bay-94-8862 and Renal-Insufficiency--Chronic

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

Steroidal mineralocorticoid-receptor-antagonists (MRAs), such as spironolactone and eplerenone, are guideline-directed therapies in patients with heart failure with reduced ejection fraction or resistant hypertension. However, the associated risk of hyperkalemia and hormonal side effects limit their broad use and downstream cardiorenal protection in high-risk patients with type 2 diabetes mellitus (T2DM) and moderate-to-advanced chronic kidney disease (CKD). The critical unmet need to improve long-term cardiorenal outcomes in such patients with CKD has sparked considerable efforts to the discovery and development of a new class of compounds. Finerenone is a novel, nonsteroidal MRA that has recently received regulatory approval with the indication of cardiorenal protection in patients with CKD associated with T2DM. Two landmark phase 3 clinical trials, FIDELIO-DKD and FIGARO-DKD, demonstrated that among patients with T2DM and a broad spectrum of CKD, finerenone reduced the risk of "hard" cardiovascular and kidney failure outcomes as compared with placebo, with a minimal risk of hyperkalemia. Subgroup analyses of these trials also provided preliminary evidence that the efficacy and safety profile of finerenone was similar and irrespective of background therapy with other guideline-directed therapies, such as sodium-glucose co-transporter type 2 (SGLT-2) inhibitors and glucagone-like peptide 1 receptor agonists. Whether the combination of finerenone with a SGLT-2 inhibitor is more beneficial in patients with T2DM and CKD as compared with either therapy alone is a crucial research question that is currently under investigation in an ongoing clinical trial.

Topics: Diabetes Mellitus, Type 2; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Mineralocorticoids; 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

The nonsteroidal mineralocorticoid antagonist finerenone is a new addition to the list of agents (angiotensin converting enzyme inhibitors and sodium glucose cotransporter 2 inhibitors) conferring renal protection to patients with diabetic kidney disease. Two recent meta-analyses using the fixed effect model in patients with chronic kidney disease (both diabetic and nondiabetic populations) came to a conflicting conclusion on the effect of finerenone on eGFR decline. This meta-analysis was undertaken exclusively in the type 2 diabetes (T2D) population to explore the robustness and heterogeneity of the effect size by conducting a random effects model meta-analysis along with draft plots and prediction intervals.. A database search was conducted using the Cochrane library, PubMed, and Embase to identify relevant citations. Analysis was conducted on the 14. A pooled population of 13,943 patients from four citations was included for analysis. The Cochrane risk of bias was used to assess the quality of the studies. There was a significant 16% reduction in the renal composite (kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes) [HR: 0.84, 95% CI 0.77-0.92,. There are significant benefits in renal outcomes associated with finerenone treatment in T2D patients with established chronic kidney disease with a side effect profile comparable to placebo.

Topics: Diabetes Mellitus, Type 2; Humans; Naphthyridines; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors

Chronic kidney diseases (CKD) and cardiovascular diseases (CVD) are the main complications in type 2 diabetic mellitus (T2DM), increasing the risk of cardiovascular and all-cause mortality. Current therapeutic strategies that delay the progression of CKD and the development of CVD include angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), sodium-glucose co-transporter 2 inhibitors (SGLT-2i) and GLP-1 receptor agonists (GLP-1RA). In the progression of CKD and CVD, mineralocorticoid receptor (MR) overactivation leads to inflammation and fibrosis in the heart, kidney and vascular system, making mineralocorticoid receptor antagonists (MRAs) as a promising therapeutic option in T2DM with CKD and CVD. Finerenone is the third generation highly selective non-steroidal MRAs. It significantly reduces the risk of cardiovascular and renal complications. Finerenone also improves the cardiovascular-renal outcomes in T2DM patients with CKD and/or chronic heart failure (CHF). It is safer and more effective than the first- and second-generation MRAs due to its higher selectivity and specificity, resulting in a lower incidence of adverse effects including hyperkalemia, renal insufficiency and androgen-like effects. Finerenone shows potent effect on improving the outcomes of CHF, refractory hypertension, and diabetic nephropathy. Recently studies have shown that finerenone may have potential therapeutic effect on diabetic retinopathy, primary aldosteronism, atrial fibrillation, pulmonary hypertension and so on. In this review, we discuss the characteristics of finerenone, the new third-generation MRA, and compared with the first- and second-generation steroidal MRAs and other nonsteroidal MRAs. We also focus on its safety and efficacy of clinical application on CKD with T2DM patients. We hope to provide new insights for the clinical application and therapeutic prospect.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Atrial Fibrillation; Diabetes Mellitus, Type 2; Heart Failure; Humans; Kidney; Renal Insufficiency, Chronic

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

Chronic kidney disease (CKD) is one of the most common complications of diabetes mellitus and an independent risk factor for cardiovascular disease. Despite guideline-directed therapy of CKD in patients with type 2 diabetes, the risk of renal failure and cardiovascular events still remains high. To date, current medications for CKD haven't reduced enough the residual risk associated with inflammation and fibrosis in patients with type 2 diabetes. Here, in this review we present the results of FIDELIO-DKD, FIGARO-DKD trials and their pooled analysis FIDELITY, aimed to evaluate the effectiveness and safety of selective non-steroidal mineralocorticoid receptor antagonist finerenone in patients with type 2 diabetes with wide range stages of CKD. Modern pathophysiological aspects of mineralocorticoid receptor hyperactivation and features of their blockade by steroidal and nonsteroidal mineralocorticoid receptor antagonists are considered, differences in pharmacological effects between them are also discussed, finerenone benefits and its adverse events, demonstrated in randomized clinical trials are considered here. The probable mechanisms of early and delayed action of finerenone, which were realized in beneficial cardiovascular and renal outcomes in patients with type 2 diabetes with CKD, are presented here. Practical points for finerenone initiation and titration are indicated, aimed to minimize the hyperkalemia risk. Current guidelines for CKD treatment in patients with type 2 diabetes are analyzed, the finerenone placement in combined nephroprotective therapy is determined.. Хроническая болезнь почек (ХБП) – одно из самых частых осложнений сахарного диабета (СД) и независимый фактор риска сердечно-сосудистых заболеваний. Несмотря на терапию ХБП у пациентов с СД 2-го типа (СД 2) в соответствии с действующими рекомендациями, риск развития у них почечной недостаточности и сердечно-сосудистых осложнений остается высоким. До настоящего времени средства лечения ХБП у пациентов с СД 2 не устраняли остаточный риск прогрессирования поражения почек, связанный с воспалением и фиброзом. В обзоре представлены результаты исследований FIDELIO-DKD, FIGARO-DKD и их объединенного анализа FIDELITY, посвященных оценке эффективности и безопасности селективного нестероидного антагониста минералокортикоидных рецепторов финеренона в лечении больных СД 2 с ХБП различных стадий. Рассмотрены современные патофизиологические аспекты гиперактивации минералокортикоидных рецепторов и особенности их блокады стероидными и нестероидными антагонистами минералокортикоидных рецепторов, различия их фармакологических эффектов, преимущества и нежелательные явления финеренона в рандомизированных исследованиях. Приведены вероятные механизмы ранних и отсроченных эффектов финеренона, которые реализовались в благотворном влиянии на сердечно-сосудистые и почечные исходы у больных СД 2 с ХБП. Предложен практический протокол инициации и титрации финеренона, нацеленный на уменьшение риска гиперкалиемии. Проанализированы современные рекомендации, касающиеся терапии ХБП у больных СД 2, определено место финеренона в нефропротективной комбинированной терапии.

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

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

This review provides an overview of the management of chronic kidney disease (CKD) associated with type 2 diabetes (T2D), how the novel treatment class of nonsteroidal mineralocorticoid receptor antagonists (MRAs) fits within the treatment landscape, and how pharmacists can contribute to the multidisciplinary care of patients with CKD associated with T2D.. Optimizing pharmacotherapy for patients with CKD associated with T2D is critical to prevent or slow progression to end-stage kidney disease and reduce the incidence of cardiovascular events. However, many patients with CKD receive suboptimal treatment, in part because of the high complexity of care required, a lack of disease recognition among providers and patients, and a failure to utilize new kidney-protective therapies. Finerenone is the first nonsteroidal, selective MRA to be approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of adult patients with CKD associated with T2D. Clinical trials have demonstrated that finerenone significantly reduces the risk of cardiorenal disease progression vs placebo and has a reduced risk of hyperkalemia compared to traditional steroidal MRAs. Initiation of finerenone should follow evaluation of baseline estimated glomerular filtration rate and serum potassium levels. Consideration of potential drug-drug interactions, follow-up monitoring of potassium levels, and coordination of changes in pharmacotherapy across the patient care team are also important.. Finerenone is a valuable addition to the treatment landscape for CKD associated with T2D. Through their expertise in -medication -management, transitions of care, and patient education, clinical pharmacists are well positioned to ensure patients receive safe and effective -treatment.

