Original Abstract

Cardiovascular-kidney-metabolic (CKM) syndrome is defined by the pathologic interconnections between obesity, diabetes, chronic kidney disease and cardiovascular disease. An important and underrecognized pathophysiologic factor underlying CKM syndrome is obesity-induced aldosterone excess. This excess aldosterone causes structural and functional alterations in the kidneys, heart and vasculature promoting development of chronic kidney disease, cardiovascular disease and heart failure. Inhibition of aldosterone signalling is a pillar in the treatment approach to CKM syndrome. Pharmacologic options include renin-angiotensin-aldosterone system (RAAS) inhibitors, angiotensin receptor-neprilysin inhibitors and steroidal (such as spironolactone) or non-steroidal (currently only finerenone) mineralocorticoid receptor antagonists. Additionally, aldosterone synthase inhibitors are currently in development. Effective anti-obesity medications such as glucagon-like peptide-1 receptor agonists inhibit aldosterone production due to their effects on adipocytes and in the kidneys. RAAS inhibition is also used to optimize the long-term management of CKM syndrome. Future research should seek to characterize the benefits of combination therapies for aldosterone excess and determine which subgroups of patients most benefit from aldosterone-targeted therapies.