Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone Research Articles

The Early Diagnosis and Treatment of Chronic Renal Insufficiency.

Chronic renal insufficiency (CRI) is becoming more common and has an increasing impact on public health. In Germany, approximately one in ten adults has CRI. Its most serious consequence is generally not the development of end-stage renal failure, but rather the markedly increased cardiovascular risk as kidney function declines. This review is based on the findings of a selective search in PubMed for literature about the treatment options for CRI, and on our overview of the existing guideline recommendations on diagnostic testing. Patients with diabetes mellitus and arterial hypertension are at especially high risk of developing CRI. For these patients, some of the guidelines recommend regular testing for albuminuria and measurement of the glomerular filtration rate (GFR), though sometimes only when specific risk constellations are present. The treatment of CRI has evolved in recent years. At first, aside from general measures, only RAS inhibitors were available as a specific therapy for CRI. With the extension of the approval of SGLT-2 inhibitors to non-diabetic CRI patients, the options for treatment have become wider. Two randomized controlled trials have revealed the benefit of SGLT-2 inhibitors with respect to their primary combined endpoints: time to a specified eGFR reduction and renal/cardiovascular death (HR 0.61 [0.51; 0.72] and 0.72 [0.64; 0.82]). The potential side effects and contraindications of SGLT-2 inhibitors must be taken into account. A further treatment option for diabetics with CRI has become available with the approval of the non-steroidal mineralocorticoid receptor antagonist finerenone. In patients with risk factors, renal function should be regularly tested.

Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone Improves Diastolic Dysfunction in Preclinical Nondiabetic Chronic Kidney Disease.

The mineralocorticoid receptor plays a significant role in the development of chronic kidney disease (CKD) and associated cardiovascular complications. Classic steroidal mineralocorticoid receptor antagonists are a therapeutic option, but their use in the clinic is limited due to the associated risk of hyperkalemia in patients with CKD. Finerenone is a nonsteroidal mineralocorticoid receptor antagonist that has been recently investigated in 2 large phase III clinical trials (FIDELIO-DKD [Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease] and FIGARO-DKD [Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease]), showing reductions in kidney and cardiovascular outcomes. We tested whether finerenone improves renal and cardiac function in a preclinical nondiabetic CKD model. Twelve weeks after 5/6 nephrectomy, the rats showed classic signs of CKD characterized by a reduced glomerular filtration rate and increased kidney weight, associated with left ventricular (LV) diastolic dysfunction and decreased LV perfusion. These changes were associated with increased cardiac fibrosis and reduced endothelial nitric oxide synthase activating phosphorylation (ser 1177). Treatment with finerenone prevented LV diastolic dysfunction and increased LV tissue perfusion associated with a reduction in cardiac fibrosis and increased endothelial nitric oxide synthase phosphorylation. Curative treatment with finerenone improves nondiabetic CKD-related LV diastolic function associated with a reduction in cardiac fibrosis and increased cardiac phosphorylated endothelial nitric oxide synthase independently from changes in kidney function. Short-term finerenone treatment decreased LV end-diastolic pressure volume relationship and increased phosphorylated endothelial nitric oxide synthase and nitric oxide synthase activity. We showed that the nonsteroidal mineralocorticoid receptor antagonist finerenone reduces renal hypertrophy and albuminuria, attenuates cardiac diastolic dysfunction and cardiac fibrosis, and improves cardiac perfusion in a preclinical nondiabetic CKD model.

Baseline characteristics of patients with heart failure with mildly reduced or preserved ejection fraction: The FINEARTS-HF trial.

To describe the baseline characteristics of participants in the FINEARTS-HF trial, contextualized with prior trials including patients with heart failure (HF) with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF). The FINEARTS-HF trial is comparing the effects of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo in reducing cardiovascular death and total worsening HF events in patients with HFmrEF/HFpEF. Patients with symptomatic HF, left ventricular ejection fraction (LVEF) ≥40%, estimated glomerular filtration rate ≥ 25 ml/min/1.73 m2, elevated natriuretic peptide levels and evidence of structural heart disease were enrolled and randomized to finerenone titrated to a maximum of 40 mg once daily or matching placebo. We validly randomized 6001 patients to finerenone or placebo (mean age 72 ± 10 years, 46% women). The majority were New York Heart Association functional class II (69%). The baseline mean LVEF was 53 ± 8% (range 34-84%); 36% of participants had a LVEF <50% and 64% had a LVEF ≥50%. The median N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 1041 (interquartile range 449-1946) pg/ml. A total of 1219 (20%) patients were enrolled during or within 7 days of a worsening HF event, and 3247 (54%) patients were enrolled within 3 months of a worsening HF event. Compared with prior large-scale HFmrEF/HFpEF trials, FINEARTS-HF participants were more likely to have recent (within 6 months) HF hospitalization and greater symptoms and functional limitations. Further, concomitant medications included a larger percentage of sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors than previous trials. FINEARTS-HF has enrolled a broad range of high-risk patients with HFmrEF and HFpEF. The trial will determine the safety and efficacy of finerenone in this population.