Topics: Adult; Diabetes Mellitus, Type 2; Humans; Mineralocorticoid Receptor Antagonists; Potassium; Renal Insufficiency, Chronic

Finerenone, a selective and nonsteroidal antagonist of the mineralocorticoid receptor, has received regulatory approval with the indication of cardiorenal protection in patients with chronic kidney disease associated with type 2 diabetes. It is rapidly and completely absorbed and undergoes first-pass metabolism in the gut wall and liver resulting in a bioavailability of 43.5%. Finerenone can be taken with or without food. The pharmacokinetics of finerenone are linear and its half-life is 2 to 3 h in the dose range of up to 20 mg. Cytochrome P450 (CYP) 3A4 (90%) and CYP2C8 (10%) are involved in the extensive biotransformation of finerenone to pharmacologically inactive metabolites, which are excreted via both renal (80%) and biliary (20%) routes. Moderate or severe renal impairment, or moderate hepatic impairment result in area-under-the-curve increases of finerenone (< 40%), which do not require a dose adjustment per se, as the starting dose is based on estimated glomerular filtration rate (eGFR) and titrated according to serum potassium levels and eGFR decline. No relevant effects of age, sex, body size or ethnicity on systemic finerenone exposure were identified. Modulators of CYP3A4 activity were found to affect finerenone exposure, consistent with its classification as a sensitive CYP3A4 substrate. Serum potassium should be monitored during drug initiation or dosage adjustment of either a moderate or weak CYP3A4 inhibitor or finerenone, and the dose of finerenone should be adjusted as appropriate. Its use with strong inhibitors is contraindicated and strong or moderate inducers of CYP3A4 should be avoided. Finerenone has no potential to affect relevant CYP enzymes and drug transporters.. Finerenone is a drug that is used to treat patients with chronic kidney disease and type 2 diabetes. Many of these patients take several medicines to treat other conditions. This review summarizes several studies showing the suitability of finerenone for these patients. Taken as a daily tablet, the dose circulates in the body before being quickly removed. The age, sex, body weight, and ethnicity of a patient do not affect dosing. As finerenone can cause an increase of serum potassium levels, potassium levels and kidney function should be measured before a patient starts treatment. The starting dose will depend on a patient’s kidney function, with the dose changed according to potassium levels and changes in kidney function. A protein called cytochrome P450 3A4 (CYP3A4) is key to removing finerenone from the body. Anyone taking medicines that strongly inhibit CYP3A4 should not take finerenone. Serum potassium levels should be measured before starting finerenone or changing the dose of either finerenone or ‘moderate’ or ‘weak’ CYP3A4 inhibitors, with the dose of finerenone adjusted as appropriate. Finerenone should not be taken alongside drugs that result in ‘moderate’ or ‘strong’ increases in CYP3A4 activity. In patients with moderate hepatic impairment, potassium should be monitored and finerenone doses be adjusted as appropriate. Finerenone is not expected to affect other drugs. Finerenone slows decline in kidney function, a treatment effect associated with reducing urine albumin. Potassium level-guided starting dose and dose changes support finerenone being effectively used and well tolerated in patients.

Topics: Cytochrome P-450 CYP3A; Diabetes Mellitus, Type 2; Humans; Mineralocorticoid Receptor Antagonists; Potassium; 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

Approximately 40% of people with type 2 diabetes (T2D) also have chronic kidney disease (CKD), which substantially increases their risk of cardiovascular (CV)-related complications and mortality. Until recently, no approved therapies have directly targeted inflammatory and fibrotic pathways that drive disease progression and organ damage in patients with CKD associated with T2D.. Finerenone is a potent, selective, nonsteroidal mineralocorticoid receptor antagonist (MRA) that targets fibrosis and inflammation by blocking overactivation of the MR in the kidneys and heart. Finerenone has been associated with significant reductions in kidney- and CV-related endpoints compared with placebo and minimal effects on serum potassium and kidney function in phase III trials involving >13,000 patients with diabetic kidney disease (DKD). In addition to reviewing the clinical data, this review compares the properties of finerenone with those of the older steroidal MRAs spironolactone and eplerenone.. Unlike spironolactone and eplerenone, finerenone has demonstrated a favorable benefit-risk profile offering an effective new treatment for patients with CKD associated with T2D. Increases in serum potassium are predictable and manageable and should not discourage the use of finerenone in clinical practice. It is important to discuss where finerenone 'fits best' within the current DKD management landscape.

Topics: Diabetes Mellitus, Type 2; Eplerenone; Humans; Mineralocorticoid Receptor Antagonists; Naphthyridines; Potassium; Renal Insufficiency, Chronic; Spironolactone

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.

Topics: Diabetes Mellitus, Type 2; Humans; Mineralocorticoid Receptor Antagonists; Naphthyridines; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic

Finerenone, an FDA-approved nonsteroidal mineralocorticoid receptor (MR) antagonist, has been evaluated in context of chronic kidney disease (CKD) and associated cardiovascular disease (CVD). In this review, we summarize pre-clinical and clinical studies focused on the impact of finerenone on these disease processes.. Activation of the MR upregulates genes encoding for facilitators of tissue damage. Finerenone binding to a helix domain in this receptor inhibits receptor function. Studies in murine models of kidney disease, heart failure, hypertension, and vascular injury demonstrate significant protective effects of finerenone against further disease progression, as well as association with reduced oxidative stress, inflammation, and fibrosis. Phase 1-3 clinical trials with finerenone show safety and efficacy in improving renal and cardiovascular outcomes in patients with CKD. Research thus far encourages the addition of finerenone to the standard of care for certain CKD patients, especially those especially at risk for or with pre-existing cardiovascular disease. Continued study of the effect of finerenone in diverse patient populations and different disease states is needed.

Topics: Animals; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Mice; Mineralocorticoid Receptor Antagonists; Naphthyridines; Receptors, Mineralocorticoid; Renal Insufficiency, Chronic

Perception of the role of the aldosterone/mineralocorticoid receptor (MR) ensemble has been extended from a previously renal epithelial-centered focus on sodium and volume homeostasis to an understanding of their role as systemic modulators of reactive oxygen species, inflammation, and fibrosis. Steroidal MR antagonists (MRAs) are included in treatment paradigms for resistant hypertension and heart failure with reduced ejection fraction, while more recently, the nonsteroidal MRA finerenone was shown to reduce renal and cardiovascular outcomes in two large phase III trials (FIDELIO-DKD and FIGARO-DKD) in patients with chronic kidney disease and type 2 diabetes, respectively. Here, we provide an overview of the pathophysiologic role of MR overactivation and preclinical evidence with the nonsteroidal MRA finerenone in a range of different disease models with respect to major components of the aggregate mode of action, including interfering with reactive oxygen species generation, inflammation, fibrosis, and hypertrophy. We describe a time-dependent effect of these mechanistic components and the potential modification of major clinical parameters, as well as the impact on clinical renal and cardiovascular outcomes as observed in FIDELIO-DKD and FIGARO-DKD. Finally, we provide an outlook on potential future clinical indications and ongoing clinical studies with finerenone, including a combination study with a sodium-glucose cotransporter-2 inhibitor.

Topics: Diabetes Mellitus, Type 2; Fibrosis; Humans; Inflammation; Mineralocorticoid Receptor Antagonists; Naphthyridines; Reactive Oxygen Species; Receptors, Mineralocorticoid; Renal Insufficiency, Chronic; Sodium; 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 is a novel, non-steroidal mineralocorticoid receptor antagonist (MRAs) that has been investigated for the management of cardiorenal conditions. This article provides an overview of recent evidence of benefits on cardiovascular (CV) outcomes.. The recently published phase III FIDELIO-DKD and FIGARO-DKD, alone and pooled, in patients with CKD and diabetes demonstrate that finerenone reduces the composite of CV death, non-fatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure (HF) with hospitalization for HF being the primary driver of this composite. Finerenone is indicated to reduce renal and CV outcomes in patients with CKD and diabetes. Future investigations of this agent include patients with non-diabetic CKD, HF with preserved ejection fraction, and with the use of sodium-glucose transporter type 2 inhibitors.

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

The main objective was to evaluate the clinical efficacy and safety of finerenone in patients with CKD associated with T2D, especially with regard to renal and cardiovascular protection.. Eight databases were searched. Mean difference (MD) with 95% confidence interval (CI) of the outcomes and risk ratio (RR) were calculated as the effect measure.. Four trials (n = 13,510) were included. Compared to placebo groups, the urinary albumin-to-creatinine ratio (UACR) mean ratio, along with the proportion of patients with a decreased eGFR (≥ 40%) and end-stage kidney disease (ESKD), was significantly lower (MD: -0.30 (95% CI: -0.32, -0.28), p < 0.00001; RR: 0.85 (95% CI: 0.78, 0.93), p = 0.0002; RR: 0.80 (95% CI: 0.65, 0.99), p = 0.04, respectively). Furthermore, the proportion of patients with cardiovascular events (CVs) was significantly lower (RR: 0.88 (95% CI: 0.80, 0.96), p = 0.003). In terms of safety, while the increase in serum potassium concentration and the incidence of hyperkalemia were significantly higher in the finerenone groups (MD: 0.16 (95% CI: 0.07, 0.26), p = 0.00006; RR: 2.03 (95% CI: 1.83, 2.26), p < 0.00001, respectively), the all-cause mortality and the incidence of adverse events (AEs) were similar to placebo (RR: 0.90 (95% CI: 0.80, 1.00), p = 0.05; RR: 1.00 (95% CI: 0.98, 1.01), p = 0.65, respectively).. The observed renal and cardiovascular benefits of finerenone were significant and did not cause unacceptable side-effects. Finerenone may represent a promising therapeutic tool for CKD associated with T2D.

