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BACKGROUND AND AIMS: Mineralocorticoid receptor antagonists (MRAs) improve cardiovascular outcomes in a variety of settings. This study aimed to assess whether cardioprotective effects of MRAs are modified by heart failure (HF) and atrial fibrillation (AF) status and to study their impact on AF events. METHODS: MEDLINE, Embase, and Cochrane Central databases were searched to 24 March 2023 for randomized controlled trials evaluating the efficacy of MRAs as compared with placebo or usual care in reducing cardiovascular outcomes and AF events in patients with or at risk for cardiovascular diseases. Random-effects models and interaction analyses were used to test for effect modification. RESULTS: Meta-analysis of seven trials (20 741 participants, mean age: 65.6 years, 32% women) showed that the efficacy of MRAs, as compared with placebo, in reducing a composite of cardiovascular death or HF hospitalization remains consistent across patients with HF [risk ratio = 0.81; 95% confidence interval (CI): 0.67-0.98] and without HF (risk ratio = 0.84; 95% CI: 0.75-0.93; interaction P = .77). Among patients with HF, MRAs reduced cardiovascular death or HF hospitalization in patients with AF (hazard ratio = 0.95; 95% CI: 0.54-1.66) to a similar extent as in those without AF (hazard ratio = 0.82; 95% CI: 0.63-1.07; interaction P = .65). Pooled data from 20 trials (21 791 participants, mean age: 65.2 years, 31.3% women) showed that MRAs reduce AF events (risk ratio = 0.76; 95% CI: 0.67-0.87) in both patients with and without prior AF. CONCLUSIONS: Mineralocorticoid receptor antagonists are similarly effective in preventing cardiovascular events in patients with and without HF and most likely retain their efficacy regardless of AF status. Mineralocorticoid receptor antagonists may also be moderately effective in preventing incident or recurrent AF events.
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Fibrilação Atrial , Insuficiência Cardíaca , Idoso , Feminino , Humanos , Masculino , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Ensaios Clínicos como AssuntoRESUMO
The overactivation of the mineralocorticoid receptor (MR) promotes pathophysiological processes related to multiple physiological systems, including the heart, vasculature, adipose tissue and kidneys. The inhibition of the MR with classical MR antagonists (MRA) has successfully improved outcomes most evidently in heart failure. However, real and perceived risk of side effects and limited tolerability associated with classical MRA have represented barriers to implementing MRA in settings where they have been already proven efficacious (heart failure with reduced ejection fraction) and studying their potential role in settings where they might be beneficial but where risk of safety events is perceived to be higher (renal disease). Novel non-steroidal MRA have distinct properties that might translate into favourable clinical effects and better safety profiles as compared with MRA currently used in clinical practice. Randomised trials have shown benefits of non-steroidal MRA in a range of clinical contexts, including diabetic kidney disease, hypertension and heart failure. This review provides an overview of the literature on the systemic impact of MR overactivation across organ systems. Moreover, we summarise the evidence from preclinical studies and clinical trials that have set the stage for a potential new paradigm of MR antagonism.
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Nefropatias Diabéticas , Insuficiência Cardíaca , Humanos , Nefropatias Diabéticas/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Mineralocorticoides/uso terapêutico , Naftiridinas/farmacologia , Naftiridinas/uso terapêutico , Receptores de Mineralocorticoides/uso terapêuticoRESUMO
The 9th Cardiovascular Outcome Trial (CVOT) Summit: Congress on Cardiovascular, Kidney, and Metabolic Outcomes was held virtually on November 30-December 1, 2023. This reference congress served as a platform for in-depth discussions and exchange on recently completed outcomes trials including dapagliflozin (DAPA-MI), semaglutide (SELECT and STEP-HFpEF) and bempedoic acid (CLEAR Outcomes), and the advances they represent in reducing the risk of major adverse cardiovascular events (MACE), improving metabolic outcomes, and treating obesity-related heart failure with preserved ejection fraction (HFpEF). A broad audience of endocrinologists, diabetologists, cardiologists, nephrologists and primary care physicians participated in online discussions on guideline updates for the management of cardiovascular disease (CVD) in diabetes, heart failure (HF) and chronic kidney disease (CKD); advances in the management of type 1 diabetes (T1D) and its comorbidities; advances in the management of CKD with SGLT2 inhibitors and non-steroidal mineralocorticoid receptor antagonists (nsMRAs); and advances in the treatment of obesity with GLP-1 and dual GIP/GLP-1 receptor agonists. The association of diabetes and obesity with nonalcoholic steatohepatitis (NASH; metabolic dysfunction-associated steatohepatitis, MASH) and cancer and possible treatments for these complications were also explored. It is generally assumed that treatment of chronic diseases is equally effective for all patients. However, as discussed at the Summit, this assumption may not be true. Therefore, it is important to enroll patients from diverse racial and ethnic groups in clinical trials and to analyze patient-reported outcomes to assess treatment efficacy, and to develop innovative approaches to tailor medications to those who benefit most with minimal side effects. Other keys to a successful management of diabetes and comorbidities, including dementia, entail the use of continuous glucose monitoring (CGM) technology and the implementation of appropriate patient-physician communication strategies. The 10th Cardiovascular Outcome Trial Summit will be held virtually on December 5-6, 2024 ( http://www.cvot.org ).
