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Mineralocorticoid receptor antagonists

TL;DR — Finerenone added to maximally tolerated RAS blockade reduced the FIDELIO-DKD kidney composite (17.8% vs 21.1%; HR 0.82, 95% CI 0.73–0.93) in type 2 diabetes with CKD (Bakris 2020, PMID 33264825). In FIDELITY, the pooled kidney outcome was 5.5% versus 7.1% (HR 0.77, 95% CI 0.67–0.88) and the cardiovascular outcome 12.7% versus 14.4% (HR 0.86, 95% CI 0.78–0.95) (Agarwal 2022, PMID 35023547). Hyperkalaemia-related permanent discontinuation was 1.7% versus 0.6% in the pooled analysis. The non-diabetic gap has since closed: FIND-CKD randomized 1,584 adults with CKD and no diabetes and slowed total eGFR slope by 0.7 mL/min/1.73 m²/year (95% CI 0.3–1.1) over 32 months, with a lower composite kidney-or-cardiovascular event risk (HR 0.77, 95% CI 0.60–0.99) (Heerspink 2026, PMID 42246672).

Steroidal and non-steroidal agents

Spironolactone and eplerenone lower blood pressure and albuminuria but are constrained by hyperkalaemia in reduced GFR. Finerenone now has randomized kidney evidence in diabetic CKD, non-diabetic CKD and type 1 diabetes (Bakris 2020, PMID 33264825) (Heerspink 2026, PMID 42246672) (Heerspink 2026, PMID 41780000).

FIDELIO-DKD

The 5,734-patient trial enrolled albuminuric CKD with type 2 diabetes on optimized RAS blockade; the kidney composite favoured finerenone (Bakris 2020, PMID 33264825).

FIDELITY

Pooling FIDELIO and FIGARO widened the GFR spectrum and improved precision for kidney and cardiovascular outcomes (Agarwal 2022, PMID 35023547).

Hyperkalaemia trade-off

Monitoring is part of the intervention. In the 890 FIDELITY participants (7% of 13,023) with stage 4 CKD, the cardiovascular composite hazard ratio was 0.78 (95% CI 0.57–1.07) and albuminuria and eGFR-decline rate were consistently reduced, but the kidney composite violated the proportional-hazards assumption — protection was seen only to about two years, after which the direction of association was inconsistent and precision was lost. Hyperkalaemia was the commonest adverse event (26% versus 13%), though permanent discontinuation for it stayed low (3% versus 2%) (Sarafidis 2023, PMID 36927680). "Benefit retained in stage 4" overstates what this subgroup shows for kidney endpoints.

Enablement

AMBER showed patiromer kept 86% versus 66% on spironolactone at week 12, a 19.5-point difference (95% CI 10.0–29.0); it tested enablement, not kidney failure (Agarwal 2019, PMID 31533906).

Combination uncertainty

Combination therapy has now been randomized, though not yet for hard outcomes. CONFIDENCE assigned 779 people with type 2 diabetes and CKD (eGFR 30–90, uACR 100–5,000 mg/g) on a RAS inhibitor 1:1:1 to finerenone, empagliflozin, or both; at 180 days the uACR reduction with combination therapy was 29% greater than with finerenone alone (ratio 0.71, 95% CI 0.61–0.82) and 32% greater than with empagliflozin alone (0.68, 0.59–0.79), with no unexpected adverse events (Agarwal 2025, PMID 40470996). A prespecified secondary analysis found combination therapy did not mitigate hyperkalaemia relative to finerenone alone (15.1% combination, 18.8% finerenone, 9.7% empagliflozin; no significant difference between combination and finerenone) and that hyperkalaemia did not mediate the albuminuria effect (Agarwal 2026, PMID 41493296). Lifetime outcome benefits of the full four-class regimen remain modelled rather than randomized (Neuen 2024, PMID 37952217); trials must still distinguish additive efficacy, toxicity, adherence and sequence on hard endpoints.