Topics: Diabetes Mellitus, Type 2; Humans; Naphthyridines; Potassium; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic

To evaluate the cardiovascular and renal benefits of finerenone, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagonlike peptide-1 receptor agonists (GLP-1 RA) in patients with Type 2 Diabetes Mellitus (T2DM) and chronic kidney disease (CKD) with network meta-analysis.. Systematic literature searches were conducted of PubMed, Cochrane Library, Web of Science, Medline and Embase covering January 1, 2000 to December 30, 2021. Randomized control trials (RCTs) comparing finerenone, SGLT-2i and GLP-1 RA in diabetics with CKD were selected. We performed a network meta-analysis to compare the two drugs and finerenone indirectly. Results were reported as risk ratio (RR) with corresponding 95% confidence interval (CI).. 18 RCTs involving 51,496 patients were included. Finerenone reduced the risk of major adverse cardiovascular events (MACE), renal outcome and hospitalization for heart failure (HHF) (RR [95% CI]; 0.88 [0.80-0.97], 0.86 [0.79-0.93], 0.79 [0.67,0.92], respectively). SGLT-2i were associated with reduced risks of MACE (RR [95% CI]; 0.84 [0.78-0.90]), renal outcome (RR [95% CI]; 0.67 [0.60-0.74], HHF (RR [95% CI]; 0.60 [0.53-0.68]), all-cause death (ACD) (RR [95% CI]; 0.89 [0.81-0.91]) and cardiovascular death (CVD) (RR [95% CI]; 0.86 [0.77-0.96]) compared to placebo. GLP-1 RA were associated with a lower risk of MACE (RR [95% CI]; 0.86 [0.78-0.94]). SGLT2i had significant effect in comparison to finerenone (finerenone vs SGLT2i: RR [95% CI]; 1.29 [1.13-1.47], 1.31 [1.07-1.61], respectively) and GLP-1 RA (GLP-1 RA vs SGLT2i: RR [95% CI]; 1.36 [1.16-1.59], 1.49 [1.18-1.89], respectively) in renal outcome and HHF.. In patients with T2DM and CKD, SGLT2i, GLP-1 RA and finerenone were comparable in MACE, ACD and CVD. SGLT2i significantly decreased the risk of renal events and HHF compared with finerenone and GLP-1 RA. Among GLP-1 RA, GLP-1 analogues showed significant effect in reducing cardiovascular events compared with exendin-4 analogues.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Network Meta-Analysis; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors

Chronic kidney disease (CKD) is a clinical condition associated with a high risk of cardiovascular (CV) events, mortality and progression to most severe stage of the disease, also known as kidney failure (KF). CKD is characterized by a wide variability of progression, which depends, in part, on the variability of individual response to nephroprotective treatments. Thus, a consistent proportion of patients have an elevated residual risk both CV and renal events, confirmed by the evidence that about 70% of CKD patients followed by the nephrologist have residual proteinuria. Among the new therapeutic strategies, which have been developed precisely with the aim of minimizing this residual risk, a class of particular interest is represented by the new non-steroidal mineralocorticoid receptor antagonists (non-steroidal MRA). These drugs exert an important anti-fibrotic and anti-proteinuric effect and, unlike steroid MRAs, are associated with a much lower incidence of adverse effects. The non-steroidal MRA molecule for which the most data is available, which is finerenone, is potent and extremely selective, and this partly explains the differences in efficacy and safety compared to steroid MRAs. In clinical trials, finerenone has been shown to significantly reduce the risk of progression to KF. Furthermore, there is also evidence that the combination of non-steroidal MRAs together with SGLT2 inhibitors may represent a valid alternative to reduce the residual risk in CKD patients. Given this evidence, non-steroidal MRAs are gaining momentum in the care, and particularly in individualized care, of CKD patients.

Topics: Humans; Mineralocorticoid Receptor Antagonists; Naphthyridines; Proteinuria; Renal Insufficiency, Chronic

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

Topics: Animals; Diabetes Mellitus, Type 2; 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

A full understanding of the mechanisms of action of aldosterone and its interaction with the mineralocorticoid receptor (MR) allows a theoretical framework to predict the therapeutic potential of MR antagonists (MRAs) in CKD, and heart failure with reduced ejection fraction.. The initial focus on the mechanisms of action of aldosterone was directed primarily on its role in modulating renal excretory function. In contrast, many recent studies have demonstrated a wider and expanded role for aldosterone in modulating inflammation, collagen formation, fibrosis, and necrosis. Increasing evidence has accrued that implicates the pathophysiological overactivation of the MR as a major determinant of progression of CKD. By promoting inflammation and fibrosis, MR overactivation constitutes a pivotal determinant of CKD progression and its associated morbidity and mortality. In accord with this mechanism of action, blockade of the MR is currently being investigated as a novel treatment regimen to slow the progression of CKD. The recently reported FIDELIO-DKD (FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease) study demonstrated that patients with CKD and type 2 diabetes who were treated with finerenone (a novel nonsteroidal MRA) manifested a lower risk of a composite primary outcome event compared with patients in the placebo arm (defined as kidney failure, or a sustained decrease of ≥40% in the estimated glomerular filtration rate from baseline, or death from renal causes). In addition, patients in the finerenone group also manifested a lower risk of a key secondary outcome event (defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure). Key Messages: Based on the success of the FIDELIO-DKD study, future studies should be implemented testing the hypothesis that a wide array of nondiabetic CKD is modulated by overactivation of the MR, and consequently may be amenable to treatment with novel nonsteroidal MRAs. Future studies are encouraged to elucidate the clinical implications of the interplay of nonsteroidal MRAs and the components of the renin-angiotensin cascade. The unique and recently reported interrelationship of fibroblast growth factor (FGF23) and aldosterone may also constitute a propitious subject for future investigation.

Topics: Aldosterone; Cardiovascular Diseases; Humans; Mineralocorticoid Receptor Antagonists; Naphthyridines; Receptors, Mineralocorticoid; Renal Insufficiency, Chronic

The efficacy and safety of finerenone are unknown. Therefore, we performed this meta-analysis to investigate the efficacy and safety of finerenone in patients with chronic kidney disease (CKD).. We systematically searched for relevant studies in the PubMed, Embase and Cochrane Library databases from database inception until December 2020. We selected randomized controlled trials assessing finerenone treatment in patients with CKD.. Four trials (n=7,048) met the inclusion criteria. Compared with placebo, finerenone significantly reduced the urine albumin-to-creatinine ratio (UACR) in patients with CKD {mean difference (MD), -0.30 [95% confidence interval (CI), -0.50, -0.11], P<0.05}, and trial sequential analysis (TSA) confirmed this result. No significant difference was observed in eGFR in patients with CKD between the finerenone and placebo groups [MD, -0.90 (95% CI, -3.84 to 2.04), P>0.05]. Overall, the frequency of adverse events was similar in the two groups [relative risk (RR), 1. 00 (95% CI, 0.98, 1.02), P>0.05], and TSA confirmed this result. However, the finerenone group exhibited a lower risk of cardiovascular disorders and a higher risk of hyperkalemia than the placebo group [RR, 0.92 (95% CI, 0.85, 0.99), P<0.05 and RR, 2.04 (95% CI, 1.77, 2.34), P<0.00001, respectively].. This meta-analysis indicated that finerenone confers an important antiproteinuric effect on patients with CKD and reduces the risk of cardiovascular disorders in these patients. Finerenone may be a promising therapy option for patients with CKD.. PROSPERO registration number: CRD42021222404.

Topics: Humans; Hyperkalemia; Naphthyridines; Renal Insufficiency, Chronic

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

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

Pharmaceutical antagonism of the mineralocorticoid receptor (MR) can protect against organ damage caused by elevated aldosterone levels in patients experiencing heart failure (HF), chronic kidney disease (CKD), primary aldosteronism, and hypertension. While traditional steroid-based MR antagonists effectively reduce mortality rates and extend patient survival, their broad application has been limited by significant side effects, most notably hyperkalaemia. Recently, finerenone (BAY 94-8862) has emerged as a next-generation non-steroidal dihydropyridine-based MR antagonist designed to minimize off-target effects while maintaining potent efficacy. In this review, the outcomes of finerenone therapy in several diseases associated with MR activity are explored. The (pre-) clinical efficacy of finerenone is compared with that of traditional steroid-based MR antagonists. Finally, recent and ongoing clinical trials using finerenone to treat chronic HF, CKD, and diabetic nephropathy are discussed. Taken together, pre-clinical and clinical evidence suggests that finerenone may achieve equivalent organ-protective effects with reduced levels of electrolyte disturbance compared with traditional steroid-based MR antagonists. This supports further clinical development of finerenone for the treatment of cardiovascular and renal disease.

Topics: Clinical Trials as Topic; Heart Failure; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Naphthyridines; Renal Insufficiency, Chronic; Treatment Outcome; Water-Electrolyte Balance

Aldosterone binds to the mineralocorticoid receptor and has an important regulatory role in body fluid and electrolyte balance. It also influences a variety of different cell functions such as oxidative stress, inflammation and organ fibrosis. The important role of the tissue-specific mineralocorticoid receptors in cardiovascular and renal injury has been shown in knockout animals and in clinical studies Mineralocorticoid receptor antagonists seem to exert their beneficial effects via anti-oxidative, anti-inflammatory and anti-fibrotic effects. Spironolactone and eplerenone were the first steroidal mineralocorticoid receptor antagonist. The established steroidal mineralocorticoid receptor antagonists show important therapeutic effects but are hampered by a variety of side effects, most importantly clinically significant hyperkaliemia. Selective non-steroidal mineralocorticoid receptor antagonists have been recently developed and demonstrate effectiveness in early clinical trials. Finereroneholds promise for the future application of this new mineralocorticoid receptor antagonist class in patients with chronic kidney disease since it has shown a significant reduction in UACR combined with a safety profile similar to that in the placebo group. However, further long-term studies investigating relevant clinical end points like reduction in cardiovascular or renal event rate are warranted.

