Abstract
The stimulation of mineralocorticoid receptors is linked to the development of hypertension and cardiovascular or renal damage in patients with diabetes, and the blockade of these receptors may be an effective treatment option. This open-label study with a 12-week treatment period assessed the antihypertensive (primary) and antialbuminuric (secondary) efficacy and safety of esaxerenone as an add-on therapy to a renin–angiotensin system inhibitor in hypertensive patients with type 2 diabetes and albuminuria (urinary albumin-creatinine ratio 30 to <1000 mg/g•Cr). Esaxerenone was administered over 12 weeks at a starting dosage of 1.25 mg/day, which was gradually titrated to 2.5 mg/day and 5 mg/day at weeks 4, 6, or 8 according to the dosage-escalation criteria based on serum K+ levels, the estimated glomerular filtration rate, and the likelihood/occurrence of hypotension. Of the 51 patients enrolled, 44 (86.3%) reached an esaxerenone dosage of 2.5 or 5 mg/day. The changes from the baseline in sitting systolic and diastolic blood pressures were −13.7 mmHg (p < 0.05) and −6.2 mmHg (p < 0.05), respectively. Significant decreases in blood pressure occurred regardless of age, baseline systolic blood pressure, glycated hemoglobin level, and estimated glomerular filtration rate. The urinary albumin-creatinine ratio decreased by 32.4% from the baseline (p < 0.05). Two consecutive serum K+ measurements ≥ 5.5 mEq/L occurred in one patient but resolved after dosage reduction. Esaxerenone showed antihypertensive and antialbuminuric effects and a low risk of hyperkalemia with dosage titration from 1.25 mg in Japanese hypertensive patients with type 2 diabetes and albuminuria receiving a renin–angiotensin system inhibitor.
Highlights
Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Aldosterone, the final product of the renin–angiotensin system (RAS), is involved in the regulation of blood electrolytes and body fluid volume by acting on the mineralocorticoid receptor (MR), a nuclear receptor in renal tubular and intestinal epithelial cells, to promote Na+ reabsorption and K+ excretion [1]
Significant reductions in systolic BP (SBP) and diastolic BP (DBP) (−13.7 and −6.2, p < 0.05 vs baseline) were observed during 12 weeks of treatment with esaxerenone, and the antihypertensive effects of the regimen studied were similar to those observed in studies of patients with essential hypertension treated with esaxerenone 2.5 mg/day [25] (NCT02890173, unpublished data)
Another study investigated the antihypertensive effects of eplerenone 50 or 100 mg/day added to angiotensin converting enzyme (ACE) inhibitor therapy in patients with type 2 diabetes (n = 91 and n = 86, respectively) and reported significant reductions in blood pressure (BP) from the baseline [15]
Summary
Aldosterone, the final product of the renin–angiotensin system (RAS), is involved in the regulation of blood electrolytes and body fluid volume by acting on the mineralocorticoid receptor (MR), a nuclear receptor in renal tubular and intestinal epithelial cells, to promote Na+ reabsorption and K+ excretion [1]. Aldosterone reduces the production of nitric oxide, a vascular relaxing factor, via MRs in vascular endothelial cells [2] and acts directly on vascular smooth muscle to constrict blood vessels [3, 4]. MR blockers, including spironolactone and eplerenone, have been developed and are commercially available as antihypertensive agents. The sustained activation of renal MRs is implicated in metabolic diseases, such as diabetes, via RASdependent and independent mechanisms, and can
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