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Annals of Medicine Dec 2023Persons with diabetes and chronic kidney disease (CKD) have a high residual risk of developing cardiovascular (CV) complications despite treatment with renin-angiotensin... (Review)
Review
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: Humans; Diabetes Mellitus, Type 2; Mineralocorticoid Receptor Antagonists; Receptors, Mineralocorticoid; Albuminuria; Diabetic Nephropathies; Renal Insufficiency, Chronic; Cardiovascular Diseases; Kidney; Fibrosis; Inflammation; Glucose; Sodium
PubMed: 36719097
DOI: 10.1080/07853890.2023.2171110 -
Nephrology, Dialysis, Transplantation :... Nov 2023Hypertension is very common and remains often poorly controlled in patients with chronic kidney disease (CKD). Accurate blood pressure (BP) measurement is the essential... (Review)
Review
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, the associated risk of hyperkalemia restricts the broad utilization of spironolactone in patients with moderate-to-advanced CKD. Evidence from the CLICK (Chlorthalidone in Chronic Kidney Disease) trial indicates that the thiazide-like diuretic chlorthalidone is effective and serves as an alternative therapeutic opportunity for patients with stage 4 CKD and uncontrolled hypertension, including those with treatment-resistant hypertension. Chlorthalidone can also mitigate the risk of hyperkalemia to enable the concomitant use of spironolactone, but this combination requires careful monitoring of BP and kidney function for the prevention of adverse events. Emerging agents, such as the non-steroidal mineralocorticoid receptor antagonist ocedurenone, dual endothelin receptor antagonist aprocitentan and the aldosterone synthase inhibitor baxdrostat offer novel targets and strategies to control BP better. Larger and longer term clinical trials are needed to demonstrate the safety and efficacy of these novel therapies in the future. In this article, we review the current standards of treatment and discuss novel developments in pathophysiology, diagnosis, outcome prediction and management of hypertension in patients with CKD.
Topics: Humans; Spironolactone; Hyperkalemia; Chlorthalidone; Hypertension; Antihypertensive Agents; Mineralocorticoid Receptor Antagonists; Renal Insufficiency, Chronic; Blood Pressure
PubMed: 37355779
DOI: 10.1093/ndt/gfad118 -
JACC. Heart Failure Aug 2023The majority of patients with heart failure with preserved ejection fraction (HFpEF) have the obesity phenotype, but no therapies specifically targeting obesity in HFpEF... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The majority of patients with heart failure with preserved ejection fraction (HFpEF) have the obesity phenotype, but no therapies specifically targeting obesity in HFpEF exist.
OBJECTIVES
The aim of this study was to describe the design and baseline characteristics of 2 trials of semaglutide, a glucagon-like peptide-1 receptor agonist, in patients with the obesity HFpEF phenotype: STEP-HFpEF (Semaglutide Treatment Effect in People with obesity and HFpEF; NCT04788511) and STEP-HFpEF DM (Semaglutide Treatment Effect in People with obesity and HFpEF and type 2 diabetes; NCT04916470).
METHODS
Both STEP-HFpEF and STEP-HFpEF DM are international multicenter, double-blind, placebo-controlled trials that randomized adults with HFpEF and a body mass index ≥30 kg/m to once-weekly semaglutide at a dose of 2.4 mg or placebo. Participants were eligible if they had a left ventricular ejection fraction (LVEF) ≥45%; NYHA functional class II to IV; a Kansas City Cardiomyopathy Questionnaire (KCCQ)-Clinical Summary Score (CSS) <90 points; and ≥1 of the following: elevated filling pressures, elevated natriuretic peptides plus structural echocardiographic abnormalities, recent heart failure hospitalization plus ongoing diuretic use, and/or structural abnormalities. The dual primary endpoints are the 52-week change in the KCCQ-CSS and body weight.
RESULTS
In STEP-HFpEF and STEP-HFpEF DM (N = 529 and N = 617, respectively), nearly half were women, and most had severe obesity (median body mass index of 37 kg/m) with typical features of HFpEF (median LVEF of 57%, frequent comorbidities, and elevated natriuretic peptides). Most participants received diuretic agents and renin-angiotensin blockers at baseline, and approximately one-third were on mineralocorticoid receptor antagonists. Sodium-glucose cotransporter-2 inhibitor use was rare in STEP-HFpEF but not in STEP HFpEF DM (32%). Patients in both trials had marked symptomatic and functional impairments (KCCQ-CSS ∼59 points, 6-minute walking distance ∼300 m).
CONCLUSIONS
In total, STEP-HFpEF program randomized 1,146 participants with the obesity phenotype of HFpEF and will determine whether semaglutide improves symptoms, physical limitations, and exercise function in addition to weight loss in this vulnerable group.
