Nonsteroidal Mineralocorticoid Receptor Research Articles

Esaxerenone Attenuates Cardiac Hypertrophy in a Pressure Overload Model in Mice

Esaxerenone, a non-steroidal mineralocorticoid receptor (MR) blocker, exhibits high selectivity for MR. While clinically used as an anti-hypertensive drug, its impact on cardiac remodeling remains poorly understood. This study investigated the effect of esaxerenone on pressure overload-induced cardiac hypertrophy in mice.Eight-week-old C57BL/6 mice underwent either transverse aortic constriction (TAC) or sham surgery. Animals were divided into 2 groups: 0.003% (3.0 mg/kg) Esaxerenone-fed (EX) and normal-fed (CNT) groups (n = 64, Sham/CNT = 12, Sham/EX = 13, TAC/CNT = 18, TAC/EX = 21). Cardiac gene expressions were analyzed using quantitative real-time PCR.Food intake and body weight variations showed no significant differences between CNT and EX groups during the 2-week experimental period. The mortality rate from 24 hours after TAC surgery to the end of the experiment was 30.8% in the CNT group, however, all mice survived following TAC surgery in EX group. CNT group showed a remarkable increase in heart weight/tibial length ratio 2 weeks after TAC compared with the Sham group. The EX group demonstrated a significant decrease in HW/TL following TAC surgery (-23.4%, P = 0.041). Masson's trichrome staining revealed that the TAC/CNT group had a significantly higher proportion of fibrotic area than the Sham/CNT group. However, the TAC/EX group had a slightly lower proportion of fibrotic area than the TAC/CNT group. In cardiac gene expression analysis, ANP and Collagen 3a1 were upregulated in the TAC group but were significantly reduced following treatment with esaxerenone.Esaxerenone attenuates cardiac hypertrophy and hypertrophy-related gene expression, resulting in improved survival in a pressure overload model in mice.

Efficacy and safety of finerenone in patients with chronic kidney disease and type 2 diabetes by diuretic use: A FIDELITY analysis.

This post hoc analysis aimed to assess the efficacy and safety of the non-steroidal mineralocorticoid receptor antagonist finerenone by baseline diuretic use in FIDELITY, a pre-specified pooled analysis of the phase III trials FIDELIO-DKD and FIGARO-DKD. Eligible patients with type 2 diabetes (T2D) and chronic kidney disease (CKD; urine albumin-to-creatinine ratio [UACR] ≥30-<300 mg/g and estimated glomerular filtration rate [eGFR] ≥25-≤90 ml/min/1.73 m2, or UACR ≥300-≤5000 mg/g and eGFR ≥25 ml/min/1.73 m2) were randomized 1:1 to finerenone or placebo. Patients were analysed by baseline diuretic use (yes/no) and type of diuretic (loop or thiazide). Key efficacy outcomes included a cardiovascular composite (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure) and a kidney composite (kidney failure, sustained ≥57% decrease in eGFR, or kidney-related death). Out of 12 990 patients, 51.6% were taking diuretics at baseline (21.6% loop; 24.2% thiazide diuretics). Finerenone reduced the risk of cardiovascular and kidney composite outcomes versus placebo; diuretic use did not modify this effect on the cardiovascular (p-interaction = 0.94) or kidney outcomes (p-interaction = 0.55). Hyperkalaemia incidences were similar between finerenone subgroups irrespective of diuretic use and lower with placebo versus finerenone (with diuretics: finerenone 13.7% vs. placebo 5.7%; without diuretics: 14.3% vs. 8.3%). The incidence of hyperkalaemia leading to hospitalization or study drug discontinuation was low across treatment groups irrespective of diuretic use. This analysis showed that the efficacy and safety of finerenone in patients with CKD and T2D was not modified by baseline diuretic use.

Initiation and sequencing of guideline-directed medical therapy for heart failure across the ejection fraction spectrum.

