Efficacy and safety of dosage-escalation of low-dosage esaxerenone added to a RAS inhibitor in hypertensive patients with type 2 diabetes and albuminuria: a single-arm, open-label study

Itoh, Hiroshi; Ito, Sadayoshi; Rakugi, Hiromi; Okuda, Yasuyuki; Nishioka, Satoshi

doi:10.1038/s41440-019-0270-2

Cited by 47 publications

(71 citation statements)

References 48 publications

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“…In our study, the extent of reductions in eGFR during treatment of PA with esaxerenone was similar to that seen with other MR blockers, indicating that correction of hyperfiltration probably contributed to the observed reduction in eGFR, which may indicate recovery of the tubuloglomerular feedback damaged by hyperaldosteronism [38]. Given that eGFR tended to return to baseline levels after the end of esaxerenone treatment in other studies [30,39], the eGFR reductions in this study are considered to be caused by hemodynamic changes rather than organic renal damage.…”

Section: Discussionsupporting

confidence: 86%

“…The phase 3 study [29] also showed that esaxerenone 2.5 mg/day was noninferior to eplerenone 50 mg/day and that esaxerenone at 5 mg/day exhibited superior BP-lowering effects over esaxerenone at 2.5 mg/day. In a study of esaxerenone in patients with moderate renal dysfunction with diabetes with albuminuria [30], incremental dose escalation starting from a low dose was able to manage serum K + elevations and renal function safely while exerting antihypertensive effects. Data from these studies provide important guidance regarding the role of esaxerenone in the management of hypertension with related comorbidities.…”

Section: Introductionmentioning

confidence: 99%

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Efficacy and safety of esaxerenone (CS-3150), a newly available nonsteroidal mineralocorticoid receptor blocker, in hypertensive patients with primary aldosteronism

et al. 2020

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Mineralocorticoid receptor (MR) blockers are very beneficial for patients with hypertension and primary aldosteronism (PA). We investigated the efficacy and safety of a newly available nonsteroidal MR blocker, esaxerenone, in Japanese patients with hypertension and PA. A multicenter, open-label study was conducted in Japan between October 2016 and July 2017. Patients with hypertension and PA received 12 weeks of treatment with esaxerenone, initiated at 2.5 mg/day and escalated to 5 mg/day during week 2 or 4 of treatment, based on individual response. The only other permitted antihypertensive therapies were stable dosages of a Ca2+ channel blocker or α-blocker. The primary efficacy outcome was a change in sitting systolic and diastolic blood pressure (SBP/DBP) from baseline to the end of treatment. Forty-four patients were included; dose escalation to 5 mg/day was implemented for 41 of these patients. Significant decreases in SBP and DBP were observed (point estimates [95% confidence interval] −17.7 [−20.6, −14.7] and −9.5 [−11.7, −7.3] mmHg, respectively; both p < 0.0001 at the end of treatment). Significant BP reductions were evident from week 2 and continued through to week 8; BP remained stable until week 12. The antihypertensive effect of esaxerenone on SBP was significantly greater in females and in patients receiving monotherapy. The major drug-related adverse events were serum K+ increase and estimated glomerular filtration rate decrease (both 4.5%, n = 2); no gynecomastia or breast pain was observed. We conclude that esaxerenone is a potent MR blocker with favorable efficacy and safety profiles in patients with hypertension and PA.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of esaxerenone (CS-3150), a newly available nonsteroidal mineralocorticoid receptor blocker, in hypertensive patients with primary aldosteronism

et al. 2020

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“…Significant reductions in the UACR were observed even when esaxerenone was added to a RAS inhibitor, consistent with clinical studies on type 2 diabetes that demonstrated a dose-dependent reduction in the UACR [24,25]. However, Adverse events (n ≥2 in either study) eGFR estimated glomerular filtration rate a In monotherapy, two patients discontinued due to adverse events, one experienced altered consciousness and the other had chest pain, and the first event was judged to be related to the study drug.…”

Section: Discussionsupporting

confidence: 83%

Antihypertensive effects and safety of esaxerenone in patients with moderate kidney dysfunction

