AIMS:Radiofrequency (RF) renal denervation (RDN) safely lowers office and 24-h blood pressure (BP). This meta-analysis examined the long-term durability of RF RDN based on randomized trials and observational studies. METHODS AND RESULTS:Patients with uncontrolled hypertension undergoing RF RDN using the Symplicity Flex™ or Spyral™ device and a minimum follow-up of 3 years were included. Key outcomes included office and 24-h BP change from baseline as well as changes in anti-hypertensive drugs. A random effects meta-analysis was conducted over 3 years, or the last reported follow-up beyond 3 years. A total of 2212 patients identified among 18 reports were evaluated for BP. The mean duration of follow-up was 4.4 years (range 3-9.4). The long-term reduction in office systolic BP from baseline in 15 reports (n = 2040) was -23.0 mmHg (95% confidence interval: -26.8 to -19.1, P < 0.05) for the random effects model and -20.5 (-21.6 to -19.4) for the fixed effect model. Twenty-four-hour ambulatory systolic BP was available in 11 reports (n = 1018) and decreased significantly by -13.6 mmHg (-16.5 to -10.8, P < 0.05). Fixed effect model results were similar. Diastolic office and 24-h BP paralleled these findings in both models. Nighttime systolic BP also decreased significantly by -14.2 mmHg (-27.6 to -0.8, P < 0.05). The number of prescribed anti-hypertensive drugs and eGFR also decreased. Heart rate remained unchanged through the final follow-up in both models. Safety events were rare, with a mean rate of renal artery complications of 0.14% (0.08-0.20%). CONCLUSION:This meta-analysis comprising 18 studies demonstrated sustained and significant office and ambulatory BP reductions following Symplicity RDN through at least 3 years without an increase in anti-hypertensive medication.

Objective:Guidelines on the treatment of hypertensive patients usually refer to 'average' patients. However, in clinical practice, individual patient characteristics may differ substantially from the average. Thus, it seems worthwhile to examine the relationship between comprehensive patient profiles and blood pressure responses.Methods:We divided the patient population from the INSIGHT trial into exploration and validation cohorts and constructed composite patient profiles based on predictors of blood pressure control (age, severity of hypertension, comorbidities, and previous treatment status). Next, we tested in the exploration cohort whether blood pressure control rates and adverse effects after 6 months of therapy across these profiles differed from those in the entire patient group. Finally, we explored whether the results from the exploration cohort could be validated using another cohort.Results:Logistic regression analysis showed that the odds of achieving blood pressure control differed substantially between patient profiles but not between treatment modalities. Patients with a less favorable profile (e.g. the combination of age above 60 years, baseline systolic pressure above 160 mmHg, and the presence of diabetes) did less well than patients with a low-risk profile (e.g. absence of organ damage). These results were confirmed in the validation cohort.Conclusion:We conclude that responses to antihypertensive treatment vary in a clinically important manner depending on the composite patient profiles. When found in other trials as well, a priori knowledge about response rates of various patient-profile treatment regimens may help choose the best treatment in individual patients and improve overall blood pressure control rates.

Chronic kidney disease (CKD) is a common comorbidity of both type 1 diabetes (T1D) and type 2 diabetes (T2D) and is associated with increased mortality, end-stage kidney disease and cardiovascular disease risk. Despite standard-of-care treatment with renin-angiotensin system inhibitors added to blood pressure and glycaemic control, people with CKD and T1D have a residual risk of CKD progression. Advances in therapeutic management have been limited over the past 3 decades, especially compared with CKD in T2D, for which new treatment options have emerged in the last 5 years. In this review article we discuss the similarities and differences between T1D and T2D populations with CKD, including epidemiology, pathophysiology and clinical findings. Additionally, we explore the use of albuminuria as a potential bridging biomarker to extrapolate clinical evidence from one population to the other. This concept could offer a promising strategy to narrow the gap in treatment availability between these populations and address the unmet therapeutic need in people with CKD and T1D. The FINE-ONE trial is investigating the non-steroidal mineralocorticoid receptor antagonist finerenone in a population with CKD and T1D using the change in urine albumin:creatinine ratio from baseline over 6 months as its primary endpoint and bridging biomarker. Similarities between the populations from FINE-ONE trial and FIDELITY (a pooled dataset of individuals with CKD and T2D included in two large phase 3 clinical trials of finerenone) may inform the translation of clinical evidence on finerenone from people with CKD and T2D to those with CKD and T1D.

