Reduction in the magnitude of serum potassium elevation in combination therapy with esaxerenone (CS‐3150) and sodium–glucose cotransporter 2 inhibitor in patients with diabetic kidney disease: Subanalysis of two phase III studies

Shikata, Kenichi; Ito, Sadayoshi; Kashihara, Naoki; Nangaku, Masaomi; Wada, Takashi; Okuda, Yasuyuki; Sawanobori, Tomoko; Sugimoto, Kotaro

doi:10.1111/jdi.13778

Cited by 10 publications

(13 citation statements)

References 39 publications

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“…Early comprehensive disease-modifying pharmacological therapy is prospective and may become a new therapy standard. Concomitant use of SGLT2 inhibitor with finerenone decreased CKD progression risk, and with esaxerenone decreased hyperkalemia risk in patients with CKD and T2DM [ 79 , 109 ]. The effects of finerenone on kidney and cardiovascular outcomes were consistent irrespective of the use of glucagon-like peptide-1 receptor agonist (GLP-1RA) [ 110 ].…”

Section: Discussionmentioning

confidence: 99%

“…A phase III study aiming at improving RAS inhibitor use in patients with HFrEF with hyperkalemia or a history of hyperkalemia leading to RAS inhibitor therapy compromise is being conducted [ 114 ]. An SGLT2 inhibitor might be another option; research has approved the concurrent use of an SGLT2 inhibitor to reduce the magnitude of serum potassium elevation without any change to the antihypertensive and albuminuria-suppressing effects in Japanese patients with T2DM and albuminuria treated with esaxerenone [ 109 ].…”

Section: Discussionmentioning

confidence: 99%

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Nonsteroidal Mineralocorticoid Receptor Antagonist Eliciting Cardiorenal Protection Is a New Option for Patients with Chronic Kidney Disease

Liu¹,

Yu²

2022

Kidney Dis

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Background: Mineralocorticoid receptor antagonists (MRAs) protect cardiorenal function by robust anti-inflammatory and antifibrotic functions beyond classical functions of maintaining fluid and electrolyte homeostasis. The application of traditional steroidal MRAs to chronic kidney disease (CKD) has been limited by adverse events, especially when combined with renin-angiotensin system (RAS) inhibitors, guideline-recommend drugs for CKD patients. Recently, the development of non-steroidal MRAs gives patients with CKD a promising option. Summary: The discovery of non-steroidal MRAs is based on the molecular structure of the mineralocorticoid receptor (MR) and differ in structure from spironolactone, a progesterone derivative. The structure of non-steroidal MRAs determines their more effective and selective inhibition of MR providing patients more benefits with fewer adverse effects than MRAs. Recently, two types of non-steroidal MRAs, finerenone and esaxerenone, have been authorized for clinical use. We elaborate on the physiological and pathophysiological mechanisms of MR, review the history of MRAs, compare two generations of MRAs, and introduce the forward clinical trials of finerenone and esaxerenone. Key Messages: Finerenone reduces the cardiovascular and kidney composite outcomes in diabetic patients with CKD eliciting a cardiorenal protection effect. Esaxerenone can effectively reduce blood pressure in hypertensive patients and albuminuria in diabetic patients with CKD. The risk of hyperkalemia is controllable and acceptable through the serum potassium-based dose titrate. Combination therapy with sodium glucose cotransport-2 (SGLT2) inhibition or a new potassium binder may be a safer and more efficient approach.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Nonsteroidal Mineralocorticoid Receptor Antagonist Eliciting Cardiorenal Protection Is a New Option for Patients with Chronic Kidney Disease

Liu¹,

Yu²

2022

Kidney Dis

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“…Overall, 27 studies involving 43,589 participants were included in the network meta-analysis according to the inclusion and exclusion criteria (Supplemental Figure 1), among which three were secondary analyses and one was pooled analysis. [33][34][35][36] One of the secondary analyses included a single-arm trial, and this particular study was included because of its internal subgroup analysis. 34 The pooled study combined data from 19 individual trials, and one of the secondary analyses combined data from two individual trials.…”

Section: Study Characteristicsmentioning

confidence: 99%

“…34 The pooled study combined data from 19 individual trials, and one of the secondary analyses combined data from two individual trials. 34,36 Overall, 47 trials provided data for the meta-analysis. The mean age of the participants was 6469 years.…”

Section: Study Characteristicsmentioning

confidence: 99%

“…[33][34][35][36] One of the secondary analyses included a single-arm trial, and this particular study was included because of its internal subgroup analysis. 34 The pooled study combined data from 19 individual trials, and one of the secondary analyses combined data from two individual trials. 34,36 Overall, 47 trials provided data for the meta-analysis.…”

Section: Study Characteristicsmentioning

confidence: 99%

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Influence of SGLT2i and RAASi and Their Combination on Risk of Hyperkalemia in DKD