Outcome and safety balance

Evidence set Kidney result Cardiovascular result Hyperkalaemia signal
FIDELIO-DKD 17.8% vs 21.1%; HR 0.82 (0.73–0.93) 13.0% vs 14.8%; HR 0.86 (0.75–0.99) Discontinuation 2.3% vs 0.9% (Bakris 2020, PMID 33264825)
FIDELITY pooled 5.5% vs 7.1%; HR 0.77 (0.67–0.88) 12.7% vs 14.4%; HR 0.86 (0.78–0.95) Permanent discontinuation 1.7% vs 0.6% (Agarwal 2022, PMID 35023547)
FIND-CKD (no diabetes) Total eGFR slope −3.3 vs −4.0/y; difference 0.7 (0.3–1.1) Kidney-or-CV composite HR 0.77 (0.60–0.99) Hyperkalaemia 17.0% vs 13.3%; discontinuation 1.5% vs 0.1% (Heerspink 2026, PMID 42246672)
INFINITY pooled (FIDELIO+FIGARO+FIND-CKD) Kidney composite HR 0.76 (0.68–0.86); kidney failure 0.85 (0.74–0.99) HF hospitalization or CV death HR 0.80 (0.70–0.91); all-cause death 0.88 (0.79–0.99) Effects consistent irrespective of glycaemic status, aetiology, eGFR, uACR and SGLT2 use (Neuen 2026, PMID 42248158)
FINE-ONE (type 1 diabetes) uACR 25% lower vs placebo at 6 months (ratio 0.75, 0.65–0.87) Not powered for CV outcomes Hyperkalaemia 10.1% vs 3.3%; surrogate endpoint only, n=242 (Heerspink 2026, PMID 41780000)
CONFIDENCE (combination) uACR reduction 29% greater than finerenone alone, 32% greater than empagliflozin alone at day 180 Not an outcome trial Phase 2, 779 randomized, albuminuria endpoint (Agarwal 2025, PMID 40470996)
AMBER enablement Not a kidney-outcome trial Not powered for CV outcomes On spironolactone at week 12: 86% vs 66% (Agarwal 2019, PMID 31533906)

FIGARO-DKD: the other half of the finerenone programme

FIDELIO-DKD tested finerenone in predominantly G3–G4 CKD with severe albuminuria; FIGARO-DKD tested the complementary population — uACR 30 to <300 with eGFR 25–90, or uACR 300–5,000 with eGFR ≥60 — in 7,437 patients on maximum-tolerated RAS blockade. Over median 3.4 years the primary outcome was cardiovascular: death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke or hospitalisation for heart failure occurred in 458/3,686 (12.4%) versus 519/3,666 (14.2%) — HR 0.87 (95% CI 0.76–0.98; p = 0.03) — driven mainly by fewer heart-failure hospitalisations (HR 0.71, 0.56–0.90). The kidney composite (kidney failure, sustained ≥40% eGFR decrease, or renal death) occurred in 9.5% versus 10.8% (HR 0.87, 0.76–1.01), not statistically significant (Pitt 2021, PMID 34449181). The two trials therefore establish a cardiorenal effect whose kidney component is significant in the higher-albuminuria population and its cardiac component in the broader one — which is why the FIDELITY pooling (PMID 35023547) rather than either trial alone is the basis for the class position.

How much of the benefit runs through albuminuria

A prespecified mediation analysis pooling FIDELIO-DKD and FIGARO-DKD (12,512 patients, median baseline uACR 514 mg/g) asked what proportion of finerenone's 4-year benefit was carried by the change in log uACR from baseline to month 4. A ≥30% uACR reduction occurred in 3,338 (53.2%) on finerenone versus 1,684 (27.0%) on placebo. Treated as a continuous variable, early albuminuria reduction mediated 84% of the treatment effect on the kidney composite and 37% on the cardiovascular composite; treated as a binary ≥30% threshold, 64% and 26% respectively (Agarwal 2023, PMID 38048573).