Topics: Animals; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Naphthyridines; Receptors, Mineralocorticoid; Renal Insufficiency, Chronic

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

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

To explore the modifying effect of glucagon-like peptide-1 receptor agonist (GLP-1RA) use on outcomes with finerenone across a wide spectrum of patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) in the pooled analysis of FIDELIO-DKD and FIGARO-DKD.. Patients with T2D and CKD treated with optimized renin-angiotensin system blockade were randomized to finerenone or placebo. Effects of finerenone on a cardiovascular composite outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and a kidney composite outcome (kidney failure, sustained ≥57% estimated glomerular filtration rate [eGFR] decline, or renal death), change in urine albumin-to-creatinine ratio (UACR), and safety were analysed by GLP-1RA use.. Of 13 026 patients, 944 (7.2%) used GLP-1RAs at baseline. Finerenone reduced the risk of the cardiovascular composite outcome (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.52-1.11 with GLP-1RA; HR 0.87, 95% CI 0.79-0.96 without GLP-1RA; P-interaction = 0.63) and the kidney composite outcome (HR 0.82, 95% CI 0.45-1.48 with GLP-1RA; HR 0.77, 95% CI 0.67-0.89 without GLP-1RA; P-interaction = 0.79) irrespective of baseline GLP-1RA use. Reduction in UACR with finerenone at Month 4 was -38% in patients with baseline GLP-1RA use compared with -31% in those without GLP-1RA use (P-interaction = 0.03). Overall safety and incidence of hyperkalaemia were similar, irrespective of GLP-1RA use.. The cardiorenal benefits of finerenone on composite cardiovascular and kidney outcomes and UACR reduction in patients with CKD and T2D appear to be maintained, regardless of GLP-1RA use. Subsequent studies are needed to investigate any potential benefit of this combination.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Humans; Naphthyridines; Renal Insufficiency, Chronic

Finerenone is a selective nonsteroidal mineralocorticoid receptor antagonist with a short half-life. Its effects on cardiorenal outcomes were thought to be mediated primarily via nonhemodynamic pathways, but office blood pressure (BP) measurements were insufficient to fully assess hemodynamic effects. This analysis assessed the effects of finerenone on 24-h ambulatory BP in patients with chronic kidney disease and type 2 diabetes.. ARTS-DN (NCT01874431) was a phase 2b trial that randomized 823 patients with type 2 diabetes and chronic kidney disease, with urine albumin-to-creatinine ratio ≥30 mg/g and estimated glomerular filtration rate of 30-90 ml/min per 1.73 m2 to placebo or finerenone (1.25-20 mg once daily in the morning) administered over 90 days. Ambulatory BP monitoring (ABPM) over 24 h was performed in a subset of 240 patients at screening, Day 60, and Day 90.. Placebo-adjusted change in 24-h ABPM systolic BP (SBP) at Day 90 was -8.3 mmHg (95% confidence interval [CI], -16.6 to 0.1) for finerenone 10 mg (n = 27), -11.2 mmHg (95% CI, -18.8 to -3.6) for finerenone 15 mg (n = 34), and -9.9 mmHg (95% CI, -17.7 to -2.0) for finerenone 20 mg (n = 31). Mean daytime and night-time SBP recordings were similarly reduced and finerenone did not increase the incidence of SBP dipping. Finerenone produced a persistent reduction in SBP over the entire 24-h interval.. Finerenone reduced 24-h, daytime, and night-time SBP. Despite a short half-life, changes in BP were persistent over 24 h with once-daily dosing in the morning.

Topics: Blood Pressure; Blood Pressure Monitoring, Ambulatory; Diabetes Mellitus, Type 2; Humans; Renal Insufficiency, Chronic

To assess the effect of finerenone on the risk of cardiovascular and kidney outcomes in patients with chronic kidney disease and type 2 diabetes, with and without obesity.. A post hoc analysis of the prespecified pooled FIDELITY dataset assessed the association between waist circumference (WC), composite cardiovascular and kidney outcomes, and the effects of finerenone. Participants were stratified by WC risk groups (representing visceral obesity) as low-risk or high-very high-risk (H-/VH-risk).. Of 12 986 patients analysed, 90.8% occupied the H-/VH-risk WC group. Incidence of the composite cardiovascular outcome was similar between finerenone and placebo in the low-risk WC group (hazard ratio [HR] 1.03; 95% confidence interval [CI], 0.72-1.47); finerenone reduced the risk in the H-/VH-risk WC group (HR 0.85; 95% CI, 0.77-0.93). For the kidney outcome, the risk was similar in the low-risk WC group (HR 0.98; 95% CI, 0.66-1.46) and reduced within the H-/VH-risk WC group (HR 0.75; 95% CI, 0.65-0.87) with finerenone versus placebo. There was no significant heterogeneity between the low-risk and H-/VH-risk WC groups for cardiovascular and kidney composite outcomes (P interaction = .26 and .34, respectively). The apparent greater benefit of finerenone on cardiorenal outcomes but lack of significant heterogeneity observed in H-/VH-risk WC patients may be because of the small size of the low-risk group. Adverse events were consistent across WC groups.. In FIDELITY, benefits of finerenone in lowering the risk of cardiovascular and kidney outcomes were not significantly modified by patient obesity.

Topics: Diabetes Mellitus, Type 2; Humans; Kidney; Obesity; 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

Finerenone significantly reduced the risk of kidney and cardiovascular (CV) outcomes in patients with chronic kidney disease and type 2 diabetes in the FIDELIO-DKD trial (NCT02540993). This exploratory subgroup analysis investigates the effect of glucagon-like peptide-1 receptor agonist (GLP-1RA) use on the treatment effect of finerenone.. Patients with type 2 diabetes, urine albumin-to-creatinine ratio (UACR) 30-5000 mg/g and estimated glomerular filtration rate 25-<75 ml/min per 1.73 m. Of the 5674 patients analysed, overall, 394 (6.9%) received GLP-1RAs at baseline. A reduction in UACR with finerenone was observed with or without baseline GLP-1RA use; ratio of least-squares means 0.63 (95% confidence interval 0.56, 0.70) with GLP-1RA use and 0.69 (95% confidence interval 0.67, 0.72) without GLP-1RA use (p value for interaction .20). Finerenone also significantly reduced the primary kidney (time to kidney failure, sustained decrease in estimated glomerular filtration rate ≥40% from baseline, or renal death) and key secondary CV outcomes (time to CV death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure) versus placebo, with no clear difference because of GLP-1RA use at baseline (p value for interaction .15 and .51 respectively) or any time during the trial. The safety profile of finerenone was similar between subgroups.. This exploratory subgroup analysis suggests that finerenone reduces UACR in patients with or without GLP-1RA use at baseline, and the effects on kidney and CV outcomes are consistent irrespective of GLP-1RA use.

Topics: Diabetes Mellitus, Type 2; Glomerular Filtration Rate; Humans; Naphthyridines; Renal Insufficiency, Chronic

Finerenone reduced risk of cardiorenal outcomes in patients with CKD and type 2 diabetes in the FIDELIO-DKD trial. We report incidences and risk factors for hyperkalemia with finerenone and placebo in FIDELIO-DKD.. Over 2.6 years' median follow-up, 597 of 2785 (21.4%) and 256 of 2775 (9.2%) patients treated with finerenone and placebo, respectively, experienced treatment-emergent ≥mild hyperkalemia; 126 of 2802 (4.5%) and 38 of 2796 (1.4%) patients, respectively, experienced moderate hyperkalemia. Independent risk factors for ≥mild hyperkalemia were higher serum potassium, lower eGFR, increased urine albumin-creatinine ratio, younger age, female sex,. Finerenone was independently associated with hyperkalemia. However, routine potassium monitoring and hyperkalemia management strategies employed in FIDELIO-DKD minimized the impact of hyperkalemia, providing a basis for clinical use of finerenone.

Topics: Aged; Diabetes Mellitus, Type 2; Female; Humans; Hyperkalemia; Incidence; Male; Middle Aged; Naphthyridines; Potassium; Proportional Hazards Models; Renal Insufficiency, Chronic; Risk Factors

Finerenone is a nonsteroidal selective mineralocorticoid receptor antagonist that recently demonstrated efficacy in delaying chronic kidney disease progression and reducing cardiovascular events in patients with chronic kidney disease and type 2 diabetes in FIDELIO-DKD, where 5734 patients were randomized 1:1 to receive either titrated finerenone doses of 10 or 20 mg once daily or placebo, with a median follow-up of 2.6 years.. Nonlinear mixed-effects population pharmacokinetic models were used to analyze the pharmacokinetics in FIDELIO-DKD, sparsely sampled in all subjects receiving finerenone. Post-hoc model parameter estimates together with dosing histories allowed the computation of individual exposures used in subsequent parametric time-to-event analyses of the primary kidney outcome.. The population pharmacokinetic model adequately captured the typical pharmacokinetics of finerenone and its variability. Either covariate effects or multivariate forward-simulations in subgroups of interest were contained within the equivalence range of 80-125% around typical exposure. The exposure-response relationship was characterized by a maximum effect model estimating a low half-maximal effect concentration at 0.166 µg/L and a maximal hazard decrease at 36.1%. Prognostic factors for the treatment-independent chronic kidney disease progression risk included a low estimated glomerular filtration rate and a high urine-to-creatinine ratio increasing the risk, while concomitant sodium-glucose transport protein 2 inhibitor use decreased the risk. Importantly, no sodium-glucose transport protein 2 inhibitor co-medication-related modification of the finerenone treatment effect per se could be identified.. None of the tested pharmacokinetic covariates had clinical relevance in FIDELIO-DKD. Finerenone effects on kidney outcomes approached saturation towards 20 mg once daily and sodium-glucose transport protein 2 inhibitor use provided additive benefits.

