Rajiv Agarwal

BACKGROUND Sodium glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and the nonsteroidal mineralocorticoid receptor antagonist (ns-MRA) finerenone all individually reduce cardiovascular, kidney, and mortality outcomes in patients with type 2 diabetes and albuminuria. However, the lifetime benefits of combination therapy with these medicines are not known. METHODS We used data from 2 SGLT2i trials (CANVAS [Canagliflozin Cardiovascular Assessment] and CREDENCE [Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation]), 2 ns-MRA trials (FIDELIO-DKD [Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease] and FIGARO-DKD [Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Diabetic Kidney Disease]), and 8 GLP …

Mineralocorticoids, such as aldosterone, and their receptors have an important role in producing cardiorenal damage. One way to abrogate cardiorenal damage is to block aldosterone, such as by blocking its synthesis. The development of aldosterone synthase inhibitors has been challenging because of the homology between aldosterone synthase (CYP11B2) and 11β-hydroxylase (CYP11A1), the rate-limiting step of cortisol synthesis. 1 To surmount this challenge, at least three aldosterone synthase inhibitors are in clinical development: baxdrostat, 2 lorundrostat, 3 and now BI 690517. In The Lancet, Katherine R Tuttle and colleagues4 report their multinational phase 2 trial of BI 690517 in people with chronic kidney disease on the maximally tolerated dose of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Initially, 586 patients, of whom 196 (33%) were women, 390 (67%) were men …

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Apparent-treatment resistant hypertension (aTRH) is defined as an elevated blood pressure (BP), despite the use of≥ 3 antihypertensive medications from different classes or the use of≥ 4 antihypertensives regardless of BP levels. Among patients receiving maintenance hemodialysis or peritoneal dialysis, using this definition, the prevalence of aTRH is estimated to be between 18% and 42%. Due to the lack of a rigorous assessment of some common causes of pseudoresistance, the burden of true-resistant hypertension in the dialysis population remains unknown. What distinguishes apparent-treatment resistance from true resistance is white-coat hypertension and adherence to medications. Accordingly, the diagnostic work-up of a dialysis patient with aTRH includes the accurate determination of BP control status with the use of home or ambulatory BP monitoring and exclusion of non-adherence to the prescribed …

The ubiquitous presence and excessive consumption of sodium in modern societies have long been recognized as major contributors to the development of endothelial dysfunction, hypertension, cardiovascular disease, chronic kidney disease, and stroke. 1 Internal derangement in the kidney’s handling of sodium and potassium balance and its interplay with the external environment greatly influence the risk of essential hypertension and its cardiovascular sequelae. 2 Because of the interdependency of sodium and potassium in regulating blood pressure, a deficit in potassium can be just as detrimental as a surplus in sodium. 3 In a meta-analysis of 33 randomized clinical trials, Whelton et al4 reported that potassium supplementation lowered systolic blood pressure by 4.4 mm Hg and diastolic blood pressure by 2.5 mm Hg and effects were greater in the trials where participants had high sodium intake. Dietary …

IntroductionThe Therapeutic Effects of Steroids in IgA Nephropathy Global (TESTING) study reported that methylprednisolone reduces the risk of major kidney events in individuals with IgA nephropathy at high risk of disease progression compared to supportive care alone but is associated with increased serious adverse events (SAEs) primarily with full-dose therapy. The risk-benefit balance of the reduced-dose methylprednisolone regimen is examined in this pre-specified analysis of the reduced-dose cohort of the TESTING trial.MethodsBetween 2017-2019, patients with IgA nephropathy, proteinuria ≥1g/day despite 3 months of renin-angiotensin-system blockade and estimated glomerular filtration rate (eGFR) 30-120mL/min/1.73m2 were randomised to reduced-dose methylprednisolone 0.4mg/kg/day or placebo. The primary outcome was a composite of a 40% eGFR decline, kidney failure or death due to …