BACKGROUND:Obesity is a core pathophysiologic contributor to cardiovascular, kidney, and metabolic (CKM) conditions. However, the association between different adiposity-related anthropometrics and cardiovascular outcomes in persons with CKM conditions has not been rigorously explored. OBJECTIVES:In this study, the authors sought to examine cardiovascular outcomes and treatment effects of finerenone according to different adiposity-related anthropometrics. METHODS:In this prespecified participant-level pooled analysis of FIDELIO-DKD, FIGARO-DKD, and FINEARTS-HF (FINE-HEART), cardiovascular outcomes and treatment effects of finerenone according to baseline body mass index (BMI), waist circumference (WC), waist-height ratio (WHtR), and waist-hip ratio (WHR) were evaluated with the use of multivariable-adjusted Cox proportional hazards regression and Poisson regression. RESULTS:Of 18,759 participants with available data for all anthropometrics, 52% had a BMI ≥30 kg/m2 and 98% had any excess adiposity. Among those with BMI <30 kg/m2, 95% had increased abdominal adiposity, especially women and older individuals. Higher BMI, WC, WHtR, and WHR were each significantly associated with a wide range of cardiovascular outcomes, including cardiovascular death or heart failure (HF) hospitalization and its individual components, major adverse cardiovascular events, new-onset atrial fibrillation, and incident HF hospitalization. BMI-adjusted WHtR and WHtR-adjusted BMI were each associated with a higher rate of cardiovascular death or HF hospitalization, and participants with elevated BMI and WHtR experienced a higher rate of cardiovascular death or HF hospitalization compared with those with elevated BMI or WHtR alone (P < 0.001). Benefits of finerenone on cardiovascular death or HF hospitalization were consistent regardless of baseline BMI (Pinteraction = 0.27) or WHtR (Pinteraction = 0.26), and absolute benefits appeared to be greater among participants with higher adiposity. Serious adverse events were less common with finerenone vs placebo, regardless of baseline BMI category (Pinteraction = 0.08). CONCLUSIONS:These findings suggest that assessment of anthropometrics capturing abdominal adiposity, in addition to BMI, may enhance obesity identification and risk stratification among individuals with CKM conditions. Finerenone consistently reduced adverse cardiovascular outcomes across a wide range of adiposity. (FINE-HEART: An Integrated Pooled Analysis of Finerenone Across 3 Phase III Trials of Heart Failure and Chronic Kidney Disease and Type 2 Diabetes; CRD42024570467).

Introduction: Finerenone, a non-steroidal mineralocorticoid receptor antagonist, improves cardiovascular and kidney outcomes in people with type 2 diabetes and chronic kidney disease (CKD). However, the long-term impact of finerenone on delaying or preventing cardiorenal events is not known. Purpose: To estimate the lifetime benefits of finerenone vs. placebo on cardiorenal morbidity and mortality in persons with type 2 diabetes and CKD. Methods: In this participant-level pooled analysis of the FIDELIO-DKD and FIGARO-DKD trials (FIDELITY), we estimated the effects of finerenone on long-term survival free from cardiorenal morbidity and mortality using validated, nonparametric, and age-based actuarial methods. The main outcome was a cardiorenal composite outcome comprised of all-cause death and the individual components of the prespecified cardiovascular (heart failure hospitalization, non-fatal myocardial infarction, or non-fatal stroke) and kidney (CKD progression [sustained ≥57% decrease in eGFR] or kidney failure) composite endpoints. Results: Among 12,990 pooled trial participants, the risk of cardiorenal morbidity or mortality was lower with finerenone (71.8 events per 1000 person-years) vs. placebo (85.4 events per 1000 patient years; HR, 0.84 [95% CI, 0.78 to 0.90]) over a median trial follow-up of 3.0 [2.3, 3.8] years. In actuarial analyses examining lifetime trajectories for a 65-year-old trial participant, mean survival free from cardiorenal morbidity or mortality was 10.2 years (95% CI, 9.7 to 10.7) with placebo and 11.5 years (95% CI, 11.0 to 12.0) with finerenone, representing an additional 1.3 years (95% CI, 0.6 to 2.0 years) of event-free survival ( Figure, Panel A ). Cardiorenal event-free survival gains were observed across a broad age range, from 1.2 years (95% CI, 0.2 to 2.3 years) at age 55 to 0.8 years (95% CI, 0.1 to 1.4 years) at age 75 ( Figure, Panel B ). Conclusions: Treatment with finerenone is projected to afford clinically relevant long-term gains in survival free from cardiorenal morbidity and mortality, reinforcing its role as a key component of guideline-directed medical therapy for persons with type 2 diabetes and CKD.

