Abstract: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 … Show more
“…(a) fast decongestion, which may cause an immediate reduction in HHF, and/or (b) a high FIB‐4 score associated with NAFLD may also be a reflection of systemic inflammation, fibrosis and associated CVDs 47 . Preclinical animal model data for finerenone showed anti‐inflammatory and antifibrotic effects, 48 and although the clinical translation may be complex, the systemic antifibrotic effects may be effective in the long‐term, particularly in patients with elevated fibrosis markers. Moreover, finerenone has fewer side effects compared with other MRA antagonists 49 …”
AimInvestigating the effect of finerenone on liver function, cardiovascular and kidney composite outcomes in patients with chronic kidney disease and type 2 diabetes, stratified by their risk of liver steatosis, inflammation and fibrosis.Materials and MethodsPost hoc analysis stratified patients (N = 13 026) by liver fibrosis and enzymes: high risk of steatosis (hepatic steatosis index >36); elevated transaminases [alanine transaminase (ALT) >33 (males) and >25 IU/L (females)]; and fibrosis‐4 (FIB‐4) index scores >3.25, >2.67 and >1.30. Liver enzymes were assessed by changes in ALT, aspartate aminotransferase and gamma‐glutamyl transferase. Composite kidney outcome was defined as onset of kidney failure, sustained estimated glomerular filtration rate decline ≥57% from baseline over ≥4 weeks or kidney death. Composite cardiovascular outcome was defined as cardiovascular death, non‐fatal myocardial infarction, non‐fatal stroke or hospitalization for heart failure.ResultsALT, aspartate aminotransferase and gamma‐glutamyl transferase levels were consistent between treatment groups and remained stable throughout. Finerenone consistently reduced the risk of composite kidney outcome, irrespective of altered liver tests. Higher FIB‐4 score was associated with higher incidence rates of composite cardiovascular outcome. Finerenone reduced the risk of composite cardiovascular outcome versus placebo in FIB‐4 subgroups by 52% (>3.25), 39% (>2.67) and 24% (>1.30) (p values for interaction = .01, .13 and .03, respectively).ConclusionsFinerenone has neutral effects on liver parameters in patients with chronic kidney disease and type 2 diabetes. Finerenone showed robust and consistent kidney benefits in patients with altered liver tests, and profound cardiovascular benefits even in patients with higher FIB‐4 scores who were at high risk of developing cardiovascular complications.
“…(a) fast decongestion, which may cause an immediate reduction in HHF, and/or (b) a high FIB‐4 score associated with NAFLD may also be a reflection of systemic inflammation, fibrosis and associated CVDs 47 . Preclinical animal model data for finerenone showed anti‐inflammatory and antifibrotic effects, 48 and although the clinical translation may be complex, the systemic antifibrotic effects may be effective in the long‐term, particularly in patients with elevated fibrosis markers. Moreover, finerenone has fewer side effects compared with other MRA antagonists 49 …”
AimInvestigating the effect of finerenone on liver function, cardiovascular and kidney composite outcomes in patients with chronic kidney disease and type 2 diabetes, stratified by their risk of liver steatosis, inflammation and fibrosis.Materials and MethodsPost hoc analysis stratified patients (N = 13 026) by liver fibrosis and enzymes: high risk of steatosis (hepatic steatosis index >36); elevated transaminases [alanine transaminase (ALT) >33 (males) and >25 IU/L (females)]; and fibrosis‐4 (FIB‐4) index scores >3.25, >2.67 and >1.30. Liver enzymes were assessed by changes in ALT, aspartate aminotransferase and gamma‐glutamyl transferase. Composite kidney outcome was defined as onset of kidney failure, sustained estimated glomerular filtration rate decline ≥57% from baseline over ≥4 weeks or kidney death. Composite cardiovascular outcome was defined as cardiovascular death, non‐fatal myocardial infarction, non‐fatal stroke or hospitalization for heart failure.ResultsALT, aspartate aminotransferase and gamma‐glutamyl transferase levels were consistent between treatment groups and remained stable throughout. Finerenone consistently reduced the risk of composite kidney outcome, irrespective of altered liver tests. Higher FIB‐4 score was associated with higher incidence rates of composite cardiovascular outcome. Finerenone reduced the risk of composite cardiovascular outcome versus placebo in FIB‐4 subgroups by 52% (>3.25), 39% (>2.67) and 24% (>1.30) (p values for interaction = .01, .13 and .03, respectively).ConclusionsFinerenone has neutral effects on liver parameters in patients with chronic kidney disease and type 2 diabetes. Finerenone showed robust and consistent kidney benefits in patients with altered liver tests, and profound cardiovascular benefits even in patients with higher FIB‐4 scores who were at high risk of developing cardiovascular complications.