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

Finerenone is a nonsteroidal selective mineralocorticoid receptor antagonist (MRA) that demonstrated efficacy in delaying the progression of chronic kidney disease (CKD) and reducing cardiovascular events in patients with CKD and type 2 diabetes mellitus in FIDELIO-DKD, where 5734 patients were randomized 1:1 to receive either finerenone or placebo, with a median follow-up of 2.6 years. Doses of finerenone 10 or 20 mg once daily were titrated based on (serum) potassium and estimated glomerular filtration rate. The MRA mode of action increases potassium.. Nonlinear mixed-effects population pharmacokinetic/pharmacodynamic models were used to analyze the finerenone dose-exposure-response relationship for potassium in FIDELIO-DKD. Individual time-varying exposures from pharmacokinetic analyses were related to the potassium response via a maximal effect, indirect-response model informed by 148,384 serum potassium measurements.. Although observed potassium levels decreased with increasing dose (i.e., inverse relation), model-based simulations for a fixed-dose setting (i.e., no dose titration) revealed the intrinsic finerenone dose-exposure-potassium response, with potassium levels increasing in a dose- and exposure-dependent manner, thus explaining the apparent conflict. The potassium limit for inclusion and uptitration from finerenone 10 to 20 mg in FIDELIO-DKD was ≤ 4.8 mmol/L. Modified limits of ≤ 5.0 mmol/L were simulated, resulting in higher hyperkalemia frequencies for both the finerenone and the placebo arms, whereas the relative hyperkalemia risk of a finerenone treatment compared with placebo did not increase.. The analyses demonstrated the effectiveness of finerenone dose titration in managing serum potassium and provide a quantitative basis to guide safe clinical use.

Topics: Diabetes Mellitus, Type 2; Female; Humans; Hyperkalemia; Male; Mineralocorticoid Receptor Antagonists; Naphthyridines; Potassium; 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

The complementary studies FIDELIO-DKD and FIGARO-DKD in patients with type 2 diabetes and chronic kidney disease (CKD) examined cardiovascular and kidney outcomes in different, overlapping stages of CKD. The purpose of the FIDELITY analysis was to perform an individual patient-level prespecified pooled efficacy and safety analysis across a broad spectrum of CKD to provide more robust estimates of safety and efficacy of finerenone compared with placebo.. For this prespecified analysis, two phase III, multicentre, double-blind trials involving patients with CKD and type 2 diabetes, randomized 1:1 to finerenone or placebo, were combined. Main time-to-event efficacy outcomes were a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure, and a composite of kidney failure, a sustained ≥57% decrease in estimated glomerular filtration rate from baseline over ≥4 weeks, or renal death. Among 13 026 patients with a median follow-up of 3.0 years (interquartile range 2.3-3.8 years), the composite cardiovascular outcome occurred in 825 (12.7%) patients receiving finerenone and 939 (14.4%) receiving placebo [hazard ratio (HR), 0.86; 95% confidence interval (CI), 0.78-0.95; P = 0.0018]. The composite kidney outcome occurred in 360 (5.5%) patients receiving finerenone and 465 (7.1%) receiving placebo (HR, 0.77; 95% CI, 0.67-0.88; P = 0.0002). Overall safety outcomes were generally similar between treatment arms. Hyperkalaemia leading to permanent treatment discontinuation occurred more frequently in patients receiving finerenone (1.7%) than placebo (0.6%).. Finerenone reduced the risk of clinically important cardiovascular and kidney outcomes vs. placebo across the spectrum of CKD in patients with type 2 diabetes.. Does finerenone, a novel selective, nonsteroidal mineralocorticoid receptor antagonist, added to maximum tolerated renin-angiotensin system inhibition reduce cardiovascular disease and kidney disease progression over a broad range of chronic kidney disease in patients with type 2 diabetes?. In a prespecified, pooled individual-level analysis from two randomized trials, we found reductions both in cardiovascular events and kidney failure outcomes with finerenone. Because 40% of the patients had an estimated glomerular filtration rate of >60 mL/min/1.73m2 they were identified solely on the basis of albuminuria.. Finerenone reduces the risk of clinical cardiovascular outcomes and kidney disease progression in a broad range of patients with chronic kidney disease and type 2 diabetes. Screening for albuminuria to identify at-risk patients among patients with type 2 diabetes facilitates reduction of both cardiovascular and kidney disease burden.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Humans; Kidney; Naphthyridines; Renal Insufficiency, Chronic

Finerenone significantly improved cardiorenal outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) in the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease trial. We explored whether baseline HbA1c level and insulin treatment influenced outcomes.. Patients with T2D, urine albumin-to-creatinine ratio (UACR) of 30-5,000 mg/g, estimated glomerular filtration rate (eGFR) of 25 to <75 mL/min/1.73 m2, and treated with optimized renin-angiotensin system blockade were randomly assigned to receive finerenone or placebo. Efficacy outcomes included kidney (kidney failure, sustained decrease ≥40% in eGFR from baseline, or renal death) and cardiovascular (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) composite endpoints. Patients were analyzed by baseline insulin use and by baseline HbA1c <7.5% (58 mmol/mol) or ≥7.5%.. Of 5,674 patients, 3,637 (64.1%) received insulin at baseline. Overall, 5,663 patients were included in the analysis for HbA1c; 2,794 (49.3%) had baseline HbA1c <7.5% (58 mmol/mol). Finerenone significantly reduced risk of the kidney composite outcome independent of baseline HbA1c level and insulin use (Pinteraction = 0.41 and 0.56, respectively). Cardiovascular composite outcome incidence was reduced with finerenone irrespective of baseline HbA1c level and insulin use (Pinteraction = 0.70 and 0.33, respectively). Although baseline HbA1c level did not affect kidney event risk, cardiovascular risk increased with higher HbA1c level. UACR reduction was consistent across subgroups. Adverse events were similar between groups regardless of baseline HbA1c level and insulin use; few finerenone-treated patients discontinued treatment because of hyperkalemia.. Finerenone reduces kidney and cardiovascular outcome risk in patients with CKD and T2D, and risks appear consistent irrespective of HbA1c levels or insulin use.

Topics: Diabetes Mellitus, Type 2; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Insulin; Insulin, Regular, Human; Male; Naphthyridines; Renal Insufficiency, Chronic

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

Finerenone, a selective, non-steroidal mineralocorticoid receptor antagonist, improves cardiovascular (CV) and kidney outcomes in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). This subgroup analysis of FIDELITY, a pre-specified, pooled, individual patient-data analysis of FIDELIO-DKD (NCT02540993) and FIGARO-DKD (NCT02545049), compared finerenone vs. placebo in patients with and without baseline history of atherosclerotic CV disease (ASCVD).. Outcomes included a composite CV outcome [CV death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure (HHF)]; CV death or HHF; a composite kidney outcome (kidney failure, sustained estimated glomerular filtration rate decrease ≥57%, or kidney-related death); all-cause mortality; and safety by baseline history of ASCVD.Of 13 026 patients, 5935 (45.6%) had a history of ASCVD. The incidence of the composite CV outcome, CV death or HHF, and all-cause mortality was higher in patients with ASCVD vs. those without, with no difference between groups in the composite kidney outcome. Finerenone consistently reduced outcomes vs. placebo in patients with and without ASCVD (P-interaction for the composite CV outcome, CV death or HHF, the composite kidney outcome, and all-cause mortality 0.38, 0.68, 0.33, and 0.38, respectively). Investigator-reported treatment-emergent adverse events were consistent between treatment arms across ASCVD subgroups.. Finerenone reduced the risk of CV and kidney outcomes consistently across the spectrum of CKD in patients with T2D, irrespective of prevalent ASCVD.

Topics: Atherosclerosis; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Heart Failure; Humans; Renal Insufficiency, Chronic

Chronic kidney disease is frequently associated with hypertension and poorly controlled blood pressure can lead to chronic kidney disease progression. Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, significantly improves cardiorenal outcomes in patients with chronic kidney disease and type 2 diabetes. This analysis explored the relationship between office systolic blood pressure (SBP) and cardiorenal outcomes with finerenone in FIDELIO-DKD trial (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease).. Patients with type 2 diabetes, urine albumin-to-creatinine ratio 30 to 5000 mg/g, and estimated glomerular filtration rate of 25 to <75 mL/min per 1.73 m. Finerenone reduced office SBP across the baseline office SBP quartiles, including patients with baseline office SBP of >148 mm Hg. Overall, patients with lower baseline office SBP quartile and greater declines from baseline in SBP were associated with better cardiorenal outcomes. The risk of primary kidney and key secondary cardiovascular composite outcomes was consistently reduced with finerenone versus placebo irrespective of baseline office SBP quartiles (. In FIDELIO-DKD, cardiorenal outcomes improved with finerenone irrespective of baseline office SBP. Reductions in office SBP accounted for a small proportion of the treatment effect on cardiorenal outcomes.. URL: https://www.. gov; Unique identifier: NCT02540993.