It is estimated that type 2 diabetes mellitus (T2DM) affects 1 in 10 of the US population or approximately33 million individuals. 1, 2 Between 20% and 40% of patients with T2DM develop chronic kidney disease (CKD) and other microvascular complications. 3 Slowing the progression of CKD associated with type 2 diabetes (CKDiT2D) is multipronged and includes both lifestyle modifications and pharmacologic interventions. Lifestyle modifications include diet, exercise, weight loss and maintenance, and cessation of smoking. Pharmacologic approaches target metabolic, hemodynamic, and proinflammatory pathways. The issue cover shows a fouragent multipronged approach that could represent the future of how to slow kidney progression in CKDiT2D, and is the central focus of this issue of Seminars in Nephrology.In our first article, Frederic Luft provides a lucid 60-year history of confronting CKDiT2D. His story …

Erratum. Finerenone in Patients With Chronic Kidney Disease and Type 2 Diabetes According to Baseline HbA1c and Insulin Use: An Analysis From the FIDELIO-DKD Study. Diabetes Care 2022;45:888–897 - PMC Back to Top Skip to main content NIH NLM Logo Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation Search PMC Full-Text Archive Search in PMC Advanced Search User Guide Journal List Diabetes Care v.46(9); 2023 Sep PMC10465986 Other Formats PDF (441K) Actions Cite Collections Share Permalink Copy RESOURCES Similar articles Cited by other articles Links to NCBI Databases Journal List Diabetes Care v.46(9); 2023 Sep PMC10465986 As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | …

Rationale & ObjectiveIt is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kidney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study.Study DesignSecondary analysis of a randomized controlled trial.Setting & ParticipantsParticipants in the CREDENCE trial.InterventionParticipants were randomly assigned to receive canagliflozin 100 mg/d or placebo.OutcomesPrimary composite outcome of kidney failure, doubling of serum creatinine concentration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Outcomes were evaluated by age at baseline (<60, 60-69, and ≥70 years) and sex in the intention …

Rationale & ObjectiveIn FIDELITY, finerenone improved cardiorenal outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). This analysis explored the efficacy and safety of finerenone in Black patients.Study DesignSubanalysis of randomized controlled trials.Setting & ParticipantsPatients with T2D and CKD.InterventionFinerenone or placebo.OutcomesComposite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure; composite of kidney failure, sustained ≥57% estimated glomerular filtration rate (eGFR) decline from baseline maintained for ≥4 weeks, or renal death.ResultsOf the 13,026 patients, 522 (4.0%) self-identified as Black. Finerenone demonstrated similar effects on the cardiovascular composite outcome in Black (HR, 0.79 [95% CI, 0.51-1.24]) and non-Black patients (HR, 0.87 [95% CI, 0.79-0.96; P = 0.5 for interaction …

Introduction: Anemia frequently occurs in chronic kidney disease (CKD), is associated with poor quality of life and cardiovascular outcomes, and its treatment represents a considerable economic burden to the healthcare system. Although effective, the current standard of care for the treatment of anemia in chronic kidney disease patients with erythropoiesis-stimulating agents requires chronic/ongoing injections, making the treatment less accessible or desirable to patients not treated by in-center maintenance hemodialysis. Furthermore, safety concerns, including an increased risk of cardiovascular events and mortality, have emerged from their use in studies targeting hemoglobin concentrations in the normal or near-normal range. The orally active hypoxia-inducible factor prolyl hydroxylase inhibitor vadadustat may offer advantages over erythropoiesis-stimulating agents by correcting anemia …