This analysis quantifies statistical mediation for finerenone; it does not prove that changing albuminuria itself causes the outcome benefit. The authors state explicitly that the finding does not extend to other agents. The 84%-versus-37% split suggests that measured early albuminuria change accounts for much less of the cardiovascular association than of the kidney association.

Steroidal MRAs are not interchangeable with finerenone

Two randomized trials have now tested spironolactone where finerenone works, and both were negative.

Moderate CKD. BARACK-D randomized 1,434 older adults (mean age 74.8 ± 8.1) with stage 3b CKD in English primary care to spironolactone 25 mg plus usual care or usual care alone. Over 3 years the composite of death, hospitalisation for heart disease, stroke, heart failure, TIA or peripheral arterial disease, or first onset of any of those conditions, occurred in 113/677 (16.7%) versus 111/695 (16.0%) — HR 1.05 (95% CI 0.81–1.37). Two-thirds of those randomized to spironolactone stopped within 6 months, most commonly for a protocol-defined eGFR fall (n = 239, 35.4%), then side effects (n = 128, 18.9%), then hyperkalaemia (n = 54, 8.0%). The authors conclude spironolactone should not be used in stage 3b CKD without another explicit indication (Hobbs 2024, PMID 39349629).

Dialysis. ACHIEVE randomized 2,538 maintenance dialysis patients across 143 programmes in 12 countries — after an open-label run-in that had already selected for tolerance — to continue spironolactone 25 mg or switch to placebo. Stopped early for futility at a planned interim analysis, the composite of cardiovascular mortality or heart-failure hospitalisation occurred at 10.46 versus 11.33 events per 100 patient-years (HR 0.92, 95% CI 0.78–1.09; p = 0.35), with all-cause death HR 0.95 (0.83–1.09) and all-cause hospitalisation HR 0.96 (0.87–1.06) over median 1.8 years (Walsh 2025, PMID 40818850).

The run-in design in ACHIEVE matters: the randomized population had already demonstrated it could tolerate spironolactone, so the null result is not explained by intolerance. Taken with BARACK-D, the evidence supports treating "MRA" as two distinct interventions in CKD rather than a class with a shared indication. What remains unresolved is whether the difference is pharmacological (non-steroidal selectivity, tissue distribution, potassium effect) or a difference in trial population and endpoint — no trial has randomized finerenone against spironolactone on kidney outcomes.

Finerenone where the kidney is not the target

FINEARTS-HF randomized 6,001 patients with heart failure and mildly reduced or preserved ejection fraction (mean eGFR 62 ± 20; 48% below 60; median uACR 18 mg/g, IQR 7–67). Over median 2.6 years the composite of sustained ≥50% eGFR decline or kidney failure was numerically higher with finerenone (75 vs 55 events; HR 1.33, 95% CI 0.94–1.89), as was the ≥57% version (41 vs 31; HR 1.28, 0.80–2.05). Finerenone caused an acute eGFR decline of −2.9 mL/min/1.73 m² (95% CI −3.4 to −2.4) in the first 3 months but did not alter the chronic slope thereafter (+0.2 mL/min/1.73 m²/year, −0.1 to 0.4), giving a total slope difference of −0.7 (−0.9 to −0.4); it reduced uACR by 30% (25–34%) at 6 months, an effect sustained through follow-up, and reduced new-onset micro- and macroalbuminuria (Mc Causland 2025, PMID 39490700).

This illustrates how an acute dip can influence an eGFR-defined kidney composite in a population with low baseline albuminuria and relatively preserved function. The dip could contribute to the numerically higher event count, but the analysis does not establish that it explains the difference; the confidence interval of 0.94–1.89 cannot distinguish harm from no effect.