Topics: Albuminuria; Blood Pressure; Diabetes Mellitus, Type 2; Double-Blind Method; Humans; Mineralocorticoid Receptor Antagonists; Naphthyridines; Renal Insufficiency, Chronic

Finerenone (Kerendia) has been approved to reduce the risk of sustained estimated glomerular filtration rate decline, end-stage kidney disease, cardiovascular death, nonfatal myocardial infarction, and hospitalization for heart failure in adults with chronic kidney disease associated with type 2 diabetes.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Naphthyridines; Renal Insufficiency, Chronic

The FIDELIO-DKD trial (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease) evaluated the effect of the nonsteroidal, selective mineralocorticoid receptor antagonist finerenone on kidney and cardiovascular outcomes in patients with chronic kidney disease and type 2 diabetes with optimized renin-angiotensin system blockade. Compared with placebo, finerenone reduced the composite kidney and cardiovascular outcomes. We report the effect of finerenone on individual cardiovascular outcomes and in patients with and without history of atherosclerotic cardiovascular disease (CVD).. This randomized, double-blind, placebo-controlled trial included patients with type 2 diabetes and urine albumin-to-creatinine ratio 30 to 5000 mg/g and an estimated glomerular filtration rate ≥25 to <75 mL per min per 1.73 m. Between September 2015 and June 2018, 13 911 patients were screened and 5674 were randomized; 45.9% of patients had CVD at baseline. Over a median follow-up of 2.6 years (interquartile range, 2.0-3.4 years), finerenone reduced the risk of the composite cardiovascular outcome compared with placebo (hazard ratio, 0.86 [95% CI, 0.75-0.99];. Among patients with chronic kidney disease and type 2 diabetes, finerenone reduced incidence of the composite cardiovascular outcome, with no evidence of differences in treatment effect based on preexisting CVD status. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02540993.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Male; Naphthyridines; Renal Insufficiency, Chronic

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

A straightforward and rapid high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) assay allowing the sensitive and selective quantitation of finerenone (BAY 94-8862) in lithium heparin human plasma is described. Finerenone is a novel, selective, nonsteroidal mineralocorticoid receptor antagonist that is in phase III clinical trials for the treatment of chronic kidney disease. Finerenone quantitation is performed after addition of its stable isotope-labelled internal standard (ISTD) by protein precipitation with acidified acetonitrile followed by HPLC-MS/MS separation and detection. The determination of finerenone concentrations was validated for a plasma volume of 0.100 mL and subsequently also for a lower plasma volume of 0.010 mL, collected e.g. in paediatric studies. The analytical range was from 0.100 µg/L (lower limit of quantification) to 200 µg/L (upper limit of quantification). Inter-day accuracy was 99.7-105.0% for the plasma volume of 0.100 mL and 101.1-104.5% for the plasma volume of 0.010 mL. Inter-day precision was ≤ 7.0%, independent of the extracted plasma volume. A moderate, concentration-independent matrix effect on ionisation was observed for both finerenone and its ISTD of 0.535-0.617, which is fully compensated by the ISTD (ISTD-normalised matrix factors were 0.98-1.03). The assay was successfully applied with both validated plasma volumes to a clinical phase I study in which the pharmacokinetics of 20 mg finerenone were compared in capillary plasma (0.010 mL) and venous plasma (0.100 mL) in a concentration range from the lower limit of quantification to 310 µg/L (capillary plasma) and 252 µg/L (venous plasma). The area under the plasma concentration versus time curve was similar in both matrices, while maximum concentrations were 37% higher in capillary plasma. In conclusion, capillary sampling should not bias pharmacokinetic exposure estimates compared with venous plasma values, if limited to sampling times in the distribution and elimination phases of finerenone.

Topics: Adult; Capillaries; Chromatography, High Pressure Liquid; Cross-Over Studies; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Naphthyridines; Renal Insufficiency, Chronic; Tandem Mass Spectrometry; Veins; Young Adult

Finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist, has favorable effects on cardiorenal outcomes in patients with predominantly stage 3 or 4 chronic kidney disease (CKD) with severely elevated albuminuria and type 2 diabetes. The use of finerenone in patients with type 2 diabetes and a wider range of CKD is unclear.. In this double-blind trial, we randomly assigned patients with CKD and type 2 diabetes 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 and an estimated glomerular filtration rate (eGFR) of 25 to 90 ml per minute per 1.73 m. A total of 7437 patients underwent randomization. Among the patients included in the analysis, during a median follow-up of 3.4 years, a primary outcome event occurred in 458 of 3686 patients (12.4%) in the finerenone group and in 519 of 3666 (14.2%) in the placebo group (hazard ratio, 0.87; 95% confidence interval [CI], 0.76 to 0.98; P = 0.03), with the benefit driven primarily by a lower incidence of hospitalization for heart failure (hazard ratio, 0.71; 95% CI, 0.56 to 0.90). The secondary composite outcome occurred in 350 patients (9.5%) in the finerenone group and in 395 (10.8%) in the placebo group (hazard ratio, 0.87; 95% CI, 0.76 to 1.01). The overall frequency of adverse events did not differ substantially between groups. The incidence of hyperkalemia-related discontinuation of the trial regimen was higher with finerenone (1.2%) than with placebo (0.4%).. Among patients with type 2 diabetes and stage 2 to 4 CKD with moderately elevated albuminuria or stage 1 or 2 CKD with severely elevated albuminuria, finerenone therapy improved cardiovascular outcomes as compared with placebo. (Funded by Bayer; FIGARO-DKD ClinicalTrials.gov number, NCT02545049.).

Topics: Aged; Albuminuria; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Hospitalization; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Naphthyridines; Proportional Hazards Models; Renal Insufficiency, Chronic

Finerenone (BAY 94-8862) is a potent non-steroidal, selective mineralocorticoid receptor antagonist being developed for the treatment of patients with type 2 diabetes and chronic kidney disease.. We present the population pharmacokinetics and pharmacodynamics (PD) analysis for efficacy and safety markers based on data from two clinical phase IIb studies: ARTS-DN (NCT01874431) and ARTS-DN Japan (NCT01968668).. The pharmacokinetics of finerenone were adequately characterized, with estimated glomerular filtration rate (eGFR) and body weight as influencing covariates. The area under the plasma concentration-time curve in Japanese patients did not differ from that in the global population, and the investigated pharmacokinetics were dose- and time-linear. In addition, the pharmacokinetic model provided robust individual exposure estimates to study exposure-response. The concentration-effect relationship over time for the efficacy marker urinary albumin:creatinine ratio (UACR) was well-characterized by a maximum effect model indicating saturation at high exposures. For the safety markers, a log-linear model and a power model were identified for serum potassium concentration and eGFR, respectively, indicating attenuation of effect gains at high exposures. There was no apparent ethnic effect on the investigated pharmacokinetic-pharmacodynamic relationships. The model-predicted times to reach the full (99%) steady-state drug effect on UACR, serum potassium, and eGFR were 138, 20, and 85 days, respectively, while the pharmacokinetic half-life was 2-3 h and steady state was achieved after 2 days, indicating timescale separation.. Our dose-exposure-response modeling and simulation indicates effects were largely saturated at finerenone 20 mg and doses of both 10 and 20 mg once daily appear safe and efficacious at reducing albuminuria.

Topics: Adult; Aged; Albumins; Albuminuria; Area Under Curve; Body Weight; Creatinine; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Glomerular Filtration Rate; Half-Life; Humans; Japan; Middle Aged; Mineralocorticoid Receptor Antagonists; Models, Theoretical; Naphthyridines; Potassium; Renal Insufficiency, Chronic; Safety; Treatment Outcome

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 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, a nonsteroidal mineralocorticoid receptor antagonist, was evaluated in Japanese patients with heart failure (HF) with reduced ejection fraction and chronic kidney disease and/or diabetes mellitus.. ARTS-HF Japan was a randomized, double-blind, phase 2b study. Patients (n=72) received oral, once-daily (o.d.) finerenone (2.5, 5, 7.5, 10 or 15 mg, up-titrated to 5, 10, 15, 20, or 20 mg, respectively, on day 30) or eplerenone (25 mg every other day, increased to 25 mg o.d. on day 30, and 50 mg on day 60) for 90 days. The primary endpoint was the proportion of individuals with a decrease of >30% in plasma NT-proBNP at day 90. Safety endpoints included the incidence of hyperkalemia. Decreases in NT-proBNP occurred in 23.1% of patients in the eplerenone group and 15.4%, 23.1%, 45.5%, 27.3% and 45.5% in the 2.5→5 mg, 5→10 mg, 7.5→15 mg, 10→20 mg and 15→20 mg finerenone groups, respectively (all P=NS). Mean changes in serum potassium levels were similar between groups.. Because of the small sample size, limited conclusions can be drawn. Considering the results of ARTS-HF and that finerenone was well tolerated in Japanese patients in ARTS-HF Japan, the safety and efficacy of finerenone should be further explored in a large outcomes trial including Japanese patients. (Circ J 2016; 80: 1113-1122).

Topics: Adult; Chronic Disease; Diabetes Mellitus; Double-Blind Method; Eplerenone; Heart Failure; Humans; Hyperkalemia; Japan; Naphthyridines; Natriuretic Peptide, Brain; Patient Safety; Peptide Fragments; Renal Insufficiency, Chronic; Spironolactone

To investigate the safety and potential efficacy of the novel non-steroidal mineralocorticoid receptor antagonist finerenone in patients with worsening chronic heart failure and reduced left ventricular ejection fraction (HFrEF) and at high risk of hyperkalaemia and worsening renal dysfunction.. The MinerAlocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF; NCT01807221) is a multicentre, randomized, double-blind, active-comparator-controlled, six-parallel-group, phase 2b dose-finding study. In total, 1060 patients with HFrEF and concomitant type 2 diabetes mellitus and/or chronic kidney disease (CKD) will be randomized within 7 days of emergency presentation to hospital for worsening chronic HF to receive finerenone (one of five doses in the range 2.5-20.0 mg once daily) or eplerenone (25 mg every second day to 50 mg once daily for 90 days). The primary objective is to investigate the safety and potential efficacy (measured as the percentage of individuals with a decrease in plasma N-terminal pro-B-type natriuretic peptide [NT-proBNP] of more than 30% relative to baseline at day 90 ± 2) of different oral doses of finerenone compared with eplerenone. Other objectives are to assess the effects of finerenone on a composite clinical endpoint (death from any cause, cardiovascular hospitalizations, or emergency presentations for worsening chronic HF), and on changes in health-related quality of life from baseline.. ARTS-HF is the first phase 2b clinical trial to investigate the effects of finerenone on plasma NT-proBNP in a high-risk population of patients who have worsening chronic HF with type 2 diabetes mellitus and/or CKD presenting at the emergency department.

