The complementary studies FIDELIO-DKD and FIGARO-DKD in patients with type 2 diabetes and chronic kidney disease (CKD) examined cardiovascular and kidney outcomes in different, overlapping stages of CKD. The purpose of the FIDELITY analysis was to perform an individual patient-level prespecified pooled efficacy and safety analysis across a broad spectrum of CKD to provide more robust estimates of safety and efficacy of finerenone compared with placebo. For this prespecified analysis, two phase III, multicentre, double-blind trials involving patients with CKD and type 2 diabetes, randomized 1:1 to finerenone or placebo, were combined. Main time-to-event efficacy outcomes were a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure, and a composite of kidney failure, a sustained ≥57% decrease in estimated glomerular filtration rate from baseline over ≥4 weeks, or renal death. Among 13 026 patients with a median follow-up of 3.0 years (interquartile range 2.3–3.8 years), the composite cardiovascular outcome occurred in 825 (12.7%) patients receiving finerenone and 939 (14.4%) receiving placebo [hazard ratio (HR), 0.86; 95% confidence interval (CI), 0.78–0.95; P = 0.0018]. The composite kidney outcome occurred in 360 (5.5%) patients receiving finerenone and 465 (7.1%) receiving placebo (HR, 0.77; 95% CI, 0.67–0.88; P = 0.0002). Overall safety outcomes were generally similar between treatment arms. Hyperkalaemia leading to permanent treatment discontinuation occurred more frequently in patients receiving finerenone (1.7%) than placebo (0.6%). Finerenone reduced the risk of clinically important cardiovascular and kidney outcomes vs. placebo across the spectrum of CKD in patients with type 2 diabetes. Does finerenone, a novel selective, nonsteroidal mineralocorticoid receptor antagonist, added to maximum tolerated renin–angiotensin system inhibition reduce cardiovascular disease and kidney disease progression over a broad range of chronic kidney disease in patients with type 2 diabetes? In a prespecified, pooled individual-level analysis from two randomized trials, we found reductions both in cardiovascular events and kidney failure outcomes with finerenone. Because 40% of the patients had an estimated glomerular filtration rate of >60 mL/min/1.73m² they were identified solely on the basis of albuminuria. Finerenone reduces the risk of clinical cardiovascular outcomes and kidney disease progression in a broad range of patients with chronic kidney disease and type 2 diabetes. Screening for albuminuria to identify at-risk patients among patients with type 2 diabetes facilitates reduction of both cardiovascular and kidney disease burden. Finerenone reduced the risk of clinically important cardiovascular and kidney outcomes versus placebo across the spectrum of chronic kidney disease in patients with type 2 diabetes.

Mineralocorticoid receptor antagonists (MRAs) improve outcomes in patients with heart failure and reduced left ventricular ejection fraction (HFrEF), but their use is limited by hyperkalaemia and/or worsening renal function (WRF). BAY 94-8862 is a highly selective and strongly potent non-steroidal MRA. We investigated its safety and tolerability in patients with HFrEF associated with mild or moderate chronic kidney disease (CKD). This randomized, controlled, phase II trial consisted of two parts. In part A, the safety and tolerability of oral BAY 94-8862 [2.5, 5, or 10 mg once daily (q.d.)] was assessed in 65 patients with HFrEF and mild CKD. In part B, BAY 94-8862 (2.5, 5, or 10 mg q.d., or 5 mg twice daily) was compared with placebo and open-label spironolactone (25 or 50 mg/day) in 392 patients with HFrEF and moderate CKD. BAY 94-8862 was associated with significantly smaller mean increases in serum potassium concentration than spironolactone (0.04–0.30 and 0.45 mmol/L, respectively, P < 0.0001–0.0107) and lower incidences of hyperkalaemia (5.3 and 12.7%, respectively, P = 0.048) and WRF. BAY 94-8862 decreased the levels of B-type natriuretic peptide (BNP), amino-terminal proBNP, and albuminuria at least as much as spironolactone. Adverse events related to BAY 94-8862 were infrequent and mostly mild. In patients with HFrEF and moderate CKD, BAY 94-8862 5–10 mg/day was at least as effective as spironolactone 25 or 50 mg/day in decreasing biomarkers of haemodynamic stress, but it was associated with lower incidences of hyperkalaemia and WRF.