KDOQI Commentary on the KDIGO 2022 Update to the Clinical Practice Guideline for Diabetes Management in CKD

The Kidney Disease: Improving Global Outcomes (KDIGO) guideline for diabetes management in chronic kidney disease (CKD) was updated in 2022, just 2 years after the previous update. The need for this rapid update is reflective of the recent and unprecedented positive results of numerous clinical trials aimed at reducing kidney and cardiovascular morbidity and mortality in people with diabetes. The Kidney Disease Outcomes Quality Initiative (KDOQI) work group for diabetes in CKD, convened by the National Kidney Foundation, provides herein a commentary on these changes, particularly the implications for health care in the United States. Changes to the KDIGO guideline mirror the evolution of sodium/glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists from purely antihyperglycemic agents to cardiorenal-metabolic therapeutics, and the lower estimated glomerular filtration rate of≥20mL/min/1.73m2 for SGLT2 inhibitor initiation. New data have also brought the addition of the first-in-class, Federal Drug Administration-approved nonsteroidal mineralocorticoid receptor antagonist finerenone as an agent to reduce cardiorenal end points. While there has been significant progress in innovation, there remain serious challenges to implementation, particularly in the United States where inequities in insurance coverage and high costs limit their use, particularly in vulnerable populations, ultimately widening health care disparities.

Effect of finerenone in patients with chronic kidney disease and type 2 diabetes by baseline anaemia status: a FIDELITY analysis

Abstract Introduction Anaemia is a common complication affecting ∼42% patients with chronic kidney disease (CKD) stages 3–5 at 1 year after diagnosis and ∼67% at 5 years, with prevalence increasing as estimated glomerular filtration rate (eGFR) decreases. Despite the fact that anaemia is associated with CKD progression, adverse cardiovascular (CV) events and premature mortality in patients with CKD, management of these patients remains suboptimal. The nonsteroidal mineralocorticoid receptor antagonist finerenone demonstrated significant cardiorenal benefits in patients with CKD and type 2 diabetes (T2D) in FIDELITY (a prespecified pooled analysis of the phase III FIDELIO-DKD and FIGARO-DKD trials). However, the effect of anaemia on CV and kidney outcomes in patients receiving finerenone has not been established. Purpose This post hoc analysis investigated the treatment effects and safety of finerenone vs placebo in patients categorised by baseline anaemia status. Methods Eligible patients with CKD (urine albumin-to-creatinine ratio [UACR] ≥30–&amp;lt;300 mg/g and eGFR ≥25–≤90 ml/min/1.73 m² or UACR ≥300–≤5000 mg/g and eGFR ≥25 ml/min/1.73 m²) and T2D, and on optimised renin–angiotensin system inhibitor were randomised 1:1 to finerenone or placebo. Anaemia was defined using the World Health Organization criteria: serum haemoglobin levels &amp;lt;13 g/dl (male) or &amp;lt;12 g/dl (female) or treatment with an erythropoiesis-stimulating agent at baseline. Key outcomes analysed by baseline anaemia status included a CV composite (CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalisation for heart failure [HHF]) and kidney composite (kidney failure, sustained eGFR decrease ≥57%, or kidney-related death), HHF, and all-cause mortality. Safety outcomes were assessed by treatment-emergent adverse events. Results Of 13,007 patients, 4293 (33.0%) had anaemia at baseline. The risk reduction on the CV composite outcome was nominally significant with finerenone vs placebo in patients with anaemia at baseline but not in those without (p-value for interaction=0.04; Figure 1). Finerenone also reduced the risk of the kidney composite outcome vs placebo, with no heterogeneity between the treatment groups and across the anaemia subgroups (Figure 1). In addition, finerenone was associated with a reduced risk of all-cause mortality and HHF outcomes vs placebo, irrespective of baseline anaemia status (Figure 1). Incidence of treatment emergent hyperkalaemia was higher in patients with anaemia at baseline in both treatment arms (21.2% finerenone vs 11.5% placebo) compared to those without anaemia (10.5% finerenone vs 4.6% placebo). Conclusions In patients with CKD and T2D, anaemia was found to be a modifier to the effect of finerenone on the CV composite outcome. There was no heterogeneity of treatment effects with finerenone vs placebo, by anaemia at baseline, on kidney composite outcome, all-cause mortality and HHF.

