Search

Modulation of the renin-angiotensin-aldosterone system is a foundation of therapy for cardiovascular and kidney diseases. Excess aldosterone plays an important role in cardiovascular disease, contributing to inflammation, fibrosis, and dysfunction in the heart, kidneys, and vasculature through both genomic and mineralocorticoid receptor (MR)-mediated as well as nongenomic mechanisms. MR antagonists have been a key therapy for attenuating the pathologic effects of aldosterone but are associated with some side effects and may not always adequately attenuate the nongenomic effects of aldosterone. Aldosterone is primarily synthesized by the CYP11B2 aldosterone synthase enzyme, which is very similar in structure to other enzymes involved in steroid biosynthesis including CYP11B1, a key enzyme involved in glucocorticoid production. Lack of specificity for CYP11B2, off-target effects on the hypothalamic-pituitary-adrenal axis, and counterproductive increased levels of bioactive steroid intermediates such as 11-deoxycorticosterone have posed challenges in the development of early aldosterone synthase inhibitors such as osilodrostat. In early-phase clinical trials, newer aldosterone synthase inhibitors demonstrated promise in lowering blood pressure in patients with treatment-resistant and uncontrolled hypertension. It is therefore plausible that these agents offer protection in other disease states including heart failure or chronic kidney disease. Further clinical evaluation will be needed to clarify the role of aldosterone synthase inhibitors, a promising class of agents that represent a potentially major therapeutic advance. [ABSTRACT FROM AUTHOR]

Despite existing treatments, patients with heart failure and chronic kidney disease (CKD) remain at high risk for adverse outcomes and progression to end-stage disease. Steroidal mineralocorticoid receptor antagonists (MRAs) such as spironolactone and eplerenone reduce mortality but remain under-prescribed due to the perceived risk of hyperkalaemia and hormonal side effects. The discovery of non-steroidal MRAs represents a major new dimension in cardiorenal disease therapy. Non-steroidal MRAs have high affinity and specificity for the mineralocorticoid receptor (MR) and differ from both steroidal agents and each other with respect to important physiochemical, pharmacodynamic, and pharmacokinetic parameters. Similar to their steroidal counterparts, they have beneficial anti-inflammatory, anti-remodelling, and anti-fibrotic properties in the kidneys, heart, and vasculature. There are several non-steroidal MRAs under development and clinical assessment; of these, only esaxerenone and finerenone are approved for treatment globally. In Japan, esaxerenone is approved for essential hypertension and has been studied in diabetic nephropathy. Compared with steroidal MRAs, finerenone more potently inhibits MR co-regulator recruitment and fibrosis and distributes more evenly between the heart and kidneys. The landmark Phase III trials FIGARO-DKD and FIDELIO-DKD demonstrated that finerenone-reduced major kidney and cardiovascular events on top of maximally tolerated renin–angiotensin–aldosterone system inhibition in patients with CKD associated with Type 2 diabetes. Non-steroidal MRAs are currently under evaluation in heart failure and for synergistic treatment with sodium–glucose contransporter 2 inhibitors. These ground-breaking agents could become an important therapy across the spectrum of cardiorenal disease. [ABSTRACT FROM AUTHOR]

Efficacy of sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors for heart failure in black patients: a systematic review and meta-analysis of randomized controlled trials Reported rate ratios for the primary outcome from one trial of an ARNI in HFpEF were 0.69 (95% CI 0.24, 1.99) in black patients compared with 0.83 (95% CI 0.71, 0.97; I p i -interaction not provided) in white patients. Black patients have a disproportionately high incidence of heart failure (HF).[1] Black patients present at an earlier age with HF and have worse outcomes compared to non-black patients.[1] Despite this, they are often underrepresented in clinical trials.[2] Targeted trials in this high-risk population such as the African American Heart Failure (A-HeFT) trial have been infrequent.[3] The disparate effects of established classes of HF therapeutics including beta-blockers, renin-angiotensin-aldosterone system (RAAS) inhibitors and mineralocorticoid receptor antagonists (MRAs) according to race have been previously described.[[4]] The efficacy of newer medical therapies in black patients with HF remains an important and unanswered question. Prior analyses have suggested that some HF therapies such as spironolactone may be less effective in black patients.[[4], [22]] Finally, our results highlight the need to increase representation of black patients in HF trials. [Extracted from the article]

Natriuretic effect of two weeks of dapagliflozin treatment in patients with type 2 diabetes and preserved kidney function during standardized sodium intake: results of the DAPASALT trial. Graph: Graphical Abstract class="chapter-para">Emerging role for SGLT2 inhibitors in mitigating the risk of hyperkalaemia in heart failure. Previous data from a cohort of over 200 000 patients with comorbidities requiring RAASi provision demonstrated that hyperkalaemia events led to down-titration of RAASi dose in 16-21% of cases, and complete discontinuation in 22-27%. [Extracted from the article]