et al. 2020

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Renin–angiotensin system inhibitors are recommended for treating hypertension with chronic kidney disease. The addition of a mineralocorticoid receptor blocker may be one option to achieve target blood pressure. We investigated the efficacy and safety of esaxerenone, a mineralocorticoid receptor blocker, in Japanese hypertensive patients with moderate kidney dysfunction. Two multicenter, open-label, nonrandomized dose escalation studies were conducted to investigate esaxerenone monotherapy and add-on therapy to renin–angiotensin system inhibitor treatment. Esaxerenone therapy was initiated at 1.25 mg/day and titrated to 2.5 and then 5 mg/day for a treatment duration of 12 weeks. Primary endpoints were changes from baseline in sitting systolic and diastolic blood pressure. Safety, pharmacokinetics, and urinary albumin-to-creatinine ratios were also assessed. Thirty-three patients received monotherapy, and 58 received add-on therapy; the mean baseline estimated glomerular filtration rates were 51.9 and 50.9 mL/min/1.73 m2, respectively. The esaxerenone dosage was increased to ≥2.5 mg/day in 100% (n = 33) and 93.1% (n = 54) of patients receiving monotherapy and add-on therapy, respectively. Reductions in sitting blood pressure from baseline to the end of treatment were similar (monotherapy: −18.5/−8.8 mmHg; add-on therapy: −17.8/−8.1 mmHg; both P < 0.001). The antihypertensive effects of esaxerenone were consistent across patient subgroups. A serum K+ level ≥5.5 mEq/L was observed in seven patients (12.1%) receiving add-on therapy but in none receiving monotherapy. All increases in serum K+ levels were transient, and no patient met predefined serum K+ level criteria for dose reduction or therapy discontinuation. No patient discontinued treatment owing to kidney function decline. Esaxerenone was effective and well tolerated in hypertensive patients with moderate kidney dysfunction.

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“…Esaxerenone has demonstrated good antihypertensive activity in a variety of patients, including those with uncomplicated grade I-III hypertension, hypertension with moderate renal impairment, hypertension with type 2 diabetes mellitus with albuminuria, and hypertension associated with primary aldosteronism (Daiichi Sankyo Co., Ltd., unpublished data, J305 and J307 studies; and published data [25][26][27][28]). The currently available clinical study data are summarized in Table 1.…”

Section: Introductionmentioning

confidence: 99%

“…The antihypertensive effects of esaxerenone persisted throughout 52 weeks of treatment even when used as a monotherapy or when it was administered as an add-on therapy with reninangiotensin system (RAS) inhibitors or calcium channel blockers (CCBs) [27]. In addition to its antihypertensive effects in hypertensive patients with type 2 diabetes and albuminuria, renoprotective effects have also been reported, with the urinary albumin/creatinine ratio decreasing by 32.4% from baseline during treatment with 5 mg/day esaxerenone, even in the presence of RAS inhibitors [26]. Similar antihypertensive and renoprotective effects have been observed in patients with moderate kidney dysfunction (Daiichi Sankyo Co., Ltd., unpublished data, J305 study).…”

Section: Introductionmentioning

confidence: 99%

Management of hyperkalemia during treatment with mineralocorticoid receptor blockers: findings from esaxerenone

2020

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The nonsteroidal mineralocorticoid receptor (MR) blocker esaxerenone has demonstrated good antihypertensive activity in a variety of patients, including those with uncomplicated grade I–III hypertension, hypertension with moderate renal dysfunction, hypertension with type 2 diabetes mellitus with albuminuria, and hypertension associated with primary aldosteronism. Hyperkalemia has long been recognized as a potential side effect occurring during treatment with MR blockers, but there is a lack of understanding and guidance about the appropriate management of hyperkalemia during antihypertensive therapy with MR blockers, especially in regard to the newer agent esaxerenone. In this article, we first highlight risk factors for hyperkalemia, including advanced chronic kidney disease, diabetes mellitus, cardiovascular disease, age, and use of renin-angiotensin-aldosterone system inhibitors. Next, we examine approaches to prevention and management, including potassium monitoring, diet, and the use of appropriate therapeutic techniques. Finally, we summarize the currently available data for esaxerenone and hyperkalemia. Proper management of serum potassium is required to ensure safe clinical use of MR blockers, including awareness of at-risk patient groups, choosing appropriate dosages for therapy initiation and dosage titration, and monitoring of serum potassium during therapy. It is critical that physicians take such factors into consideration to optimize MR blocker therapy in patients with hypertension.

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Efficacy and safety of dosage-escalation of low-dosage esaxerenone added to a RAS inhibitor in hypertensive patients with type 2 diabetes and albuminuria: a single-arm, open-label study

Cited by 47 publications

References 48 publications

Efficacy and safety of esaxerenone (CS-3150), a newly available nonsteroidal mineralocorticoid receptor blocker, in hypertensive patients with primary aldosteronism

Efficacy and safety of esaxerenone (CS-3150), a newly available nonsteroidal mineralocorticoid receptor blocker, in hypertensive patients with primary aldosteronism

Antihypertensive effects and safety of esaxerenone in patients with moderate kidney dysfunction

Management of hyperkalemia during treatment with mineralocorticoid receptor blockers: findings from esaxerenone

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