BACKGROUND:Uncontrolled hypertension is common in patients with chronic kidney disease (CKD), putting these patients at high risk for adverse cardiovascular events. Radiofrequency renal denervation (RDN) lowers blood pressure (BP) in patients with hypertension. The Global SYMPLICITY Registry DEFINE enrolled over 3500 patients with uncontrolled hypertension worldwide, including patients with moderate-to-severe CKD. METHODS:Patients were categorized by their baseline estimated glomerular filtration rate (estimated glomerular filtration rate [eGFR], mL/min per 1.73 m2): eGFR ≥60 (no-CKD, n=2539), eGFR ≥45 to <60 (stage 3a, n=496), eGFR ≥30 to <45 (stage 3b, n=256). BP changes from baseline through 3 years were compared between groups. One-year data for 74 CKD stage 4 patients were also assessed. Safety events and eGFR were reported at all time points. RESULTS:Average baseline office systolic BP was similar across the 3 comparator groups (range: 162.8±26.4-164.7±24.8 mm Hg). At 3 years, office systolic BP reductions from baseline were -17.2±28.1 mm Hg, -12.1±30.3 mm Hg, and -13.0±27.3 mm Hg in the no-CKD, CKD 3a, and CKD 3b groups, respectively (all P<0.0001). A mild decline in eGFR through 1 year occurred in the no-CKD group but not in any CKD group. Three-year mortality was 4.3%, 7.0%, and 15.2% in no-CKD, CKD 3a, and CKD 3b groups, respectively. Adverse renal events were rare (<1.0%) across all 3 groups. Antihypertensive medication burden remained high in the no-CKD and CKD 3a groups but declined over 3 years in the CKD 3b group (P=0.007). CONCLUSIONS:In patients with uncontrolled hypertension and moderate-to-severe CKD, radiofrequency RDN results in clinically meaningful and durable BP reduction without renal or vascular safety concerns. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01534299.

Background: Mineralocorticoid receptor antagonists (MRAs) mechanistically may alter pathways of cardiac fibrosis and electrical stability. The non-steroidal MRA finerenone has been shown to improve cardiovascular and kidney outcomes in patients with cardio-kidney-metabolic (CKM) syndrome, but its effects on cause-specific death, namely sudden death (SD), is uncertain. Methods: We conducted a participant-level pooled analysis of three large phase 3 trials of finerenone vs. placebo to evaluate the effect of the non-steroidal MRA finerenone on SD in participants with CKM syndrome. In this prespecified analysis, we pooled participants from 2 trials of chronic kidney disease with type 2 diabetes (FIDELIO-DKD and FIGARO-DKD) and a trial of HF with mildly reduced or preserved ejection fraction (FINEARTS-HF). SD was centrally adjudicated by the clinical endpoint committees. Independent predictors of SD were identified with multivariable Cox models using a stepwise forward selection. Treatment effects of finerenone (vs. placebo) were evaluated using Cox regression models stratified by region and trial. Results: Of the 18,991 participants, 418 (2.2%) (0.77 per 100 patient-years) experienced a SD during median follow-up of 2.9 years. An increased risk of SD was associated with age, male sex, a history of HF, lower estimated glomerular filtration rate, higher urine albumin/creatinine ratio, and lower baseline systolic blood pressure ( Panel A ). SD occurred in 188 (2.0%) participants randomized to finerenone and in 230 (2.5%) receiving placebo (HR 0.81, 95% CI 0.67, 0.98, p=0.034) ( Panel B ). Risk reductions were consistent irrespective of number of baseline CKM conditions (P interaction =0.93) and by trial (P interaction =0.71) ( Panel C ). Consistent results were observed analyzing non-SD as a competing risk (HR 0.81, 95% CI 0.67, 0.98, p=0.034). Conclusion: The non-steroidal MRA finerenone significantly reduced the risk of SD across the CKM spectrum.