Strong evidence supports the importance of rapid sequence or simultaneous initiation of quadruple guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) for substantially reducing risk of mortality and hospitalization. Barring absolute contraindications for each individual medication, employing the strategy of rapid sequence, simultaneous, and/or in-hospital initiation at the time of HF diagnosis best ensures patients with HFrEF have the opportunity to benefit from proven medications and achieve large absolute risk reductions for adverse clinical outcomes. However, despite guideline recommendations supporting this approach, implementation in clinical practice remains persistently low, with less than one-fifth of eligible patients being prescribed the quadruple GDMT regimen. Additionally, for heart failure with mildly reduced or preserved ejection fraction (HFpEF), sodium-glucose co-transporter 2 inhibitors (SGLT2i) and non-steroidal mineralocorticoid receptor antagonists (MRA)constitute foundational therapy for all eligible patients with significant clinicalbenefits within just weeks of medication initiation. Nonetheless, the burden of symptoms, functional limitations, and hospitalizations remains substantial for many of these patients, even with SGLT2iand non-steroidal MRA therapy. Additional evidence supports consideration of adjunctive therapies for HF with EF > 40% that can be tailored to the patient phenotype, including glucagon-like peptide-1 receptor agonists (GLP-1 RA) for patients with obesity, as well as angiotensin receptor-neprilysin inhibitors (ARNI) for patients with EF below normal. This article reviews the evidence-based sequencing of GDMT for HF across the spectrum of EF, emphasizing the rationale and benefits of early up-front initiation of quadruple medical therapy for HFrEF, rapid initiation of SGLT2i for HF regardless of EF, and prompt phenotype-specific tailored approach to adjunctive therapies for HF with EF > 40%.

Effects of the Nonsteroidal MRA Finerenone With and Without Concomitant SGLT2 Inhibitor Use in Heart Failure.

Patients with heart failure (HF) with mildly reduced or preserved ejection fraction face heightened long-term risks of morbidity and mortality. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and the nonsteroidal mineralocorticoid receptor antagonist finerenone have both been shown to reduce the risk of cardiovascular events in this population, but the effects of their combined use are not known. FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure) was a randomized, double-blind, placebo-controlled trial of finerenone in patients with HF and left ventricular ejection fraction ≥40%. Baseline SGLT2i use was a prespecified subgroup. The primary outcome was a composite of total (first and recurrent) worsening HF events and cardiovascular death. We first assessed for evidence of treatment heterogeneity on the basis of baseline SGLT2i use. We further examined SGLT2i uptake during the trial and evaluated the treatment effects of finerenone accounting for baseline and during-trial use of SGLT2i in time-varying analyses. Among 6001 participants, 817 (13.6%) were treated with an SGLT2i at baseline. During 2.6 years median follow-up, treatment with finerenone similarly reduced the risk of the primary outcome in participants treated with an SGLT2i (rate ratio, 0.83 [95% CI, 0.60-1.16]) and without an SGLT2i at baseline (rate ratio, 0.85 [95% CI, 0.74-0.98]; Pinteraction=0.76). In follow-up, 980 participants initiated SGLT2i, which was less frequent in the finerenone arm compared with placebo (17.7% versus 20.1%; hazard ratio, 0.86 [95% CI, 0.76-0.97]). Time-updated analyses accounting for baseline and subsequent use of SGLT2i did not meaningfully alter the treatment effects of finerenone on the primary end point. The treatment benefits of the nonsteroidal mineralocorticoid receptor antagonist finerenone were observed irrespective of concomitant use of an SGLT2i. These data suggest that the combined use of SGLT2i and a nonsteroidal mineralocorticoid receptor antagonist may provide additive protection against cardiovascular events in patients with HF with mildly reduced or preserved ejection fraction. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04435626.

Improving Renal Protection in Chronic Kidney Disease Associated with Type 2 Diabetes: The Role of Finerenone.

Chronic kidney disease (CKD) is a major complication of type 2 diabetes mellitus (T2D), which often leads to diabetic kidney disease (DKD). Traditional therapies, including renin- angiotensin-aldosterone system inhibitors and sodium-glucose cotransporter-2 inhibitors, are effective in slowing CKD progression. However, these approaches are insufficient to comprehensively inhibit mineralocorticoid receptor (MR) overactivation in the kidneys, which remains a significant driver of inflammation, fibrosis, and oxidative stress. These pathological processes accelerate kidney damage and cardiovascular complications. Finerenone-a nonsteroidal mineralocorticoid receptor antagonist-represents a new frontier in renal protection. Unlike steroidal mineralocorticoid antagonists (MRAs), finerenone offers a more selective MR blockade, reducing kidney inflammation and fibrosis without significantly raising serum potassium levels. Landmark trials have demonstrated the ability of finerenone to significantly reduce kidney and cardiovascular events in patients with T2D and CKD. Clinical evidence has highlighted finerenone as an effective option for slowing DKD progression while maintaining a favorable safety profile. Based on these findings, recent guidelines have incorporated finerenone as a recommended therapy for patients with T2D and CKD, emphasizing its role in reducing both renal and cardiovascular risks. This review provides a comprehensive overview of the available data to offer a deeper understanding of the potential of finerenone to transform CKD management for T2D patients.