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Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Diabetes Mellitus , Insuficiência Cardíaca , Insuficiência Renal Crônica , Humanos , Insuficiência Cardíaca/complicações , Automonitorização da Glicemia , Volume Sistólico , Glicemia , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Obesidade/complicações , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/terapia , Diabetes Mellitus/tratamento farmacológico , Rim , Diabetes Mellitus Tipo 2/tratamento farmacológicoRESUMO
BACKGROUND AND HYPOTHESIS: Finerenone, a non-steroidal mineralocorticoid receptor antagonist, improved kidney, and cardiovascular outcomes in patients with CKD and T2D in two Phase 3 outcome trials. The FIND-CKD study investigates the effect of finerenone in adults with CKD without diabetes. METHODS: FIND-CKD (NCT05047263 and EU CT 2023-506897-11-00) is a randomized, double-blind, placebo-controlled Phase 3 trial in patients with CKD of non-diabetic aetiology. Adults with a urinary albumin-creatinine ratio (UACR) of ≥ 200 to ≤3500 mg/g and eGFR ≥ 25 to <90 mL/min/1.73 m2 receiving a maximum tolerated dose of a renin-angiotensin-system (RAS) inhibitor were randomized 1:1 to once daily placebo or finerenone 10 or 20 mg depending on eGFR above or below 60 mL/min/1.73 m2. The primary efficacy outcome is total eGFR slope, defined as the mean annual rate of change in eGFR from baseline to Month 32. Secondary efficacy outcomes include a combined cardiorenal composite outcome comprising time to kidney failure, sustained ≥57% decrease in eGFR, hospitalization for heart failure, or cardiovascular death, as well as separate kidney and cardiovascular composite outcomes. Adverse events are recorded to assess tolerability and safety. RESULTS: Across 24 countries, 3231 patients were screened and 1584 were randomized to study treatment. The most common causes of CKD were chronic glomerulonephritis (57.0%) and hypertensive/ischaemic nephropathy (29.0%). Immunoglobulin A nephropathy was the most common glomerulonephritis (26.3% of the total population). At baseline, mean eGFR and median UACR were 46.7 mL/min/1.73 m2 and 818.9 mg/g, respectively. Diuretics were used by 282 participants (17.8%), statins by 851 (53.7%), and calcium channel blockers by 794 (50.1%). SGLT2 inhibitors were used in 16.9% of patients; these individuals had a similar mean eGFR (45.6 vs 46.8 mL/min/1.73 m2) and slightly higher median UACR (871.9 vs 808.3 mg/g) compared to those not using SGLT2 inhibitors at baseline. CONCLUSIONS: FIND-CKD is the first Phase 3 trial of finerenone in patients with CKD of non-diabetic aetiology.