Introduction: The non-steroidal mineralocorticoid receptor antagonist finerenone reduces the risk of heart failure (HF) hospitalization in people with type 2 diabetes and chronic kidney disease (CKD), but whether these benefits vary according to baseline HF risk is uncertain. Purpose: To evaluate the relative and absolute effects of finerenone on HF outcomes across different levels of HF risk, based on the Thrombolysis in Myocardial Infarction Risk Score for Heart Failure in Diabetes (TRS-HF DM ). Methods: We conducted a post-hoc individual participant data analysis of the FIDELITY program, consisting of the FIDELIO-DKD and FIGARO-DKD trials, which assessed the efficacy and safety of finerenone versus placebo on clinical outcomes in people with type 2 diabetes and albuminuric CKD. TRS-HF DM is a validated integer-based score (0-7 points) to predict HF events based on 5 clinical variables (history of HF [2 points], history of atrial fibrillation, history of coronary artery disease, eGFR <60 mL/min/1.73m 2 , UACR 30-300 mg/g, UACR >300 mg/g [2 points]). Participants were categorized into 4 groups according to TRS-HF DM score at baseline (0-1, 2, 3, 4+). Relative and absolute treatment effects on HF hospitalization or cardiovascular death were examined across TRS-HF DM score categories. Results: Of 12,990 participants, 12,984 (99.95%) had available data to calculate TRS-HF DM . The proportion of participants who had a score of 0-1, 2, 3, and 4+, were 7.3%, 34.9%, 37.9%, and 19.9%, respectively. Compared with placebo, finerenone reduced the risk of time-to-first HF hospitalization or cardiovascular death (HR, 0.83; 95% CI, 0.74-0.93) with consistent relative effect across TRS-HF DM risk categories (P interaction =0.89; Figure 1 ). Relative effects on HF hospitalization (HR, 0.78; 95% CI, 0.66-0.92) and cardiovascular death (HR, 0.88; 95% CI, 0.76-1.02) were similarly consistent across TRS-HF DM risk categories (P interaction =0.42 and 0.90, respectively; Figure 1 ). Absolute risk reductions for HF hospitalization or cardiovascular death appeared greater across higher TRS-HF DM risk categories with fewer corresponding numbers needed to treat to prevent one outcome ( Figure 2 ). Conclusions: In people with type 2 diabetes and CKD, finerenone reduces the risk of HF hospitalization or cardiovascular death, with greater absolute benefits in people at higher risk for HF events.

BACKGROUND:The risk associated with white-coat hypertension is controversial. We evaluated mortality risks in white-coat hypertension subtypes defined according to the circadian pattern of blood pressure (BP) elevation over 24 h. METHODS:In 44 119 patients with elevated office BP, white-coat hypertension subtypes were defined as normal BP in all circadian periods (day, night, and 24-h, 12 192 patients), normal 24-h, with nocturnal BP elevation (4368), and normal daytime, with 24-h BP elevation (3525). Associations of each subtype with all-cause and cardiovascular mortality were estimated by Cox-regression models, adjusted for clinical confounders, compared to a reference group of 7690 patients with normal both office and ambulatory (all periods) BP. RESULTS:Compared to the reference group, white-coat hypertension defined by normal BP in all circadian periods was not associated with an increased risk of all-cause [hazard ratio, 0.94 [95% confidence interval, 95% CI,0.85-1.03]) or cardiovascular death (hazard ratio, 0.91 [95% CI,0.76-1.08]). In contrast, white-coat hypertension defined by normal daytime, but with elevated 24-h BP, was associated with increased risks of all-cause (hazard ratio, 1.27 [95% CI,1.13-1.42]) and cardiovascular death (hazard ratio, 1.37 [95% CI,1.12-1.68]). The group of white-coat hypertension defined by normal 24-h BP, but with nocturnal BP elevation had increased crude rates of death, but risks were not significantly increased after adjusting for confounders. CONCLUSION:White-coat hypertension is a heterogeneous condition in terms of associated risk of death. A definition based only on a normal daytime BP may mask a significant group of patients with increased 24-h or night BP, who exhibit an increased risk of mortality.