Efficacy and Safety of Finerenone Across the Ejection Fraction Spectrum in Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Analysis of the FINEARTS-HF Trial.

The effects of treatments for heart failure (HF) may vary among patients according to left ventricular ejection fraction (LVEF). In FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure), the nonsteroidal mineralocorticoid receptor antagonist finerenone reduced the risk of cardiovascular death and total worsening HF events in patients with HF with mildly reduced or preserved ejection fraction. We examined the effect of finerenone according to LVEF in FINEARTS-HF. FINEARTS-HF was a randomized, placebo-controlled trial examining the efficacy and safety of finerenone in patients with HF and LVEF ≥40%. The treatment effect of finerenone was examined in prespecified analyses according to LVEF categories (<50%, ≥50% to <60%, and ≥60%) and with LVEF as a continuous variable. The primary outcome was a composite of total (first and recurrent) worsening HF events and cardiovascular death. Baseline LVEF data were available for 5993 of the 6001 participants in FINEARTS-HF. Mean and median LVEF were 53±8% and 53% (interquartile range, 46%-58%), respectively. LVEF was <50% in 2172 (36%), between 50% and <60% in 2674 (45%), and ≥60% in 1147 (19%). Patients with higher LVEF were older, were more commonly female, were less likely to have a history of coronary artery disease, and more frequently had a history of hypertension and chronic kidney disease compared with those with a lower LVEF. Finerenone reduced the risk of cardiovascular death and total HF events consistently across LVEF categories (LVEF <50% rate ratio, 0.84 [95% CI, 0.68-1.03]; LVEF ≥50% to <60% rate ratio, 0.80 [0.66-0.97]; and LVEF ≥60% rate ratio, 0.94 [0.70-1.25]; Pinteraction=0.70). There was no modification of the benefit of finerenone across the range of LVEF when analyzed as a continuous variable (Pinteraction=0.28). There was a similar consistent effect of finerenone on reducing the total number of worsening HF events (continuous Pinteraction=0.26). In patients with HF with mildly reduced or preserved ejection fraction, finerenone reduced the risk of cardiovascular death and worsening HF events, irrespective of LVEF. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04435626. URL: https://eudract.ema.europa.eu; Unique identifier: 2020-000306-29.

Acute Kidney Injury Associated With Finerenone Use in Type 2 Diabetes Mellitus Patients: A Case Report

Abstract Individuals with diabetes are at an increased risk of cardiovascular (CV) disease. The risk further increases in the presence of kidney involvement. Nonsteroidal mineralocorticoid receptor antagonist finerenone has shown beneficial effects on cardiorenal outcomes in type 2 diabetes mellitus (T2DM) and has been recommended by various guidelines for the reduction of chronic kidney disease progression and CV events. Here, we present an individual with T2DM and early renal insufficiency, who had acute worsening of renal parameters after finerenone therapy, which reverted back to baseline levels after the therapy was discontinued. A 58-year-old male with T2DM of 13 years duration presented with loss of appetite, weight loss of 4 kg during the last 6 months, cough for 1 week, fever with chills on and off for the last 1 month, and fluctuating blood sugars. Investigations revealed elevated renal parameters, uncontrolled blood sugars, hyperuricemia, anemia, eosinophilia, and hyperlipidemia. A nephrologist’s opinion was taken and, on his advice, conservative renal care was continued. Finerenone (10 mg) was initiated as a cardiorenal protective measure along with other supportive measures. After three doses of finerenone, there was a sudden worsening of the renal parameters. Blood urea increased from 73 to 100 mg/dL, serum creatinine increased from 1.7 to 4.7 mg/dL, and serum potassium from 4.3 to 5.4 mEq/L. After finerenone was stopped, along with good hydration and renal supportive measures, the renal parameters and serum potassium levels reverted back to baseline levels. Occasionally, finerenone may induce acute worsening of renal parameters. When initiating treatment with this drug, apart from repeating serum potassium, renal parameters may also need to be reassessed.

Comparative Efficacy and Safety of Cardio-Renoprotective Pharmacological Interventions in Chronic Kidney Disease: An Umbrella Review of Network Meta-Analyses and a Multicriteria Decision Analysis.