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

Abstract Introduction Globally, approximately 85% of patients with chronic kidney disease (CKD) suffer from hypertension; this population is at increased risk of cardiovascular (CV) disease. Thiazide and loop diuretics are commonly used to treat hypertension and heart failure, respectively, in these patients. Diuretics alter potassium levels, which are also associated with CV outcomes. Purpose This post hoc exploratory analysis assessed the effect of the nonsteroidal mineralocorticoid receptor antagonist finerenone on CV and safety outcomes by baseline diuretic use in the FIDELITY dataset. We assessed whether the efficacy and safety of finerenone would be consistent regardless of diuretic use status at baseline, despite the effects these medications have on potassium. Methods In FIDELITY, a pooled analysis of the FIDELIO-DKD and FIGARO-DKD phase III clinical trials, eligible patients with type 2 diabetes (T2D) and CKD (urine albumin-to-creatinine ratio [UACR] ≥30–&amp;lt;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 up-titrated to the maximum tolerated dose of renin–angiotensin system inhibitor during the run-in phase of the studies. For this analysis, patients were categorized by baseline diuretic use (yes/no for any diuretic and diuretic type) with additional on-treatment sensitivity analyses by post-baseline diuretic status. A composite CV outcome (CV death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure) assessed efficacy. Safety was assessed considering treatment-emergent adverse events. Results Of 13,026 patients, 51.5% were treated with diuretics at baseline (21.5% on loop and 24.2% on thiazide diuretics). Finerenone reduced the risk of the composite CV outcome vs. placebo and this effect was not modified by baseline diuretic use (Yes: hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.77–0.97; No: HR: 0.86; 95% CI: 0.74–1.00; P-value for interaction = 0.95). On-treatment analysis showed concomitant diuretic use with study treatment to be mainly constant among patients during the follow-up period and sensitivity analyses revealed consistently lower incidence rates with finerenone vs. placebo on composite CV outcome across the three diuretic subgroups by corresponding on-treatment use/non-use. Hyperkalaemia rates for patients on finerenone were overall comparable by diuretic use (Yes: 13.8% vs. 5.7% for placebo; No: 14.3% vs. 8.3% for placebo). The incidence of hyperkalaemia leading to hospitalization or discontinuation of study drug for both treatment groups was low irrespective of diuretic use. Conclusion In this analysis, finerenone reduced the risk of CV outcomes in patients with CKD and T2D irrespective of baseline diuretic use. Overall, the incidence of hyperkalaemia leading to hospitalization was low across all subgroups of diuretic users.

Abstract 17437: Estimated Lifetime Benefits of Combination Therapy With SGLT2 Inhibitors, GLP-1 Receptor Agonists, and Non-Steroidal MRAs in Patients With Type 2 Diabetes and Albuminuria

Introduction: Sodium glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and the non-steroidal mineralocorticoid receptor antagonist finerenone all reduce cardiovascular events and mortality in patients with type 2 diabetes. However, the lifetime benefits of combination therapy with all three medications are not known. Aim: To estimate lifetime gains in cardiovascular event-free and overall survival with combination SGLT2i, GLP-1RA, and finerenone in patients with type 2 diabetes and albuminuria. Methods: We used individual participant data from the CANVAS and CREDENCE trials and trial-level data from 8 GLP-1RA trials and 2 finerenone trials (FIDELIO and FIGARO) to estimate the relative effects of combination therapy on cardiovascular and mortality outcomes. Using nonparametric age-based methods, we applied combined treatment effects to placebo treated patients with urinary albumin:creatinine ratio ≥30 mg/g in the pooled CANVAS and CREDENCE trials. Results: The aggregate hazard ratio comparing combination therapy versus conventional standard of care for major adverse cardiovascular events (MACE; nonfatal myocardial infarction, nonfatal stroke or cardiovascular death) was 0.65 (95% CI 0.55-0.76) (Figure). For a 50-year-old, estimated event-free survival from MACE was 18.0 years with placebo and 21.2 years with combination therapy (3.2 years gained, 95% CI 2.1-4.2; Figure). Estimated gains in survival free from hospitalised heart failure, cardiovascular death, and all-cause death with combination therapy in a 50-year-old person were 3.3 (95% CI 2.5-4.1), 2.2 (95% CI 1.2-3.1), and 2.5 years (95% CI 1.4-3.5) respectively, with benefits evident across all ages studied. Conclusions: Combination treatment with SGLT2i, GLP-1RA and finerenone in patients with type 2 diabetes and albuminuria is projected to afford clinically important gains in cardiovascular event-free and overall survival.