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AIMS: To perform dose-exposure-response analyses to determine the effects of finerenone doses. MATERIALS AND METHODS: Two randomized, double-blind, placebo-controlled phase 3 trials enrolling 13 026 randomized participants with type 2 diabetes (T2D) from global sites, each with an estimated glomerular filtration rate (eGFR) of 25 to 90 mL/min/1.73 m2 , a urine albumin-creatinine ratio (UACR) of 30 to 5000 mg/g, and serum potassium ≤ 4.8 mmol/L were included. Interventions were titrated doses of finerenone 10 or 20 mg versus placebo on top of standard of care. The outcomes were trajectories of plasma finerenone and serum potassium concentrations, UACR, eGFR and kidney composite outcomes, assessed using nonlinear mixed-effects population pharmacokinetic (PK)/pharmacodynamic (PD) and parametric time-to-event models. RESULTS: For potassium, lower serum levels and lower rates of hyperkalaemia were associated with higher doses of finerenone 20 mg compared to 10 mg (p < 0.001). The PK/PD model analysis linked this observed inverse association to potassium-guided dose titration. Simulations of a hypothetical trial with constant finerenone doses revealed a shallow but increasing exposure-potassium response relationship. Similarly, increasing finerenone exposures led to less than dose-proportional increasing reductions in modelled UACR. Modelled UACR explained 95% of finerenone's treatment effect in slowing chronic eGFR decline. No UACR-independent finerenone effects were identified. Neither sodium-glucose cotransporter-2 (SGLT2) inhibitor nor glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment significantly modified the effects of finerenone in reducing UACR and eGFR decline. Modelled eGFR explained 87% of finerenone's treatment effect on kidney outcomes. No eGFR-independent effects were identified. CONCLUSIONS: The analyses provide strong evidence for the effectiveness of finerenone dose titration in controlling serum potassium elevations. UACR and eGFR are predictive of kidney outcomes during finerenone treatment. Finerenone's kidney efficacy is independent of concomitant use of SGLT2 inhibitors and GLP-1RAs.
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Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Naftiridinas , Insuficiência Renal Crônica , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Potássio/uso terapêutico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Método Duplo-CegoRESUMO
Chronic kidney disease (CKD) represents a global health concern, associated with an increased risk of cardiovascular morbidity and mortality and decreased quality of life. Many patients with type 1 diabetes (T1D) will develop CKD over their lifetime. Uncontrolled glucose levels, which occur in patients with T1D as well as type 2 diabetes (T2D), are associated with substantial mortality and cardiovascular disease burden. T2D and T1D share common pathological features of CKD, which is thought to be driven by haemodynamic dysfunction, metabolic disturbances, and subsequently an influx of inflammatory and profibrotic mediators, both of which are major interrelated contributors to CKD progression. The mineralocorticoid receptor is also involved, and, under conditions of oxidative stress, salt loading and hyperglycaemia, it switches from homeostatic regulator to pathophysiological mediator by promoting oxidative stress, inflammation and fibrosis. Progressive glomerular and tubular injury leads to macroalbuminuria a progressive reduction in the glomerular filtration rate and eventually end-stage renal disease. Finerenone, a non-steroidal, selective mineralocorticoid receptor antagonist, is approved for treatment of patients with CKD associated with T2D; however, the benefit of finerenone in patients with T1D has yet to be determined. This narrative review will discuss treatment of CKD in T1D and the potential future role of finerenone in this setting.
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Chronic kidney disease (CKD) in patients with type 2 diabetes (T2D) is a major health challenge associated with a disproportionately high burden of end-stage renal disease, cardiovascular disease and death. This review summarizes the rationale, clinical evidence and practical implementation for non-steroidal mineralocorticoid receptor antagonists (nsMRAs), a drug class now approved and recommended for patients with T2D and CKD at risk of cardiorenal disease progression. Three nsMRAs (finerenone, esaxerenone and apararenone) have been evaluated but finerenone is currently the only approved nsMRA for this indication. Two large-scale, placebo-controlled, Phase 3 studies evaluated finerenone added to a maximally tolerated dose of an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker. Over >2 years of treatment, finerenone was associated with a significant reduction in composite endpoints of renal and cardiovascular outcomes versus placebo. Esaxerenone or apararenone have both shown significant improvements in albuminuria versus placebo. In general, nsMRAs were well tolerated. Hyperkalaemia was the most notable treatment-related adverse event and could generally be managed through serum potassium monitoring and dose adjustments. The nsMRAs are now an important component of recommended treatment for CKD associated with T2D, providing a significant reduction in the risk of cardiorenal progression beyond what can be achieved with glucose and blood pressure control.