Topics: Comorbidity; Diabetes Mellitus, Type 2; Double-Blind Method; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Naphthyridines; Natriuretic Agents; Natriuretic Peptide, Brain; Peptide Fragments; Renal Insufficiency, Chronic; Spironolactone

In FIGARO-DKD, finerenone reduced the risk of cardiovascular events in patients with type 2 diabetes (T2D) and stage 1-4 chronic kidney disease (CKD). In FIDELIO-DKD, finerenone improved kidney and cardiovascular outcomes in patients with advanced CKD. This analysis further explores kidney outcomes in FIGARO-DKD.. FIGARO-DKD (NCT02545049) included patients with urine albumin-to-creatinine ratio (UACR) 30-<300 mg/g and estimated glomerular filtration rate (eGFR) 25-90 mL/min/1.73 m2 or UACR 300-5000 mg/g and eGFR ≥60 mL/min/1.73 m2. Outcomes included two composite kidney endpoints, a composite of ≥40% decrease in eGFR from baseline sustained over ≥4 weeks, kidney failure or renal death, and a composite of ≥57% decrease in eGFR from baseline sustained over ≥4 weeks, kidney failure or renal death. Changes in albuminuria and eGFR slope were also analyzed. Kidney and CV outcomes were evaluated by baseline UACR.. A lower incidence rate for the eGFR ≥40% kidney composite endpoint was observed with finerenone compared with placebo, but the between-group difference was not significant [hazard ratio (HR) = 0.87; 95% confidence interval (CI): 0.76-1.01; P = .069]. A greater treatment effect was observed on the eGFR ≥57% kidney composite endpoint (HR = 0.77; 95% CI: 0.60-0.99; P = 0.041) with a 36% relative risk reduction for end-stage kidney disease. A larger magnitude of effect on kidney outcomes was observed with finerenone versus placebo for patients with severely increased albuminuria than with moderately increased albuminuria. Improvements in UACR, eGFR slope and cardiovascular risk were evident in both subgroups with finerenone.. The present analyses suggest that finerenone protects against kidney disease progression and cardiovascular events in patients with T2D and early- or late-stage CKD.

Topics: Albuminuria; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glomerular Filtration Rate; Humans; Kidney; Renal Insufficiency, Chronic

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

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.

Topics: Animals; Fibrosis; Heart Diseases; Heart Failure; Hypertrophy; Male; Metabolic Syndrome; Mineralocorticoid Receptor Antagonists; Naphthyridines; Rats; Receptors, Mineralocorticoid; Renal Insufficiency, Chronic; Stroke Volume

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

The use of finerenone is now included in the 2022 revision to standard treatment guidelines for patients with type 2 diabetes and chronic kidney disease.Finerenone is a costly addition to standard treatment. Patients may need to receive prescription preauthorization from their insurer.

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

It is currently unclear whether chronic kidney disease (CKD)-associated cardiovascular risk in type 2 diabetes (T2D) is modifiable.. To examine whether cardiovascular risk can be modified with finerenone in patients with T2D and CKD.. Incidence rates from Finerenone in Chronic Kidney Disease and Type 2 Diabetes: Combined FIDELIO-DKD and FIGARO-DKD Trial Programme Analysis (FIDELITY), a pooled analysis of 2 phase 3 trials (including patients with CKD and T2D randomly assigned to receive finerenone or placebo) were combined with National Health and Nutrition Examination Survey data to simulate the number of composite cardiovascular events that may be prevented per year with finerenone at a population level. Data were analyzed over 4 years of consecutive National Health and Nutrition Examination Survey data cycles (2015-2016 and 2017-2018).. Incidence rates of cardiovascular events (composite of cardiovascular death, nonfatal stroke, nonfatal myocardial infarction, or hospitalization for heart failure) were estimated over a median of 3.0 years by estimated glomerular filtration rate (eGFR) and albuminuria categories. The outcome was analyzed using Cox proportional hazards models stratified by study, region, eGFR and albuminuria categories at screening, and cardiovascular disease history.. This subanalysis included a total of 13 026 participants (mean [SD] age, 64.8 [9.5] years; 9088 male [69.8%]). Lower eGFR and higher albuminuria were associated with higher incidences of cardiovascular events. For recipients in the placebo group with an eGFR of 90 or greater, incidence rates per 100 patient-years were 2.38 (95% CI, 1.03-4.29) in those with a urine albumin to creatinine ratio (UACR) less than 300 mg/g and 3.78 (95% CI, 2.91-4.75) in those with UACR of 300 mg/g or greater. In those with eGFR less than 30, incidence rates increased to 6.54 (95% CI, 4.19-9.40) vs 8.74 (95% CI, 6.78-10.93), respectively. In both continuous and categorical models, finerenone was associated with a reduction in composite cardiovascular risk (hazard ratio, 0.86; 95% CI, 0.78-0.95; P = .002) irrespective of eGFR and UACR (P value for interaction = .66). In 6.4 million treatment-eligible individuals (95% CI, 5.4-7.4 million), 1 year of finerenone treatment was simulated to prevent 38 359 cardiovascular events (95% CI, 31 741-44 852), including approximately 14 000 hospitalizations for heart failure, with 66% (25 357 of 38 360) prevented in patients with eGFR of 60 or greater.. Results of this subanalysis of the FIDELITY analysis suggest that CKD-associated composite cardiovascular risk may be modifiable with finerenone treatment in patients with T2D, those with eGFR of 25 or higher, and those with UACR of 30 mg/g or greater. UACR screening to identify patients with T2D and albuminuria with eGFR of 60 or greater may provide significant opportunities for population benefits.

Topics: Albuminuria; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Heart Failure; Humans; Male; Middle Aged; Nutrition Surveys; Renal Insufficiency, Chronic; Risk Factors

We hypothesized that triple therapy with inhibitors of the renin-angiotensin system (RAS), sodium-glucose transporter (SGLT)-2, and the mineralocorticoid receptor (MR) would be superior to dual RAS/SGLT2 blockade in attenuating CKD progression in Col4a3 -deficient mice, a model of Alport syndrome. Late-onset ramipril monotherapy or dual ramipril/empagliflozin therapy attenuated CKD and prolonged overall survival by 2 weeks. Adding the nonsteroidal MR antagonist finerenone extended survival by 4 weeks. Pathomics and RNA sequencing revealed significant protective effects on the tubulointerstitium when adding finerenone to RAS/SGLT2 inhibition. Thus, triple RAS/SGLT2/MR blockade has synergistic effects and might attenuate CKD progression in patients with Alport syndrome and possibly other progressive chronic kidney disorders.. Dual inhibition of the renin-angiotensin system (RAS) plus sodium-glucose transporter (SGLT)-2 or the mineralocorticoid receptor (MR) demonstrated additive renoprotective effects in large clinical trials. We hypothesized that triple therapy with RAS/SGLT2/MR inhibitors would be superior to dual RAS/SGLT2 blockade in attenuating CKD progression.. We performed a preclinical randomized controlled trial (PCTE0000266) in Col4a3 -deficient mice with established Alport nephropathy. Treatment was initiated late (age 6 weeks) in mice with elevated serum creatinine and albuminuria and with glomerulosclerosis, interstitial fibrosis, and tubular atrophy. We block-randomized 40 male and 40 female mice to either nil (vehicle) or late-onset food admixes of ramipril monotherapy (10 mg/kg), ramipril plus empagliflozin (30 mg/kg), or ramipril plus empagliflozin plus finerenone (10 mg/kg). Primary end point was mean survival.. Mean survival was 63.7±10.0 days (vehicle), 77.3±5.3 days (ramipril), 80.3±11.0 days (dual), and 103.1±20.3 days (triple). Sex did not affect outcome. Histopathology, pathomics, and RNA sequencing revealed that finerenone mainly suppressed the residual interstitial inflammation and fibrosis despite dual RAS/SGLT2 inhibition.. Experiments in mice suggest that triple RAS/SGLT2/MR blockade may substantially improve renal outcomes in Alport syndrome and possibly other progressive CKDs because of synergistic effects on the glomerular and tubulointerstitial compartments.

