Esaxerenone (CS-3150) in Patients with Type 2 Diabetes and Microalbuminuria (ESAX-DN)

Background and objectivesDiabetic kidney disease is an important complication of type 2 diabetes. In a phase 2b study, adding esaxerenone to renin-angiotensin system inhibitors dose dependently reduced the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and microalbuminuria. This 52-week phase 3 study further investigated the effects of esaxerenone on the urinary albumin-to-creatinine ratio in this patient group.Design, setting, participants, & measurementsIn this multicenter, randomized, double-blind study, patients with type 2 diabetes and a urinary albumin-to-creatinine ratio of 45 to <300 mg/g creatinine treated with renin-angiotensin system inhibitors were randomized to esaxerenone or placebo for 52 weeks (n=455). Esaxerenone was initiated at 1.25 mg/d and titrated to 2.5 mg/d on the basis of serum potassium monitoring. The primary endpoint was the proportion of patients achieving urinary albumin-to-creatinine ratio remission (<30 mg/g creatinine and ≥30% reduction from baseline on two consecutive occasions).ResultsOverall, 49 (22%) and nine (4%) patients in the esaxerenone and placebo groups, respectively, achieved urinary albumin-to-creatinine ratio remission (absolute difference 18%; 95% confidence interval, 12% to 25%; P<0.001). The percent change in urinary albumin-to-creatinine ratio from baseline to end of treatment was significantly higher with esaxerenone versus placebo (−58% versus 8%; geometric least-squares mean ratio to placebo 0.38, 95% confidence interval, 0.33 to 0.44). There was a significant improvement with esaxerenone versus placebo in time to first remission (hazard ratio, 5.13; 95% confidence interval, 3.27 to 8.04) and time to first transition to urinary albumin-to-creatinine ratio ≥300 mg/g creatinine (hazard ratio, 0.23; 95% confidence interval, 0.11 to 0.48). More patients had a serum potassium level ≥6.0 or ≥5.5 mEq/L on two consecutive measurements in the esaxerenone group (20 [9%]) versus placebo (5 [2%]); these events were asymptomatic and resolved after dosage reduction or treatment discontinuation.ConclusionsAdding esaxerenone to existing renin-angiotensin system inhibitor therapy in patients with type 2 diabetes and microalbuminuria increased the likelihood of albuminuria returning to normal levels, and reduced progression of albuminuria to higher levels.

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Efficacy and Safety of Esaxerenone (CS-3150) for the Treatment of Type 2 Diabetes with Microalbuminuria

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.14751218 ◽

2019 ◽

Vol 14 (8) ◽

pp. 1161-1172 ◽

Cited By ~ 20

Author(s):

Sadayoshi Ito ◽

Kenichi Shikata ◽

Masaomi Nangaku ◽

Yasuyuki Okuda ◽

Tomoko Sawanobori

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Adverse Events ◽

Renin Angiotensin System ◽

Urinary Albumin ◽

Creatinine Ratio ◽

Angiotensin System ◽

Renin Angiotensin

Background and objectivesThe progression of kidney disease in some patients with type 2 diabetes mellitus may not be adequately suppressed by renin-angiotensin system inhibitors. Esaxerenone (CS-3150) is a nonsteroidal mineralocorticoid receptor blocker that has shown kidney protective effects in preclinical studies, and it is a potential add-on therapy to treat diabetic kidney disease. This phase 2 study evaluated the efficacy and safety of esaxerenone in Japanese patients with type 2 diabetes mellitus and microalbuminuria.Design, setting, participants, & measurementsThis multicenter, randomized, double-blind, placebo-controlled trial enrolled 365 hypertensive or normotensive patients with type 2 diabetes mellitus and microalbuminuria (urinary albumin-to-creatinine ratio ≥45 to <300 mg/g creatinine) treated with renin-angiotensin system inhibitor who had eGFR≥30 ml/min per 1.73 m2. Participants were randomized to receive 0.625, 1.25, 2.5, or 5 mg/d esaxerenone or placebo for 12 weeks. The primary end point was the change in urinary albumin-to-creatinine ratio from baseline to week 12 (with last observation carried forward).ResultsEsaxerenone treatment at 1.25, 2.5, and 5 mg/d significantly reduced urinary albumin-to-creatinine ratio by the end of treatment (38%, 50%, and 56%, respectively) compared with placebo (7%; all P<0.001). The urinary albumin-to-creatinine ratio remission rate (defined as urinary albumin-to-creatinine ratio <30 mg/g creatinine at the end of treatment and ≥30% decrease from baseline) was 21% in the 2.5- and 5-mg/d groups versus 3% for placebo (both P<0.05). Adverse events occurred slightly more frequently with esaxerenone versus placebo, but the frequencies of drug-related adverse events and discontinuation rates were similar in the placebo and the 0.625-, 1.25-, and 2.5-mg/d groups. Drug-related adverse events and treatment discontinuations were marginally higher in the 5-mg/d group. The most common drug-related adverse event was hyperkalemia, which was dose proportional.ConclusionsAdding esaxerenone at 1.25, 2.5, and 5 mg/d for 12 weeks to an ongoing renin-angiotensin system inhibitor significantly reduces urinary albumin-to-creatinine ratio in patients with type 2 diabetes mellitus and microalbuminuria.