Taming resistant hypertension: The promise of novel pharmacologic approaches and renal denervation.

Resistant hypertension is associated with an exceedingly high cardiovascular risk and there remains an unmet therapeutic need driven by pathophysiologic pathways unaddressed by guideline-recommended therapy. While spironolactone is widely considered as the preferable fourth-line drug, its broad application is limited by its side effect profile, especially off-target steroid receptor-mediated effects and hyperkalaemia in at-risk subpopulations. Recent landmark trials have reported promising safety and efficacy results for a number of novel compounds targeting relevant pathophysiologic pathways that remain unopposed by contemporary drugs. These include the dual endothelin receptor antagonist, aprocitentan, the aldosterone synthase inhibitor, baxdrostat and the nonsteroidal mineralocorticoid receptor antagonist finerenone. Furthermore, the evidence base for consideration of catheter-based renal denervation as a safe and effective adjunct therapeutic approach across the clinical spectrum of hypertension has been further substantiated. This review will summarise the recently published evidence on novel antihypertensive drugs and renal denervation in the context of resistant hypertension.

Obesity-Related Kidney Disease: Current Understanding and Future Perspectives.

Obesity is a serious chronic disease and an independent risk factor for the new onset and progression of chronic kidney disease (CKD). CKD prevalence is expected to increase, at least partly due to the continuous rise in the prevalence of obesity. The concept of obesity-related kidney disease (OKD) has been introduced to describe the still incompletely understood interplay between obesity, CKD, and other cardiometabolic conditions, including risk factors for OKD and cardiovascular disease, such as diabetes and hypertension. Current therapeutics target obesity and CKD individually. Non-pharmacological interventions play a major part, but the efficacy and clinical applicability of lifestyle changes and metabolic surgery remain debatable, because the strategies do not benefit everyone, and it remains questionable whether lifestyle changes can be sustained in the long term. Pharmacological interventions, such as sodium-glucose co-transporter 2 inhibitors and the non-steroidal mineralocorticoid receptor antagonist finerenone, provide kidney protection but have limited or no impact on body weight. Medicines based on glucagon-like peptide-1 (GLP-1) induce clinically relevant weight loss and may also offer kidney benefits. An urgent medical need remains for investigations to better understand the intertwined pathophysiologies in OKD, paving the way for the best possible therapeutic strategies in this increasingly prevalent disease complex.

New Paradigms for CKD Management in Patients With T2D.

At the end of the activity, participants will be able to: Identify the risks of kidney disease and their consequences in patients with type 2 diabetes (T2D). Appropriately screen for the presence of chronic kidney disease (CKD) in patients with T2D. Initiate evidence-based therapy to slow the progression of kidney disease in patients with T2D and CKD. Become familiar with the novel nonsteroidal mineralocorticoid receptor antagonist finerenone and its role in the treatment of patients with T2D and CKD.