Ischaemic heart disease (IHD) remains a major cause of death and morbidity. Klotho is a well-known anti-ageing factor with relevant cardioprotective actions, at least when renal dysfunction is present, but its actions are much less known when renal function is preserved. This study investigated Klotho as a biomarker and potential novel treatment of IHD-associated complications after myocardial infarction (MI) under preserved renal function. Association between circulating Klotho levels and cardiac injury was investigated in patients after ST-elevation MI (STEMI). Biochemical, in vivo and in vitro cardiac function and histological and molecular studies were performed to determine the effect of recombinant Klotho in the failing hearts of mice after MI. We demonstrated that STEMI patients showed lower systemic Klotho levels, with the lowest Klotho tertile in those patients with higher N-terminal pro B-type natriuretic peptide (NT-proBNP) levels. Mice also showed a decrease in systemic Klotho levels after MI induction. Furthermore, recombinant Klotho administration in mice reduced infarct area and attenuated cardiac hypertrophy and fibrosis. We also demonstrated that Klotho treatment prevented reduction in ejection fraction and MI-related ECG changes, including prolonged QRS, JT, QTc, and TpeakTend intervals and premature ventricular contractions. In adult mouse cardiomyocytes, Klotho treatment restricted systolic calcium (Ca2+) release and cell shortening disturbances after MI. Klotho prevented increased diastolic Ca2+ leak and pro-arrhythmogenic events in PMI mice by blocking activation of the Ca2+/calmodulin-dependent kinase type II (CaMKII) pathway, preventing ryanodine receptor type 2 (RyR2) hyperphosphorylation. In conclusion, Klotho supplementation protected against functional and structural cardiac remodelling and ameliorated ventricular arrhythmic events by preventing intracardiomyocyte Ca2+ mishandling in mice following MI. These data uncover a new cardioprotective role of Klotho, emerging as a biomarker of ventricular injury and potential treatment for patients after MI. (c) 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

BACKGROUND Anemia is common in patients with chronic kidney disease and type 2 diabetes. Finerenone improved heart and kidney outcomes in patients with chronic kidney disease and type 2 diabetes in FIDELITY. OBJECTIVES This post hoc analysis investigated the efficacy and safety of finerenone vs placebo by baseline anemia status. METHODS Anemia was defined as serum hemoglobin levels <13 g/dL (male) or <12 g/dL (female) or treatment with an erythropoiesis-stimulating agent at baseline. Outcomes included cardiovascular (CV) and kidney composites, hospitalization for heart failure, and all-cause mortality. Safety was assessed through treatment-emergent adverse events. RESULTS Of 12,971 patients, 33% had anemia at baseline. Finerenone reduced the risk of the CV composite outcome to a greater extent in patients with vs without anemia (HR: 0.75 [95% CI: 0.65-0.88] vs HR: 0.93 [95% CI: 0.82-1.05]; P for interaction = 0.03). Finerenone reduced the risk of the kidney composite outcome vs placebo, with no heterogeneity between patients with vs without anemia (HR: 0.79 [95% CI: 0.65-0.95] and HR: 0.74 [95% CI: 0.60-0.91]; P for interaction = 0.77). The risk of hospitalization for heart failure and all-cause mortality was lower with finerenone vs placebo, irrespective of anemia status. Patients with anemia experienced higher incidence of treatment-emergent hyperkalemia vs those without. CONCLUSIONS Finerenone demonstrated CV and kidney benefit in patients with and without anemia. The benefit of finerenone on CV outcomes was greater in patients with vs without anemia at baseline. Anemia is likely a marker for higher-risk patients who are more susceptible to the benefits of finerenone. (Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease [FIDELIO-DKD], NCT02540993; Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Diabetic Kidney Disease [FIGARO-DKD], NCT02545049) (JACC Adv. 2025;4:101524) (c) 2025 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Background: The nsMRA finerenone, has been shown to reduce the risk of kidney disease progression and CV events in patients with T2D and CKD. Diuretics are widely used in the management of patients with CKD, yet there are limited data on the prognostic relevance of diuretic intensification in this population. Methods: This was a post hoc analysis of FIDELITY, a participant-level pooled analysis of the FIDELIO-DKD and FIGARO-DKD trials, which enrolled patients with T2D and CKD. We evaluated the association between the need for new loop diuretic (LD) initiation and rates of subsequent all-cause mortality. We then assessed the treatment effect of finerenone relative to placebo on new LD initiation among diuretic-naïve individuals overall and according to baseline eGFR and UACR. We finally examined the effects of finerenone on an expanded composite CV endpoint adding new diuretic initiation to the prespecified FIDELITY endpoint of CV death, non-fatal MI, non-fatal stroke, and hospitalization for HF. Results: Among 12, 990 participants in FIDELITY, 10,194 (78%) were not treated with a LD at baseline and new diuretic initiation occurred in 2,107(22%) in follow up. New LD requirement was more frequent among those with lower eGFR and higher UACR at baseline ( Figure 1 ). Patients requiring new diuretic initiation experienced rates of subsequent mortality that were nearly quadruple (8.8 [7.8-9.9] per 100 patient-years) that of those not requiring diuretic initiation (1.9 [1.7-2.0] per 100 patient-years). Treatment with finerenone reduced new initiations of LDs by 17% (HR 0.83; 95% CI: 0.76-0.91, p<0.001) in FIDELITY ( Figure 1A ). Relative to placebo, the reduction in the incidence of new LD initiations with finerenone was also consistent across the spectrum of both eGFR ( Figure 1B ) and UACR ( Figure 1C ). Adding new LD initiation to the prespecified FIDELITY CV composite endpoint nearly doubled the number of events from 1,764 to 3,286 and underscored the cardiovascular benefits of finerenone (HR 0.85; 95% CI: 0.80-0.91, p<0.001). Conclusions: In patients with T2D and CKD, new requirement for diuretic initiation occurred in ~1 in 5 patients and was associated with higher rates of subsequent mortality. Treatment with finerenone significantly reduced new LD initiation, an effect that was consistent across the kidney function spectrum. These data highlight the diuretic-sparing potential of finerenone in patients with T2D and CKD.

