bay-94-8862 and Diabetic-Nephropathies

Only a few meta-analyses evaluated the effect of finerenone on cardiovascular events in type 2 diabetes mellitus with chronic kidney disease. The main aim of this meta-analysis was to gain more reliable assessments of the efficacy and safety of finerenone for prevention of cardiovascular events in diabetic kidney disease. We searched for finerenone in the treatment of diabetic kidney disease from database (PubMed, Embase, and ClinicalTrials.gov ) until December 30, 2021. Relative risks (RRs) with 95% confidence intervals (CIs) calculated by the Mantel-Haenszel random-effects model were used as summary statistics for the categorical data. We included 4 studies that met the inclusion criteria with 13,943 participants. The finerenone group demonstrated a great benefit in reducing the incidence of major adverse cardiac events (RR: 0.88; 95% CI 0.80-0.96; P = 0.003), all-cause mortality (RR: 0.89; 95% CI 0.80-0.99; P = 0.04), myocardial infarction (RR: 0.79; 95% CI 0.67-0.92; P = 0.003), and new-onset hypertension (RR: 0.71; 95% CI 0.62-0.81; P < 0.00001). No difference was found in adverse events between the finerenone and placebo groups (RR: 1.00; 95% CI [0.98-1.01], P = 0.59), whereas a higher risk of hyperkalemia was observed in the finerenone group than in the placebo group (RR = 2.04, 95% CI 1.80-2.32; P < 0.00001). Besides, cerebrovascular events and new-onset atrial fibrillation did not increase in patients taking finerenone. Overall, finerenone treatment showed a great benefit of reducing the risk of major adverse cardiac events, all-cause mortality, myocardial infarction, and new-onset hypertension events in patients with type 2 diabetes mellitus and chronic kidney disease.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Hypertension; Myocardial Infarction; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic

Persons with diabetes and chronic kidney disease (CKD) have a high residual risk of developing cardiovascular (CV) complications despite treatment with renin-angiotensin system blockers and sodium-glucose cotransporter type 2 inhibitors. Overactivation of mineralocorticoid receptors plays a key role in the progression of renal and CV disease, mainly by promoting inflammation and fibrosis. Finerenone is a nonsteroidal selective mineralocorticoid antagonist. Recent clinical trials, such as FIDELIO-DKD and FIGARO-DKD and the combined analysis FIDELITY have demonstrated that finerenone decreases albuminuria, risk of CKD progression, and CV risk in subjects with type 2 diabetes (T2D) and CKD. As a result, finerenone should thus be considered as part of a holistic approach to kidney and CV risk in persons with T2D and CKD. In this narrative review, the impact of finerenone treatment on the CV system in persons with type 2 diabetes and CKD is analyzed from a practical point of view.Key messages:Despite inhibition of renin-angiotensin system and sodium-glucose cotransporter type 2, persons with type 2 diabetes (T2D) and chronic kidney disease (CKD) remain on high cardiovascular (CV) residual risk.Overactivation of mineralocorticoid receptors plays a key role in the progression of renal and CV disease, mainly by promoting inflammation and fibrosis that is not targeted by traditional treatments.Finerenone is a nonsteroidal selective mineralocorticoid antagonist that decreases not only albuminuria, but also the risk of CKD progression, and CV risk in subjects with T2D and CKD.

Topics: Albuminuria; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Fibrosis; Glucose; Humans; Inflammation; Kidney; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid; Renal Insufficiency, Chronic; Sodium

Chronic kidney disease (CKD) is the most common cause of end-stage renal disease in patients with type 2 diabetes mellitus (T2DM). CKD increases the risk of cardiovascular diseases; therefore, its prevention and treatment are important. The prevention of diabetic kidney disease (DKD) can be achieved through intensive glycemic control and blood pressure management. Additionally, DKD treatment aims to reduce albuminuria and improve kidney function. In patients with T2DM, renin-angiotensin-aldosterone system inhibitors, sodium glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists can delay the progression of DKD. Hence, there is a need for novel treatments that can effectively suppress DKD progression. Finerenone is a first-in-class nonsteroidal mineralocorticoid receptor antagonist with clinically proven efficacy in improving albuminuria, estimated glomerular filtration rate, and risk of cardiovascular events in early and advanced DKD. Therefore, finerenone is a promising treatment option to delay DKD progression. This article reviews the mechanism of renal effects and major clinical outcomes of finerenone in DKD.

Topics: Albuminuria; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Humans; Kidney; Mineralocorticoid Receptor Antagonists; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors

In developed countries, diabetes mellitus (DM) is one of the main causes of end stage renal disease (ESRD). In addition, the development of chronic kidney disease (CKD) further increases the already significantly increased cardiovascular (CV) risk in patients with diabetes. Both albuminuria and impaired renal function predict CV disease-related morbidity. The multifactorial pathogenesis of DM-related CKD involves structural, physiological, hemodynamic, and inflammatory processes. Instead of a so-called glucocentric approach, current evidence suggests that a multimodal, interdisciplinary treatment approach is needed to also prevent further progression of CKD and reduce the risk of cardiovascular events. Combined antihypertensive, antihyperglycemic and hypolipidemic therapy is the basis of a comprehensive approach to prevent the progression of diabetic kidney disease. According to recent evidence, adjunctive therapy with the non-steroidal mineralocorticoid receptor antagonist (MRA) finerenone - in addition to the use of an ACE (angiotensin converting enzyme) or AT1 (angiotensin II receptor subtype 1) blocker and an SGLT2 (sodium-glucose cotransporter-2) inhibitor - represents an effective therapeutic tool to improve nephroprotection in CKD. The aim of this review is to provide brief information on this promising pharmacotherapeutic approach to the treatment of diabetic kidney disease.

Topics: Albuminuria; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Humans; Mineralocorticoid Receptor Antagonists; Renal Insufficiency, Chronic

The phase III clinical trial of the nonsteroidal mineralocorticoid receptor antagonist finerenone (BAY 94-8862) has been completed, aiming to investigate renal and cardiovascular outcomes in type 2 diabetes (T2D) with chronic kidney disease (CKD). However, the efficacy and safety of finerenone in renal function remain controversial. The purpose of this study was to explore the efficacy and safety of finerenone in treating the patients with diabetic kidney disease (DKD).. Databases of PubMed, Cochrane Library, Embase, and Web of Science were searched for randomized controlled trials (RCTs) on patients with DKD receiving finerenone treatment from inception to September 2021. Data including patient characteristics and interested outcomes were extracted, and the dichotomous data and continuous variables were evaluated using risk ratio (RR) with 95% confidence intervals (CIs) and mean differences (MD) with 95% CIs, respectively.. A total of 4 RCTs involving 13,945 patients were included in this meta-analysis. Analysis results demonstrated that patients receiving finerenone showed a significant decrease in changing urinary albumin-to-creatinine ratio (UACR) from baseline (MD: -0.30; 95% CI [-0.33, -0.27], p = 0.46, I2 = 0%) (p < 0.05). The number of patients with ≥40% reduction in estimated glomerular filtration rate (eGFR) from baseline in the finerenone group was significantly smaller than that in the placebo group (RR: 0.85; 95% CI [0.78, 0.93], p = 0.60, I2 = 0%) (p < 0.05). No difference was found in adverse events between the finerenone and placebo groups (RR: 1.00; 95% CI [0.98, 1.01], p = 0.94, I2 = 0%) (p = 0.65). The incidence of hyperkalemia was higher in the finerenone group than that in the placebo group (RR: 2.03; 95% CI [1.83, 2.26], p = 0.95, I2 = 0%) (p < 0.05).. Finerenone contributes to the reduction of UACR and can ameliorate the deterioration of renal function in patients with T2D and CKD. The higher risk of hyperkalemia was found in the finerenone group compared with placebo; however, there was no difference in the risk of overall adverse events.