#4486 VALIDATION OF A CKD PROGRESSION RISK PREDICTION MODEL IN THE FIDELITY TRIAL POPULATION

Abstract Background and Aims Chronic kidney disease (CKD) is often underrecognised until later stages when most of the kidney function is lost and the therapeutic window for disease-modifying therapy is narrow [1]. We previously developed a lab-based risk prediction model to accurately predict CKD progression in adults at all stages of CKD [2]. Here, we describe a validation of our model in the clinical trial population of FIDELITY, a prespecified pooled analysis of the phase III FIDELIO-DKD (NCT02540993) and FIGARO-DKD (NCT02545049) trials for the nonsteroidal mineralocorticoid receptor antagonist finerenone [3]. Method We performed a post hoc analysis of all participants from the FIDELITY database, irrespective of estimated glomerular filtration rate (eGFR) or albuminuria stage. Baseline values for the underlying laboratory tests required for the model, Klinrisk, were extracted from the complete blood count, comprehensive metabolic panel and urine albumin-to-creatinine ratio (UACR). The predicted outcome was a ≥40% decline in eGFR or kidney failure. We calculated discrimination ability of the model and calibration using area under the curve (AUC), Brier scores and calibration plots in the overall population, and stratified by treatment assignment. Sensitivity analyses examined the accuracy of the models in predicting ≥57% decline in eGFR, as well as the change in risk score over time. Kidney Disease: Improving Global Outcomes (KDIGO) heat map categories were used as the reference standard. Results We included 13,026 participants with a mean age of 64.8 ± 9.5 years, mean eGFR of 57.6 ± 21.7 ml/min/1.73 m2, and median UACR of 58.2 mg/mmol (interquartile range 22.4–129.6). At time horizons of 2 and 4 years, 984 and 1795 patients experienced a primary outcome event, respectively. The Klinrisk model predicted progression accurately, with an AUC of 0.81 (95% confidence interval [CI] 0.79–0.82) at 2 years and 0.86 (95% CI 0.84–0.87) at 4 years, compared with the KDIGO heatmap categories (AUC of 0.59 [95% CI 0.58–0.60] at 2 years and 0.66 [95% CI 0.65–0.68] at 4 years). Calibration was appropriate (Brier score of 0.067 [95% CI 0.064–0.070] at 2 years and 0.115 [95% CI 0.109–0.120] at 4 years). Similar discrimination accuracy was seen for the ≥57% decline outcome (C-statistic 0.88, 95% CI 0.87–0.90) at 3 years. Conclusion Based on routinely collected lab data, our machine learning model (Klinrisk) accurately predicts CKD progression events in a well characterized global clinical trial population. Prospective implementation of the model in clinical trial enrolment as well as clinical care pathways is needed.

Therapeutic Advances in Diabetic Kidney Disease.

Although sodium glucose co-transporter type 2 (SGLT-2) inhibitors were initially introduced as glucose-lowering medications, it was later discovered that cardiorenal protection is the most important treatment effect of these agents. A triad of landmark trials consistently showed the benefits of SGLT-2 inhibitors on kidney and cardiovascular outcomes in patients with chronic kidney disease (CKD), irrespective of the presence or absence of Type 2 diabetes (T2D). Furthermore, finerenone is a novel, selective, nonsteroidal mineralocorticoid receptor antagonist (MRA) that safely and effectively improved cardiorenal outcomes in a large Phase 3 clinical trial program that included >13,000 patients with T2D and a wide spectrum of CKD. These two drug categories have shared and distinct mechanisms of action, generating the hypothesis that an overadditive cardiorenal benefit with their combined use may be biologically plausible. In this article, we describe the mechanism of action, and we provide an overview of the evidence for cardiorenal protection with SGLT-2 inhibitors and the nonsteroidal MRA finerenone in patients with CKD associated with T2D.

Benefits of the Non-Steroidal Mineralocorticoid Receptor Antagonist Finerenone in Metabolic Syndrome-Related Heart Failure with Preserved Ejection Fraction.

The mineralocorticoid receptor (MR) plays an important role in the development of chronic kidney disease (CKD) and associated cardiovascular complications. Antagonizing the overactivation of the MR with MR antagonists (MRA) is a therapeutic option, but their use in patients with CKD is limited due to the associated risk of hyperkalemia. Finerenone is a non-steroidal MRA associated with an improved benefit-risk profile in comparison to steroidal MRAs. In this study, we decided to test whether finerenone improves renal and cardiac function in male hypertensive and diabetic ZSF1 rats as an established preclinical HFpEF model. Finerenone was administered at 10 mg/kg/day for 12 weeks. Cardiac function/hemodynamics were assessed in vivo. ZSF1 rats showed classical signs of CKD with increased BUN, UACR, hypertrophy, and fibrosis of the kidney together with characteristic signs of HFpEF including cardiac fibrosis, diastolic dysfunction, and decreased cardiac perfusion. Finerenone treatment did not impact kidney function but reduced renal hypertrophy and cardiac fibrosis. Interestingly, finerenone ameliorated diastolic dysfunction and cardiac perfusion in ZSF1 rats. In summary, we show for the first time that non-steroidal MR antagonism by finerenone attenuates cardiac diastolic dysfunction and improves cardiac perfusion in a preclinical HFpEF model. These cardiac benefits were found to be largely independent of renal benefits.