Topics: Humans; Female; Male; Heart Failure; Stroke Volume; Ventricular Function, Left; Diabetes Mellitus, Type 2; Sodium-Glucose Transporter 2 Inhibitors; Obesity; Diuretics; Phenotype; Double-Blind Method
PubMed: 37294245
DOI: 10.1016/j.jchf.2023.05.010 -
Cells Jul 2023Diabetes is the most frequent cause of kidney disease that progresses to end-stage renal disease worldwide, and diabetic kidney disease is significantly related to... (Review)
Review
Diabetes is the most frequent cause of kidney disease that progresses to end-stage renal disease worldwide, and diabetic kidney disease is significantly related to unfavorable cardiovascular outcomes. Since the 1990s, specific therapies have emerged and been approved to slow the progression of diabetic kidney disease, namely, renin-angiotensin-aldosterone system blockers (including angiotensin-converting enzyme inhibitors (ACEi) angiotensin receptor blockers (ARBs), the non-steroidal mineralocorticoid receptor antagonist (NS-MRA), finerenone, and sodium-glucose cotransporter-2 (SGLT2) inhibitors). Mechanistically, these different classes of agents bring different anti-inflammatory, anti-fibrotic, and complementary hemodynamic effects to patients with diabetic kidney disease such that they have additive benefits on slowing disease progression. Within the coming year, there will be data on renal outcomes using the glucagon-like peptide-1 receptor agonist, semaglutide. All the aforementioned medications have also been shown to improve cardiovascular outcomes. Thus, all three classes (maximally dosed ACEi or ARB, low-dose SGLT-2 inhibitors, and the NS-MRA, finerenone) form the "pillars of therapy" such that, when used together, they maximally slow diabetic kidney disease progression. Ongoing studies aim to expand these pillars with additional medications to potentially normalize the decline in kidney function and reduce associated cardiovascular mortality.
Topics: Humans; Diabetic Nephropathies; Angiotensin-Converting Enzyme Inhibitors; Angiotensin Receptor Antagonists; Renin-Angiotensin System; Kidney Failure, Chronic; Mineralocorticoid Receptor Antagonists; Diabetes Mellitus
PubMed: 37566054
DOI: 10.3390/cells12151975 -
Frontiers in Endocrinology 2023Diabetic kidney disease (DKD) is a chronic complication of diabetes and the leading cause of end-stage renal disease (ESRD) worldwide. Currently, there are limited... (Review)
Review
Diabetic kidney disease (DKD) is a chronic complication of diabetes and the leading cause of end-stage renal disease (ESRD) worldwide. Currently, there are limited therapeutic drugs available for DKD. While previous research has primarily focused on glomerular injury, recent studies have increasingly emphasized the role of renal tubular injury in the pathogenesis of DKD. Various factors, including hyperglycemia, lipid accumulation, oxidative stress, hypoxia, RAAS, ER stress, inflammation, EMT and programmed cell death, have been shown to induce renal tubular injury and contribute to the progression of DKD. Additionally, traditional hypoglycemic drugs, anti-inflammation therapies, anti-senescence therapies, mineralocorticoid receptor antagonists, and stem cell therapies have demonstrated their potential to alleviate renal tubular injury in DKD. This review will provide insights into the latest research on the mechanisms and treatments of renal tubular injury in DKD.
Topics: Humans; Diabetic Nephropathies; Kidney Failure, Chronic; Apoptosis; Hyperglycemia; Hypoglycemic Agents; Diabetes Mellitus
PubMed: 37600689
DOI: 10.3389/fendo.2023.1238927 -
JAMA Sep 2023Excess aldosterone production contributes to hypertension in both classical hyperaldosteronism and obesity-associated hypertension. Therapies that reduce aldosterone...
IMPORTANCE
Excess aldosterone production contributes to hypertension in both classical hyperaldosteronism and obesity-associated hypertension. Therapies that reduce aldosterone synthesis may lower blood pressure.
OBJECTIVE
To compare the safety and efficacy of lorundrostat, an aldosterone synthase inhibitor, with placebo, and characterize dose-dependent safety and efficacy to inform dose selection in future trials.
DESIGN, SETTING, AND PARTICIPANTS
Randomized, placebo-controlled, dose-ranging trial among adults with uncontrolled hypertension taking 2 or more antihypertensive medications. An initial cohort of 163 participants with suppressed plasma renin (plasma renin activity [PRA] ≤1.0 ng/mL/h) and elevated plasma aldosterone (≥1.0 ng/dL) were enrolled, with subsequent enrollment of 37 participants with PRA greater than 1.0 ng/mL/h.
INTERVENTIONS
Participants were randomized to placebo or 1 of 5 dosages of lorundrostat in the initial cohort (12.5 mg, 50 mg, or 100 mg once daily or 12.5 mg or 25 mg twice daily). In the second cohort, participants were randomized in a 1:6 ratio to placebo or lorundrostat, 100 mg once daily.
MAIN OUTCOMES AND MEASURES
The primary end point was change in automated office systolic blood pressure from baseline to study week 8.
