Aldosterone synthase inhibitors for cardiorenal protection: ready for prime time?

Background: Aldosterone, through its genomic and non-genomic effects, plays an important role in cardiovascular and renal injury. Steroidal mineralocorticoid receptor antagonists (MRAs) are fundamental to offset the aldosterone-mediated cardiorenal damage, but side effects may limit their use in a substantial proportion of patients. On the other hand, non-steroidal mineralocorticoid receptor antagonists (NS-MRA) showed improved selectivity and safety profile. However, interfering with the MRA could only partially inhibit aldosterone mediated effect both because of escaping mechanisms and potential non-genomic activity.

Summary: Inhibiting aldosterone synthesis could be a promising strategy to abolish aldosterone-mediated cardiovascular side effects. Aldosterone is primarily synthesized by the CYP11B2 enzyme, which is very similar to CYP11B1, a key enzyme involved in glucocorticoid production. Lack of specificity for CYP11B2 and consequent off-target effects hampered the development of first-generation aldosterone synthase inhibitors (ASIs). The subsequent development of highly specific ASIs led to successful clinical trials in patients with resistant and uncontrolled hypertension.

Key messages: A recent randomized clinical trial showed a significant benefit of ASIs in patients with chronic kidney disease and albuminuria. However, further outcome based clinical trials are needed to confirm the promising role of ASIs in cardiorenal damage.