Finerenone in chronic kidney disease and type 2 diabetes: the known and the unknown

The novel nonsteroidal mineralocorticoid receptor antagonist finerenone has been shown to reduce the risk of kidney and cardiovascular outcomes in patients with type 2 diabetes and chronic kidney disease. In this issue of Kidney International, Bakris etal. present new data on the kidney efficacy of finerenone across subgroups of estimated glomerular filtration rate and urinary albumin-to-creatinine ratio, as well as safety data. We attempt to place these results in context by discussing the benefits and risks of finerenone, as well as the generalizability of the study findings to routine care settings.

Abstract 15337: Chronic Oral Finerenone Treatment Does Not Improve Left Ventricular Diastolic Compliance in Swine With Repetitive Pressure Overload-Induced HFpEF

Introduction: The non-steroidal mineralocorticoid receptor antagonist finerenone has emerged as a potential treatment for heart failure with preserved ejection fraction (HFpEF) based, in part, on initial evidence of its anti-fibrotic properties. However, it is unclear whether chronic oral finerenone therapy can reverse established cardiac fibrosis. Accordingly, we tested the efficacy of chronic oral finerenone in a porcine model of HFpEF characterized by interstitial fibrosis and reduced left ventricular (LV) diastolic compliance in the absence of co-morbidities or anatomic LV hypertrophy. Methods: Swine (n=12) were subjected to daily (1 hr) episodes of repetitive LV pressure overload (RPO) for 2 weeks using phenylephrine (24 mg/hr) to transiently elevate LVEDP to ~30 mm Hg. After 2 weeks, RPO was discontinued and animals were followed for an additional 4 weeks, during which a subset received oral finerenone (20 mg/day; n=6). LV end-diastolic volume (EDV) and pressure (EDP) were measured at normal and elevated preload to assess LV compliance (ΔLVEDV/ΔLVEDP) and post-mortem picrosirius red staining was performed to quantify interstitial fibrosis vs. normal controls (n=8). Results: Four-weeks after cessation of RPO, untreated animals exhibited a significant increase in interstitial fibrosis vs. normal controls that was attenuated in finerenone-treated animals ( Figure A ). Despite this regression of interstitial collagen, a persistent reduction in LV diastolic compliance was observed after finerenone treatment (1.18 ± 0.33 mL/mmHg vs. 2.11 ± 0.22 mL/mmHg in normal controls; p=0.04) that was comparable to that of untreated animals after RPO (0.97 ± 0.22 mL/mmHg; p=0.61; Figure B ). Conclusion: Four weeks of chronic oral finerenone treatment does not restore LV diastolic compliance in swine with RPO-induced HFpEF despite regression of interstitial collagen content, suggesting that other factors may contribute to diastolic stiffening in this model.

Association of Finerenone Use With Reduction in Treatment-Emergent Pneumonia and COVID-19 Adverse Events Among Patients With Type 2 Diabetes and Chronic Kidney Disease

Patients with chronic kidney disease and type 2 diabetes have a higher risk of developing pneumonia as well as an increased risk of severe COVID-19-associated adverse events and mortality. Therefore, the anti-inflammatory effects of mineralocorticoid receptor antagonists via blockade of the mineralocorticoid receptor may alter the risk of pneumonia and COVID-19-associated adverse events in patients with chronic kidney disease and type 2 diabetes. To evaluate whether the selective, nonsteroidal mineralocorticoid receptor antagonist finerenone is associated with protection against pneumonia and COVID-19 adverse events in patients with type 2 diabetes and chronic kidney disease. This secondary analysis used patient-level data from FIDELITY, a prespecified pooled analysis of 2 multicenter, double-blind, placebo-controlled, event-driven, phase 3 randomized clinical trials: FIDELIO-DKD and FIGARO-DKD, conducted between September 2015 and February 2021. Patients in FIDELIO-DKD or FIGARO-DKD with type 2 diabetes and chronic kidney disease (urine albumin to creatine ratio, 30-5000 mg/g, estimated glomerular filtration rate ≥25 mL/min/1.73 m2) were assessed. Data were analyzed from May 15, 2021, to July 28, 2022. Patients were randomized to finerenone (10 or 20 mg once daily) or matching placebo. The main outcomes were investigator-reported incidences of treatment-emergent infective pneumonia adverse events and serious adverse events (during and up to 3 days after treatment) and any COVID-19 adverse events. Of 13 026 randomized patients (mean [SD] age, 64.8 [9.5] years; 9088 [69.8%] men), 12 999 were included in the FIDELITY safety population (6510 patients receiving finerenone; 6489 patients receiving placebo). Over a median (range) treatment duration of 2.6 (0-5.1) years, finerenone was consistently associated with reduced risk of pneumonia and serious pneumonia vs placebo. Overall, 307 patients (4.7%) treated with finerenone and 434 patients (6.7%) treated with placebo experienced pneumonia (hazard ratio [HR], 0.71; 95% CI, 0.64-0.79; P < .001). Serious pneumonia occurred in 171 patients (2.6%) treated with finerenone and 250 patients (3.9%) treated with placebo (HR, 0.69; 95% CI, 0.60-0.79; P < .001). Incidence proportions of COVID-19 adverse events were 86 patients (1.3%) in the finerenone group and 118 patients (1.8%) in the placebo group (HR, 0.73; 95% CI, 0.60-0.89; P = .002). These findings suggest that mineralocorticoid receptor blockade with finerenone was associated with protection against pneumonia and COVID-19 adverse events in patients with type 2 diabetes and chronic kidney disease. Further clinical studies may be warranted. ClinicalTrials.gov identifiers: FIDELIO-DKD: NCT02540993; FIGARO-DKD: NCT02545049.