Topics: Animals; Antihypertensive Agents; Diabetes Mellitus, Type 2; Female; Fibrosis; Glucose Transport Proteins, Facilitative; Male; Mice; Nephritis, Hereditary; Ramipril; Receptors, Mineralocorticoid; Renal Insufficiency, Chronic; Renin-Angiotensin System; Sodium; Sodium-Glucose Transporter 2

Topics: Heart; Humans; Kidney; Naphthyridines; Renal Insufficiency, Chronic

Topics: Diabetes Mellitus, Type 2; Humans; Naphthyridines; Patients; Renal Insufficiency, Chronic

The non-steroidal mineralocorticoid receptor antagonist (MRA) finerenone (FIN) improves kidney and cardiovascular outcomes in patients with chronic kidney disease (CKD) in type 2 diabetes (T2D). We explored the effect of FIN in a novel model of type 1 diabetic Munich Wistar Frömter (MWF) rat (D) induced by injection of streptozotocin (15 mg/kg) and additional exposure to a high-fat/high-sucrose diet. Oral treatment with FIN (10 mg/kg/day in rat chow) in diabetic animals (D-FIN) was compared to a group of D rats receiving no treatment and a group of non-diabetic untreated MWF rats (C) (n = 7-10 animals per group). After 6 weeks, D and D-FIN exhibited significantly elevated blood glucose levels (271.7 ± 67.1 mg/dl and 266.3 ± 46.8 mg/dl) as compared to C (110.3 ± 4.4 mg/dl; p < 0.05). D showed a 10-fold increase of kidney damage markers Kim-1 and Ngal which was significantly suppressed in D-FIN. Blood pressure, pulse wave velocity (PWV) and arterial collagen deposition were lower in D-FIN, associated to an improvement in endothelial function due to a reduction in pro-contractile prostaglandins, as well as reactive oxygen species (ROS) and inflammatory cytokines (IL-1, IL-6, TNFα and TGFβ) in perivascular and perirenal adipose tissue (PVAT and PRAT, respectively). In addition, FIN restored the imbalance observed in CKD between the procalcifying BMP-2 and the nephroprotective BMP-7 in plasma, kidney, PVAT, and PRAT. Our data show that treatment with FIN improves kidney and vascular damage in a new rat model of DKD with T1D associated with a reduction in inflammation, fibrosis and osteogenic factors independently from changes in glucose homeostasis.

Topics: Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Kidney; Pulse Wave Analysis; Rats; Rats, Wistar; Renal Insufficiency, Chronic

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

In the Netherlands, more than one million patients have type 2 diabetes (T2D), and approximately 36% of these patients have chronic kidney disease (CKD). Yearly medical costs related to T2D and CKD account for approximately €1.3 billion and €805 million, respectively. The FIDELIO-DKD trial showed that the addition of finerenone to the standard of care (SoC) lowers the risk of CKD progression and cardiovascular (CV) events in patients with CKD stages 2-4 associated with T2D. This study investigates the cost-effectiveness of adding finerenone to the SoC of patients with advanced CKD and T2D compared to SoC monotherapy.. The validated FINE-CKD model is a Markov cohort model which simulates the disease pathway of patients over a lifetime time horizon. The model was adapted to reflect the Dutch societal perspective. The model estimated the incremental costs, utilities, and incremental cost-effectiveness ratio (ICER). Sensitivity and scenario analyses were performed to assess the effect of parameter uncertainty on model robustness.. When used in conjunction with SoC, finerenone extended time free of CV events and renal replacement therapy by respectively 0.30 and 0.31 life years compared to SoC alone, resulting in an extension of 0.20 quality-adjusted life years (QALYs). The reduction in renal and CV events led to a €6136 decrease in total lifetime costs per patient compared to SoC alone, establishing finerenone as a dominant treatment option. Finerenone in addition to SoC had a 83% probability of being dominant and a 93% probability of being cost-effective at a willingness-to-pay threshold of €20,000.. By reducing the risk of CKD progression and CV events, finerenone saves costs to society while gaining QALYs in patients with T2D and advanced CKD in the Netherlands.

Topics: Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Humans; Netherlands; Renal Insufficiency, Chronic

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

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

Agarwal R, Filippatos G, Pitt B, et al.

Topics: Diabetes Mellitus, Type 2; Humans; Kidney; Naphthyridines; Renal Insufficiency, Chronic

Finerenone 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.. Non-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.. The 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%.. We 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.

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

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

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

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

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

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

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

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

Topics: Humans; Naphthyridines; Renal Insufficiency, Chronic

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

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

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

Topics: Albuminuria; Diabetes Mellitus, Type 2; Disease Progression; Humans; Naphthyridines; Renal Insufficiency, Chronic

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

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

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

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

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

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

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

Topics: Atrial Fibrillation; Diabetes Mellitus; Humans; Naphthyridines; Renal Insufficiency, Chronic

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

Development of albuminuria and arterial stiffness in Munich Wistar Frömter (MWF) rats, a model of chronic kidney disease, is related to alterations in extracellular matrix, increased oxidative stress, and endothelial dysfunction. Finerenone (FIN), a novel, nonsteroidal, potent, and selective mineralocorticoid receptor antagonist, improves endothelial dysfunction through enhancing nitric oxide (NO) bioavailability and decreasing superoxide anion levels due to an upregulation in vascular and renal superoxide dismutase activity. We hypothesize that FIN reduces arterial stiffness in this model associated to the reduction in albuminuria and matrix metalloproteinase (MMP)-2/9 activity.. Twelve-week-old MWF rats with established albuminuria and age-matched normoalbuminuric Wistar (W) rats were treated with FIN (10 mg/kg/day, once-daily oral gavage) or with vehicle (control, C) for 4 weeks.. Arterial stiffness was significantly higher in mesenteric arteries (MA) of MWF-C as compared to W-C. FIN treatment significantly lowered β-index, a measure of intrinsic stiffness independent of geometry, in MWF (βMWF-FIN = 7.7 ± 0.4 vs. βMWF-C = 9.2 ± 0.5, p < 0.05) positively correlating with urinary albumin excretion. Elastin fenestrae area in the internal elastic lamina of MA from MWF-FIN was significantly larger (+377%, p < 0.05). FIN increased plasma pro-MMP-2 and decreased plasma MMP-2 and MMP-9 activities, correlating with reductions in β-index. MA from MWF-FIN exhibited higher NO bioavailability and reduced superoxide anion levels compared to MWF-C.. FIN treatment reduces intrinsic arterial stiffness in MA from MWF rats associated with changes in elastin organization, normalization of MMP-2 and MMP-9 activities, and reduction of oxidative stress. Moreover, reduction of arterial stiffness correlates with reduction in albuminuria.

Topics: Albuminuria; Animals; Cardiovascular Diseases; Disease Models, Animal; Endothelium, Vascular; Humans; Kidney; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mesenteric Arteries; Mineralocorticoid Receptor Antagonists; Naphthyridines; Oxidative Stress; Rats; Rats, Wistar; Renal Insufficiency, Chronic; Signal Transduction; Vascular Stiffness

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

Managing the cardiovascular complications of renal failure is a major therapeutic challenge in clinical practice. Mineralocorticoid Receptor (MR) blockade is a highly effective strategy for the management of heart failure, but the use of MR antagonists (MRA) is limited by their side effects rendering them contraindicated in patients with renal failure. Finerenone is a new non-steroidal MRA that shows fewer hyperkaliaemic events than the traditional steroidal MRAs and could therefore represent an alternative to these molecules in patients with damaged kidney function. The aim of this study is to characterize the effects of Finerenone on the cardiac complications of renal failure in a mouse model of chronic kidney disease (CKD). CKD was induced by subtotal nephrectomy (Nx), and finerenone was administered at a low dose (2.5 mg/kg/d) from week 4 to week 10 post-Nx. Cardiac function was assessed by echocardiography and invasive hemodynamics while cardiac fibrosis was measured by Sirius Red staining. Renal failure induced cardiac systolic and diastolic dysfunctions in the untreated CKD mice, as well as minor changes on cardiac structure. We also observed alterations in the phosphorylation of proteins playing key roles in the calcium handling (Phospholamban, Calmodulin kinase II) in these mice. Finerenone prevented most of these lesions with no effects on neither the renal dysfunction nor kaliemia. The benefits of finerenone suggest that activation of MR is involved in the cardiac complication of renal failure and strengthen previous studies showing beneficial effects of MRA in patients with CKD.

Topics: Animals; Disease Models, Animal; Eplerenone; Heart Failure, Diastolic; Hemodynamics; Humans; Mice; Mineralocorticoid Receptor Antagonists; Naphthyridines; Receptors, Mineralocorticoid; Renal Insufficiency, Chronic

Acute kidney injury induced by ischemia/reperfusion (IR) is a frequent complication in hospitalized patients. Mineralocorticoid receptor antagonism has shown to be helpful against renal IR consequences; however, the potential benefit of novel nonsteroidal mineralocorticoid receptor antagonists such as finerenone has to be further explored. In this study, we evaluated the efficacy of finerenone to prevent the acute and chronic consequences of ischemic acute kidney injury. For the acute study (24 hours), 18 rats were divided into sham, bilateral renal ischemia of 25 minutes, and rats that received 3 doses of finerenone at 48, 24, and 1 hour before the ischemia. For the chronic study (4 months), 23 rats were divided into sham, rats that underwent 45 minutes of bilateral ischemia, and rats treated with finerenone at days 2 and 1 and 1 hour before IR. We found that after 24 hours of reperfusion, the untreated IR rats presented kidney dysfunction and tubular injury. Kidney injury molecule-1 and neutrophil gelatinase associated to lipolacin mRNA levels were increased. In contrast, the rats treated with finerenone displayed normal kidney function and significantly lesser tubular injury and kidney injury molecule-1 and neutrophil gelatinase associated to lipolacin levels. After 4 months, the IR rats developed chronic kidney disease, evidenced by kidney dysfunction, increased proteinuria and renal vascular resistance, tubular dilation, extensive tubule-interstitial fibrosis, and an increase in kidney transforming growth factor-β and collagen-I mRNA. The transition from acute kidney injury to chronic kidney disease was fully prevented by finerenone. Altogether, our data show that in the rat, finerenone is able to prevent acute kidney injury induced by IR and the chronic and progressive deterioration of kidney function and structure.

Topics: Acute Kidney Injury; Animals; Cell Adhesion Molecules; Disease Models, Animal; Kidney; Lipocalin-2; Male; Malondialdehyde; Mineralocorticoid Receptor Antagonists; Naphthyridines; Oxidative Stress; Rats; Rats, Wistar; Renal Insufficiency, Chronic; Reperfusion Injury