Avosentan for Overt Diabetic Nephropathy MANN, Johannes F. E; GREEN, Damian; JAMERSON, Kenneth ...
Journal of the American Society of Nephrology,
03/2010, Letnik:
21, Številka:
3
Journal Article
Recenzirano
Odprti dostop
In the short term, the endothelin antagonist avosentan reduces proteinuria, but whether this translates to protection from progressive loss of renal function is unknown. We examined the effects of ...avosentan on progression of overt diabetic nephropathy in a multicenter, multinational, double-blind, placebo-controlled trial. We randomly assigned 1392 participants with type 2 diabetes to oral avosentan (25 or 50 mg) or placebo in addition to continued angiotensin-converting enzyme inhibition and/or angiotensin receptor blockade. The composite primary outcome was the time to doubling of serum creatinine, ESRD, or death. Secondary outcomes included changes in albumin-to-creatinine ratio (ACR) and cardiovascular outcomes. We terminated the trial prematurely after a median follow-up of 4 months (maximum 16 months) because of an excess of cardiovascular events with avosentan. We did not detect a difference in the frequency of the primary outcome between groups. Avosentan significantly reduced ACR: In patients who were treated with avosentan 25 mg/d, 50 mg/d, and placebo, the median reduction in ACR was 44.3, 49.3, and 9.7%, respectively. Adverse events led to discontinuation of trial medication significantly more often for avosentan than for placebo (19.6 and 18.2 versus 11.5% for placebo), dominated by fluid overload and congestive heart failure; death occurred in 21 (4.6%; P = 0.225), 17 (3.6%; P = 0.194), and 12 (2.6%), respectively. In conclusion, avosentan reduces albuminuria when added to standard treatment in people with type 2 diabetes and overt nephropathy but induces significant fluid overload and congestive heart failure.
Aims
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.
Materials and Methods
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 m2 receiving optimized renin‐angiotensin system blockade were randomized to finerenone or placebo.
Results
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.
Conclusions
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.
...in clinical practice the diagnosis of PA is complicated because: (1) aldosterone secretion in PA is relatively autonomous from the renin-angiotensis system, and increases in response to multiple ...stimuli (upright posture, dietary factors, adrenocorticotropin 1–24, gonadotropin-releasing hormone, vasopressin, serotonin receptor-4 agonists) which contributes to the large variability of PAC 11. The positive correlation between APCCs, CACNA1D mutation rate and aldosterone levels suggests that specific calcium channel blockers might represent a new targeted therapy for patients with high aldosterone levels caused for selective mutations in voltage-gated L-type Ca2+ channels. ...PA is a very prevalent form of arterial hypertension with a specific pharmacological treatment consisting of MRAs. Spironolactone could also be used in subjects not attaining BP control with 2 drugs, either being angiotensin converting enzyme inhibitors or angiotensin receptor blockers combined with a calcium channel blocker or a thiazide diuretic.
Fibroblast growth factor-23 (FGF)-23 is a phosphaturic hormone involved in mineral bone metabolism that helps control phosphate homeostasis and reduces 1,25-dihydroxyvitamin D synthesis. Recent data ...have highlighted the relevant direct FGF-23 effects on the myocardium, and high plasma levels of FGF-23 have been associated with adverse cardiovascular outcomes in humans, such as heart failure and arrhythmias. Therefore, FGF-23 has emerged as a novel biomarker of cardiovascular risk in the last decade. Indeed, experimental data suggest FGF-23 as a direct mediator of cardiac hypertrophy development, cardiac fibrosis and cardiac dysfunction via specific myocardial FGF receptor (FGFR) activation. Therefore, the FGF-23/FGFR pathway might be a suitable therapeutic target for reducing the deleterious effects of FGF-23 on the cardiovascular system. More research is needed to fully understand the intracellular FGF-23-dependent mechanisms, clarify the downstream pathways and identify which could be the most appropriate targets for better therapeutic intervention. This review updates the current knowledge on both clinical and experimental studies and highlights the evidence linking FGF-23 to cardiovascular events. The aim of this review is to establish the specific role of FGF-23 in the heart, its detrimental effects on cardiac tissue and the possible new therapeutic opportunities to block these effects.
This document summarizes the available evidence and provides recommendations on the use of home blood pressure monitoring in clinical practice and in research. It updates the previous recommendations ...on the same topic issued in year 2000. The main topics addressed include the methodology of home blood pressure monitoring, its diagnostic and therapeutic thresholds, its clinical applications in hypertension, with specific reference to special populations, and its applications in research. The final section deals with the problems related to the implementation of these recommendations in clinical practice.
: The issue of a potential danger of antihypertensive drugs related to cancer susceptibility is currently generating a major debate in the scientific community, concerns in the public and emphasized ...interest from the media. The present article is a thorough review of what is known on the various classes of antihypertensive drugs concerning the risk of developing different neoplasms and about the suggested pathophysiological mechanisms, whenever available. The main limitations of evidence derived from studies currently available in this setting are also discussed, high-lightening the need for newly developed approaches to generate more accurate recommendations and informed advice for physicians.