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Hyperkalemia; Naphthyridines; Renal Insufficiency, Chronic

Clinical trials of the mineralocorticoid receptor antagonist (MRA) finerenone published recently suggest that they improve outcomes in patients with diabetic kidney disease (DKD). This review summarises key research from the last two years to provide clinicians with a synopsis of recent findings.. Large international trials, such as Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (5674 participants) and Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (7437 participants), suggest that in proteinuric patients with DKD and estimated glomerular filtration rate >25 ml/min/1.73 m2, already on renin-angiotensin-aldosterone system inhibitors, addition of finerenone provided modest further improvement in composite renal and cardiovascular outcomes. Proteinuria was reduced; there was also a small drop in systolic blood pressure. Hyperkalaemia remained a concern, although the incidence is lower with finerenone. Emerging data suggest that newer potassium binding agents may mitigate this risk. Preclinical studies suggest additive benefits when MRA and sodium-glucose co-transporter 2 (SGLT-2) inhibitors are used in combination.. The nonsteroidal MRA finerenone could improve renal and cardiac outcomes further in diabetics with kidney disease when added to renin-angiotensin system inhibitors. Hyperkalaemia is probably less worrisome, but real-world data is needed. Combinations with other new nephroprotective agents (such as SGLT2i inhibitors) has the potential to provide increasing benefit. Benefits of finerenone in chronic kidney disease without diabetes remains to be seen.

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Hyperkalemia; Male; Mineralocorticoid Receptor Antagonists; Naphthyridines; Renal Insufficiency, Chronic

In patients with type 2 diabetes, chronic kidney disease (CKD) is the most common cause of kidney failure. With its increasing prevalence and limited treatment options, CKD is a major contributor to the global burden of disease. Although recent guidelines for the control of hypertension and hyperglycaemia, as well as the use of renin-angiotensin system inhibitors and, more recently, sodium-glucose co-transporter-2 inhibitors, have improved outcomes for patients with CKD and diabetes, there is still a high residual risk of CKD progression and adverse cardiovascular events. In this review, we discuss the recently published FIDELIO-DKD and FIGARO-DKD studies and FIDELITY prespecified individual patient analysis. Together, these studies have established finerenone, a novel non-steroidal mineralocorticoid receptor antagonist, as an effective treatment for kidney and cardiovascular protection and welcome addition to the pillars of treatment to slow CKD progression in patients with type 2 diabetes.

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Mineralocorticoid Receptor Antagonists; Naphthyridines; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors

Diabetic kidney disease (DKD) represents a leading cause of morbidity and mortality in subjects with diabetes and develops in more than one third of diabetic patients. Steroidal mineralocorticoid receptor antagonists (MRAs - eplerenone and spironolactone) reduce mortality in patients with heart failure with reduced ejection fraction (HFrEF). However, in clinical practice the use of steroidal MRAs is limited by the significant risk of hyperkalemia, especially in patients with impaired renal function. Finerenone, a novel nonsteroidal MRA, shows a higher selectivity and binding affinity for mineralocorticoid receptor (MR) compared to steroidal MRAs and has been shown to reduce chronic kidney disease (CKD) progression and cardiovascular mortality in patients with CKD and T2DM.. This review summarizes the current evidence on efficacy and safety of finerenone in the treatment of patients with CKD and T2DM, and discusses its mechanisms of action investigated in preclinical studies.. Pharmacological properties of finerenone and its unique tissue distribution are responsible for a lower risk of hyperkalemia. Therefore, finerenone represents a valuable therapeutic tool in patients with CKD/diabetic kidney disease (DKD). Recent studies have shown that finerenone delays the progression of CKD and reduce cardiovascular events in patients with DKD, highlighting its safety and efficacy in this high-risk population.

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Eplerenone; Heart Failure; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Naphthyridines; Receptors, Mineralocorticoid; Renal Insufficiency, Chronic; Spironolactone; Stroke Volume

Finerenone is a novel non-steroidal mineralocorticoid antagonist (MRA) recently approved for the treatment of chronic kidney disease (CKD) in people with type 2 diabetes (T2D). We aim to conduct a systematic review of finerenone to know the efficacy and safety of finerenone in CKD with or without T2D.. A systematic search in the electronic database of PubMed and Google Scholar was made from inception until September 09, 2022, using several MeSH keywords related to finerenone. Ongoing trials were additionally searched from ClinicalTrials.Gov.. Five phase 2 and three phase 3, randomized, double-blind, placebo- or active-controlled studies of finerenone have been published to date and several other randomized and real-world studies of finerenone are currently undergoing.. In short-term studies in patients with CKD and reduced ejection heart failure, with or without T2D, finerenone 20 mg appears to have a better renal outcome compared with spironolactone and a better mortality outcome compared with eplerenone, with significantly lesser hyperkalemia compared to both spironolactone and finerenone. In long-term studies in patients with CKD and T2D, finerenone 10/20 mg significantly reduces the progression of renal disease and reduced CV endpoints (especially heart failure hospitalization) compared to placebo. Finerenone has no effect on HbA1c, body weight, and sexual side effects including gynecomastia, and has only a modest effect on blood pressure. However, hyperkalemia leading to drug withdrawal was significantly higher with finerenone compared to placebo. Safety data in real-world settings is a pressing priority.

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Eplerenone; Glycated Hemoglobin; Heart Failure; Humans; Hyperkalemia; Male; Mineralocorticoid Receptor Antagonists; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Spironolactone

Finerenone (Kerendia

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Approval; Drug Development; Glomerular Filtration Rate; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Naphthyridines; Renal Insufficiency, Chronic

Chronic kidney disease (CKD) is a progressive and irreversible disease often associated with type 2 diabetes (T2D). CKD is associated with an elevated risk of cardiovascular (CV) events, increased mortality, and diminished quality of life. Finerenone is a new treatment for patients with CKD and T2D that delays CKD progression and reduces CV complications.. To describe the approach and structure of a costeffectiveness model for finerenone for patients with CKD and T2D and compare it with existing economic models in CKD.. A de novo cost-effectiveness model (FINE-CKD model), reflective of FIDELIO-DKD results, was developed for finerenone. The FINE-CKD model was designed and implemented in accordance with published guidance on modeling and was developed with input from economic and clinical experts. The final model approach was evaluated against existing modeling structures in CKD identified through a systematic literature review.. The FINE-CKD model structure follows recommended modeling guidelines and has been designed in accordance with the best practices of modeling in CKD, while also incorporating important features of the FIDELIO-DKD design and results. The approach is consistent with the published literature, ensuring transparency and minimizing uncertainty that can arise from unnecessary complexity. The FINE-CKD model allows for reliable assessment of benefits and costs related to the use of finerenone in patients with CKD and T2D, and it is a reliable assessment of cost-effectiveness.