Luo

Zhou

et al. 2023

CJASN

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Background This network meta-analysis investigated the effect of various combined regimens of sodium-glucose cotransporter-2 inhibitors (SGLT2is) and renin-angiotensin-aldosterone system inhibitors (RAASis) on the occurrence of hyperkalemia in diabetic kidney disease. Methods The risk of hyperkalemia was compared using the random-effects model of network meta-analysis, with results expressed as odds ratios (ORs) with 95% confidence intervals (CIs). The comparative effects of all medications and their combinations with placebo were ranked using the surface under the cumulative ranking probabilities. Results In total, 27 eligible studies involving 43,589 participants with diabetic kidney disease were included. Major findings showed that the use of mineralocorticoid receptor antagonists (MRAs) on top of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) prominently increased hyperkalemia incidence when compared with placebo (OR, 6.08; 95% CI, 2.30 to 16.08), ACEI (OR, 3.07; 95% CI, 1.14 to 8.31), ARB (OR, 2.57; 95% CI, 1.10 to 6.02), SGLT2i (OR, 9.22; 95% CI, 2.99 to 28.46), renin inhibitors+ACEI/ARB (OR, 2.23; 95% CI, 1.14 to 4.36), or SGLT2i+ACEI/ARB (OR, 4.10; 95% CI, 2.32 to 7.26). Subgroup analysis among different generations of MRA found that spironolactone had the strongest effect in combination with ACEI/ARB, even higher than the combined use of ACEI and ARB (OR, 2.89; 95% CI, 1.26 to 6.63). In addition, SGLT2i had a significantly lower incidence of hyperkalemia compared with ACEI (OR, 0.33; 95% CI, 0.12 to 0.91), ARB (OR, 0.28; 95% CI, 0.13 to 0.61), dual RAASi (ACEI combined with ARB; OR, 0.17; 95% CI, 0.06 to 0.47), or MRA or renin inhibitors combined with ACEI/ARB (OR, 0.11; 95% CI, 0.04 to 0.33; OR, 0.24; 95% CI, 0.08 to 0.76, respectively.). Moreover, adding SGLT2i to the combination of MRA and ACEI/ARB, as well as the combinations of different RAASis, markedly reduced the occurrence of hyperkalemia. Conclusions Among the therapeutic drugs with the potential risk of increasing serum potassium in patients with diabetic kidney disease, MRA added an extra risk of hyperkalemia while SGLT2i had the opposite effect and could even reverse the elevation of serum potassium caused by the combined regimen, including MRAs.

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Efficacy and Safety of Esaxerenone in Hypertensive Patients with Diabetes Mellitus Undergoing Treatment with Sodium-Glucose Cotransporter 2 Inhibitors (EAGLE-DH)

Motoki,

Inobe,

Fukui

et al. 2023

Adv Ther

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Introduction The EAGLE-DH study assessed the efficacy and safety of esaxerenone in hypertensive patients with diabetes mellitus receiving sodium-glucose cotransporter 2 (SGLT2) inhibitors. Methods In this multicenter, open-label, prospective, interventional study, esaxerenone was started at 1.25 or 2.5 mg/day and could be gradually increased to 5 mg/day on the basis of blood pressure (BP) and serum potassium levels. Oral hypoglycemic or antihypertensive medications prior to obtaining consent was continued. Data were evaluated in the total population and creatinine-based estimated glomerular filtration rate (eGFR) subcohorts (eGFR ≥ 60 mL/min/1.73 m 2 [G1–G2 subcohort] and 30 to < 60 mL/min/1.73 m 2 [G3 subcohort]). Results In total, 93 patients were evaluated (G1–G2, n = 49; G3, n = 44). Morning home systolic/diastolic BP values (SBP/DBP) were significantly reduced from baseline to week 12 (− 11.8 ± 10.8/− 5.1 ± 6.3 mmHg, both P < 0.001) and week 24 (− 12.9 ± 10.5/− 5.7 ± 6.3 mmHg, both P < 0.001). Similar results were observed in both eGFR subcohorts. The urinary albumin-to-creatinine ratio significantly decreased from baseline to week 24 in the total population (geometric percentage change, − 49.1%, P < 0.001) and in both eGFR subcohorts. The incidences of treatment-emergent adverse events (TEAEs) and drug-related TEAEs were 45.2% and 12.9%, respectively; most were mild or moderate. Serum potassium levels increased over the first 2 weeks of esaxerenone treatment, gradually decreased by week 12, and remained constant to week 24. One patient in the G1–G2 subcohort had serum potassium levels ≥ 5.5 mEq/L. No patients had serum potassium ≥ 6.0 mEq/L. Conclusion Esaxerenone effectively lowered BP, was safe, and showed renoprotective effects in hypertensive patients with diabetes mellitus receiving treatment with SGLT2 inhibitors. Esaxerenone and SGLT2 inhibitors did not interfere with either drug’s efficacy and may reduce the frequency of serum potassium elevations, suggesting they are a compatible combination. Clinical Trial Registration jRCTs031200273. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-023-02633-8.

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Reduction in the magnitude of serum potassium elevation in combination therapy with esaxerenone (CS‐3150) and sodium–glucose cotransporter 2 inhibitor in patients with diabetic kidney disease: Subanalysis of two phase III studies

Cited by 10 publications

References 39 publications

Nonsteroidal Mineralocorticoid Receptor Antagonist Eliciting Cardiorenal Protection Is a New Option for Patients with Chronic Kidney Disease

Nonsteroidal Mineralocorticoid Receptor Antagonist Eliciting Cardiorenal Protection Is a New Option for Patients with Chronic Kidney Disease

Influence of SGLT2i and RAASi and Their Combination on Risk of Hyperkalemia in DKD

Efficacy and Safety of Esaxerenone in Hypertensive Patients with Diabetes Mellitus Undergoing Treatment with Sodium-Glucose Cotransporter 2 Inhibitors (EAGLE-DH)

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