Sodium-glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP1a), and non-steroidal mineralocorticoid receptor antagonists (ns-MRA) are promising treatments for chronic kidney disease. This umbrella review of network meta-analyses evaluated their effects on cardiovascular outcomes, kidney disease progression, and adverse events, using the TOPSIS method to identify the optimal intervention based on P-scores. A total of 19 network meta-analyses and 44 randomized controlled trials involving 86,150 chronic kidney disease patients were included. Compared to placebo, SGLT2i were associated with reduced risks of cardiovascular events [Hazard ratio (HR): 0.776, 95% confidence intervals (CI): 0.727-0.998], kidney disease progression (HR: 0.679, 95% CI: 0.629-0.733), acute kidney injury (HR: 0.873, 95% CI: 0.773-0.907), and serious adverse events (HR: 0.881, 95% CI: 0.847-0.916). GLP1a and ns-MRA were also associated with significant reductions in cardiovascular and kidney-specific composite outcomes. Indirect evidence showed that SGLT2i demonstrated a lower risk of kidney disease progression compared to GLP1a (HR: 0.826, 95% CI: 0.716-0.952) and ns-MRA (HR: 0.818, 95% CI: 0.673-0.995), representing the best intervention across all endpoints. In conclusion, while SGLT2i, GLP1a, and ns-MRA all reduce cardiovascular and kidney disease risks in chronic kidney disease, SGLT2i appears to provide the most favorable balance of efficacy and safety.

Finerenone in Heart Failure-A Novel Therapeutic Approach.

This review will discuss heart failure, introduce a new drug finerenone, and discuss clinical studies with a focus on its effects on heart failure. Heart failure is a condition or syndrome characterized by an impairment of the pumping ability of the heart, thus no longer keeping up with the demands of the body. There are several types of heart failure; among them are heart failure with reduced ejection fraction, with mildly reduced ejection fraction and with preserved ejection fraction. Heart failure can be caused by several factors including lifestyle factors and diseases such as hypertension, type 2 diabetes mellitus and other cardiovascular diseases. Chronic kidney disease is also a risk factor of heart failure, as it leads to a state of inflammation that can impair the cardiovascular system over time. The novel nonsteroidal mineralocorticoid receptor antagonist finerenone antagonizes the mineralocorticoid receptor and thereby decreases the amount of fibrosis and inflammation that is observed in many heart failure patients. It shows an equal tissue distribution among heart and kidney, a high affinity and selectivity for the mineralocorticoid receptor and little risk of hyperkalemia and feminization. It also exhibits a reduction in the incidence of cardiovascular outcomes among patients with chronic kidney disease and type 2 diabetes mellitus. Therefore, finerenone has been proposed as a beneficial medication for reducing heart failure, especially in patients with diabetes and chronic kidney disease. Further studies are to be conducted to clarify the effects of finerenone alone and in combination with other drugs.

Cardiovascular Disease in Patients with Chronic Kidney Disease: Current Understanding, Preventative Strategies, and Future Directions.

Chronic kidney disease (CKD) presents a significant burden on global health, with cardiovascular disease (CVD) being a leading cause of mortality in this population. Despite advancements in pharmacotherapies, preventing CVD in CKD patients remains challenging due to the intricate interplay of traditional risk factors and novel pathophysiological processes. This review aims to elucidate the current understanding of CVD prevention in CKD, encompassing epidemiology, risk factors, diagnostic considerations, and pharmacological therapeutic strategies. CKD patients exhibit a unique cardiovascular risk profile characterized by traditional risk factors such as hypertension and dyslipidemia, as well as CKD-specific factors including albuminuria, vascular calcification, and valvulopathies. The utility of coronary artery calcium scoring in risk stratification and the efficacy of aspirin, lipid-lowering agents, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 inhibitors, and nonsteroidal mineralocorticoid receptor antagonists in CVD prevention are discussed. Despite promising findings, challenges such as lack of specific guidelines and data gaps persist, highlighting the need for multidisciplinary efforts to address the CVD burden in the CKD population effectively. Further research is warranted to optimize preventative strategies and improve outcomes in this high-risk population.

SGLT2 Inhibitors and Finerenone: A friendly Duo in the Treatment of Diabetic Kidney Disease?