AimsEffects of glycated hemoglobin (HbA1c), HbA1c variability, diabetes duration and insulin use on cardiorenal outcomes and diabetes progression in chronic kidney disease (CKD) and type 2 diabetes (T2D) are poorly understood. This post-hoc analysis of the prespecified, pooled FIDELITY dataset investigated the efficacy and safety of finerenone by these factors.Materials and methodsComposite 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).ResultsIn 13,026 participants, risk reductions in the cardiovascular and kidney composite outcomes with finerenone vs placebo were consistent across HbA1c quartiles (P-interaction 0.52 and 0.09, respectively), HbA1c variability (P-interaction 0.48 and 0.10), diabetes duration (P-interaction 0.12 and 0.75) and insulin use (P-interaction 0.16 and 0.52). HbA1c variability in the first year of treatment was associated with higher risk of cardiovascular and kidney events (hazard ratio [HR] 1.20; 95% confidence interval [CI] 1.07-1.35; P= 0.0016 and HR 1.36; 95% CI 1.21-1.52; P< 0.0001, 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 due to hyperkalemia were low.Conclusions …

Objective: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.Methods: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 m 2 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.Results:

Aims 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). Methods and results 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 …

Background Patients with stage 4 CKD and type 2 diabetes have limited treatment options to reduce their persistent cardiovascular and kidney risk. In Finerenone in Chronic Kidney Disease and Type 2 Diabetes (FIDELITY), a prespecified pooled analysis of Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) and Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD), finerenone improved heart-kidney outcomes in participants with CKD and type 2 diabetes.Methods This FIDELITY subgroup analysis investigated the effects of finerenone in participants with stage 4 CKD (eGFR, 30 ml/min per 1.73 m2). Efficacy outcomes included a cardiovascular composite (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and a kidney composite (kidney failure …

ImportanceIt is currently unclear whether chronic kidney disease (CKD)–associated cardiovascular risk in type 2 diabetes (T2D) is modifiable.ObjectiveTo examine whether cardiovascular risk can be modified with finerenone in patients with T2D and CKD.Design, Setting, and ParticipantsIncidence 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 …

IntroductionRelationships between glycemic-lowering effects of sodium glucose co-transporter 2 inhibitors and impact on kidney and cardiovascular outcomes are uncertain.Research design and methodsWe analyzed 4395 individuals with prebaseline and postbaseline hemoglobin A1c (HbA1c) randomized to canagliflozin (n=2193) or placebo (n=2202) in The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial. Effects on HbA1c were assessed using mixed models. Mediation of treatment effects by achieved glycemic control was analyzed using proportional hazards regression with and without adjustment for achieved HbA1c. End points included combined kidney or cardiovascular death, end-stage kidney disease or doubling of serum creatinine (primary trial outcome), and individual end point components.ResultsHbA1c lowering was modified by baseline estimated …

Hypertension is very common and remains often poorly controlled in patients with chronic kidney disease (CKD). Accurate blood pressure (BP) measurement is the essential first step in the diagnosis and management of hypertension. Dietary sodium restriction is often overlooked, but can improve BP control, especially among patients treated with an agent to block the renin–angiotensin system. In the presence of very high albuminuria, international guidelines consistently and strongly recommend the use of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker as the antihypertensive agent of first choice. Long-acting dihydropyridine calcium channel blockers and diuretics are reasonable second- and third-line therapeutic options. For patients with treatment-resistant hypertension, guidelines recommend the addition of spironolactone to the baseline antihypertensive regimen. However …

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 …

Treatment-resistant hypertension is common among patients with advanced chronic kidney disease (CKD). In people with preserved kidney function, spironolactone is an evidence-based treatment. However, the risk for hyperkalemia limits its use in people with more advanced CKD. In the Chlorthalidone in Chronic Kidney Disease (CLICK) trial, 160 patients with stage 4 CKD and poorly controlled hypertension as confirmed by 24-hour ambulatory blood pressure (ABP) monitoring were randomly assigned to either placebo or chlorthalidone 12.5 mg daily in a 1:1 ratio stratified by prior loop diuretic use. The primary endpoint was the change in 24-hour systolic ABP from baseline to 12 weeks. The trial showed a treatment-induced reduction of 24-hour systolic ABP by 10.5 mmHg. Of the 160 patients randomized, 113 (71%) had resistant hypertension, of which 90 (80%) were on loop diuretics and the mean number …