Individual Atrasentan Exposure is Associated With Long-term Kidney and Heart Failure Outcomes in Patients With Type 2 Diabetes and Chronic Kidney Disease.
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SUBMITTER: Koomen JV
PROVIDER: S-EPMC8246733 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundDiabetes mellitus (DM), chronic kidney disease (CKD), and heart failure (HF) are pathophysiologically linked and increasing in prevalence in Asian populations, but little is known about the interplay of DM and CKD on outcomes in HF.ObjectivesThis study sought to investigate outcomes in patients with heart failure with preserved ejection fraction (HFpEF) vs heart failure with reduced ejection fraction (HFrEF) in relation to the presence of DM and CKD.MethodsUsing the multinational ASIAN-HF registry, we investigated associations between DM only, CKD only, and DM+CKD with: 1) composite of 1-year mortality or HF hospitalization; and 2) Kansas City Cardiomyopathy Questionnaire scores, according to HF subtype.ResultsIn 5,239 patients with HF (74.6% HFrEF, 25.4% HFpEF; mean age 63 years; 29.1% female), 1,107 (21.1%) had DM only, 1,087 (20.7%) had CKD only, and 1,400 (26.7%) had DM+CKD. Compared with patients without DM nor CKD, DM+CKD was associated with 1-year all-cause mortality or HF hospitalization in HFrEF (adjusted HR: 2.07; 95% CI: 1.68-2.55) and HFpEF (HR: 2.37; 95% CI: 1.40-4.02). In HFrEF, DM only and CKD only were associated with 1-year all-cause mortality or HF hospitalization (both HRs: 1.43; 95% CI: 1.14-1.80), while in HFpEF, CKD only (HR: 2.54; 95% CI: 1.46-4.41) but not DM only (HR: 1.01; 95% CI: 0.52-1.95) was associated with increased risk (interaction P < 0.01). Adjusted Kansas City Cardiomyopathy Questionnaire scores were lower in patients with DM+CKD (HFrEF: mean 60.50, SEM 0.77, HFpEF: mean 70.10, SEM 1.06; P < 0.001) than with no DM or CKD (HFrEF: mean 66.00, SEM 0.65; and HFpEF: mean 75.80, SEM 0.99).ConclusionsCombined DM and CKD adversely effected outcomes independently of HF subtype, with CKD a consistent predictor of worse outcomes. Strategies to prevent and treat DM and CKD in HF are urgently required.
| S-EPMC10442874 | biostudies-literature
Project description:A recent phase II clinical trial (Reducing Residual Albuminuria in Subjects with Diabetes and Nephropathy with AtRasentan trial and an identical trial in Japan (RADAR/JAPAN)) showed that the endothelin A receptor antagonist atrasentan lowers albuminuria, blood pressure, cholesterol, hemoglobin, and increases body weight in patients with type 2 diabetes and nephropathy. We previously developed an algorithm, the Parameter Response Efficacy (PRE) score, which translates short-term drug effects into predictions of long-term effects on clinical outcomes.We used the PRE score on data from the RADAR/JAPAN study to predict the effect of atrasentan on renal and heart failure outcomes.We performed a post-hoc analysis of the RADAR/JAPAN randomized clinical trials in which 211 patients with type-2 diabetes and nephropathy were randomly assigned to atrasentan 0.75?mg/day, 1.25?mg/day, or placebo. A PRE score was developed in a background set of completed clinical trials using multivariate Cox models. The score was applied to baseline and week-12 risk marker levels of RADAR/JAPAN participants, to predict atrasentan effects on clinical outcomes. Outcomes were defined as doubling serum creatinine or end-stage renal disease and hospitalization for heart failure.The PRE score predicted renal risk changes of -23% and -30% for atrasentan 0.75 and 1.25?mg/day, respectively. PRE scores also predicted a small non-significant increase in heart failure risk for atrasentan 0.75 and 1.25?mg/day (+2% vs. +7%). Selecting patients with >30% albuminuria reduction from baseline (responders) improved renal outcome to almost 50% risk reduction, whereas non-responders showed no renal benefit.Based on the RADAR/JAPAN study, with short-term changes in risk markers, atrasentan is expected to decrease renal risk without increased risk of heart failure. Within this population albuminuria responders appear to contribute to the predicted improvements, whereas non-responders showed no benefit. The ongoing hard outcome trial (SONAR) in type 2 diabetic patients with >30% albuminuria reduction to atrasentan will allow us to assess the validity of these predictions.