For decades, achieving glycemic control, target blood pressure, and renin-angiotensin-aldosterone system (RAAS) blockade remained to be the therapeutic interventions for retarding diabetic kidney disease (DKD) progression. The management of DKD showed major transformation when SGLT2 inhibitors were recommended to reduce the risk of progressive deterioration in estimated glomerular filtration rate (eGFR), end-stage renal disease (ESRD), and renal death following results of CREDENCE and DAPA-CKD trials. Despite currently available therapeutic approaches, the risk of cardiac death, progression to ESRD, and requirement of renal replacement therapy remains high. Finerenone is the newer potent selective nonsteroidal mineralocorticoid receptor antagonist (MRA) that showed reduction in primary composite renal and CV outcomes in FIDELIO-DKD and FIGARO-DKD studies, respectively. While SGLT2 inhibitors have direct effects on cellular and metabolic functions besides reduction in glomerular hyperfiltration, finerenone primarily inhibits mineralocorticoid pathway-dependent inflammation and fibrosis. The renal benefits of dapagliflozin in the DAPA-CKD trial were regardless of MRA, and likewise, the benefits of finerenone in FIDELIO and FIGARO studies were irrespective of SGLT2i. Moreover, the risk of serious hyperkalemia with MRA was significantly reduced by concomitant use of SGLT2 inhibitors, making this combination a safer choice. Even though available data support the fact that this duo possibly has distinct as well as complementary mechanisms in protecting renal and cardiac functions, strong evidence to recommend routine use of the combination of SGLT2 inhibitors and MRA in DKD is currently lacking. However, the results of the ongoing CONFIDENCE study evaluating superiority of dual therapy of empagliflozin and finerenone will be worthwhile to understand the benefits of this friendly duo.

Finerenone, Obesity, and HeartFailureWith Mildly Reduced/Preserved Ejection Fraction: Prespecified Analysis of FINEARTS-HF.

Obesity is associated with excessive adipocyte-derived aldosterone secretion, independent of the classical renin-angiotensin-aldosterone cascade, and mineralocorticoid receptor antagonists may be more effective in patients with heart failure (HF) and obesity. This study sought to examine the effects of the nonsteroidal mineralocorticoid receptor antagonist finerenone compared with placebo, according to body mass index (BMI) in FINEARTS-HF (FINerenone trial to investigate Efficacy and sAfety superioR to placebo in paTientS with HeartFailure). A total of 6,001 patients with HF with NYHA functional class II, III, and IV, a left ventricular ejection fraction of≥40%, evidence of structural heart disease, and elevated natriuretic peptide levels were randomized to finerenone or placebo. BMI (kg/m2) was examined using World Health Organization categories, namely, underweight/normal weight (<25.0 kg/m2; n=1,306); overweight (25.0-29.9 kg/m2; n=1,990); obesity class I (30.0-34.9 kg/m2; n=1,546); obesity class II (35.0-39.9kg/m2; n=751); and obesity class III (≥40 kg/m2; n=395). The primary outcome was cardiovascular death and total worsening HF events. Data on baseline BMI were available for 5,988 patients (median: 29.2 kg/m2; Q1-Q3: 25.5-33.6 kg/m2). Compared with patients who were underweight/normal weight, those with obesity class II or III had a higher risk of the primary outcome (underweight/normal weight, reference; overweight, unadjusted rate ratio: 0.96 [95%CI: 0.81-1.15]; obesity class I: 1.04 [95%CI: 0.86-1.26]; obesity class II-III: 1.26 [95%CI: 1.03-1.54]). The effect of finerenone on the primary outcome did not vary by baseline BMI (underweight/normal weight, rate ratio: 0.80 [95%CI: 0.62-1.04]; overweight: 0.91 [95%CI: 0.72-1.15]; obesity class I: 0.92 [95%CI: 0.72-1.19]; obesity class II-III: 0.67 [95%CI: 0.50-0.89]; Pinteraction=0.32). However, when BMI was examined as a continuous variable, the beneficial effect of finerenone seemed to be greater in those with a higher BMI (Pinteraction=0.005). A similar pattern was observed for total worsening HF events. Consistent effects across baseline BMI were observed for cardiovascular and all-cause death and improvement in the Kansas City Cardiomyopathy Questionnaire scores. In patients with HF with mildly reduced/preserved ejection fraction, the beneficial effects of finerenone on clinical events and symptoms were consistent, irrespective of BMI at baseline, possibly with a greater effect on the primary outcome in patients with higher BMI. (FINEARTS-HF [FINerenone trial to investigate Efficacy and sAfety superioR to placebo in paTientS with Heart Failure]; NCT04435626).