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Naphthyridines; Quality of Life; Renal Insufficiency, Chronic

We aim to review the mechanism of action and safety profile of mineralocorticoid receptor antagonists (MRAs) and discuss the differences between selective and non-selective MRAs. More specifically, finerenone is a new medication that is currently under investigation for its promising cardiovascular and nephrological effects.. MRAs are well known for their utility in treating heart failure, refractory hypertension, and diverse nephropathies, namely, diabetic nephropathy. As their name denotes, MRAs inhibit the action of aldosterone at the mineralocorticoid receptor, preventing receptor activation. This prevents remodeling, decreases inflammation, and improves proteinuria. There are not significant differences in outcomes between selective and non-selective MRAs. A new selective MRA named finerenone (originally BAY 94-8862) has shown promising results in several trials (ARTS-HF and ARTS-DN) and smaller studies. Finerenone may have a dose-dependent benefit over older MRAs, decreasing rates of albuminuria and levels of BNP and NT-ProBNP without causing a significant increase in serum potassium levels. This medication is not yet approved as it is still in phase 3 clinical trials (FIGARO-DKD and FIDELIO-DKD trials). MRAs are beneficial in several disease states. Newer medications, such as finerenone, should be considered in patients with heart failure and diabetic nephropathy who may benefit from a reduction in albuminuria and BNP/NT-ProBNP. Data surrounding finerenone are limited to date. However, results from ongoing clinical trials, as well as new trials to evaluate use in other pathologies, could validate the implementation of this medication in daily practice.

Topics: Diabetic Nephropathies; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Naphthyridines; Spironolactone

Type 2 diabetes is the leading cause of impaired kidney function, albuminuria, and renal replacement therapy globally, thus placing a large burden on health-care systems. Current treatment strategies rely on intensive glucose lowering as well as strict blood pressure control through blockade of the renin-angiotensin-aldosterone system. Such approaches might slow decline in kidney function, but many patients progress to end-stage kidney failure despite optimal therapy. In recent clinical trials, new-generation glucose-lowering drug classes, the sodium-glucose co-transporter-2 inhibitors and agents that target the incretin pathway, have been shown to improve kidney outcomes in patients with type 2 diabetes. Other new approaches, which have been developed on the basis of an improved understanding of the mechanisms that contribute to kidney damage in the context of diabetes, include use of drugs that block endothelin receptors (eg, atrasentan) and non-steroidal mineralocorticoid receptors (eg, finerenone). In this Review, we provide an overview of recent clinical data relevant to these new therapeutic approaches for management of kidney disease in the context of type 2 diabetes.

Topics: Antihypertensive Agents; Atrasentan; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Endothelin Receptor Antagonists; Humans; Hypoglycemic Agents; Incretins; Mineralocorticoid Receptor Antagonists; Naphthyridines; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors

Type 2 diabetes (T2D) is associated with an increased risk of diabetic kidney disease (DKD), cardiovascular disease, and heart failure, in part through activation of the renin-angiotensin-aldosterone system (RAAS). Although recent cardiovascular outcome trials have identified newer therapeutic agents such as sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1)-receptor agonists that reduce the risk of these complications, patients still exhibit residual cardiorenal morbidity and mortality. Accordingly, the identification of pharmacological agents that attenuate micro- and macrovascular complications related to T2D is a major priority. Our aim was to review evidence for the role of novel mineralocorticoid receptor antagonists (MRAs) that are being developed as adjunctive therapies to reduce the risk of DKD and cardiovascular disease in the setting of T2D.. Dual RAAS blockade with angiotensin-converting enzyme (ACE) inhibitor plus angiotensin receptor blockade (ARB) or ARB plus renin inhibition increases serious adverse events such as acute kidney injury and stroke. Due to the potential for these serious side effects, more recent interest has focused on newer, more selective non-steroidal MRAs such as finerenone as cardiorenal protective therapies. Finerenone reduces albuminuria in the setting of DKD in patients with T2D and has a lower risk of hyperkalemia compared to currently available MRAs. Novel MRAs such as finerenone have the potential to reduce the risk of DKD progression in patients with T2D. The impact of finerenone on hard, long-term cardiorenal endpoints is being examined in the FIGARO and FIDELIO trials in patients with DKD.

Topics: Adult; Albuminuria; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Naphthyridines; Renin; Renin-Angiotensin System

Cardiovascular and renal diseases are one of the main health problems in all industrialized countries. Their incidence is constantly increasing due to the aging of the population and the greater prevalence of obesity and type 2 diabetes. Clinical evidence suggests that aldosterone and the activation of mineralocorticoid receptors (MR) have a role in the pathophysiology of cardiovascular and renal diseases. Moreover, clinical studies demonstrate the benefits of mineralocorticoid receptor antagonists (MRAs) on mortality and progression of heart and kidney disease. In addition to renal effects on body fluid homeostasis, aldosterone has multiple extrarenal effects including the induction of inflammation, vascular rigidity, collagen formation and stimulation of fibrosis. Given the fundamental role of MR activation in renal and cardiac fibrosis, effective and selective blocking of the signal with MRAs can be used in the clinical practice to prevent or slow down the progression of heart and kidney diseases. The aim of the present work is to review the role of MRAs in light of the new evidence as well as its potential use as an antifibrotic in chronic kidney disease (CKD). The initial clinical results suggest that MRAs are potentially useful in treating patients with chronic kidney disease, particularly in cases of diabetic nephropathy. We don't yet have efficacy and safety data on the progression of kidney disease up to the end stage (ESRD) and filling this gap represents an important target for future trials.

Topics: Aldosterone; Body Fluids; Cardiovascular Diseases; Clinical Trials as Topic; Cytokines; Diabetic Nephropathies; Eplerenone; Fibrosis; Heart; Heart Diseases; Homeostasis; Humans; Kidney; Mineralocorticoid Receptor Antagonists; Naphthyridines; Receptors, Mineralocorticoid; Renal Insufficiency, Chronic; Spironolactone

Characterization of mice with cell-specific deletion or overexpression of the mineralocorticoid receptor (MR) shed a new light on its role in health and disease. Pathophysiological MR activation contributes to a plethora of deleterious molecular mechanisms in the development of cardiorenal diseases like chronic kidney disease (CKD) and heart failure (HF). Accordingly, the available steroidal MR antagonists (MRAs) spironolactone (first generation MRA) and eplerenone (second generation MRA) have been shown to be effective in reducing cardiovascular (CV) mortality and morbidity in patients with chronic HF and a reduced left ventricular ejection fraction (HFrEF). However, they remain underutilized, in large part owing to the risk inducing severe adverse events including hyperkalemia and worsening of kidney function, particularly when given on top of inhibitors of the renin angiotensin system (RAS) to patients with concomitant kidney dysfunction. Novel, potent, and selective non-steroidal MRAs (third generation) were identified in drug discovery campaigns and a few entered clinical development recently. One of these is finerenone with different physicochemical, pharmacokinetics, and pharmacological properties in comparison with the steroidal MRAs. Available data from five clinical phase II trials with finerenone in more than 2,000 patients with HF and additional CKD and/or diabetes as well as in patients with diabetic kidney disease demonstrated that neither hyperkalemia nor reductions in kidney function were limiting factors to its use. Moreover, finerenone demonstrated a nominally improved outcome compared to eplerenone in a phase IIb trial with 1,066 patients with HFrEF and concomitant type 2 diabetes mellitus (T2DM) and/or CKD.