Cardiorenal benefits of mineralocorticoid antagonists in CKD and type2 diabetes : Lessons from the FIGARO-DKD trial.

Diabetic kidney disease (DKD) develops in almost half of all patients with diabetes and is the most common cause of chronic kidney disease (CKD) worldwide. Despite the high risk of chronic renal failure in these patients, only few therapeutic strategies are available. The use of renin-angiotensin system blockers to reduce the incidence of kidney failure in patients with DKD was established years ago and remains the hallmark of therapy. The past 2years have seen adramatic change in our therapeutic arsenal for CKD. Sodium-glucose co-transporter‑2 inhibitors (SGLT2s) have been successfully introduced for the treatment of CKD. Afurther addition is anovel compound antagonizing the activation of the mineralocorticoid receptor: finerenone. Finerenone reduces albuminuria and surrogate markers of cardiovascular disease in patients who are already on optimal therapy. In the past, treatment with other mineralocorticoid receptor antagonists was hampered by asignificantly increased risk of hyperkalemia. Finerenone had amuch smaller effect on hyperkalemia. Together with areduced effect on blood pressure and no signs of gynecomastia, this therapeutic strategy had amore specific anti-inflammatory effect and a smaller effect on the volume/electrolyte axis. In the FIDELIO-DKD study comparing the actions of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo, finerenone reduced the progression of DKD and the incidence of cardiovascular events, with arelatively safe adverse event profile. In this article, we summarize the available evidence on the cardioprotective and nephroprotective effects of finerenone and analyze the molecular mechanisms involved. In addition, we discuss the potential future role of mineralocorticoid receptor inhibition in the treatment of patients with diabetic CKD.

Results From Drug-Drug Interaction Studies In Vitro and In Vivo Investigating the Inhibitory Effect of Finerenone on the Drug Transporters BCRP, OATP1B1, and OATP1B3.

Background and ObjectivesIn vitro and in vivo studies were performed with the novel, selective, nonsteroidal mineralocorticoid receptor antagonist finerenone to assess the relevance of inhibitory effects on the transporters breast cancer resistance protein (BCRP), organic anion transporting polypeptide 1B1 (OATP1B1), and OATP1B3. These transporters are involved in the disposition of a number of drugs, including statins. Statins are also a frequent comedication in patients receiving finerenone. Therefore, inhibitory effects on BCRP and OATPs are of potential clinical relevance.MethodsThe effect on the transport of specific substrates of BCRP and OATP1B1/1B3 was assessed in cell-based in vitro assays with finerenone or its metabolites. A fixed-sequence crossover study in 14 healthy male volunteers investigated the effects of finerenone (40 mg once daily) on the pharmacokinetics of the index substrate rosuvastatin (5 mg) administered alone, simultaneously with, or approximately 4 h before finerenone. The effect of finerenone on the endogenous OATP substrates coproporphyrin I and III was also assessed.ResultsBased on in vitro findings and threshold values proposed in regulatory guidelines, finerenone appeared to be a potentially relevant inhibitor of all three transporters. Relevant inhibition could also not be ruled out for the finerenone metabolites M1a (OATP1B1) and M3a (OATP1B1 and OAT1B3), which prompted an investigation into the relevance of these findings in vivo. After administration on a background of finerenone 40 mg, all point estimates of area under the curve ratios (114.47% [rosuvastatin], 99.62% [coproporphyrin I; simultaneous], and 105.28% [rosuvastatin; 4 h separation]) and maximum concentration ratios (111.24% [rosuvastatin], 101.22% [coproporphyrin I], 89.14% [coproporphyrin III; simultaneous], and 96.84% [rosuvastatin; 4 h separation]) of the investigated substrates were within 80.0–125%. In addition, the 90% confidence intervals of the ratios were within the conventional no-effect boundaries of 80.0% and 125% for rosuvastatin after temporally separated administration, and for coproporphyrin I and III.ConclusionAdministration of finerenone 40 mg once daily confers no risk of clinically relevant drug–drug interactions with substrates of BCRP, OATP1B1, or OATP1B3. The potential for relevant inhibition of these transporters suggested by in vitro findings was not confirmed in vivo.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13318-022-00794-5.