Finerenone, Serum Potassium, and Clinical Outcomes in Heart Failure With Mildly Reduced or Preserved Ejection Fraction

Treatment with finerenone, a nonsteroidal mineralocorticoid receptor antagonist (MRA), improved outcomes in patients with heart failure with mildly reduced or preserved ejection fraction in FINEARTS-HF, but was associated with increased levels of serum potassium in follow-up. To investigate the frequency and predictors of serum potassium level greater than 5.5 mmol/L and less than 3.5 mmol/L and examine the treatment effect associated with finerenone, relative to placebo, on clinical outcomes based on postrandomization potassium levels. Secondary analysis of the FINEARTS-HF multicenter, randomized clinical trial, performed between September 14, 2020, and January 10, 2023, with a median follow-up of 32 months (final date of follow-up: June 14, 2024). Patients with heart failure and left ventricular ejection fraction greater than or equal to 40%, New York Heart Association class II to IV symptoms, and elevated natriuretic peptides were included. Participants received finerenone or placebo. The primary outcome was a composite of total worsening heart failure events or cardiovascular death. A total of 6001 participants were included (3003 randomized to receive finerenone and 2998 randomized to receive placebo). The increase in serum potassium was greater in the finerenone group than the placebo group at 1 month (median [IQR] difference, 0.19 [0.17-0.21] mmol/L) and 3 months (median [IQR] difference, 0.23 [0.21-0.25] mmol/L), which persisted for the remainder of trial follow-up. Finerenone increased the risks of potassium level increasing to greater than 5.5 mmol/L (hazard ratio [HR], 2.16 [95% CI, 1.83-2.56]; P < .001) and decreased the risks for potassium level decreasing to less than 3.5 mmol/L (HR, 0.46 [95% CI, 0.38-0.56]; P < .001). Both low (< 3.5 mmol/L; HR, 2.49 [95% CI, 1.8-3.43]) and high (>5.5 mmol/L; HR, 1.64 [95% CI, 1.04-2.58]) potassium levels were associated with higher subsequent risks of the primary outcome in both treatment groups. Nevertheless, the risk of the primary outcome was generally lower in patients treated with finerenone compared with placebo, even in those whose potassium level increased to greater than 5.5 mmol/L. In patients with heart failure with mildly reduced or preserved ejection fraction, finerenone resulted in more frequent hyperkalemia and less frequent hypokalemia. However, with protocol-directed surveillance and dose adjustment, clinical benefit associated with finerenone relative to placebo was maintained even in those whose potassium level increased to greater than 5.5 mmol/L. ClinicalTrials.gov Identifier: NCT04435626.

Pharmacologic Treatment of Pulmonary Hypertension Due to Heart Failure with Preserved Ejection Fraction: Are There More Arrows on Our Bow?

Pulmonary hypertension (PH) associated with heart failure with preserved ejection fraction (PH-HFpEF) represents a frequent form of PH related to left ventricular dysfunction. The pathophysiology of PH-HFpEF is intricate, and varied and includes vascular, cardiac, and pulmonary factors that contribute synergistically to developing this clinical syndrome. Improved knowledge of the pathophysiology of PH-HFpEF has paved the way for the use of new drugs such as angiotensin receptor neprilysin inhibitors (ARNIs), non-steroidal mineral corticoid receptor antagonist (nsMRA), sodium-glucose cotransporter inhibitors (SGLT2is), levosimendan, and glucagon-like peptide 1 (GLP-1) agonists. ARNIs are a widely used drug for the treatment of PH associated with heart failure with reduced ejection fraction. They have also recently been used in PH-HFpEF patients with hemodynamic benefits that need to be confirmed in future research. Finerenone is an innovative non-steroidal mineralocorticoid receptor antagonist that exhibits notable cardioprotective and renoprotective properties in individuals suffering from chronic diabetic kidney disease. It also enhances outcomes for patients with heart failure, whether they have mildly reduced or preserved ejection fraction. Moreover, in experimental studies, finerenone has been found to lower pulmonary artery pressure, reduce muscularization, and decrease the wall thickness of pulmonary arteries. SGLT2i have revolutionized the treatment of patients with heart failure irrespective of left ventricular ejection fraction, and their treatment is also associated with an improvement in the hemodynamics profile in patients with PH-HFpEF. Levosimendan is a widely used inodilator in the treatment of acute and advanced heart failure. In addition, its use in patients with PH-HFpEF (supported by the positive effects on pulmonary hemodynamics that levosimendan exerts) has recently demonstrated hemodynamic benefit in a small phase 2 study that paved the way for phase 3 studies and the creation of an oral formulation of levosimendan. Finally, GLP1 agonists are a class of drugs that, in preliminary evidence, have shown a positive effect on cardiac hemodynamics, mainly by facilitating left ventricular unloading. These effects, along with the reduction in insulin resistance and weight loss, likely lead to beneficial outcomes for PH-HFpEF patients, especially those with obesity as a comorbidity.