Topics: Animals; Cardio-Renal Syndrome; Diabetic Nephropathies; Endothelial Cells; Eplerenone; Fibroblasts; Heart Failure; Humans; Macrophages; Mineralocorticoid Receptor Antagonists; Muscle, Smooth, Vascular; Myocytes, Cardiac; Myocytes, Smooth Muscle; Naphthyridines; Receptors, Mineralocorticoid; Spironolactone; Stroke Volume

The purpose of this review is to provide an overview of recent preclinical and clinical studies, which demonstrate new insights for the treatment of diabetic kidney disease (DKD) and to outline future directions with respect to novel therapies.. Positive findings with respect to new glucose-lowering agents such as sodium-dependent glucose transporter 2 inhibitors may lead to a change in the way we treat diabetic individuals with or at risk of DKD. Additional positive phase 2 clinical studies with drugs that have hemodynamic actions such as endothelin antagonists and mineralocorticoid receptor antagonists have led to larger phase 3 trials with atrasentan and finerenone, respectively, in order to address if these drugs indeed delay the development of end-stage renal disease. A number of other pathways are currently under active preclinical investigation and hopefully over the next decade will lead to promising drug candidates for subsequent clinical trials.. DKD remains an area of active preclinical and clinical investigation. Positive results with some of the more promising agents should lead to strategies to reverse, attenuate or prevent DKD.

Topics: Angiotensin II Type 2 Receptor Blockers; Antihypertensive Agents; Atrasentan; Diabetes Mellitus; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Endothelin Receptor Antagonists; Humans; Hypoglycemic Agents; Kidney Failure, Chronic; Mineralocorticoid Receptor Antagonists; Naphthyridines; Pyrrolidines; Renal Artery; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors; Sympathectomy

Topics: Aldosterone; Diabetic Nephropathies; Drug Therapy, Combination; Humans; Mineralocorticoid Receptor Antagonists; Naphthyridines

The mineralocorticoid receptor antagonists (MRAs) spironolactone and eplerenone reduce the risk of hospitalizations and mortality in patients with heart failure (HF) with reduced ejection fraction (HFrEF), and attenuate progression of diabetic kidney disease. However, their use is limited by the fear of inducing hyperkalemia, especially in patients with renal dysfunction. Finerenone is a novel nonsteroidal MRA, with higher selectivity toward the mineralocorticoid receptor (MR) compared to spironolactone and stronger MR-binding affinity than eplerenone.. This paper discusses the chemistry, pharmacokinetics, clinical efficacy and safety of finerenone.. The selectivity and greater binding affinity of finerenone to the MR may reduce the risk of hyperkalemia and renal dysfunction and thereby overcome the reluctance to start and uptitrate MRAs in patients with HF and diabetic kidney disease. Studies conducted in patients with HFrEF and moderate chronic kidney disease and diabetic kidney disease, showed promising results. Phase III trials will have to show whether finerenone might become the third-generation MRA for the treatment of HF and diabetic kidney disease.

Topics: Animals; Diabetic Nephropathies; Heart Failure; Hospitalization; Humans; Mineralocorticoid Receptor Antagonists; Naphthyridines

Topics: Animals; Diabetic Nephropathies; Drug Design; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid

Despite available interventions, people with type 2 diabetes (T2D) remain at risk of chronic kidney disease (CKD). Finerenone, a potent and selective nonsteroidal mineralocorticoid receptor antagonist, and sodium-glucose cotransporter 2 inhibitors (SGLT2is) can reduce both kidney and cardiovascular risks in people with CKD and T2D. Here we outline the design of a study to investigate whether dual therapy with finerenone and an SGLT2i is superior to either agent alone.. CONFIDENCE (NCT05254002) is a randomized, controlled, double-blind, double-dummy, international, multicenter, three-armed, parallel-group, 7.5 - to 8.5-month, Phase 2 study in 807 adults with T2D, stage 2-3 CKD and a urine albumin:creatinine ratio (UACR) ≥300-<5000 mg/g. The primary objective is to demonstrate that 6 months of dual therapy comprising finerenone and the SGLT2i empagliflozin is superior for reducing albuminuria versus either agent alone. Interventions will be once-daily finerenone 10 mg or 20 mg (target dose) plus empagliflozin 10 mg, or empagliflozin 10 mg alone, or finerenone 10 mg or 20 mg (target dose) alone.. The primary outcome is a relative change from baseline in UACR among the three groups. Secondary outcomes will further characterize efficacy and safety, including changes in estimated glomerular filtration rate and incident hyperkalemia.. CONFIDENCE is evaluating the safety, tolerability and efficacy of dual use of finerenone and an SGLT2i in adults with CKD and T2D. Should an additive effect be shown, early and efficient intervention with dual finerenone and SGLT2i therapy could slow disease progression and provide long-term benefits for people with CKD and T2D.

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Renal Insufficiency, Chronic

In FIDELIO-DKD, finerenone significantly improved cardiorenal outcomes in patients with chronic kidney disease and type 2 diabetes (T2D). This post hoc analysis explores finerenone in patients from the Asian region.. In FIDELIO-DKD, 5,674 patients with T2D and urine albumin-to-creatinine ratio (UACR) ≥30-<300 mg/g and estimated glomerular filtration rate (eGFR) ≥25-<60 mL/min/1.73 m2 or UACR ≥300-≤5,000 mg/g and eGFR ≥25-<75 mL/min/1.73 m2, treated with optimized renin-angiotensin system blockade, were randomized 1:1 to finerenone or placebo. Efficacy outcomes included a primary kidney composite (time to kidney failure, sustained decrease of ≥40% in eGFR from baseline, and death from renal causes) and secondary cardiovascular (CV) (time to CV death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure) and kidney (time to kidney failure, sustained decrease of ≥57% in eGFR from baseline, and death from renal causes) composites.. Of 1,327 patients in the Asian subgroup, 665 received finerenone. Finerenone reduced the ≥40% and ≥57% eGFR kidney and CV composite outcomes versus placebo in the Asian subgroup (hazard ratio [HR]: 0.70; 95% confidence interval [CI]: 0.56-0.87, HR: 0.73; 95% CI: 0.55-0.97, and HR: 0.85; 95% CI: 0.59-1.21, respectively), with no apparent differences versus patients from the rest of the world (HR: 0.88; 95% CI: 0.77-1.02; p interaction 0.09, HR: 0.78; 95% CI: 0.64-0.95; p interaction 0.71, and HR: 0.86; 95% CI: 0.74-1.00; p interaction 0.95, respectively). The safety profile of finerenone was similar across subgroups.. Finerenone produces similar cardiorenal benefits in Asian and non-Asian patients.