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Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Insuficiência Renal Crônica , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/induzido quimicamente , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Mineralocorticoides , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/induzido quimicamenteRESUMO
BACKGROUND: Chronic kidney disease (CKD) poses a significant health risk in contemporary society. Current CKD treatments primarily involve renin-angiotensin-aldosterone system inhibitors and mineralocorticoid receptor antagonists, albeit associated with hyperkalemia risks. A novel selective mineralocorticoid receptor antagonist, finerenone, offers a promising, safer alternative for CKD therapy. This review comprehensively assesses the role and efficacy of finerenone in CKD treatment by analyzing clinical and animal studies. Emerging evidence consistently supports finerenone's ability to effectively slow the progression of CKD. By targeting the mineralocorticoid receptor, finerenone not only mitigates renal damage but also exhibits a favorable safety profile, minimizing hyperkalemia concerns. CONCLUSION: Finerenone emerges as a valuable addition to CKD therapy, demonstrating potential benefits in delaying CKD progression while minimizing side effects. Nevertheless, further clinical trials are necessary to provide a comprehensive understanding of its safety and efficacy.
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Diabetes Mellitus Tipo 2 , Hiperpotassemia , Insuficiência Renal Crônica , Animais , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Hiperpotassemia/induzido quimicamente , Hiperpotassemia/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/induzido quimicamente , Naftiridinas/efeitos adversos , Diabetes Mellitus Tipo 2/complicaçõesRESUMO
Given the substantial burden of chronic kidney disease associated with type 2 diabetes, an aggressive approach to treatment is required. Despite the benefits of guideline-directed therapy, there remains a high residual risk of continuing progression of chronic kidney disease and of cardiovascular events. Historically, a linear approach to pharmacologic management of chronic kidney disease has been used, in which drugs are added, then adjusted, optimized, or stopped in a stepwise manner based on their efficacy, toxicity, effects on a patient's quality of life, and cost. However, there are disadvantages to this approach, which may result in missing a window of opportunity to slow chronic kidney disease progression. Instead, a pillar approach has been proposed to enable earlier treatment that simultaneously targets multiple pathways involved in disease progression. Combination therapy in patients with chronic kidney disease associated with type 2 diabetes is being investigated in several clinical trials. In this article, we discuss current treatment options for patients with chronic kidney disease associated with type 2 diabetes and provide a rationale for tailored combinations of therapies with complementary mechanisms of action to optimize therapy using a pillar-based treatment strategy. [This article includes a plain language summary as an additional file].
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Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Quimioterapia Combinada , Insuficiência Renal Crônica , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/etiologia , Hipoglicemiantes/uso terapêutico , Nefropatias Diabéticas/tratamento farmacológicoRESUMO
BACKGROUND AND AIMS: To investigate the cardiovascular effects of sodium-glucose co-transporter-2 inhibitors (SGLT2i) with concomitant mineralocorticoid receptor antagonist (MRA) use in heart failure (HF) regardless of ejection fraction (EF) and explore the risk of MRA-associated adverse events in individuals randomized to SGLT2i vs. placebo. METHODS: PubMed/MEDLINE, Web of Science, Embase, and clinical trial registries were searched for randomized controlled trials/post-hoc analyses evaluating SGLT2i in HF with or without MRA use (PROSPERO: CRD42023397129). The main outcomes were composite of first hospitalization or urgent visit for HF/cardiovascular death (HHF/CVD), HHF, and CVD. Others were all-cause mortality, composite renal and safety outcomes. Hazard ratios (HR)/risk ratios were extracted. Fixed-effects meta-analyses and subgroup analyses were performed. RESULTS: Five eligible studies were included, pooling data from 21 947 people with HF (type 2 diabetes mellitus, n = 10 805). Compared to placebo, randomization to SGLT2i showed a similar reduction in HHF/CVD and HHF in people who were or were not using MRAs [HHF/CVD: hazard ratio (HR) 0.75; 95% confidence interval (CI) 0.68-0.81 vs. HR 0.79; 95% CI 0.72-0.86; P-interaction = .43; HHF: HR 0.74; 95% CI 0.67-0.83 vs. HR 0.71; 95% CI 0.63-0.80; P-interaction = .53], with a suggestion of greater relative reduction in CVD in chronic HF people randomized to SGLT2i and using MRAs irrespective of EF (HR 0.81; 95% CI 0.72-0.91 vs. HR 0.98; 95% CI 0.86-1.13; P-interaction = .034). SGLT2i reduced all-cause mortality (P-interaction = .27) and adverse renal endpoints regardless of MRA use (P-interaction = .73) despite a higher risk of volume depletion with concomitant MRAs (P-interaction = .082). SGLT2i attenuated the risk of mild hyperkalaemia (P-interaction < .001) and severe hyperkalaemia (P-interaction = .051) associated with MRA use. CONCLUSIONS: MRAs did not influence SGLT2i effects on the composite of HHF/CVD, HHF or all-cause mortality; however, findings hinted at a more pronounced relative reduction in CVD in chronic HF patients regardless of EF who were randomized to SGLT2i and receiving an MRA compared to those randomized to SGLT2i and not receiving MRAs. SGLT2i attenuated the risk of MRA-associated treatment-emergent hyperkalaemia. These findings warrant further validation in well-designed randomized controlled trials.