Objectives: The effects of acute physical exercise in patients with resistant hypertension remain largely unexplored compared with hypertensive patients in general. We assessed the short-term effects of acute moderate-intensity (MICE) and high-intensity interval exercise (HIIE) on the clinic (BP) and 24-h ambulatory blood pressure (ABP) of patients with resistant hypertension. Methods: Using a crossover randomized controlled design, 10 participants (56 +/- 7 years) with resistant hypertension performed three experimental sessions: MICE, HIIE, and control. MICE consisted of continuous treadmill exercise at an intensity of 3-4 metabolic equivalents of energy (METs) until completing 3 kcal/kg and was energy-matched to HIIE (which included six to eight intervals of 3 min duration at 6-7 METs interspersed with 1.5-min rests at 3 METs). In the control session, participants remained seated for 50 min. Flow-mediated vasodilation, autonomic nervous system balance (heart rate variability), exerkines [interleukin (IL)-6, IL-8, IL-15, vascular endothelial growth factor A, irisin, adiponectin, and angiopoietin] and 71 inflammatory-related proteins were also measured. Results: Compared with baseline, HIIE and MICE reduced clinic SBP immediately ( P < 0.001 for both) and 90 min ( P = 0.001 and P = 0.041, respectively) postexercise. HIIE and MICE also reduced clinic DBP immediately postexercise ( P = 0.003 and P = 0.025). By contrast, no changes were found in the control session. On the other hand, no significant effects were noted for 24 h ABP measures or for the rest of variables. Conclusion: Although in patients with resistant hypertension, acute aerobic exercise induces short-term reductions in clinic BP, this stimulus does not suffice to reduce 24 h ABP or to impact on potential biological mechanisms.

Objective: To evaluate the efficacy and safety of finerenone, a non-steroidal mineralocorticoid receptor antagonist, in individuals with type 2 diabetes (T2D) and either chronic kidney disease (CKD) or heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF). Research Design and Methods: In this prespecified participant-level pooled analysis of all phase III clinical trials evaluating finerenone versus placebo conducted to date (FINE-HEART), the safety and efficacy of finerenone was evaluated among participants with a history of T2D. Treatment effects on the primary outcome of cardiovascular death and other secondary outcomes were evaluated according to baseline glycated hemoglobin (HbA1c) and glucose-lowering therapy (GLT) regimen using stratified Cox proportional hazards models. Results: Of 18,991 FINE-HEART participants, 15,365 (80.9%) had T2D and available HbA1c at baseline (mean age, 66±10 years; 32% women; mean HbA1c, 7.6±1.4%). The most common GLT regimens were insulin alone (n=2,652), insulin and metformin (n=2,005), metformin alone (n=1,616), metformin and sulfonylurea (n=1,039), and “other” (n=8,117; including SGLT2i and GLP-1RA). Over a median follow-up of 2.9 years, treatment effects of finerenone vs. placebo on cardiovascular death were consistent across baseline HbA1c (Pinteraction=0.75) and GLT regimen (Pinteraction=0.46). Finerenone consistently reduced the kidney composite outcome, HF hospitalization, major adverse cardiovascular events, and all-cause mortality, irrespective of baseline HbA1c and GLT regimen. Treatment effects of finerenone were also consistent across number of background GLTs and irrespective of concomitant treatment with a SGLT2i or GLP-1RA. Conclusions: Finerenone consistently reduced morbidity and mortality in individuals with T2D across a broad range of glycemia and glucose-lowering regimens.