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Humans; Renal Insufficiency; Renal Insufficiency, Chronic

Despite guideline-recommended treatments, including renin angiotensin system inhibition, up to 40 % of individuals with type 1 diabetes develop chronic kidney disease (CKD) putting them at risk of kidney failure. Finerenone is approved to reduce the risk of kidney failure in individuals with type 2 diabetes. We postulate that finerenone will demonstrate benefits on kidney outcomes in people with type 1 diabetes.. FINE-ONE (NCT05901831) is a randomised, placebo-controlled, double-blind phase III trial of 7.5 months' duration in ∼220 adults with type 1 diabetes, urine albumin/creatinine ratio (UACR) of ≥ 200-< 5000 mg/g (≥ 22.6-< 565 mg/mmol) and eGFR of ≥ 25-< 90 ml/min/1.73 m. The primary endpoint is relative change in UACR from baseline over 6 months. UACR is used as a bridging biomarker (BB), since the treatment effect of finerenone on UACR was associated with its efficacy on kidney outcomes in the type 2 diabetes trials. Based on regulatory authority feedback, UACR can be used as a BB for kidney outcomes to support registration of finerenone in type 1 diabetes, provided necessary criteria are met. Secondary outcomes include incidences of treatment-emergent adverse events, treatment-emergent serious adverse events and hyperkalaemia.. FINE-ONE will evaluate the efficacy and safety of finerenone in type 1 diabetes and CKD. Finerenone could become the first registered treatment for CKD associated with type 1 diabetes in almost 30 years.. ClinicalTrials.gov NCT05901831.

Topics: Adult; Biomarkers; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Glomerular Filtration Rate; Humans; Renal Insufficiency; Renal Insufficiency, Chronic

The nonsteroidal mineralocorticoid receptor antagonist finerenone and the sodium-glucose cotransporter-2 inhibitor (SGLT-2i) canagliflozin reduce cardiorenal risk in albuminuric patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). At first glance, the results of Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) (ClinicalTrials.gov, NCT02540993) and Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) appear disparate. In FIDELIO-DKD, the primary endpoint had an 18% [95% confidence interval (CI) 7-27] relative risk reduction; in CREDENCE, the primary endpoint had a 30% (95% CI 18-41) relative risk reduction. Unlike CREDENCE, the FIDELIO-DKD trial included patients with high albuminuria but excluded patients with symptomatic heart failure with reduced ejection fraction. The primary endpoint in the FIDELIO-DKD trial was kidney specific and included a sustained decline in the estimated glomerular filtration rate (eGFR) of ≥40% from baseline. In contrast, the primary endpoint in the CREDENCE trial included a sustained decline in eGFR of ≥57% from baseline and cardiovascular (CV) death. This post hoc exploratory analysis investigated how differences in trial design-inclusion/exclusion criteria and definition of primary outcomes-influenced observed treatment effects.. Patients from FIDELIO-DKD who met the CKD inclusion criteria of the CREDENCE study (urine albumin: creatinine ratio >300-5000 mg/g and an eGFR of 30-<90 mL/min/1.73 m2 at screening) were included in this analysis. The primary endpoint was a cardiorenal composite (CV death, kidney failure, eGFR decrease of ≥57% sustained for ≥4 weeks or renal death). Patients with symptomatic heart failure with reduced ejection fraction were excluded from FIDELIO-DKD. Therefore, in a sensitivity analysis, we further adjusted for the baseline prevalence of heart failure.. Of 4619/5674 (81.4%) patients who met the subgroup inclusion criteria, 49.6% were treated with finerenone and 50.4% received placebo. The rate of the cardiorenal composite endpoint was 43.9/1000 patient-years with finerenone compared with 59.5/1000 patient-years with placebo. The relative risk was significantly reduced by 26% with finerenone versus placebo [hazard ratio (HR) 0.74 (95% CI 0.63-0.87)]. In CREDENCE, the rate of the cardiorenal composite endpoint was 43.2/1000 patient-years with canagliflozin compared with 61.2/1000 patient-years with placebo; a 30% risk reduction was observed with canagliflozin [HR 0.70 (95% CI 0.59-0.82)].. This analysis highlights the pitfalls of direct comparisons between trials. When key differences in trial design are considered, FIDELIO-DKD and CREDENCE demonstrate cardiorenal benefits of a similar magnitude.

Topics: Canagliflozin; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Heart Failure; Humans; Naphthyridines; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors

This prespecified analysis of the FIDELIO-DKD trial compared the effects of finerenone, a selective non-steroidal mineralocorticoid receptor antagonist, on cardiorenal outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) by history of heart failure (HF).. In FIDELIO-DKD, finerenone improved cardiorenal outcome in patients with CKD and T2D irrespective of baseline HF history.

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Naphthyridines; Renal Insufficiency, Chronic

Finerenone reduced the risk of kidney and cardiovascular events in people with chronic kidney disease (CKD) and type 2 diabetes in the FIDELIO-DKD and FIGARO-DKD phase 3 studies. Effects of finerenone on outcomes in patients taking sodium-glucose cotransporter 2 inhibitors (SGLT2is) were evaluated in a prespecified pooled analysis of these studies.. Patients with type 2 diabetes and urine albumin-to-creatinine ratio (UACR) ≥30 to ≤5,000 mg/g and estimated glomerular filtration rate (eGFR) ≥25 mL/min/1.73 m2 were randomly assigned to finerenone or placebo; SGLT2is were permitted at any time. Outcomes included cardiovascular composite (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and kidney composite (kidney failure, sustained ≥57% eGFR decline, or renal death) end points, changes in UACR and eGFR, and safety outcomes.. Among 13,026 patients, 877 (6.7%) received an SGLT2i at baseline and 1,113 (8.5%) initiated one during the trial. For the cardiovascular composite, the hazard ratios (HRs) were 0.87 (95% CI 0.79-0.96) without SGLT2i and 0.67 (95% CI 0.42-1.07) with SGLT2i. For the kidney composite, the HRs were 0.80 (95% CI 0.69-0.92) without SGLT2i and 0.42 (95% CI 0.16-1.08) with SGLT2i. Baseline SGLT2i use did not affect risk reduction for the cardiovascular or kidney composites with finerenone (Pinteraction = 0.46 and 0.29, respectively); neither did SGLT2i use concomitant with study treatment.. Benefits of finerenone compared with placebo on cardiorenal outcomes in patients with CKD and type 2 diabetes were observed irrespective of SGLT2i use.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Glucose; Humans; Renal Insufficiency, Chronic; Sodium

Finerenone is a new mineralocorticoid receptor antagonist with a different structure, volume of distribution and half-life compared to spironolactone. This drug has been tested in two large, randomized trials including diabetic patients with chronic kidney disease (in terms of glomerular filtration rate and albuminuria) and already treated by renin-angiotensin system blockade. Results are positive on hard renal- and cardiac endpoints. Risk of hyperkalaemia is higher than with placebo but is considered as acceptable. An open question that will be tested in further studies is the role of finerenone in the context of a treatment by gliflozins, drugs that also showed cardiorenal protection.. La finérénone est un antagoniste non stéroïdien du récepteur des minéralocorticoïdes avec une structure, un volume de distribution et une demi-vie différents de la spironolactone. Cette molécule a récemment été testée dans deux grands essais randomisés et contrôlés chez des patients avec une néphropathie diabétique avérée (en termes de débit de filtration glomérulaire et d’albuminurie) et un blocage optimal du système rénine-angiotensine-aldostérone (SRAA). Les résultats attestent d’une néphroprotection et d’une cardioprotection conférées par cette molécule, en addition aux bloqueurs du SRAA, sur des critères de jugement durs. Le risque d’hyperkaliémie était supérieur au placebo, mais acceptable. Une question ouverte reste celle de la place de cette molécule par rapport aux gliflozines, ayant aussi prouvé une protection cardiorénale.