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Insuficiência Cardíaca , Hiperpotassemia , Antagonistas de Receptores de Mineralocorticoides , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hiperpotassemia/induzido quimicamente , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêuticoRESUMO
BACKGROUND: Chronic kidney disease and type 2 diabetes are independently associated with heart failure (HF), a leading cause of morbidity and mortality. In the FIDELIO-DKD (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease) and FIGARO-DKD (Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease) trials, finerenone (a selective, nonsteroidal mineralocorticoid receptor antagonist) improved cardiovascular outcomes in patients with albuminuric chronic kidney disease and type 2 diabetes. These prespecified analyses from FIGARO-DKD assessed the effect of finerenone on clinically important HF outcomes. METHODS: Patients with type 2 diabetes and albuminuric chronic kidney disease (urine albumin-to-creatinine ratio ≥30 to <300 mg/g and estimated glomerular filtration rate ≥25 to ≤90 mL per min per 1.73 m2, or urine albumin-to-creatinine ratio ≥300 to ≤5000 mg/g and estimated glomerular filtration rate ≥60 mL per min per 1.73 m2), without symptomatic HF with reduced ejection fraction, were randomized to finerenone or placebo. Time-to-first-event outcomes included new-onset HF (first hospitalization for HF [HHF] in patients without a history of HF at baseline); cardiovascular death or first HHF; HF-related death or first HHF; first HHF; cardiovascular death or total (first or recurrent) HHF; HF-related death or total HHF; and total HHF. Outcomes were evaluated in the overall population and in prespecified subgroups categorized by baseline HF history (as reported by the investigators). RESULTS: Overall, 7352 patients were included in these analyses; 571 (7.8%) had a history of HF at baseline. New-onset HF was significantly reduced with finerenone versus placebo (1.9% versus 2.8%; hazard ratio [HR], 0.68 [95% CI, 0.50-0.93]; P=0.0162). In the overall population, the incidences of all HF outcomes analyzed were significantly lower with finerenone than placebo, including an 18% lower risk of cardiovascular death or first HHF (HR, 0.82 [95% CI, 0.70-0.95]; P=0.011), a 29% lower risk of first HHF (HR, 0.71 [95% CI, 0.56-0.90]; P=0.0043) and a 30% lower rate of total HHF (rate ratio, 0.70 [95% CI, 0.52-0.94]). The effects of finerenone on improving HF outcomes were not modified by a history of HF. The incidence of treatment-emergent adverse events was balanced between treatment groups. CONCLUSIONS: The results from these FIGARO-DKD analyses demonstrate that finerenone reduces new-onset HF and improves other HF outcomes in patients with chronic kidney disease and type 2 diabetes, irrespective of a history of HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02545049.
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Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insuficiência Cardíaca/prevenção & controle , Naftiridinas/uso terapêutico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Idoso , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Naftiridinas/farmacologiaRESUMO
Approximately 30%-40% of patients with type 1 or type 2 diabetes (T1D/T2D) develop diabetic kidney disease (DKD), which can lead to end-stage kidney disease (ESKD). Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and sodium-glucose cotransporter 2 (SGLT2) inhibitors have been investigated as treatments for DKD. However, these drugs do not prevent overactivation of the mineralocorticoid receptor (MR). Studies have shown a correlation between MR hyperactivation, renal injury, and DKD. Finerenone, a novel and selective nonsteroidal mineralocorticoid receptor antagonist (NS-MRA), was approved for the treatment of patients with DKD, and is associated with lower rates of hyperkalemia. Other NS-MRAs (such as KBP-5074, BR-4628, esaxerenone, and apararenone) may also be effective drugs for the treatment of DKD. This review summarizes the effects of pharmacological MR blockade on diabetes and diabetes-associated CKD, with a particular focus on the therapeutic mechanisms of NS-MRAs in preclinical studies and ongoing clinical studies. Further investigation of combined treatment with renoprotective drugs and NS-MRAs to improve the treatment of DKD is needed.