Trial Population Primary/kidney result Reading
FIDELIO-DKD (PMID 33264825) T2D, uACR 30–5,000, eGFR 25–75 Kidney composite significant Kidney indication anchor
FIGARO-DKD (PMID 34449181) T2D, lower-albuminuria/higher-eGFR spectrum, n=7,437 CV composite HR 0.87 (0.76–0.98); kidney HR 0.87 (0.76–1.01) Cardiac benefit; kidney not significant alone
FIDELITY pooled (PMID 35023547) Both above, n=13,026 Basis for guideline recommendations Pooling required for both outcomes
BARACK-D (PMID 39349629) Stage 3b CKD, mean age 74.8, n=1,434 Composite HR 1.05 (0.81–1.37); 67% stopped by 6 months Spironolactone not a substitute
ACHIEVE (PMID 40818850) Maintenance dialysis, n=2,538, run-in selected CV death/HF hospitalisation HR 0.92 (0.78–1.09); stopped for futility Negative in kidney failure
FINEARTS-HF kidney analysis (PMID 39490700) HFmrEF/HFpEF, n=6,001, median uACR 18 mg/g Kidney composite HR 1.33 (0.94–1.89); uACR −30%; chronic slope unchanged Acute dip counted as events

Hyperkalaemia with finerenone, quantified and modifiable

The hyperkalaemia risk that limits mineralocorticoid receptor antagonism has been characterised in detail. In a post hoc safety analysis of FIDELIO-DKD over median 2.6 years, treatment-emergent hyperkalaemia of at least mild severity (serum potassium >5.5 mmol/L) occurred in 597/2,785 (21.4%) on finerenone versus 256/2,775 (9.2%) on placebo, and moderate hyperkalaemia (>6.0 mmol/L) in 126/2,802 (4.5%) versus 38/2,796 (1.4%), with cumulative incidences estimated by Aalen–Johansen using death as a competing risk (Agarwal 2022, PMID 34732509).

Independent predictors of at least mild hyperkalaemia were higher baseline serum potassium, lower eGFR, higher uACR, younger age, female sex, β-blocker use and finerenone assignment. Diuretic or SGLT2 inhibitor use reduced risk. Short-term post-baseline increases in serum potassium and decreases in eGFR predicted subsequent hyperkalaemia in both arms — but by month 4 the magnitude of increased risk for any given change from baseline was smaller with finerenone than with placebo (Agarwal 2022, PMID 34732509).

Three points are practically consequential. The absolute excess of moderate hyperkalaemia was 3.1 percentage points over 2.6 years, against the cardiorenal benefit established in the same trial — a trade-off that can be stated numerically rather than qualitatively. SGLT2 inhibitor co-prescription reduces the risk, which is a pharmacological argument for the combination that CONFIDENCE (PMID 40470996) later tested directly, and which the CONFIDENCE hyperkalaemia analysis (PMID 41493296) addresses. And the protocol itself — withholding drug at potassium >5.5 mmol/L until ≤5.0, then restarting at 10 mg, with sham interruption in the placebo arm — is the monitoring strategy under which the trial's benefit was obtained, so the effect estimate is conditional on that level of surveillance.

Interleukin-6 as the next cardiorenal target

The inflammation hypothesis that CANTOS supported in a CKD subgroup (see pathophysiology and progression) is now being tested prospectively in a CKD-enriched population. ZEUS (NCT05021835) is a multinational, double-blind, placebo-controlled, event-driven trial randomising 6,376 participants with atherosclerotic cardiovascular disease, CKD and hs-CRP ≥2 mg/L 1:1 to ziltivekimab 15 mg subcutaneously monthly or placebo. At randomisation, mean age was 69.5 years, 27.5% were women, 92.0% had hypertension, 65.7% diabetes and 41.3% heart failure; mean eGFR was 44.5 mL/min/1.73 m², mean LDL 77.7 mg/dL, median hs-CRP 4.5 mg/L and median IL-6 4.9 pg/mL. SGLT2 inhibitors were in use by 36.8% and GLP-1 receptor agonists by 11.3% at enrolment. The primary outcome is 3-point major adverse cardiovascular events, with secondary outcomes including an expanded MACE composite and heart-failure hospitalisation or cardiovascular death (Ridker 2026, PMID 41369941).