Topics: Albuminuria; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Naphthyridines; Renal Insufficiency, Chronic

Topics: Animals; Diabetes Mellitus; Diabetic Nephropathies; Humans; Mineralocorticoid Receptor Antagonists; Naphthyridines; Renal Insufficiency, Chronic

Finerenone, a nonsteroidal, selective mineralocorticoid receptor antagonist, reduced albuminuria in short-term trials involving patients with chronic kidney disease (CKD) and type 2 diabetes. However, its long-term effects on kidney and cardiovascular outcomes are unknown.. In this double-blind trial, we randomly assigned 5734 patients with CKD and type 2 diabetes in a 1:1 ratio to receive finerenone or placebo. Eligible patients had a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 30 to less than 300, an estimated glomerular filtration rate (eGFR) of 25 to less than 60 ml per minute per 1.73 m. During a median follow-up of 2.6 years, a primary outcome event occurred in 504 of 2833 patients (17.8%) in the finerenone group and 600 of 2841 patients (21.1%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.93; P = 0.001). A key secondary outcome event occurred in 367 patients (13.0%) and 420 patients (14.8%) in the respective groups (hazard ratio, 0.86; 95% CI, 0.75 to 0.99; P = 0.03). Overall, the frequency of adverse events was similar in the two groups. The incidence of hyperkalemia-related discontinuation of the trial regimen was higher with finerenone than with placebo (2.3% and 0.9%, respectively).. In patients with CKD and type 2 diabetes, treatment with finerenone resulted in lower risks of CKD progression and cardiovascular events than placebo. (Funded by Bayer; FIDELIO-DKD ClinicalTrials.gov number, NCT02540993.).

Topics: Aged; Albuminuria; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Female; Glomerular Filtration Rate; Humans; Hyperkalemia; Male; Naphthyridines; Renal Insufficiency, Chronic; Treatment Outcome

Among diabetics, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality, and progression of their underlying disease. Finerenone is a novel, non-steroidal, selective mineralocorticoid-receptor antagonist which has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD), while revealing only a low risk of hyperkalemia. However, the effect of finerenone on renal and CV outcomes has not been investigated in long-term trials yet.. The Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease -(FIDELIO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important renal and CV outcomes in T2D patients with CKD. FIDELIO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 5.5 years. FIDELIO-DKD randomized 5,734 patients with an estimated glomerular filtration rate (eGFR) ≥25-<75 mL/min/1.73 m2 and albuminuria (urinary albumin-to-creatinine ratio ≥30-≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of kidney failure, a sustained decrease of eGFR ≥40% from baseline over at least 4 weeks, or renal death.. FIDELIO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of renal and CV events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen.

Topics: Aged; Albuminuria; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Double-Blind Method; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Naphthyridines; Research Design; Treatment Outcome

Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials.. The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m2 and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure.. FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen.. EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Double-Blind Method; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Naphthyridines; Renal Insufficiency, Chronic; Research Design; Treatment Outcome

Finerenone (BAY 94-8862) is a novel non-steroidal mineralocorticoid receptor antagonist. The aim of this study was to compare the efficacy and safety of seven once-daily oral doses of finerenone (1.25-20mg) and placebo in 96 patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) receiving a RAS blocker.. ARTS-DN Japan was a multicenter, randomized, double-blind, placebo-controlled, phase 2b study.. Analysis of the urinary albumin-to-creatinine ratio (UACR) at day 90 relative to baseline indicated a nominally significant effect of finerenone. The UACR at day 90 relative to baseline for each finerenone treatment group was numerically reduced compared with placebo. No serious adverse events (AEs) or deaths were reported and no patients experienced treatment-emergent AEs resulting in discontinuation of study drug. Small mean increases in serum potassium level were observed in the finerenone treatment groups (0.025-0.167mmol/L) compared with the placebo group (-0.075mmol/L); no patients developed hyperkalemia.. When given in addition to a RAS inhibitor, finerenone reduced albuminuria without adverse effects on serum potassium levels or renal function in Japanese patients with T2DM and DN.

Topics: Aged; Albuminuria; Biomarkers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Japan; Kidney; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Naphthyridines; Renal Insufficiency; Renin-Angiotensin System; Reproducibility of Results

Steroidal mineralocorticoid receptor antagonists, when added to a renin-angiotensin system blocker, further reduce proteinuria in patients with chronic kidney disease but may be underused because of a high risk of adverse events.. To evaluate the safety and efficacy of different oral doses of the nonsteroidal mineralocorticoid receptor antagonist finerenone, given for 90 days to patients with diabetes and high or very high albuminuria who are receiving an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker.. Randomized, double-blind, placebo-controlled, parallel-group study conducted at 148 sites in 23 countries. Patients were recruited from June 2013 to February 2014 and the study was completed in August 2014. Of 1501 screened patients, 823 were randomized and 821 received study drug.. Participants were randomly assigned to receive oral, once-daily finerenone (1.25 mg/d, n = 96; 2.5 mg/d, n = 92; 5 mg/d, n = 100; 7.5 mg/d, n = 97; 10 mg/d, n = 98; 15 mg/d, n = 125; and 25 mg/d, n = 119) or matching placebo (n = 94) for 90 days.. The primary outcome was the ratio of the urinary albumin-creatinine ratio (UACR) at day 90 vs at baseline. Safety end points were changes from baseline in serum potassium and estimated glomerular filtration rate.. The mean age of the participants was 64.2 years; 78% were male. At baseline, 36.7% of patients treated had very high albuminuria (UACR ≥300 mg/g) and 40.0% had an estimated glomerular filtration rate of 60 mL/min/1.73 m2 or lower. Finerenone demonstrated a dose-dependent reduction in UACR. The primary outcome, the placebo-corrected mean ratio of the UACR at day 90 relative to baseline, was reduced in the finerenone 7.5-, 10-, 15-, and 20-mg/d groups (for 7.5 mg/d, 0.79 [90% CI, 0.68-0.91; P = .004]; for 10 mg/d, 0.76 [90% CI, 0.65-0.88; P = .001]; for 15 mg/d, 0.67 [90% CI, 0.58-0.77; P<.001]; for 20 mg/d, 0.62 [90% CI, 0.54-0.72; P < .001]). The prespecified secondary outcome of hyperkalemia leading to discontinuation was not observed in the placebo and finerenone 10-mg/d groups; incidences in the finerenone 7.5-, 15-, and 20-mg/d groups were 2.1%, 3.2%, and 1.7%, respectively. There were no differences in the incidence of the prespecified secondary outcome of an estimated glomerular filtration rate decrease of 30% or more or in incidences of adverse events and serious adverse events between the placebo and finerenone groups.. Among patients with diabetic nephropathy, most receiving an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, the addition of finerenone compared with placebo resulted in improvement in the urinary albumin-creatinine ratio. Further trials are needed to compare finerenone with other active medications.. clinicaltrials.gov Identifier: NCT1874431.