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Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Insuficiência Renal Crônica , Humanos , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Nefropatias Diabéticas/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Rim , Receptores de Mineralocorticoides , Insuficiência Renal Crônica/complicaçõesRESUMO
In FIDELITY, a prespecified pooled analysis of the FIDELIO-DKD and FIGARO-DKD studies, finerenone was found to improve cardiorenal outcomes in patients with type 2 diabetes, a urine albumin-to-creatinine ratio of 30-5000 mg/g, an estimated glomerular filtration rate (eGFR) of 25 ml/min per 1.73 m2 or more and also receiving optimized renin-angiotensin system blockade treatment. This present analysis focused on the efficacy and safety of finerenone on kidney outcomes. Among 13,026 patients with a median follow-up of three years, finerenone significantly reduced the hazard of a kidney composite outcome (time to kidney failure, sustained 57% or more decrease in eGFR from baseline, or kidney death) by 23% versus placebo (hazard ratio, 0.77; 95% confidence interval, 0.67-0.88), with a three-year absolute between-group difference of 1.7% (95% confidence interval, 0.7-2.6). Hazard ratios were directionally consistent for a prespecified baseline eGFR and urine albumin-to-creatinine ratio categories (Pinteraction = 0.62 and Pinteraction = 0.67, respectively), although there was a high degree of uncertainty in the 30-300 mg/g subgroup. Finerenone significantly reduced the hazard of end-stage kidney disease (ESKD) by 20% versus placebo (0.80; 0.64-0.99). Adverse events were similar between treatment arms, although hyperkalemia leading to treatment discontinuation occurred significantly more frequently with finerenone versus placebo (2.4% vs 0.8% and 0.6% vs 0.3% in patients with eGFR less than 60 vs. greater than or equal to 60 ml/min per 1.73 m2, respectively). Thus, finerenone improved kidney outcomes, reduced the hazard of ESKD, and is well tolerated in patients with chronic kidney disease and type 2 diabetes.
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Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Falência Renal Crônica , Insuficiência Renal Crônica , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/urina , Creatinina/urina , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/etiologia , Método Duplo-Cego , Rim , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/tratamento farmacológico , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/etiologia , AlbuminasRESUMO
Diabetic kidney disease (DKD) is one of the fastest growing causes of chronic kidney disease and associated morbidity and mortality. Preclinical research has demonstrated the involvement of inflammation in its pathogenesis and in the progression of kidney damage, supporting clinical trials designed to explore anti-inflammatory strategies. However, the recent success of sodium-glucose cotransporter-2 inhibitors and the nonsteroidal mineralocorticoid receptor antagonist finerenone has changed both guidelines and standard of care, rendering obsolete older studies directly targeting inflammatory mediators and the clinical development was discontinued for most anti-inflammatory drugs undergoing clinical trials for DKD in 2016. Given the contribution of inflammation to the pathogenesis of DKD, we review the impact on kidney inflammation of the current standard of care, therapies undergoing clinical trials, or repositioned drugs for DKD. Moreover, we review recent advances in the molecular regulation of inflammation in DKD and discuss potential novel therapeutic strategies with clinical relevance. Finally, we provide a road map for future research aimed at integrating the growing knowledge on inflammation and DKD into clinical practice to foster improvement of patient outcomes.