A mean baseline eGFR of 44.5 makes ZEUS effectively a CKD trial with cardiovascular endpoints, and its background SGLT2 inhibitor use of 36.8% means any benefit will be additive to a partially modernised regimen. It is the first adequately powered prospective test of anti-inflammatory therapy in this population.

Decision and interpretation matrix

Dimension Question Guardrail
Diagnostic axis Cause + G category + A category Avoid treating eGFR as the diagnosis
Time axis Chronicity and trajectory Separate acute change from persistent disease
Risk axis Kidney failure + cardiovascular events + death Show competing events
Treatment axis Eligibility, absolute benefit, harm, burden Do not rank drugs by relative effect alone
Measurement axis Assay, equation, repeatability State what was actually measured
Equity axis Testing, referral, access, affordability Audit downstream care, not labels only
Patient axis Symptoms, function, life participation Include outcomes patients prioritize
Evidence axis RCT, cohort, model, guideline Do not collapse designs

Evidence ledger

This ledger makes the page’s evidentiary mix inspectable. It does not imply that every source answers every question.

PMID Record used Role and boundary
33264825 Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. (Bakris 2020, PMID 33264825) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
35023547 Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. (Agarwal 2022, PMID 35023547) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
36927680 Finerenone outcomes in stage 4 CKD and type 2 diabetes. (Sarafidis 2023, PMID 36927680) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
31533906 Patiromer to enable spironolactone in resistant hypertension and CKD: AMBER. (Agarwal 2019, PMID 31533906) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
37952217 Estimated Lifetime Cardiovascular, Kidney, and Mortality Benefits of Combination Treatment With SGLT2 Inhibitors, GLP-1 Receptor Agonists, and Nonsteroidal MRA Compared With Conventional Care in Patients With Type 2 Diabetes and Albuminuria. (Neuen 2024, PMID 37952217) Modelled projection; the estimate follows from the model inputs and assumptions, not from observed randomized follow-up.
38490803 KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. (KDIGO CKD Work Group 2024, PMID 38490803) Guideline or commentary; recommendation evidence depends on its review.
38519239 Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease: known knowns and known unknowns. (Levin 2024, PMID 38519239) Guideline or commentary; recommendation evidence depends on its review.
11565518 Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. (Brenner 2001, PMID 11565518) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
11565517 Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. (Lewis 2001, PMID 11565517) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
11565519 The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. (Parving 2001, PMID 11565519) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
18707986 Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk: the ONTARGET study. (Mann 2008, PMID 18707986) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
24206457 Combined angiotensin inhibition for the treatment of diabetic nephropathy. (Fried 2013, PMID 24206457) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
32970396 Dapagliflozin in Patients with Chronic Kidney Disease. (Heerspink 2020, PMID 32970396) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
34619108 Effect of dapagliflozin on the rate of decline in kidney function in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial. (Heerspink 2021, PMID 34619108) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
36331190 Empagliflozin in Patients with Chronic Kidney Disease. (EMPA-KIDNEY Collaborative Group 2023, PMID 36331190) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
38061371 Effects of empagliflozin on progression of chronic kidney disease: a prespecified secondary analysis from the EMPA-KIDNEY trial. (EMPA-KIDNEY Collaborative Group 2024, PMID 38061371) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
30990260 Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. (Perkovic 2019, PMID 30990260) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
38785209 Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. (Perkovic 2024, PMID 38785209) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
38914124 Effects of semaglutide with and without concomitant SGLT2 inhibitor use in participants with type 2 diabetes and chronic kidney disease in the FLOW trial. (Mann 2024, PMID 38914124) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
30697905 SGLT2 inhibitors and cardiovascular, renal and safety outcomes in T2D and CKD: meta-analysis. (Toyama 2019, PMID 30697905) Synthesis; heterogeneity and included-study definitions constrain transport.
36316605 SGLT2 inhibitors in advanced CKD: systematic review and meta-analysis. (Cao 2023, PMID 36316605) Synthesis; heterogeneity and included-study definitions constrain transport.
36272755 Executive summary of KDIGO 2022 Diabetes Management in CKD guideline. (Rossing 2022, PMID 36272755) Guideline or commentary; recommendation evidence depends on its review.
33637203 Executive summary of KDIGO 2021 Blood Pressure in CKD guideline. (Cheung 2021, PMID 33637203) Guideline or commentary; recommendation evidence depends on its review.
40542996 Novel potassium binders, hyperkalemia and RAAS inhibitor optimization: meta-analysis. (Huang 2025, PMID 40542996) Synthesis; heterogeneity and included-study definitions constrain transport.
32061315 Global, regional, and national burden of chronic kidney disease, 1990-2017. (GBD CKD Collaboration 2020, PMID 32061315) Modelled projection; the estimate follows from the model inputs and assumptions, not from observed randomized follow-up.
42246672 Finerenone in Persons with Chronic Kidney Disease without Diabetes (FIND-CKD). (Heerspink 2026, PMID 42246672) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
42248158 Finerenone across CKD: individual participant data pooled analysis (INFINITY). (Neuen 2026, PMID 42248158) Synthesis; heterogeneity and included-study definitions constrain transport.
41780000 Finerenone in Type 1 Diabetes and Chronic Kidney Disease (FINE-ONE). (Heerspink 2026, PMID 41780000) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
40470996 Finerenone with Empagliflozin in Chronic Kidney Disease and Type 2 Diabetes (CONFIDENCE). (Agarwal 2025, PMID 40470996) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.
41493296 Hyperkalaemia with empagliflozin, finerenone or both: CONFIDENCE secondary analysis. (Agarwal 2026, PMID 41493296) Intervention study; eligibility, comparator, endpoint and follow-up bound inference.