Topics: Administration, Oral; Aged; Albuminuria; Analysis of Variance; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Glomerular Filtration Rate; Humans; Hyperkalemia; Incidence; Least-Squares Analysis; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Naphthyridines; Potassium

Finerenone decreases albuminuria in patients having heart failure with reduced ejection fraction and mild-to-moderate (stage 2-3) chronic kidney disease. The MinerAlocorticoid Receptor Antagonist Tolerability Study-Diabetic Nephropathy (ARTS-DN; NCT01874431) is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 2b study. ARTS-DN investigated whether the mineralocorticoid receptor antagonist finerenone reduces albuminuria without causing major alterations in serum potassium levels in patients with type 2 diabetes mellitus and a clinical diagnosis of DN who were receiving a renin-angiotensin-system (RAS) inhibitor.. Patients were randomized to oral finerenone 1.25-20 mg or placebo once daily. The primary objectives were to assess the ratio of the urinary albumin-to-creatinine ratio at day 90 to that at baseline in patients receiving finerenone, and to compare it with that in the placebo group. Additional exploratory analyses included evaluating changes from baseline in serum potassium levels, efficacy and safety biomarkers, and health-related quality of life.. Of 1,501 patients screened, 821 (the sample population) received at least one dose of finerenone/placebo. Baseline characteristics included: male, 77.8%; white, 84.2%; very high albuminuria (formerly macroalbuminuria), 38.4%; high albuminuria (formerly microalbuminuria), 60.3%; median (range) estimated glomerular filtration rate, 66.3 (24.5-130.7) ml/min/1.73 m(2); and systolic blood pressure (mean ± standard deviation), 138.1 ± 14.4 mm Hg. There was a history of cardiovascular disease in 39.6%, diabetic neuropathy in 20.0%, and diabetic retinopathy in 19.9% of patients.. ARTS-DN is the first phase 2b trial of finerenone in combination with a RAS inhibitor in patients with type 2 diabetes mellitus and a clinical diagnosis of DN.

Topics: Aged; Albuminuria; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Familial Primary Pulmonary Hypertension; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Naphthyridines; Potassium

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Hypoglycemic Agents; Mineralocorticoid Receptor Antagonists; Naphthyridines; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors

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 et al. 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.

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Humans; Mineralocorticoid Receptor Antagonists; Renal Insufficiency, Chronic

Finerenone reduces the risk of cardiovascular events in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). We investigated the causes of mortality in the FIDELITY population.. The FIDELITY prespecified pooled data analysis from FIDELIO-DKD and FIGARO-DKD excluded patients with heart failure and reduced ejection fraction. Outcomes included intention-to-treat and prespecified on-treatment analyses of the risk of all-cause and cardiovascular mortality. Of 13 026 patients [mean age, 64.8 years; mean estimated glomerular filtration rate (eGFR), 57.6 mL/min/1.73 m2], 99.8% were on renin-angiotensin system inhibitors. Finerenone reduced the incidence of all-cause and cardiovascular mortality vs. placebo (8.5% vs. 9.4% and 4.9% vs. 5.6%, respectively) and demonstrated significant on-treatment reductions [hazard ratio (HR), 0.82; 95% confidence interval (CI), 0.70-0.96; P = 0.014 and HR, 0.82; 95% CI, 0.67-0.99; P = 0.040, respectively]. Cardiovascular-related mortality was most common, and finerenone lowered the incidence of sudden cardiac death vs. placebo [1.3% (incidence rate 0.44/100 patient-years) vs. 1.8% (0.58/100 patient-years), respectively; HR, 0.75; 95% CI, 0.57-0.996; P = 0.046]. The effects of finerenone on mortality were similar across all Kidney Disease: Improving Global Outcomes risk groups. Event probability with finerenone at 4 years was consistent irrespective of baseline urine albumin-to-creatinine ratio, but seemingly more pronounced in patients with higher baseline eGFR.. In FIDELITY, finerenone significantly reduced the risk of all-cause and cardiovascular mortality vs. placebo in patients with T2D across a broad spectrum of CKD stages while on treatment, as well as sudden cardiac death in the intention-to-treat population.. FIDELIO-DKD and FIGARO-DKD are registered with ClinicalTrials.gov, numbers NCT02540993 and NCT02545049, respectively (funded by Bayer AG).

Topics: Death, Sudden, Cardiac; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Heart Failure; Humans; Middle Aged; Mineralocorticoid Receptor Antagonists; Renal Insufficiency, Chronic

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Heart Failure; Humans; Naphthyridines; Renal Insufficiency, Chronic

To evaluate the effect of finerenone by baseline HbA1c, HbA1c variability, diabetes duration and baseline insulin use on cardiorenal outcomes and diabetes progression.. Composite efficacy outcomes included cardiovascular (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for heart failure), kidney (kidney failure, sustained ≥ 57% estimated glomerular filtration rate decline or renal death) and diabetes progression (new insulin initiation, increase in antidiabetic medication, 1.0% increase in HbA1c from baseline, new diabetic ketoacidosis diagnosis or uncontrolled diabetes).. In 13 026 participants, risk reductions in the cardiovascular and kidney composite outcomes with finerenone versus placebo were consistent across HbA1c quartiles (P interaction .52 and .09, respectively), HbA1c variability (P interaction .48 and .10), diabetes duration (P interaction .12 and .75) and insulin use (P interaction .16 and .52). HbA1c variability in the first year of treatment was associated with a higher risk of cardiovascular and kidney events (hazard ratio [HR] 1.20; 95% confidence interval [CI] 1.07-1.35; P = .0016 and HR 1.36; 95% CI 1.21-1.52; P < .0001, respectively). There was no effect on diabetes progression with finerenone or placebo (HR 1.00; 95% CI 0.95-1.04). Finerenone was well-tolerated across subgroups; discontinuation and hospitalization because of hyperkalaemia were low.. Finerenone efficacy was not modified by baseline HbA1c, HbA1c variability, diabetes duration or baseline insulin use. Greater HbA1c variability appeared to be associated with an increased risk of cardiorenal outcomes.

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Glycated Hemoglobin; Humans; Insulin; Renal Insufficiency, Chronic

Vision loss in diabetic retinopathy features damage to the blood-retinal barrier and neovascularization, with hypertension and the renin-angiotensin system (RAS) having causal roles. We evaluated if finerenone, a non-steroidal mineralocorticoid receptor (MR) antagonist, reduced vascular pathology and inflammation in diabetic and neovascular retinopathy. Diabetic and hypertensive transgenic (mRen-2)27 rats overexpressing the RAS received the MR antagonist finerenone (10 mg/kg/day, oral gavage) or the angiotensin-converting enzyme inhibitor perindopril (10 mg/kg/day, drinking water) for 12 weeks. As retinal neovascularization does not develop in diabetic rodents, finerenone (5 mg/kg/day, i.p.) was evaluated in murine oxygen-induced retinopathy (OIR). Retinal vasculopathy was assessed by measuring gliosis, vascular leakage, neovascularization, and VEGF. Inflammation was investigated by quantitating retinal microglia/macrophages, pro-inflammatory mediators, and anti-inflammatory regulatory T-cells (Tregs). In diabetes, both treatments reduced systolic blood pressure, gliosis, vascular leakage, and microglial/macrophage density, but only finerenone lowered VEGF, ICAM-1, and IL-1ß. In OIR, finerenone reduced neovascularization, vascular leakage, and microglial density, and increased Tregs in the blood, spleen, and retina. Our findings, in the context of the FIDELIO-DKD and FIGARO-DKD trials reporting the benefits of finerenone on renal and cardiovascular outcomes in diabetic kidney disease, indicate the potential of finerenone as an effective oral treatment for diabetic retinopathy.