To evaluate efficacy and safety of RLY5016 (a non-absorbed, orally administered, potassium [K⁺]-binding polymer) on serum K⁺ levels in patients with chronic heart failure (HF) receiving standard therapy and spironolactone. One hundred and five patients with HF and a history of hyperkalaemia resulting in discontinuation of a renin–angiotensin–aldosterone system inhibitor/blocker and/or beta-adrenergic blocking agent or chronic kidney disease (CKD) with an estimated glomerular filtration rate of 5.5 mEq/L); and the proportion titrated to spironolactone 50 mg/day. Safety assessments included adverse events (AEs) and clinical laboratory tests. RLY5016 (n= 55) and placebo (n= 49) patients had similar baseline characteristics. At the end of treatment, compared with placebo, RLY5016 had significantly lowered serum K⁺ levels with a difference between groups of −0.45 mEq/L (P < 0.001); a lower incidence of hyperkalaemia (7.3% RLY5016 vs. 24.5% placebo, P= 0.015); and a higher proportion of patients on spironolactone 50 mg/day (91% RLY5016 vs. 74% placebo, P= 0.019). In patients with CKD (n= 66), the difference in K⁺ between groups was −0.52 mEq/L (P= 0.031), and the incidence of hyperkalaemia was 6.7% RLY5016 vs. 38.5% placebo (P= 0.041). Adverse events were mainly gastrointestinal, and mild or moderate in severity. Adverse events resulting in study withdrawal were similar (7% RLY5016, 6% placebo). There were no drug-related serious AEs. Hypokalaemia (K⁺ <3.5 mEq/L) occurred in 6% of RLY5016 patients vs. 0% of placebo patients (P= 0.094). RLY5016 prevented hyperkalaemia and was relatively well tolerated in patients with HF receiving standard therapy and spironolactone (25–50 mg/day) (ClinicalTrials.gov registry identifier: NCT00868439).

To investigate the impact of patiromer on the serum potassium level and its ability to enable specified target doses of renin–angiotensin–aldosterone system inhibitor (RAASi) use in patients with heart failure and reduced ejection fraction (HFrEF). A total of 1642 patients with HFrEF and current or a history of RAASi-related hyperkalemia were screened and 1195 were enrolled in the run-in phase with patiromer and optimization of the RAASi therapy [≥50% recommended dose of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, and 50 mg of mineralocorticoid receptor antagonist (MRA) spironolactone or eplerenone]. Specified target doses of the RAASi therapy were achieved in 878 (84.6%) patients; 439 were randomized to patiromer and 439 to placebo. All patients, physicians, and outcome assessors were blinded to treatment assignment. The primary endpoint was between-group difference in the adjusted mean change in serum potassium. Five hierarchical secondary endpoints were assessed. At the end of treatment, the median (interquartile range) duration of follow-up was 27 (13–43) weeks, the adjusted mean change in potassium was +0.03 mmol/l in the patiromer group and +0.13 mmol/l in the placebo group [difference in the adjusted mean change between patiromer and placebo: −0.10 mmol/l (95% confidence interval, CI −0.13, 0.07); P < 0.001]. Risk of hyperkalemia >5.5 mmol/l [hazard ratio (HR) 0.63; 95% CI 0.45, 0.87; P = 0.006), reduction of MRA dose (HR 0.62; 95% CI 0.45, 0.87; P = 0.006), and total adjusted hyperkalemia events/100 person-years (77.7 vs. 118.2; HR 0.66; 95% CI 0.53, 0.81; P < 0.001) were lower with patiromer. Hyperkalemia-related morbidity-adjusted events (win ratio 1.53, P < 0.001) and total RAASi use score (win ratio 1.25, P = 0.048) favored the patiromer arm. Adverse events were similar between groups. Concurrent use of patiromer and high-dose MRAs reduces the risk of recurrent hyperkalemia (ClinicalTrials.gov: NCT03888066). Study design, primary and secondary endpoints of the DIAMOND trial.

Background— Aldosterone blockade is recommended for patients with congestive heart failure after acute myocardial infarction complicated by left ventricular systolic dysfunction; however, the perceived risk of hyperkalemia may limit implementation of this therapeutic approach. This subanalysis examined the relationship between eplerenone, serum potassium (K ⁺ ), and clinical outcomes in the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Methods and Results— Hospitalized patients with congestive heart failure after acute myocardial infarction complicated by left ventricular systolic dysfunction (left ventricular ejection fraction ≤40%) treated with standard therapy were randomized 3 to 14 days after the acute myocardial infarction to additional treatment with eplerenone (25 to 50 mg/d; n=3319) or placebo (n=3313). Patients were excluded if baseline K ⁺ was >5.0 mEq/L or serum creatinine was >2.5 mg/dL. In patients receiving standard therapy, the addition of eplerenone resulted in a 4.4% absolute increase in the incidence of K ⁺ >5.5 mEq/L, a 1.6% increase of K ⁺ ≥6.0 mEq/L, and a 4.7% absolute decrease in hypokalemia (K ⁺ <3.5 mEq/L). Four independent baseline predictors of hyperkalemia (defined as ≥6.0 mEq/L) were identified: potassium (K ⁺ greater than the median; 4.3 mEq/L), estimated glomerular filtration rate (≤60 mL · min ⁻¹ · 1.73 m ⁻² ), history of diabetes mellitus, and prior use of antiarrhythmic agents. None of these independent baseline risk factors significantly impacted the cardiovascular benefit of eplerenone for reducing all-cause mortality. Conclusions— Use of selective aldosterone blockade with eplerenone within the dose range of 25 to 50 mg/d in post–acute myocardial infarction patients with heart failure and left ventricular systolic dysfunction who are treated with standard therapy improves outcomes without an excess of risk of hyperkalemia (≥6.0 mEq/L) when periodic monitoring of serum K ⁺ is instituted.