| S-EPMC7735387 | biostudies-literature
Project description:BackgroundData on rates of heart failure (HF) hospitalizations, recurrent hospitalizations, and outcomes related to HF hospitalizations in chronic kidney disease (CKD) are limited.ObjectivesThis study examined rates of HF hospitalizations and re-hospitalizations within a large CKD population and evaluated the burden of HF hospitalizations with the risk of subsequent CKD progression and death.MethodsThe prospective CRIC (Chronic Renal Insufficiency Cohort) study measured the estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (ACR) at baseline. The crude rates and rate ratios of HF hospitalizations and 30-day HF re-hospitalizations were calculated using Poisson regression models. Cox regression was used to assess the association of the frequency of HF hospitalizations within the first 2 years of follow-up with risk of subsequent CKD progression and death.ResultsAmong 3,791 participants, the crude rate of HF admissions was 5.8 per 100 person-years (with higher rates of HF with preserved ejection fraction vs. HF with reduced ejection fraction). The adjusted rate of HF was higher with a lower eGFR (vs. eGFR >45 ml/min/1.73 m2); the rate ratios were 1.7 and 2.2 for eGFR 30 to 44 and <30 ml/min/1.73 m2 (vs. >45 ml/min/1.73 m2), respectively. Similarly, the adjusted rates of HF hospitalization were significantly higher in those with higher urine ACR (vs. urine ACR <30 mg/g); the rate ratios were 1.9 and 2.6 for urine ACR 30 to 299 and ≥300 mg/g, respectively. Overall, 20.6% of participants had a subsequent HF re-admission within 30 days. HF hospitalization within 2 years of study entry was associated with greater adjusted risks for CKD progression (1 hospitalization: hazard ratio [HR]: 1.93; 95% confidence interval [CI]: 1.40 to 2.67; 2+ hospitalizations: HR: 2.14; 95% CI: 1.30 to 3.54) and all-cause death (1 hospitalization: HR: 2.20; 95% CI: 1.71 to 2.84; 2+ hospitalizations: HR: 3.06; 95% CI: 2.23 to 4.18).ConclusionsWithin a large U.S. CKD population, the rates of HF hospitalizations and re-hospitalization were high, with even higher rates across categories of lower eGFR and higher urine ACR. Patients with CKD hospitalized with HF had greater risks of CKD progression and death. HF prevention and treatment should be a public health priority to improve CKD outcomes.
| S-EPMC6590908 | biostudies-literature
Project description:BACKGROUND:Diabetes mellitus is an increasingly prevalent condition among heart failure (HF) patients. The long-term morbidity and mortality among patients with and without diabetes with HF with reduced (HFrEF), borderline (HFbEF), and preserved ejection fraction (HFpEF) are not well described. METHODS:Using the Get With The Guidelines (GWTG)-HF Registry linked to Centers for Medicare & Medicaid Services claims data, we evaluated differences between HF patients with and without diabetes. Adjusted Cox proportional-hazard models controlling for patient and hospital characteristics were used to evaluate mortality and readmission outcomes. RESULTS:A cohort of 86,659 HF patients aged??65?years was followed for 3?years from discharge. Unadjusted all-cause mortality was between 4.4% and 5.5% and all-cause hospitalization was between 19.4% and 22.6% for all groups at 30 days. For all-cause mortality at 3?years from hospital discharge, diabetes was associated with an adjusted hazard ratio of 1.27 (95% CI 1.07-1.49, P?=?.0051) for HFrEF, 0.95 (95% CI 0.55-1.65, P?=?.8536) for HFbEF, 1.02 (95% CI 0.87-1.19, P?=?.8551) for HFpEF. For all-cause readmission, diabetes was associated with an adjusted hazard ratio of 1.06 (95% CI 0.87-1.29, P?=?.5585) for HFrEF, 1.48 (95% CI 1.15-1.90, P?=?.0023) for HFbEF, and 1.06 (95% CI 0.91-1.22, P?=?.4747) for HFpEF. CONCLUSIONS:HFrEF and HFbEF patients with diabetes are at increased risk for mortality and rehospitalization after hospitalization for HF, independent of other patient and hospital characteristics. Among HFpEF patients, diabetes does not appear to be independently associated with significant additional risks.