“…Mineral receptors (MR) are expressed by several cell types of both epithelial and non-epithelial origin [6,36,99]. MR antagonism on non-epithelial cells (including fibroblasts, vascular smooth muscle cells, podocytes, and inflammatory cells) explain the anti-inflammatory and anti-fibrotic activities of finerenone in the kidneys and across multiple organs level [100,101]. Some lines of evidence support the notion that combination therapy of SGLT2i and finerenone may have a synergic effect through common and distinct pathophysiological pathways and possibly will reduce the residual cardio-renal risk noted after the registration trials of main molecules (Figure 5) [102].…”
Section: Finerenone and Perspectives: Stand Alone Or In Sglt2i Joint ...mentioning
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, and diabetes remains the leading cause of end-stage kidney disease in affected patients. To date, current medications for CKD and type 2 diabetes mellitus have not reset residual risk in patients due to a high grade of inflammation and fibrosis contributing to kidney and heart disease. This question-and-answer-based review will discuss the pharmacological and clinical differences between finerenone and other mineralocorticoid receptor antagonists and then move on to the main evidence in the cardiovascular and renal fields, closing, finally, on the potential role of therapeutic combination with sodium-glucose cotransporter 2 inhibitors (SGLT2is).
“…Other drugs are still untested or tested in low-power phase-2 trials with inconclusive results, like a trial that tested the IL-α antagonist Xilonix. 116 Sodium-glucose cotransporter-2 inhibitors (reduction of IL-1β) release by macrophages in vitro, an NLRP3-inflammasome induced effect 117 ) and mineralocorticoid receptor antagonists (interference on NF-κB activation induced by mineralocorticoid receptors 118 ) have anti-inflammatory properties, but these properties are still poorly characterized in clinical studies.…”
Section: Compendium On Increased Risk Of Cardiovascular Complications...mentioning
With a global burden of 844 million, chronic kidney disease (CKD) is now considered a public health priority. Cardiovascular risk is pervasive in this population, and low-grade systemic inflammation is an established driver of adverse cardiovascular outcomes in these patients. Accelerated cellular senescence, gut microbiota-dependent immune activation, posttranslational lipoprotein modifications, neuroimmune interactions, osmotic and nonosmotic sodium accumulation, acute kidney injury, and precipitation of crystals in the kidney and the vascular system all concur in determining the unique severity of inflammation in CKD. Cohort studies documented a strong link between various biomarkers of inflammation and the risk of progression to kidney failure and cardiovascular events in patients with CKD. Interventions targeting diverse steps of the innate immune response may reduce the risk of cardiovascular and kidney disease. Among these, inhibition of IL-1β (interleukin-1 beta) signaling by canakinumab reduced the risk for cardiovascular events in patients with coronary heart disease, and this protection was equally strong in patients with and without CKD. Several old (colchicine) and new drugs targeting the innate immune system, like the IL-6 (interleukin 6) antagonist ziltivekimab, are being tested in large randomized clinical trials to thoroughly test the hypothesis that mitigating inflammation may translate into better cardiovascular and kidney outcomes in patients with CKD.
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