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Effects of sodium-glucose cotransporter 2 inhibitors on urinary excretion of intact and total angiotensinogen in patients with type 2 diabetes

Journal of Investigative Medicine ◽

10.1136/jim-2017-000445 ◽

2017 ◽

Vol 65 (7) ◽

pp. 1057-1061 ◽

Cited By ~ 17

Author(s):

Takuo Yoshimoto ◽

Takayuki Furuki ◽

Hiroyuki Kobori ◽

Masaaki Miyakawa ◽

Hitomi Imachi ◽

...

Keyword(s):

Blood Pressure ◽

Type 2 Diabetes ◽

Renin Angiotensin System ◽

Sglt2 Inhibitors ◽

Creatinine Ratio ◽

Angiotensin System ◽

Renin Angiotensin ◽

Urinary Angiotensinogen ◽

Sodium Glucose Cotransporter

We conducted a descriptive case study to examine the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on urinary angiotensinogen excretion, which represents the function of the intrarenal renin–angiotensin system, in patients with type 2 diabetes. An SGLT2 inhibitor (canagliflozin 100 mg/day, ipragliflozin 25 mg/day, dapagliflozin 5 mg/day, luseogliflozin 2.5 mg/day or tofogliflozin 20 mg/day) was administered for 1 month (n=9). ELISA kits were used to measure both urinary intact and total angiotensinogen levels. Treatment with SGLT2 inhibitors significantly decreased hemoglobin A1c, body weight, systolic blood pressure and diastolic blood pressure (8.5±1.3 to 7.5%±1.0%, 82.5±20.2 to 80.6±20.9 kg, 143±8 to 128±14 mm Hg, 78±10 to 67±9 mm Hg, p<0.05, respectively), while urinary albumin/creatinine ratio was not significantly changed (58.6±58.9 to 29.2±60.7 mg/g, p=0.16). Both total urinary angiotensinogen/creatinine ratio and intact urinary angiotensinogen/creatinine ratio tended to decrease after administration of SGLT2 inhibitors. However, these changes were not significant (p=0.19 and p=0.08, respectively). These data suggest that treatment with SGLT2 inhibitors does not activate the intrarenal renin–angiotensin system in patients with type 2 diabetes.

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1071-P: Long-Term Renin-Angiotensin System Inhibitor Use and Risk of Pneumonia and Pneumonia-Related Death in Type 2 Diabetes

Diabetes ◽

10.2337/db21-1071-p ◽

2021 ◽

Vol 70 (Supplement 1) ◽

pp. 1071-P

Author(s):

MAI SHI ◽

AIMIN YANG ◽

ERIC S.H. LAU ◽

HONGJIANG WU ◽

BAOQI FAN ◽

...

Keyword(s):

Type 2 Diabetes ◽

Renin Angiotensin System ◽

Angiotensin System ◽

Renin Angiotensin

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Finerenone and Cardiovascular Outcomes in Patients with Chronic Kidney Disease and Type 2 Diabetes

Circulation ◽

10.1161/circulationaha.120.051898 ◽

2020 ◽

Cited By ~ 1

Author(s):

Gerasimos Filippatos ◽

Stefan D. Anker ◽

Rajiv Agarwal ◽

Bertram Pitt ◽

Luis M. Ruilope ◽

...

Keyword(s):

Heart Failure ◽

Type 2 Diabetes ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Renin Angiotensin System ◽

Mineralocorticoid Receptor Antagonist ◽

Angiotensin System ◽

Renin Angiotensin ◽

History Of

Background: The FIDELIO-DKD trial evaluated the effect of the nonsteroidal, selective mineralocorticoid receptor antagonist finerenone on kidney and cardiovascular (CV) outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) with optimized renin-angiotensin system blockade. Compared with placebo, finerenone reduced the composite kidney and CV outcomes. We report the effect of finerenone on individual CV outcomes and in patients with and without history of atherosclerotic CV disease (CVD). Methods: This randomized, double-blind, placebo-controlled trial included patients with T2D and urine albumin-to-creatinine ratio 30-5000 mg/g and an estimated glomerular filtration rate (eGFR) ≥25-<75 mL/min/1.73 m 2 , treated with optimized renin-angiotensin system blockade. Patients with a history of heart failure with reduced ejection fraction were excluded. Patients were randomized 1:1 to receive finerenone or placebo. The composite CV outcome included time to CV death, myocardial infarction, stroke, or hospitalization for heart failure. Prespecified CV analyses included analyses of the components of this composite and outcomes according to CVD history at baseline. Results: Between September 2015 and June 2018, 13,911 patients were screened and 5674 were randomized; 45.9% of patients had CVD at baseline. Over a median follow-up of 2.6 years (interquartile range, 2.0-3.4 years), finerenone reduced the risk of the composite CV outcome compared with placebo (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75-0.99; P=0.034), with no significant interaction between patients with and without CVD (HR, 0.85; 95% CI, 0.71-1.01 in patients with a history of CVD; HR, 0.86; 95% CI, 0.68-1.08 in patients without a history of CVD; P-value for interaction, 0.85). The incidence of treatment-emergent adverse events was similar between treatment arms, with a low incidence of hyperkalemia-related permanent treatment discontinuation (2.3% with finerenone vs 0.8% with placebo in patients with CVD and 2.2% with finerenone vs 1.0% with placebo in patients without CVD). Conclusions: Among patients with CKD and T2D, finerenone reduced incidence of the composite CV outcome, with no evidence of differences in treatment effect based on pre-existing CVD status. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT02540993 (Funded by Bayer AG)

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