| S-EPMC7664459 | biostudies-literature
Project description:Diabetes mellitus, heart failure (HF), and chronic kidney disease are common comorbidities, but overall use and safety of antihyperglycemic medications (AHMs) among patients with these comorbidities are poorly understood.Using Get With the Guidelines-Heart Failure and linked Medicare Part D data, we assessed AHM use within 90 days of hospital discharge among HF patients with diabetes mellitus discharged from Get With the Guidelines-Heart Failure hospitals between January 1, 2006, and October 1, 2011. We further summarized use by renal function and assessed renal contraindicated AHM use for patients with estimated glomerular filtration rate <30 mL/min/1.73m(2). Among 8791 patients meeting inclusion criteria, the median age was 77 (interquartile range 71-83), 62.3% were female, median body mass index was 29.7 (interquartile range 25.5-35.3), median hemoglobin A1c was 6.8 (interquartile range 6.2-7.8), and 34% had ejection fraction <40%. 74.9% of patients filled a prescription for an AHM, with insulin (39.5%), sulfonylureas (32.4%), and metformin (17%) being the most commonly used AHMs. Insulin use was higher and sulfonylurea/metformin use was lower among patients with lower renal function classes. Among 1512 patients with estimated glomerular filtration rate <30 mL/min/1.73m(2), 35.4% filled prescriptions for renal contraindicated AHMs per prescribing information, though there was a trend toward lower renal contraindicated AHM use over time (Cochran-Mantel-Haenszel row-mean score test P=0.048). Although use of other AHMs was low overall, thiazolidinediones were used in 6.6% of HF patients, and dipeptidyl peptidase-4 inhibitors were used in 5.1%, with trends for decreasing thiazolidinedione use and increased dipeptidyl peptidase-4 inhibitor use over time (P<0.001).Treatment of diabetes mellitus in patients with HF and chronic kidney disease is complex, and these patients are commonly treated with renal contraindicated AHMs, including over 6% receiving a thiazolidinedione, despite known concerns regarding HF. More research regarding safety and efficacy of various AHMs among HF patients is needed.
| S-EPMC4948953 | biostudies-literature
Project description:BackgroundDigitalis glycosides are known to improve the hemodynamic and neurohormonal perturbations that contribute to heart failure (HF)-induced renal dysfunction (RD). The objective of this study was to determine if randomization to digoxin is associated with improvement in renal function (IRF) and to evaluate if patients with digoxin-induced IRF have improved clinical outcomes.Methods and resultsPatients in the Digitalis Investigation Group (DIG) dataset with protocol-driven 1-year serum creatinine levels (performed in a central laboratory; n = 980) were studied. IRF was defined as a postrandomization ?20% increase in estimated glomerular filtration rate (eGFR). IRF occurred in 15.5% of the population (mean improvement in eGFR 34.5 ± 15.4%) and was more common in patients randomized to digoxin (adjusted odds ratio 1.6; P = .02). In patients without IRF, digoxin was not associated with reduced death or hospitalization (adjusted hazard ratio [HR] 0.96, 95% CI 0.8-1.2; P = .67). However, in the group with IRF, digoxin was associated with substantially improved hospitalization-free survival (adjusted HR 0.49, 95% CI 0.3-0.8; P = .006; P interaction = .026).ConclusionsIn this subset of the DIG trial, digoxin was associated with long-term improvement in kidney function and, in patients demonstrating this favorable renal response, reduction in death or hospitalization. Additional research is necessary to confirm these hypothesis-generating findings.
| S-EPMC3694335 | biostudies-literature
Project description:A chronic heart failure model was prepared using thoracic aortic narrowing surgery, and cardiac function, serum markers and renal pathologic changes were evaluated in comparison model mice at weeks 4, 8, 12, and 16 after surgery. Proteomic analysis was performed on mouse kidneys 16 weeks after operation
2024-01-04 | PXD048237 |
Project description:Plasma exposure of the endothelin receptor antagonist atrasentan varies between individuals and is associated with nephroprotective effects and the risk of heart failure. We examined the influence of genetic polymorphisms on atrasentan plasma exposure and pharmacodynamic effects. We performed a substudy of the Study of Diabetic Nephropathy With Atrasentan (SONAR) trial which enrolled adults with type 2 diabetes and chronic kidney disease (estimated glomerular filtration rate: 25-75 mL/min/1.73 m2 , and a urine albumin-to-creatinine ratio of 300-5,000 mg/g). Single nucleotide polymorphisms (SNPs) were determined for prespecified membrane transporters, metabolizing enzymes, and the endothelin-1 peptide. The associations among genotype, atrasentan plasma exposure, and the effect of atrasentan on the prespecified kidney and heart failure hospitalization (HHF) outcomes was assessed with Cox proportional hazards regression models. Of 3,668 patients randomized, 2,329 (63.5%) consented to genotype analysis. Two SNPs in the SLCO1B1 gene (rs4149056 and rs2306283), encoding the hepatic organic anion transporter 1B1 (OATP1B1), showed the strongest association with atrasentan plasma exposure. Based on their SLCO1B1 genotype, patients were classified into normal (atrasentan area under the plasma-concentration time curve from zero to infinity (AUC0-inf ) 41.3 ng·h/mL) or slow (atrasentan AUC0-inf 49.7 ng·h/mL, P < 0.001) OATP1B1 transporter phenotypes. Among patients with a normal OATP1B1 phenotype, the hazard ratio (HR) with atrasentan for the primary kidney and HHF outcomes were 0.61 (95% confidence interval (CI): 0.45-0.81) and 1.35 (95% CI: 0.84-2.13), respectively. In the slow transporter phenotype, HRs for kidney and HHF outcomes were 1.95 (95% CI: 0.95-4.03, P-interaction normal phenotype = 0.004), and 4.18 (95% CI: 1.37-12.7, P-interaction normal phenotype = 0.060), respectively. OATP1B1 gene polymorphisms are associated with significant between-patient variability in atrasentan plasma exposure and long-term efficacy and safety.