It has been suggested that a blunted nocturnal blood pressure (BP) decline is associated with a poor prognosis. Nevertheless, it remains unclear if an abnormal dipping is deleterious per se or it ...merely reflects an elevated BP during sleep. We aimed to assess the prognostic value of nocturnal BP decline, with or without concomitant elevated nocturnal BP.
Vital status and cause of death were obtained from death certificates in 59 124 patients, enrolled in the Spanish ABPM Registry between 2004 and 2014 (median follow-up: 10 years). The association between night-to-day ratio (NDR) and dipping patterns (extreme dippers, dippers, reduced dippers, and risers) with all-cause and cardiovascular mortality were evaluated by Cox-proportional models adjusted for clinical confounders and 24 h blood pressure.
NDR was associated with all-cause mortality hazard ratio for 1SD change: 1.15; 95% confidence interval (CI) 1.13-1.17. Reduced dippers (1.13; 1.06-1.20) and risers (1.41; 1.32-1.51) were associated with an increased risk of all-cause death, whereas extreme dippers (0.90; 0.79-1.02) were not. Elevated NDR (≥0.9) in the absence of elevated night SBP (<120 mmHg) was associated with an increased risk of death (1.13; 1.04-1.22), as well as elevated night SBP but normal NDR (1.38; 1.26-1.50), and the combination of both abnormalities (1.56; 1.46-1.66). Similar results were obtained for cardiovascular mortality.
Abnormalities in the circadian pattern are associated with an increased risk of all-cause and cardiovascular mortality. This is maintained even in the absence of nocturnal BP elevation.
Aldosterone blockade is recommended for patients with congestive heart failure after acute myocardial infarction complicated by left ventricular systolic dysfunction; however, the perceived risk of ...hyperkalemia may limit implementation of this therapeutic approach. This subanalysis examined the relationship between eplerenone, serum potassium (K(+)), and clinical outcomes in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS).
Hospitalized patients with congestive heart failure after acute myocardial infarction complicated by left ventricular systolic dysfunction (left ventricular ejection fraction < or =40%) treated with standard therapy were randomized 3 to 14 days after the acute myocardial infarction to additional treatment with eplerenone (25 to 50 mg/d; n=3319) or placebo (n=3313). Patients were excluded if baseline K(+) was >5.0 mEq/L or serum creatinine was >2.5 mg/dL. In patients receiving standard therapy, the addition of eplerenone resulted in a 4.4% absolute increase in the incidence of K(+) >5.5 mEq/L, a 1.6% increase of K(+) > or =6.0 mEq/L, and a 4.7% absolute decrease in hypokalemia (K(+) <3.5 mEq/L). Four independent baseline predictors of hyperkalemia (defined as > or =6.0 mEq/L) were identified: potassium (K(+) greater than the median; 4.3 mEq/L), estimated glomerular filtration rate (< or =60 mL . min(-1) . 1.73 m(-2)), history of diabetes mellitus, and prior use of antiarrhythmic agents. None of these independent baseline risk factors significantly impacted the cardiovascular benefit of eplerenone for reducing all-cause mortality.
Use of selective aldosterone blockade with eplerenone within the dose range of 25 to 50 mg/d in post-acute myocardial infarction patients with heart failure and left ventricular systolic dysfunction who are treated with standard therapy improves outcomes without an excess of risk of hyperkalemia (> or =6.0 mEq/L) when periodic monitoring of serum K(+) is instituted.
The nonsteroidal mineralocorticoid receptor antagonist finerenone and the sodium-glucose co-transporter-2 inhibitor canagliflozin reduce cardiorenal risk in albuminuric patients with chronic kidney ...disease (CKD) and type 2 diabetes (T2D). At first glance, the results of FIDELIO-DKD (ClinicalTrials.gov, NCT02540993) and CREDENCE appear disparate. In FIDELIO-DKD, the primary end-point had a 18% (95% CI 7% to 27%) relative risk reduction; in CREDENCE the primary end-point had a 30% (95% CI 18% to 41%) relative risk reduction. Unlike CREDENCE, FIDELIO-DKD trial included patients with high albuminuria but excluded patients with symptomatic heart failure with reduced ejection fraction. The primary end-point in the FIDELIO-DKD trial was kidney specific and included a sustained decline in eGFR of ≥40% from baseline. In contrast, the primary end-point in the CREDENCE trial was included a sustained decline in eGFR of ≥57% from baseline and cardiovascular 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-to-creatinine ratio >300-5000 mg/g and an estimated glomerular filtration rate of 30-<90 ml/min/1.73 m2 at screening) were included in this analysis. The primary end point was a cardiorenal composite (cardiovascular death, kidney failure, estimated glomerular filtration rate 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 end point was 43.9/1000 patient years with finerenone compared to 59.5/1000 patient years with placebo. The relative risk was significantly reduced by 26% with finerenone versus placebo (hazard ratio 0.74, 95% CI 0.63-0.87).In CREDENCE, the rate of the cardiorenal composite end point was 43.2/1000 patient years with canagliflozin compared to 61.2/1000 patient years with placebo; a 30% risk reduction was observed with canagliflozin (hazard ratio 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.
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