The potential for improving cardio-renal outcomes in chronic kidney disease with the aldosterone synthase inhibitor vicadrostat (BI 690517): a rationale for the EASi-KIDNEY trial.

Patients with chronic kidney disease (CKD) are at risk of progressive loss of kidney function, heart failure, and cardiovascular death despite current proven therapies, including renin-angiotensin system inhibitors (RASi), sodium glucose co-transporter-2 inhibitors (SGLT2i), and statin-based regimens. RASi and SGLT2i reduce risk of CKD progression irrespective of primary cause of kidney disease, suggesting they target final common pathways. Targeting aldosterone overactivity with a nonsteroidal mineralocorticoid receptor antagonist (MRA) also reduces cardiorenal risk in patients with albuminuric diabetic kidney disease already treated with RASi. Together, these observations provide the rationale for trials to assess effects of inhibiting the aldosterone pathway in a broader range of patients with CKD, including those with non-diabetic causes of CKD or low albuminuria. Aldosterone synthase inhibitors (ASi) have emerged as an alternative to MRAs for aldosterone pathway inhibition. Phase II data from 586 patients with albuminuric CKD have shown that 10 mg of an ASi, vicadrostat (BI 690517), reduced urine albumin-to-creatinine ratio by ∼40% compared to placebo with or without concurrent empagliflozin treatment. MRA and ASi increase risk of hyperkalaemia. Combining their use with an SGLT2i may mitigate some of this risk, improving tolerability, and allowing a wider range of patients to be treated (including those with higher levels of blood potassium than in previous trials). The EASi-KIDNEY (NCT06531824) double-blind placebo-controlled trial will test this approach by assessing the safety and cardiorenal efficacy of vicadrostat in combination with empagliflozin in ∼11,000 patients with CKD. It will be sufficiently large to assess effects in patients with and without diabetes separately.

Integrating the new pharmacological standard of care with traditional nutritional interventions in non-dialysis CKD.

Chronic kidney disease (CKD) is widely recognized as a leading and growing contributor to global morbidity and mortality worldwide. Nutritional therapy is the basic treatment for metabolic control, and may contribute to nephroprotection; however, the absence of solid evidence on slowing CKD progression together with poor adherence to dietary prescription limit de facto itsefficacy and prevent itsmore widespread use. Sodium-glucose transport protein 2 inhibitors (SGLT2is) are now considered the new standard of care in CKD; in addition, novel potassium binders, glucagon-like peptide-1 receptor antagonists (GLP1-RAs) and nonsteroidal mineralocorticoid receptor antagonists (nsMRAs) show either direct (SGLT2i, GLP1-RA, nsMRA) or indirect (potassium binders that enable the optimal use of renin-angiotensin-aldosterone system inhibitors) nephroprotective effects. These drugs could potentially lead to a more permissive diet, thereby allowing the patient to reap the benefits of this approach. In particular, SGLT2is, and to a lesser extent also GLP1-RAs and nsMRAsin patients with diabetic kidney disease, can counterbalance hyperfiltration as well as the higher protein intake often recorded in obese patients; on the other hand, potassium binders can facilitate following plant-based diets, which are considered healthy because of the high content of essential micronutrients such as antioxidant vitamins, minerals, alkalies, and fibers. In this review paper, we discuss the current pharmacological paradigm shift that places a new, broader standard of care in light of its interaction with nutritional therapy in order to optimize the global approach to patients with CKDnotondialysis.

Proteinuria and Progression of Renal Damage: The Main Pathogenetic Mechanisms and Pharmacological Approach.

The integrity of the glomerular filtration barrier maintains protein excretion below 150 mg/day. When urinary proteins increase, this indicates damage to the filtration barrier. However, proteinuria is not only a marker of kidney damage but also exacerbates it through various mechanisms involving the glomerular and tubulointerstitial compartments. Therefore, it is essential to intervene with renoprotective action that reduces the proteinuria. In this context, Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are cornerstone treatments. Recent advancements include sodium-glucose cotransporter 2 inhibitors, initially used for glycemic control, now recognized for their renoprotective properties in both diabetic and non-diabetic populations. Another drug, Finerenone, a selective non-steroidal mineralocorticoid receptor antagonist, has emerged as a promising agent, offering anti-inflammatory and antifibrotic benefits with fewer side effects than traditional steroidal options. Finally, dual inhibition of angiotensin II and endothelin-1 receptors through agents like Sparsentan presents a novel approach with significant antiproteinuric effects in IgA nephropathy and focal segmental glomerulosclerosis. This brief review summarizes the mechanisms by which proteinuria promotes kidney damage and the renoprotective therapeutic approaches available, which can be combined with lifestyle modifications and specific treatments for underlying diseases to mitigate the progression of chronic kidney disease.