INTRODUCTION:The efficacy and safety of finerenone (a nonsteroidal mineralocorticoid receptor antagonist) versus placebo were assessed according to different changes in estimated glomerular filtration rate (eGFR) using data from FIDELITY, a pooled individual-level analysis of two clinical trials. METHODS:Patients had chronic kidney disease (eGFR of 25 ml/min/1.73 m2 or greater) and type 2 diabetes with optimized renin-angiotensin system blockade. Risk of composite cardiovascular and composite kidney outcomes was analyzed by baseline eGFR change at month one in the total population and by treatment group. RESULTS:Of 12,798 patients, 25.1% had a >10% eGFR decline, 31.2% had a >0-10% decline, 26.8% had a 0-10% increase, and 16.8% had a >10% increase after one month of treatment. Factors associated with acute eGFR decline included higher baseline urine albumin-to-creatinine ratio, eGFR, systolic blood pressure, diuretic or beta-blocker use, and finerenone use. Finerenone significantly reduced composite cardiovascular and kidney outcomes overall and had similar beneficial effect across eGFR subgroups of >10% decline, >0-10% decline, 0-10% increase, and >10% increase for composite cardiovascular (hazard ratio [95% Confidence Interval] of 0.74 [0.61-0.90], 0.87 [0.73-1.04], 1.06 [0.87-1.28], and 0.78 [0.61-0.99], respectively) and kidney outcomes (0.67 [0.53-0.85], 0.78 [0.61-1.01], 0.56 [0.40-0.77], and 0.75 [0.50-1.14], respectively) (P interaction 0.048 and 0.23, respectively). When modeled as a continuous variable, finerenone reduced the risk of cardiovascular and kidney outcomes, irrespective of acute eGFR change (P interaction 0.58 and 0.36, respectively). CONCLUSIONS:The cardiovascular and kidney benefits of finerenone were not modified by an acute eGFR change after drug initiation.

AIMS:This post hoc analysis aimed to assess the efficacy and safety of the non-steroidal mineralocorticoid receptor antagonist finerenone by baseline diuretic use in FIDELITY, a pre-specified pooled analysis of the phase III trials FIDELIO-DKD and FIGARO-DKD. METHODS AND RESULTS:Eligible patients with type 2 diabetes (T2D) and chronic kidney disease (CKD; urine albumin-to-creatinine ratio [UACR] ≥30-<300 mg/g and estimated glomerular filtration rate [eGFR] ≥25-≤90 ml/min/1.73 m2, or UACR ≥300-≤5000 mg/g and eGFR ≥25 ml/min/1.73 m2) were randomized 1:1 to finerenone or placebo. Patients were analysed by baseline diuretic use (yes/no) and type of diuretic (loop or thiazide). Key efficacy outcomes included a cardiovascular composite (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure) and a kidney composite (kidney failure, sustained ≥57% decrease in eGFR, or kidney-related death). Out of 12 990 patients, 51.6% were taking diuretics at baseline (21.6% loop; 24.2% thiazide diuretics). Finerenone reduced the risk of cardiovascular and kidney composite outcomes versus placebo; diuretic use did not modify this effect on the cardiovascular (p-interaction = 0.94) or kidney outcomes (p-interaction = 0.55). Hyperkalaemia incidences were similar between finerenone subgroups irrespective of diuretic use and lower with placebo versus finerenone (with diuretics: finerenone 13.7% vs. placebo 5.7%; without diuretics: 14.3% vs. 8.3%). The incidence of hyperkalaemia leading to hospitalization or study drug discontinuation was low across treatment groups irrespective of diuretic use. CONCLUSION:This analysis showed that the efficacy and safety of finerenone in patients with CKD and T2D was not modified by baseline diuretic use.

