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Cardiorenal benefits of mineralocorticoid antagonists in CKD and type 2 diabetes

Lessons from the FIGARO-DKD trial

Kardiorenaler Nutzen von Mineralokortikoidrezeptorantagonisten bei chronischer Nierenerkrankung und Typ-2-Diabetes

Erfahrungen aus der FIGARO-CKD- und FIDELITY-Studie

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Abstract

Diabetic kidney disease (DKD) develops in almost half of all patients with diabetes and is the most common cause of chronic kidney disease (CKD) worldwide. Despite the high risk of chronic renal failure in these patients, only few therapeutic strategies are available. The use of renin–angiotensin system blockers to reduce the incidence of kidney failure in patients with DKD was established years ago and remains the hallmark of therapy. The past 2 years have seen a dramatic change in our therapeutic arsenal for CKD. Sodium–glucose co-transporter‑2 inhibitors (SGLT2s) have been successfully introduced for the treatment of CKD. A further addition is a novel compound antagonizing the activation of the mineralocorticoid receptor: finerenone. Finerenone reduces albuminuria and surrogate markers of cardiovascular disease in patients who are already on optimal therapy. In the past, treatment with other mineralocorticoid receptor antagonists was hampered by a significantly increased risk of hyperkalemia. Finerenone had a much smaller effect on hyperkalemia. Together with a reduced effect on blood pressure and no signs of gynecomastia, this therapeutic strategy had a more specific anti-inflammatory effect and a smaller effect on the volume/electrolyte axis. In the FIDELIO-DKD study comparing the actions of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo, finerenone reduced the progression of DKD and the incidence of cardiovascular events, with a relatively safe adverse event profile. In this article, we summarize the available evidence on the cardioprotective and nephroprotective effects of finerenone and analyze the molecular mechanisms involved. In addition, we discuss the potential future role of mineralocorticoid receptor inhibition in the treatment of patients with diabetic CKD.

Zusammenfassung

Die diabetische Nephropathie ist eine der häufigsten Ursachen der chronischen Nierenerkrankungen und entwickelt sich bei ungefähr der Hälfte aller Patienten mit Diabetes mellitus. Trotz der Häufigkeit der Erkrankung sind die therapeutischen Strategien für die diabetische Nephropathie begrenzt. Lange Zeit war v. a. der Einsatz von Inhibitoren des Renin-Angiotensin-Systems verbunden mit der Blutdrucksenkung die Grundlage der Therapie. In den letzten Jahren sind neue interessante Therapiestrategien eingeführt worden. Zum einen handelt es sich um die sog. SGLT-2-Inhibitoren („sodium–glucose co-transporter‑2 inhibitors“), welche die Progression der chronischen Nierenerkrankung und die Inzidenz der terminalen Niereninsuffizienz nachhaltig beeinflussen. Zum anderen besteht eine Therapiestrategie in neuen Inhibitoren der Mineralokortikoidrezeptoren. Der neue, nichtsteroidale Mineralokortikoidrezeptorantagonist Finerenon reduziert die Albuminurie sowie Surrogatparameter kardiovaskulärer Erkrankungen bei Patienten mit chronischer Niereninsuffizienz und Diabetes, die bereits unter optimaler Therapie stehen. Eine der wichtigen Vorteile dieser Therapiestrategie ist die geringere Auswirkung auf den Kaliumhaushalt als bei anderen Mineralokortikoidrezeptorantagonisten. Dies ist auf eine spezifischere Wirkung dieser Substanz auf Inflammation und Fibrose bei geringerer Wirkung auf den Volumen‑/Elektrolythaushalt und damit auf den Blutdruck zurückzuführen, auch trat keine Gynäkomastie auf. In der FIDELIO-DKD-Studie zum Vergleich der Wirkung von Finerenon mit Placebo verminderte sich unter Finerenon das Fortschreiten der diabetische Nephropathie und die Inzidenz kardiovaskulärer Ereignisse bei einem relativ günstigen Nebenwirkungsprofil. In der vorliegenden Arbeit wird die verfügbare Evidenz zu den kardioprotektiven und nephroprotektiven Wirkungen von Finerenon zusammengefasst und die beteiligten molekularen Mechanismen ausgewertet. Darüber hinaus wird der potentielle zukünftige klinische Stellenwert des Mineralokortikoidrezeptorantagonismus in der Therapie der diabetischen Nephropathie erörtert.

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  1. Hannover Medical School MHH, Carl-Neuberg-Str. 1, 30625, Hannover, Germany

    Hermann Haller MD

  2. Mount Desert Island Biological Laboratory MDIBL, Bar Harbor, USA

    Hermann Haller MD

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H. Haller has received lecture fees from AstraZeneca, Bayer, Vifor, Otsuka, Glaxo and honoraria for consulting from AstraZeneca, Bayer, Vifor, Travere.

For this article no studies with human participants or animals were performed by any of the authors. All studies mentioned were in accordance with the ethical standards indicated in each case.

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Haller, H. Cardiorenal benefits of mineralocorticoid antagonists in CKD and type 2 diabetes. Herz 47, 401–409 (2022). https://doi.org/10.1007/s00059-022-05138-2

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