Finerenone and diabetic renal disease: a narrative review

Overactivation of mineralocorticoid receptors occurs in cardiorenal diseases. Many patients with type 2 diabetes often progress to chronic kidney disease (CKD) and require dialysis. Finerenone is the first oral non-steroidal mineralocorticoid receptor antagonist used in patients with diabetic kidney disease and heart failure. Finerenone (Kerendia®) is more potent than spironolactone in reducing inflammation and fibrosis in CKD and exerts its effect equally on the heart and kidneys, improving cardiovascular outcomes. Research demonstrates that finerenone improves proteinuria and glomerular filtration rate if taken alone or in combination with sodium-glucose transporter 2 inhibitors. Finerenone has been found to decrease mortality in patients with diabetic renal disease and improve quality of life. Its side effects, unlike those of spironolactone, do not include gynecomastia. However, it can result in hyperkalemia, which needs to be monitored. In this review, we aim to investigate the mechanisms of action of finerenone and its implications in patients with type 2 diabetes.

KDOQI US Commentary on the KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of CKD

The Kidney Disease Outcomes Quality Initiative (KDOQI) convened a work group to review the 2024 KDIGO (Kidney Disease: Improving Global Outcomes) guideline for the management of chronic kidney disease (CKD). The KDOQI Work Group reviewed the KDIGO guideline statements and practice points and provided perspective for implementation within the context of clinical practice in the United States. In general, the KDOQI Work Group concurs with several recommendations and practice points proposed by the KDIGO guidelines regarding CKD evaluation, risk assessment, and management options (both lifestyle and medications) for slowing CKD progression, addressing CKD-related complications, and improving cardiovascular outcomes. The KDOQI Work Group acknowledges the growing evidence base to support the use of several novel agents such as sodium/glucose cotransporter 2 inhibitors for several CKD etiologies, and glucagon-like peptide 1 receptor agonists and nonsteroidal mineralocorticoid receptor antagonists for type 2 CKD in setting of diabetes. Further, KDIGO guidelines emphasize the importance of team-based care which was also recognized by the work group as a key factor to address the growing CKD burden. In this commentary, the Work Group has also assessed and discussed various barriers and potential opportunities for implementing the recommendations put forth in the 2024 KDIGO guidelines while the scientific community continues to focus on enhancing early identification of CKD and discovering newer therapies for managing kidney disease.

Finerenone: A Third-Generation MRA and Its Impact on Cardiovascular Health-Insights from Randomized Controlled Trials.

Introduction: Finerenone, a third-generation non-steroidal mineralocorticoid receptor antagonist (MRA), offers a targeted approach to managing cardiovascular outcomes, particularly in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). Unlike traditional MRAs such as spironolactone and eplerenone, which can cause off-target hormonal side effects and hyperkalemia, Finerenone selectively binds to mineralocorticoid receptors, reducing these risks. Recent randomized controlled trials have demonstrated Finerenone's potential to improve cardiovascular outcomes, making it a promising alternative in the management of heart failure and other cardiovascular conditions associated with CKD and T2D. Methods: We conducted a scoping review using PRISMA guidelines. A search for "Finerenone" in the PubMed, Embase, and Cochrane Library databases included randomized controlled trials (RCTs), post hoc analyses, and relevant meta-analyses on cardiovascular outcomes. Data were synthesized narratively, assessing study quality through strengths and limitations. Discussion: Finerenone has shown significant benefits and a superior safety profile compared with traditional MRAs like spironolactone and eplerenone in managing CKD, T2D, and heart failure. It effectively reduces cardiovascular and renal events while minimizing risks such as hyperkalemia and hormonal side effects associated with steroidal MRAs. Future studies, including the REDEFINE-HF, FINALITY-HF, and CONFIRMATION-HF trials, will further explore Finerenone's potential across diverse heart failure phenotypes, including its role in heart failure with mildly reduced and preserved ejection fractions, potentially establishing it as a cornerstone therapy in heart failure management. Conclusions: Finerenone represents a significant advancement in MRA therapy, offering enhanced safety and efficacy in managing cardiovascular outcomes in CKD and T2D patients. The current evidence supports its use as a promising alternative to traditional MRAs, particularly in patients intolerant to steroidal MRAs. Further trials are needed to fully establish its potential across diverse patient populations, including those with varying heart failure phenotypes.