The non-steroidal mineralocorticoid receptor antagonist finerenone is a novel therapeutic option for patients with Type 2 diabetes and chronic kidney disease.

Despite strong preclinical data supporting the use of mineralocorticoid receptor antagonists (MRAs) to provide cardiorenal protection in rodent models of diabetes, the clinical evidence of their utility in treating chronic kidney disease (CKD) has been limited. Two major clinical trials (FIDELIO-DKD and FIGARO-DKD) including more than 13,000 patients with albuminuric CKD and Type 2 diabetes randomized to placebo or finerenone (MRA) have recently provided exciting results showing a significant risk reduction for kidney and cardiovascular outcomes. In this review, we will summarize the major findings of these trials, together with post-hoc and pooled analyses that have allowed evaluation of the efficacy and safety of finerenone across the spectrum of CKD, revealing significant protective effects of finerenone against kidney failure, new-onset atrial fibrillation or flutter, new-onset heart failure, cardiovascular death, and first and total heart-failure hospitalizations. Moreover, we will discuss the current evidence that supports the combined use of MRAs with sodium-glucose co-transporter-2 inhibitors, either by providing an additive cardiorenal benefit or by decreasing the risk of hyperkalemia. Although the mechanisms of protection by finerenone have only been partially explored in patients, rodent studies have shed light on its anti-inflammatory and anti-fibrotic effects in models of kidney disease, which is one of the main drivers for testing the efficacy of finerenone in non-diabetic CKD patients in the ongoing FIND-CKD trial.

Dose-Exposure-Response Analysis of the Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone on UACR and eGFR: An Analysis from FIDELIO-DKD.

Background and ObjectiveFinerenone reduces the risk of kidney failure in patients with chronic kidney disease and type 2 diabetes. Changes in the urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) are surrogates for kidney failure. We performed dose–exposure–response analyses to determine the effects of finerenone on these surrogates in the presence and absence of sodium glucose co-transporter-2 inhibitors (SGLT2is) using individual patient data from the FIDELIO-DKD study.MethodsNon-linear mixed-effects population pharmacokinetic/pharmacodynamic models were used to quantify disease progression in terms of UACR and eGFR during standard of care and pharmacodynamic effects of finerenone in the presence and absence of SGLT2i use.ResultsThe population pharmacokinetic/pharmacodynamic models adequately described effects of finerenone exposure in reducing UACR and slowing eGFR decline over time. The reduction in UACR achieved with finerenone during the first year predicted its subsequent effect in slowing progressive eGFR decline. SGLT2i use did not modify the effects of finerenone. The population pharmacokinetic/pharmacodynamic model demonstrated with 97.5% confidence that finerenone was at least 94.1% as efficacious in reducing UACR in patients using an SGLT2i compared with patients not using an SGLT2i based on the 95% confidence interval of the SGLT2i-finerenone interaction from 94.1 to 122%. The 95% confidence interval of the SGLT2i-finerenone interaction for the UACR-mediated effect on chronic eGFR decline was 9.5–144%.ConclusionsWe developed a model that accurately describes the finerenone dose–exposure–response relationship for UACR and eGFR. The model demonstrated that the early UACR effect of finerenone predicted its long-term effect on eGFR decline. These effects were independent of concomitant SGLT2i use.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-022-01124-3.