approval of finerenone to reduce the progression of disease in DKD is based on the positive findings from the FIDELIO-DKD trial. These patients with DKD are a subset of DKD patients with significant microalbuminuria (uCR > 22.6 mg/mol) as these are what the subjects had in the trials. So, it makes sense to ensure that these patients must be on an ACEi or ARB (unless contra-indicated) AND an SGLT2 inhibitor. Finerenone is not replacing any existing agents but an addition to our current armamentarium of agents to reduce the progression of renal complications.
References:
- Agarwal R, Kolkhof P, Bakris G et al. Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine. Eur Heart J 2021;42:152–161.
- Kolkhof P, Jaisser F, Kim SY, Filippatos G, Nowack C, Pitt B. Steroidal and novel non-steroidal mineralocorticoid receptor antagonists in heart failure and cardiorenal diseases: comparison at bench and bedside. Handb Exp Pharmacol 2017; 243:271–305.
- Bakris GL, Agarwal R, Anker SD et al.; FIDELIO-DKD Investigators. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med 2020;383:2219–2229.
- Pitt B, Filippatos G, Agarwal R et al.; FIGARO-DKD Investigators. Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N Engl J Med 2021. doi:10.1056/NEJMoa2110956.