Background: Mineralocorticoid receptor antagonists (MRAs) mechanistically reduce inflammation, oxidative stress and endothelial dysfunction. There is growing interest in understanding the composite cardiovascular (CV) protection afforded by therapies like the nonsteroidal MRA finerenone with systemic actions in patients with cardio-kidney-metabolic (CKM) syndrome. Methods: In this participant-level pre-specified pooled analysis from three large phase 3 clinical trials (FIDELIO-DKD, FIGARO-DKD, and FINEARTS-HF), we assessed the association between various nonfatal CV events (myocardial infarction, stroke, and heart failure hospitalization) and rates of subsequent mortality using time-updated models. We then examined the treatment effects of finerenone vs. placebo on major adverse cardiovascular events (MACE, a composite of CV death, nonfatal myocardial infarction, nonfatal stroke, or heart failure hospitalization), which was a prespecified secondary endpoint in the FINE-HEART pooled analysis, using Cox regression models stratified by trial and region. Results: During a median of 2.9 years of follow-up, among the 18,991 participants, 1,544 (8.1%) experienced heart failure hospitalization, 500 (2.6%) nonfatal myocardial infarction, 570 (3.0%) nonfatal stroke, and 892 (4.7%) CV death. Patients with incident myocardial infarction, stroke, and heart failure hospitalization consistently experienced markedly higher subsequent risks of mortality ( Figure 1 ). Mortality was highest after heart failure hospitalization (incidence rate 23.4 [21.4-25.8] per 100py compared with 3.2 [3.1-3.4] per 100py for individuals without nonfatal CV events). Finerenone reduced the composite of CV death, nonfatal myocardial infarction, nonfatal stroke, or heart failure hospitalization (HR 0.91; 95% CI, 0.85–0.98; P = 0.010, Figure 2). Results were essentially unchanged in a sensitivity analysis including undetermined deaths as CV deaths (HR 0.90; 95% CI, 0.84–0.96; P = 0.002). The treatment effect on MACE was consistent across FINEARTS-HF (HR 0.95; 95% CI 0.86–1.05), FIDELIO-DKD (HR 0.88; 95% CI 0.76–1.02), and FIGARO-DKD (HR 0.87; 95% CI 0.76–1.00); P int =0.55. Risk reductions did not differ by the number of CKM conditions ( P int =0.98). Conclusion: Among patients with cardio-kidney-metabolic syndrome, major adverse cardiovascular events were frequent, prognostically meaningful, and reduced with the non-steroidal MRA finerenone.

AIMS:Hypokalaemia is associated with cardiovascular events and mortality in patients with chronic kidney disease (CKD). This exploratory FIDELITY analysis, a prespecified pooled patient-dataset from FIDELIO-DKD and FIGARO-DKD, investigated the incidence and effect of hypokalaemia in patients with CKD and type 2 diabetes (T2D) treated with finerenone vs. placebo. METHODS AND RESULTS:Outcomes include the incidence of treatment-emergent hypokalaemia (serum potassium <4.0 or <3.5 mmol/L) and the effect of finerenone on cardiovascular composite outcome (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure) and arrhythmia composite outcome (new diagnosis of atrial fibrillation/atrial flutter, hospitalization due to arrhythmia, or sudden cardiac death) by baseline serum potassium subgroups. In the FIDELITY population, treatment-emergent hypokalaemia with serum potassium <4.0 and <3.5 mmol/L occurred in 41.1% and 7.5%, respectively. Hazards of cardiovascular and arrhythmia composite outcomes were higher in patients with baseline serum potassium <4.0 vs. 4.0-4.5 mmol/L [hazard ratio (HR) 1.16; 95% confidence interval (CI) 1.02-1.32, P = 0.022 and HR 1.20; 95% CI 1.00-1.44, P = 0.055, respectively]. Finerenone reduced the incidence of hypokalaemia with serum potassium <4.0 mmol/L (HR 0.63; 95% CI 0.60-0.66) and <3.5 mmol/L (HR 0.46; 95% CI 0.40-0.53) vs. placebo. Finerenone lessened the hazard of cardiovascular and arrhythmia events vs. placebo, irrespective of baseline serum potassium. CONCLUSION:A substantial proportion of patients with CKD and T2D experienced hypokalaemia, which was associated with an increased hazard of adverse cardiovascular outcomes. Finerenone reduced the incidence of hypokalaemia. Finerenone reduced the hazard of cardiovascular and arrhythmia outcomes irrespective of serum potassium subgroups. Clinical trials registration: FIDELIO-DKD and FIGARO-DKD are registered with ClinicalTrials.gov, numbers NCT02540993 and NCT02545049, respectively (funded by Bayer AG).