| S-EPMC9804438 | biostudies-literature
Project description:AimsSodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to reduce the risk of hospitalization for heart failure (HHF) and composite kidney outcomes, but the mediators underlying these benefits are unknown.Materials and methodsAmong participants from VERTIS CV, a trial of patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease randomized to ertugliflozin versus placebo, Cox proportional hazards regression models were used to evaluate the percentage mediation of ertugliflozin efficacy on the first HHF and kidney composite outcome in 26 potential mediators. Time-dependent approaches were used to evaluate associations between early (change from baseline to the first post-baseline measurement) and average (weighted average of change from baseline using all post-baseline measurements) changes in covariates with clinical outcomes.ResultsFor the HHF analyses, early changes in four biomarkers (haemoglobin, haematocrit, serum albumin and urate) and average changes in seven biomarkers (early biomarkers + weight, chloride and serum protein) were identified as fulfilling the criteria as mediators of ertugliflozin effects on the risk of HHF. Similar results were observed for the composite kidney outcome, with early changes in four biomarkers (glycated haemoglobin, haemoglobin, haematocrit and urate), and average changes in five biomarkers [early biomarkers (not glycated haemoglobin) + weight, serum albumin] mediating the effects of ertugliflozin on the kidney outcome.ConclusionsIn these analyses from the VERTIS CV trial, markers of volume status and haemoconcentration and/or haematopoiesis were the strongest mediators of the effect of ertugliflozin on reducing risk of HHF and composite kidney outcomes in the early and average change periods.ClinicaltrialsGov identifierNCT01986881.
| S-EPMC9357198 | biostudies-literature
Project description:AimsAlthough diabetes mellitus (DM) is a common co-morbidity in chronic heart failure (HF) patients, European data on concurrent HF and DM treatment are lacking. Therefore, we have studied the HF treatment of patients with and without DM. Additionally, with the recent breakthrough of sodium-glucose cotransporter 2 (SGLT2) inhibitors in the field of HF, we studied the potential impact of this new drug in a large cohort of HF patients.Methods and resultsA total of 7488 patients with chronic HF with a left ventricular ejection fraction <50% from 34 Dutch outpatient HF clinics between 2013 and 2016 were analysed on diabetic status and background HF therapy. Average age of the total population was 72.8 years (±11.7 years), and 64% of the patients were male. Diabetes was present in 29% of the patients (N = 2174). Diabetics had a worse renal function (mean estimated glomerular filtration rate 56 vs. 61 mL/min/1.73 m2 , P < 0.001). Renin-angiotensin system inhibitors were less often prescribed in diabetics compared with non-diabetics (79% vs. 82%, P = 0.001), while no significant differences regarding other guideline-recommended HF drugs were found. Target doses of beta-blockers (23% vs. 16%, P < 0.001), renin-angiotensin system inhibitors (47% vs. 43%, P = 0.009), and mineralocorticoid receptor antagonists (57% vs. 51%, P = 0.005) were more often prescribed in diabetics than non-diabetics. Based on the latest trials on SGLT2 inhibitors, 31-64% of all HF patients would fulfil the eligibility or enrichment criteria (with vs. without N-terminal prohormone BNP criterion).ConclusionsIn this large real-world HF registry, a high prevalence of DM was observed and diabetics more often received guideline-recommended target doses. Based on current evidence, the majority of patients would fulfil the enrichment criteria of SGLT2 trials in HF and the impact of this new drug class will be large.
| S-EPMC8788034 | biostudies-literature