RESULTS
Between July 2021 and June 2022, 200 participants were randomized, with final follow-up in September 2022. Following 8 weeks of treatment in participants with suppressed PRA, changes in office systolic blood pressure of -14.1, -13.2, -6.9, and -4.1 mm Hg were observed with 100 mg, 50 mg, and 12.5 mg once daily of lorundrostat and placebo, respectively. Observed reductions in systolic blood pressure in individuals receiving twice-daily doses of 25 mg and 12.5 mg of lorundrostat were -10.1 and -13.8 mm Hg, respectively. The least-squares mean difference between placebo and treatment in systolic blood pressure was -9.6 mm Hg (90% CI, -15.8 to -3.4 mm Hg; P = .01) for the 50-mg once-daily dose and -7.8 mm Hg (90% CI, -14.1 to -1.5 mm Hg; P = .04) for 100 mg daily. Among participants without suppressed PRA, 100 mg once daily of lorundrostat decreased systolic blood pressure by 11.4 mm Hg (SD, 2.5 mm Hg), which was similar to blood pressure reduction among participants with suppressed PRA receiving the same dose. Six participants had increases in serum potassium above 6.0 mmol/L that corrected with dose reduction or drug discontinuation. No instances of cortisol insufficiency occurred.
CONCLUSIONS AND RELEVANCE
Among individuals with uncontrolled hypertension, use of lorundrostat was effective at lowering blood pressure compared with placebo, which will require further confirmatory studies.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT05001945.
Topics: Adult; Humans; Aldosterone; Cytochrome P-450 CYP11B2; Renin; Hypertension; Blood Pressure; Hypotension; Hyperaldosteronism; Mineralocorticoid Receptor Antagonists
PubMed: 37690061
DOI: 10.1001/jama.2023.16029 -
ESC Heart Failure May 2024In the last years, major progress has occurred in heart failure (HF) management. The 2023 ESC focused update of the 2021 HF guidelines introduced new key recommendations... (Review)
Review
In the last years, major progress has occurred in heart failure (HF) management. The 2023 ESC focused update of the 2021 HF guidelines introduced new key recommendations based on the results of the last years of science. First, two drugs, sodium-glucose co-transporter-2 (SGLT2) inhibitors and finerenone, a novel nonsteroidal, selective mineralocorticoid receptor antagonist (MRA), are recommended for the prevention of HF in patients with diabetic chronic kidney disease (CKD). Second, SGLT2 inhibitors are now recommended for the treatment of HF across the entire left ventricular ejection fraction spectrum. The benefits of quadruple therapy in patients with HF with reduced ejection fraction (HFrEF) are well established. Its rapid and early up-titration along with a close follow-up with frequent clinical and laboratory re-assessment after an episode of acute HF (the so-called 'high-intensity care' strategy) was associated with better outcomes in the STRONG-HF trial. Patients experiencing an episode of worsening HF might require a fifth drug, vericiguat. In the STEP-HFpEF-DM and STEP-HFpEF trials, semaglutide 2.4 mg once weekly administered for 1 year decreased body weight and significantly improved quality of life and the 6 min walk distance in obese patients with HF with preserved ejection fraction (HFpEF) with or without a history of diabetes. Further data on safety and efficacy, including also hard endpoints, are needed to support the addition of acetazolamide or hydrochlorothiazide to a standard diuretic regimen in patients hospitalized due to acute HF. In the meantime, PUSH-AHF supported the use of natriuresis-guided diuretic therapy. Further options and most recent evidence for the treatment of HF, including specific drugs for cardiomyopathies (i.e., mavacamten in hypertrophic cardiomyopathy and tafamidis in transthyretin cardiac amyloidosis), device therapies, cardiac contractility modulation and percutaneous treatment of valvulopathies, with the recent finding from the TRILUMINATE Pivotal trial, are also reviewed in this article.
PubMed: 38806171
DOI: 10.1002/ehf2.14857 -
Cardiovascular Diabetology Jun 2023Finerenone is a novel non-steroidal mineralocorticoid receptor (MR) antagonist (MRA) with high binding affinity, high MR selectivity and a short plasma half-life. In two... (Review)
Review
Finerenone is a novel non-steroidal mineralocorticoid receptor (MR) antagonist (MRA) with high binding affinity, high MR selectivity and a short plasma half-life. In two major endpoint-driven clinical trials in patients with chronic kidney disease and type 2 diabetes mellitus (FIDELIO-DKD and FIGARO-DKD), finerenone induced significant cardiorenal protective actions, and has been recently approved for treatment of these patients. Heart failure with preserved ejection fraction (HFpEF) is a devastating clinical syndrome with increasing prevalence and poor prognosis. Pharmacological therapy of HFpEF is very limited and new therapeutic options are urgently needed. Finerenone has been shown to improve multiple pathophysiological parameters of HFpEF in preclinical models. In consonance, pre-specified subgroup analyses of FIDELIO-DKD and FIGARO-DKD suggested a potential beneficial effect of finerenone in HFpEF. This review will discuss the pharmacodynamic and -kinetic profile of finerenone. We will provide a general overview over the complex pathophysiology of HFpEF and data from pre-clinical studies, focusing on how finerenone improves multiple components of this pathophysiology. Finally, we will discuss current and future clinical trials with finerenone in heart failure patients focusing on HFpEF.
Topics: Humans; Heart Failure; Mineralocorticoid Receptor Antagonists; Diabetes Mellitus, Type 2; Stroke Volume
PubMed: 37386461
DOI: 10.1186/s12933-023-01899-0