Apararenone in patients with diabetic nephropathy: results of a randomized, double-blind, placebo-controlled phase 2 dose–response study and open-label extension study

Wada, Takashi; Inagaki, Masaya; Yoshinari, Toru; Terata, Ryuji; Totsuka, Naoko; Gotou, Miki; Hashimoto, Gaia

doi:10.1007/s10157-020-01963-z

Cited by 67 publications

(66 citation statements)

References 23 publications

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“…Unfortunately, and likewise in most other studies, there was a risk of hyperkalemia [ 24 ]. Similar results were achieved by Wada et al [ 25 ] The study compared the efficacy and safety of apararenone treatment vs. placebo in patients with stage 2 DN. During the follow-up, UACR decreased.…”

Section: Novel Selective Nonsteroidal Mra Therapy In Patients With Ckdsupporting

confidence: 76%

Mineralocorticoid Receptor Antagonists—Use in Chronic Kidney Disease

Baran

Krzemińska

Szlagor

et al. 2021

IJMS

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Mineralocorticoid receptor antagonists (MRA) are drugs with a potentially broad spectrum of action. They have been reported to have healing effects in many diseases, such as chronic heart failure, hypertension, or nephrotic syndrome. Numerous studies suggest that mineralocorticoid receptor activation is pathogenic and a progression factor of chronic kidney disease (CKD); however, results of studies on the use of MRA in the treatment of CKD are inconclusive. Current guidelines recommend against the use of MRA in patients with advanced CKD. Although, there is growing interest on their use in this population due to treatment benefits. In this review, we summarize studies which were purposed to evaluate the impact of MRA therapy on CKD patients. Despite many benefits of this treatment e.g., reducing cardiovascular mortality or alleviating proteinuria, steroidal MRA (such as spironolactone or eplerenone) have a low safety profile. They often lead to hyperkalemia complications which are dangerous in patients with CKD, and diabetic nephropathy, especially in hemodialysis patients. Studies on recently developed nonsteroidal MRA showed that they have fewer side effects. In our review, we discuss steroidal and nonsteroidal MRA treatment effects on the estimated glomerular filtration rate (eGFR), proteinuria, the cardiovascular system, and hyperkalemia in CKD patients. We present new content and recent publications in this field.

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Section: Novel Selective Nonsteroidal Mra Therapy In Patients With Ckdsupporting

confidence: 76%

Mineralocorticoid Receptor Antagonists—Use in Chronic Kidney Disease

Baran

Krzemińska

Szlagor

et al. 2021

IJMS

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“…Given that multiple potential markers of fibrosis were significantly reduced in the apararenone group, all showing a tendency to improve, these findings suggest that apararenone could have an antifibrotic effect on the liver. Apararenone has also been reported to have renal‐protective effects in patients with diabetic nephropathy 14 ; therefore, it could show a potent antifibrotic effect in both the liver and the kidney. Further studies are needed to confirm this in the future.…”

Section: Discussionmentioning

confidence: 99%

“…Patients were treated with apararenone 10 mg or placebo once daily for 72 weeks. As this was the first clinical study of apararenone in patients with NASH, the highest dose of apararenone used in a previous study of patients with diabetic nephropathy (10 mg/day) 14 was selected to confirm the effect of apararenone in patients with NASH.…”

Section: Methodsmentioning

confidence: 99%

“…Apararenone (MT‐3995) is a nonsteroidal compound with highly selective MR antagonistic activity 12–14 . Apararenone has been evaluated in several clinical studies in healthy adults; its safety and pharmacokinetic profiles have been confirmed, 12–14 and it was well tolerated in healthy subjects and in patients with diabetic nephropathy 14 …”

Section: Introductionmentioning

confidence: 99%

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Efficacy and safety of apararenone (MT‐3995) in patients with nonalcoholic steatohepatitis: A randomized controlled study

Okanoue

Sakamoto

Harada

et al. 2021

Hepatology Research

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Aim To evaluate the efficacy, safety, and tolerability of apararenone 10 mg/day in patients with nonalcoholic steatohepatitis (NASH). Methods In this multicenter, randomized, double‐blind, placebo‐controlled phase II study, patients received apararenone 10 mg or placebo once daily for 72 weeks. The primary efficacy end‐point was percent change in serum alanine aminotransferase (ALT) from baseline to 24 weeks after randomization. Secondary efficacy end‐points included changes in liver fibrosis markers. Adverse drug reactions (ADRs) and serum potassium levels were evaluated. Results Forty‐eight patients were randomly assigned to treatment (placebo, 23; apararenone, 25). The percent change in ALT at 24 weeks was −3.0% and −13.7% with placebo and apararenone, respectively (p = 0.308). The apararenone group showed greater reductions from baseline in fibrosis markers (type IV collagen 7S and procollagen‐3 N‐terminal peptide) and noninvasive tests of fibrosis (enhanced liver fibrosis score and Fibrosis‐4 index) at all time points versus placebo. The percentage of patients with improvement of 1 point or more in fibrosis stage/without nonalcoholic fatty liver disease activity score worsening was 41.7% with apararenone and 26.1% with placebo (p = 0.203). Adverse drug reactions were reported in three (13.0%) and three (12.5%) patients in the placebo and apararenone groups, respectively. Serum potassium levels increased in the apararenone group during the study and decreased to near baseline after the end of treatment. Conclusions In patients with NASH, apararenone 10 mg/day for 72 weeks was effective in decreasing ALT levels, improved multiple potential fibrosis markers, and was safe and well tolerated. Pathological findings showed anti‐inflammatory and antifibrotic effects of apararenone.

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“…The only published study of apararenone use was performed in DKD patients [107]. It included 293 Japanese patients with type 2 DM and albuminuria.…”

Section: Non-steroidalmentioning

confidence: 99%

Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease

et al. 2021

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Diabetes mellitus is a global health issue and main cause of chronic kidney disease. Both diseases are also linked through high cardiovascular morbidity and mortality. Diabetic kidney disease (DKD) is present in up to 40% of diabetic patients; therefore, prevention and treatment of DKD are of utmost importance. Much research has been dedicated to the optimization of DKD treatment. In the last few years, mineralocorticoid receptor antagonists (MRA) have experienced a renaissance in this field with the development of non-steroidal MRA. Steroidal MRA have known cardiorenal benefits, but their use is limited by side effects, especially hyperkalemia. Non-steroidal MRA still block the damaging effects of mineralocorticoid receptor overactivation (extracellular fluid volume expansion, inflammation, fibrosis), but with fewer side effects (hormonal, hyperkalemia) than steroidal MRA. This review article summarizes the current knowledge and newer research conducted on MRA in DKD.

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Apararenone in patients with diabetic nephropathy: results of a randomized, double-blind, placebo-controlled phase 2 dose–response study and open-label extension study

Cited by 67 publications

References 23 publications

Mineralocorticoid Receptor Antagonists—Use in Chronic Kidney Disease

Mineralocorticoid Receptor Antagonists—Use in Chronic Kidney Disease

Efficacy and safety of apararenone (MT‐3995) in patients with nonalcoholic steatohepatitis: A randomized controlled study

Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease

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