Topics: Animals; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; Gliosis; Inflammation; Mice; Mineralocorticoid Receptor Antagonists; Naphthyridines; Neovascularization, Pathologic; Rats; Rodentia; T-Lymphocytes, Regulatory; Vascular Endothelial Growth Factor A; Vascular System Injuries

Contemporary patterns of care of patients with chronic kidney disease (CKD) associated with type 2 diabetes (T2D) and the adoption of finerenone are not known. The FINE-REAL study (NCT05348733) is a prospective observational study in patients with CKD and T2D to provide insights into the use of the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone in clinical practice.. FINE-REAL is an international, prospective, multicenter, single-arm study enrolling approximately 5500 adults with CKD and T2D in an estimated 200 sites across 22 countries. The study is anticipated to be ongoing until 2027.. The primary objective is to describe treatment patterns in patients with CKD and T2D treated with finerenone in routine clinical practice. Secondary objectives include assessment of safety with finerenone. Other endpoints include characterization of healthcare resource utilization and occurrence of newly diagnosed diabetic retinopathy or its progression from baseline in patients with existing disease. A biobank is being organized for future explorative analyses with inclusion of participants from the United States.. FINE-REAL is the first prospective observational study with a nonsteroidal MRA in a population with CKD and T2D and is expected to provide meaningful insights into the treatment of CKD associated with T2D. FINE-REAL will inform decision-making with respect to initiation of finerenone in patients with CKD and T2D.

Topics: Adult; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Humans; Mineralocorticoid Receptor Antagonists; Prospective Studies; Renal Insufficiency, Chronic

Diabetic tubulopathy (DT) is a recently recognized key pathology of diabetic kidney disease (DKD). The mitochondria-centric view of DT is emerging as a vital pathological factor in different types of metabolic diseases, such as DKD. Finerenone (FIN), a novel non-steroidal mineralocorticoid receptor antagonist, attenuates kidney inflammation and fibrosis in DKD, but the precise pathomechanisms remain unclear. The role of mineralocorticoid receptor (MR) in perturbing mitochondrial function via the PI3K/Akt/eNOS signaling pathway, including mitochondrial dynamics and mitophagy, was investigated under a diabetic state and high glucose (HG) ambiance. To elucidate how the activation of MR provokes mitochondrial dysfunction in DT, human kidney proximal tubular epithelial (HK-2) cells were exposed to HG, and then mitochondrial dynamics, mitophagy, mitochondrial ROS (mitoROS), signaling molecules PI3K, Akt, Akt phosphorylation and eNOS were probed. The above molecules or proteins were also explored in the kidneys of diabetic and FIN-treated mice. FIN treatment reduced oxidative stress, mitochondrial fragmentation, and apoptosis while restoring the mitophagy via PI3K/Akt/eNOS signaling pathway in HK-2 cells exposed to HG ambiance and tubular cells of DM mice. These findings linked MR activation to mitochondrial dysfunction via PI3K/Akt/eNOS signaling pathway in DT and highlight a pivotal but previously undiscovered role of FIN in alleviating renal tubule injury for the treatment of DKD.

Topics: Animals; Diabetes Mellitus; Diabetic Nephropathies; Humans; Mice; Mineralocorticoid Receptor Antagonists; Mitochondria; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction

Diabetes is associated with aldosterone excess and the overactivation of its mineralocorticoid receptor (MR) which leads to the development of many cardiovascular dysfunctions. Therefore, MR antagonists have been found to exert favorable effects on the cardiovascular system. Finerenone is a new nonsteroidal MR antagonist approved for the treatment of chronic kidney disease associated with type 2 diabetes. Clinical studies have demonstrated that finerenone improves cardiovascular outcomes. However, its influence on hemostasis in the cardioprotective effect is unknown. Therefore, the main aim of our study was to evaluate the effects of finerenone (10 mg/kg, p.o.) on selected hemostasis parameters in streptozotocin (180 mg/kg, i.p.)-induced diabetes. Since regulation of the MR activity is sex-dependent, the study was conducted in both female and male mice. The most beneficial effects of finerenone were observed in diabetic female mice which included a decrease in thrombus formation, attenuation of platelet activity, inhibition of the coagulation system, and activation of fibrinolysis. In contrast, in male diabetic mice only an attenuation of the coagulation system was observed. Furthermore, finerenone also exerted unfavorable effects, but only in normoglycemic mice, manifested as a slight increase in platelet activity in males and an enhancement of the coagulation system activity in females. Our study is the first to show the sex-dependent and glycemia-dependent effects of finerenone on hemostasis in diabetes. The occurrence of beneficial effects only in female diabetic mice requires in-depth study.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Hemostasis; Male; Mice; Renal Insufficiency, Chronic; Streptozocin

Topics: Albuminuria; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Naphthyridines

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Kidney; Male; Naphthyridines; Renal Insufficiency, Chronic

Topics: Cardiovascular Diseases; Diabetes Mellitus; Diabetic Nephropathies; Female; Humans; Male; Naphthyridines; Renal Insufficiency, Chronic

Topics: Cardiovascular Diseases; Diabetes Mellitus; Diabetic Nephropathies; Female; Humans; Male; Naphthyridines; Renal Insufficiency, Chronic

Topics: Cardiovascular Diseases; Diabetes Mellitus; Diabetic Nephropathies; Female; Humans; Male; Naphthyridines; Renal Insufficiency, Chronic

Topics: Cardiovascular Diseases; Diabetes Mellitus; Diabetic Nephropathies; Female; Humans; Male; Naphthyridines; Renal Insufficiency, Chronic

Topics: Albuminuria; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Naphthyridines; Renal Insufficiency, Chronic

Despite the standard of care, patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) progress to dialysis, are hospitalized for heart failure and die prematurely. Overactivation of the mineralocorticoid receptor (MR) causes inflammation and fibrosis that damages the kidney and heart. Finerenone, a nonsteroidal, selective MR antagonist, confers kidney and heart protection in both animal models and Phase II clinical studies; the effects on serum potassium and kidney function are minimal. Comprising the largest CKD outcomes program to date, 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) are Phase III trials investigating the efficacy and safety of finerenone on kidney failure and cardiovascular outcomes from early to advanced CKD in T2D. By including echocardiograms and biomarkers, they extend our understanding of pathophysiology; by including quality of life measurements, they provide patient-centered outcomes; and by including understudied yet high-risk cardiorenal subpopulations, they have the potential to widen the scope of therapy in T2D with CKD. Trial registration number: FIDELIO-DKD (NCT02540993) and FIGARO-DKD (NCT02545049).

Topics: Animals; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Mineralocorticoid Receptor Antagonists; Naphthyridines; Quality of Life; Renal Dialysis; Renal Insufficiency, Chronic

Hemodynamic alterations, metabolic dysfunction, inflammation, and fibrosis are the main drivers of diabetic kidney disease (DKD) progression. Targeting inflammation and fibrosis as a driver, the FIDELIO-DKD (Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes) trial reported by Bakris et al. provides evidence of a new therapeutic class for treating DKD.

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Mineralocorticoid Receptor Antagonists; Naphthyridines; Randomized Controlled Trials as Topic; Receptors, Mineralocorticoid

Topics: Albuminuria; Diabetes Mellitus; Diabetic Nephropathies; Humans; Naphthyridines; Renin-Angiotensin System

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Humans; Mineralocorticoid Receptor Antagonists; Naphthyridines; Renal Insufficiency, Chronic

Topics: Diabetic Nephropathies; Humans; Naphthyridines; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic

Topics: Diabetic Nephropathies; Humans; Naphthyridines

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Heart Failure; Humans; Naphthyridines

Topics: Albuminuria; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Male; Naphthyridines