What can and cannot be concluded

  • Risk associations do not by themselves establish that changing the marker changes risk.
  • A relative effect must be paired with baseline risk, follow-up and the exact endpoint.
  • Albuminuria, acute eGFR change, chronic eGFR slope and kidney failure are not interchangeable.
  • Subgroup consistency is not evidence that every subgroup had adequate power.
  • Guideline recommendations combine evidence with values, feasibility, cost and service capacity.
  • Older adults require competing-mortality and treatment-burden framing.
  • Dialysis and transplantation comparisons are vulnerable to eligibility and immortal-time bias.
  • Modelled lifetime benefit is not a randomized observed benefit.
  • A biochemical response without a patient-important outcome remains a surrogate result.
  • This page is research synthesis, not individualized medical advice.

Research-design checklist

  • Define CKD cause, G category, A category and chronicity at baseline.
  • Report the creatinine or cystatin C equation and laboratory calibration.
  • Prespecify acute and chronic eGFR slopes when haemodynamic effects are expected.
  • Keep sustained GFR decline, kidney failure and replacement therapy separable.
  • Report absolute event risks, follow-up and confidence intervals with relative effects.
  • Treat death as a competing event where it can preclude kidney failure.
  • Measure hyperkalaemia, acute kidney injury and treatment discontinuation consistently.
  • Include symptoms, function, life participation and treatment burden.
  • Describe background RAS, SGLT2, MRA and GLP-1 therapy explicitly.
  • Prespecify albuminuria and cause strata without over-reading underpowered interactions.
  • Record screening, prescribing, persistence and monitoring as separate implementation steps.
  • Report representation, access and affordability variables needed for equity analysis.

Open questions

  • Does finerenone reduce kidney failure, as opposed to eGFR slope, in non-diabetic CKD? FIND-CKD's primary endpoint was total eGFR slope; the composite kidney-or-cardiovascular hazard ratio of 0.77 (0.60–0.99) was hierarchically tested and the kidney-only component crossed 1.0 (0.78, 0.60–1.01) (Heerspink 2026, PMID 42246672). → OQ-2
  • Why did the FIDELITY stage-4 kidney benefit fail the proportional-hazards assumption after roughly two years, and does that reflect power, competing events or attenuating effect (Sarafidis 2023, PMID 36927680)?
  • Does the finerenone–SGLT2 combination translate its 29% extra albuminuria reduction into fewer kidney-failure events? CONFIDENCE was a 180-day phase 2 albuminuria trial (Agarwal 2025, PMID 40470996). → OQ-1
  • Does the FINE-ONE albuminuria result in type 1 diabetes predict a kidney-outcome benefit, given that 242 participants and six months cannot test it (Heerspink 2026, PMID 41780000)?