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Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Insuficiência Renal Crônica , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Diabetes Mellitus Tipo 2/complicações , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Insuficiência Renal Crônica/complicações , Inflamação/tratamento farmacológico , Inflamação/complicaçõesRESUMO
Concerns about hyperkalemia may result in the underuse of established and novel therapies that improve kidney and/or cardiovascular (CV) outcomes in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Hyperkalemia-related issues are of particular relevance in patients with CKD, who are commonly receiving other hyperkalemia-inducing agents such as renin-angiotensin-aldosterone system inhibitors and nonsteroidal mineralocorticoid receptor antagonists. In contrast, sodium/glucose transporter 2 (SGLT2) inhibitors mitigate the risk of serious hyperkalemia in clinical trials. We aim to review recent evidence surrounding the risk of hyperkalemia in patients with T2DM and CKD treated with established and novel therapies for diabetic kidney disease, focusing on SGLT2 inhibitors and nonsteroidal mineralocorticoid receptor antagonists. We conclude that SGLT2 inhibitors can be used safely in patients with T2DM at high CV risk with CKD without increasing the risk of hyperkalemia. Routine potassium monitoring is generally required when finerenone is used as a kidney- and CV-protective agent in patients with T2DM. Based on existing data, when added to the standard of care, combining SGLT2 inhibitors with finerenone is safe and has the potential to exert additional cardiorenal benefits in patients with diabetic kidney disease. The use of potassium binders should be considered to enable optimal doses of guideline-based therapies for patients with diabetic kidney disease to maximize the kidney and CV benefits.
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Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Hiperpotassemia , Insuficiência Renal Crônica , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Hiperpotassemia/etiologia , Hiperpotassemia/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/induzido quimicamente , PotássioRESUMO
BACKGROUND: In the Netherlands, more than one million patients have type 2 diabetes (T2D), and approximately 36% of these patients have chronic kidney disease (CKD). Yearly medical costs related to T2D and CKD account for approximately 1.3 billion and 805 million, respectively. The FIDELIO-DKD trial showed that the addition of finerenone to the standard of care (SoC) lowers the risk of CKD progression and cardiovascular (CV) events in patients with CKD stages 2-4 associated with T2D. This study investigates the cost-effectiveness of adding finerenone to the SoC of patients with advanced CKD and T2D compared to SoC monotherapy. METHODS: The validated FINE-CKD model is a Markov cohort model which simulates the disease pathway of patients over a lifetime time horizon. The model was adapted to reflect the Dutch societal perspective. The model estimated the incremental costs, utilities, and incremental cost-effectiveness ratio (ICER). Sensitivity and scenario analyses were performed to assess the effect of parameter uncertainty on model robustness. RESULTS: When used in conjunction with SoC, finerenone extended time free of CV events and renal replacement therapy by respectively 0.30 and 0.31 life years compared to SoC alone, resulting in an extension of 0.20 quality-adjusted life years (QALYs). The reduction in renal and CV events led to a 6136 decrease in total lifetime costs per patient compared to SoC alone, establishing finerenone as a dominant treatment option. Finerenone in addition to SoC had a 83% probability of being dominant and a 93% probability of being cost-effective at a willingness-to-pay threshold of 20,000. CONCLUSION: By reducing the risk of CKD progression and CV events, finerenone saves costs to society while gaining QALYs in patients with T2D and advanced CKD in the Netherlands.
Assuntos
Diabetes Mellitus Tipo 2 , Insuficiência Renal Crônica , Humanos , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Análise Custo-Benefício , Países Baixos/epidemiologia , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/epidemiologiaRESUMO
BACKGROUND: The overactivation of mineralocorticoid receptor (MR) plays a key pathological role in the progression of cardiovascular and renal diseases by promoting pro-inflammatory and pro-fibrotic signaling. Recently, it has been found that finerenone, a novel nonsteroidal selective MR antagonist, can robustly improve cardiorenal outcomes in patients with type 2 diabetes (T2D) and a wide spectrum of chronic kidney disease (CKD). However, the mechanisms underlying the cardiorenal benefits of finerenone are poorly understood. Further, whether the clinical benefits are mediated by an improvement in vascular stiffness is not confirmed. Therefore, the current study aims to evaluate the effects of finerenone on vascular stiffness as assessed using cardio ankle vascular index (CAVI) and relevant cardiorenal biomarkers in patients with T2D and CKD. METHODS: The Effects of Finerenone on Vascular Stiffness and Cardiorenal Biomarkers in Type 2 Diabetes and Chronic Kidney Disease (FIVE-STAR) is an ongoing, investigator-initiated, multicenter, prospective, placebo-controlled, double-blind, randomized clinical trial in Japan. Its target sample size is 100 subjects. Recruitment will be performed from September 2023 to July 2024. After obtaining informed consent, eligible participants with T2D and CKD (25 mL/min/1.73 m2 ≤ estimated glomerular filtration ratio [eGFR] < 90 mL/min/1.73 m2 and 30 mg/g Cr ≤ urinary albumin-to-creatinine ratio [UACR] < 3500 mg/g Cr) will be equally randomized to receive 24-week treatment with either finerenone (starting dose at 10 mg once daily in participants with a baseline eGFR < 60 mL/min/1.73 m2 or at 20 mg once daily in those with a baseline eGFR ≥ 60 mL/min/1.73 m2) or dose-matched placebo. The primary endpoint is the change from baseline in CAVI at 24 weeks. The secondary endpoints are changes from baseline in UACR at 12 and 24 weeks and relevant serum and urinary biomarkers at 24 weeks. As an exploratory endpoint, proteomic analysis using the Olink® Target 96 panels will be also performed. DISCUSSION: FIVE-STAR is the first trial evaluating the therapeutic impact of finerenone on vascular stiffness and relevant cardiorenal biomarkers in patients with T2D and CKD. This study will provide mechanistic insights on the clinical benefits of finerenone based on recent cardiovascular and renal outcome trials. Trial registration Unique Trial Number, NCT05887817 ( https://clinicaltrials.gov/ct2/show/NCT05887817 ) and jRCTs021230011 ( https://jrct.niph.go.jp/latest-detail/jRCTs021230011 ).
Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Insuficiência Renal Crônica , Rigidez Vascular , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Estudos Prospectivos , Proteômica , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/tratamento farmacológico , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Método Duplo-Cego , BiomarcadoresRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Humanos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Volume SistólicoRESUMO
In recent years, several novel agents have become available to treat individuals with type 2 diabetes (T2D), such as sodium-glucose cotransporter-2 inhibitors (SGLT-2i), tirzepatide, which is a dual glucose-dependent insulinotropic polypeptide receptor agonist (GIP RA)/glucagon-like peptide-1 receptor agonist (GLP-1 RA), and finerenone, a non-steroidal mineralocorticoid receptor antagonist (MRA) that confers significant renal and cardiovascular benefits in individuals with (CKD). New medications have the potential to improve the lives of individuals with diabetes. However, clinicians are challenged to understand the benefits and potential risks associated with these new and emerging treatment options. In this article, we discuss how use of network meta-analyses (NMA) can fill this need.
Assuntos
Diabetes Mellitus Tipo 2 , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Metanálise em Rede , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Peptídeo 1 Semelhante ao Glucagon , Rim , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hipoglicemiantes/efeitos adversosRESUMO
INTRODUCTION: In FIDELIO-DKD, finerenone significantly improved cardiorenal outcomes in patients with chronic kidney disease and type 2 diabetes (T2D). This post hoc analysis explores finerenone in patients from the Asian region. METHODS: In FIDELIO-DKD, 5,674 patients with T2D and urine albumin-to-creatinine ratio (UACR) ≥30-<300 mg/g and estimated glomerular filtration rate (eGFR) ≥25-<60 mL/min/1.73 m2 or UACR ≥300-≤5,000 mg/g and eGFR ≥25-<75 mL/min/1.73 m2, treated with optimized renin-angiotensin system blockade, were randomized 1:1 to finerenone or placebo. Efficacy outcomes included a primary kidney composite (time to kidney failure, sustained decrease of ≥40% in eGFR from baseline, and death from renal causes) and secondary cardiovascular (CV) (time to CV death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure) and kidney (time to kidney failure, sustained decrease of ≥57% in eGFR from baseline, and death from renal causes) composites. RESULTS: Of 1,327 patients in the Asian subgroup, 665 received finerenone. Finerenone reduced the ≥40% and ≥57% eGFR kidney and CV composite outcomes versus placebo in the Asian subgroup (hazard ratio [HR]: 0.70; 95% confidence interval [CI]: 0.56-0.87, HR: 0.73; 95% CI: 0.55-0.97, and HR: 0.85; 95% CI: 0.59-1.21, respectively), with no apparent differences versus patients from the rest of the world (HR: 0.88; 95% CI: 0.77-1.02; p interaction 0.09, HR: 0.78; 95% CI: 0.64-0.95; p interaction 0.71, and HR: 0.86; 95% CI: 0.74-1.00; p interaction 0.95, respectively). The safety profile of finerenone was similar across subgroups. CONCLUSION: Finerenone produces similar cardiorenal benefits in Asian and non-Asian patients.