  • If combination therapy does not mitigate hyperkalaemia relative to finerenone alone (Agarwal 2026, PMID 41493296), what monitoring schedule makes layered therapy deliverable outside trial conditions?

  • Is the finerenone–spironolactone difference pharmacological or an artefact of trial population and endpoint? Two randomized trials of spironolactone in CKD (BARACK-D, PMID 39349629) and dialysis (ACHIEVE, PMID 40818850) were null, but no trial has randomized finerenone against spironolactone on kidney outcomes.

  • Does the mediation result generalize? Early albuminuria reduction mediated 84% of finerenone's kidney benefit and 37% of its cardiovascular benefit, but the authors state the finding is not readily extendable to other drugs (Agarwal 2023, PMID 38048573).
  • Was the numerically higher kidney-event count with finerenone in FINEARTS-HF harm or endpoint artefact? The acute dip was −2.9 mL/min/1.73 m² while chronic slope was unchanged and albuminuria fell 30% (Mc Causland 2025, PMID 39490700).

  • Why is 67% early discontinuation acceptable evidence of ineffectiveness in BARACK-D but the same design feature (run-in selection for tolerance) in ACHIEVE also produced a null result (Hobbs 2024, PMID 39349629) (Walsh 2025, PMID 40818850)?

  • Is the finerenone hyperkalaemia risk acceptable outside trial surveillance? The 21.4%-versus-9.2% mild and 4.5%-versus-1.4% moderate rates were obtained under a protocol of scheduled potassium measurement with drug withholding at >5.5 mmol/L and restart at 10 mg (Agarwal 2022, PMID 34732509).

  • Why do younger age and female sex independently predict hyperkalaemia on finerenone (Agarwal 2022, PMID 34732509)? Neither is explained by the usual eGFR and potassium mechanisms.
  • Does IL-6 inhibition reduce cardiovascular events in CKD, and does it affect kidney outcomes? ZEUS randomised 6,376 participants with mean eGFR 44.5 mL/min/1.73 m² (Ridker 2026, PMID 41369941).

References

  1. Bakris et al. Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. N Engl J Med. 2020;383(23):2219-2229. PMID 33264825
  2. Agarwal et al. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. Eur Heart J. 2022;43(6):474-484. PMID 35023547
  3. Sarafidis et al. Finerenone outcomes in stage 4 CKD and type 2 diabetes. Clin J Am Soc Nephrol. 2023;18(5):602-612. PMID 36927680
  4. Agarwal et al. Patiromer to enable spironolactone in resistant hypertension and CKD: AMBER. Lancet. 2019;394(10208):1540-1550. PMID 31533906
  5. Neuen et al. Estimated Lifetime Cardiovascular, Kidney, and Mortality Benefits of Combination Treatment With SGLT2 Inhibitors, GLP-1 Receptor Agonists, and Nonsteroidal MRA Compared With Conventional Care in Patients With Type 2 Diabetes and Albuminuria. Circulation. 2024;149(6):450-462. PMID 37952217
  6. KDIGO CKD Work Group et al. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2024;105(4S):S117-S314. PMID 38490803
  7. Levin et al. Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease: known knowns and known unknowns. Kidney Int. 2024;105(4):684-701. PMID 38519239
  8. Brenner et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345(12):861-869. PMID 11565518
  9. Lewis et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345(12):851-860. PMID 11565517
  10. Parving et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345(12):870-878. PMID 11565519
  11. Mann et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk: the ONTARGET study. Lancet. 2008;372(9638):547-553. PMID 18707986
  12. Fried et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013;369(20):1892-1903. PMID 24206457
  13. Heerspink et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436-1446. PMID 32970396
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