Highlights
– In MIRO‑CKD, balcinrenone combined with dapagliflozin produced dose‑dependent reductions in urine albumin‑to‑creatinine ratio (UACR) compared with dapagliflozin alone at 12 weeks (−22.8% for balcinrenone 15 mg; −32.8% for balcinrenone 40 mg).
– Treatment was generally well tolerated; investigator‑reported hyperkalaemia events were low and similar across groups (5–7%).
– The trial was a global, randomized, double‑blind, active‑controlled phase 2b study (NCT06350123) and supports further evaluation of combined non‑steroidal MRA and SGLT2 inhibitor therapy for CKD with albuminuria.
Background
Chronic kidney disease (CKD) with albuminuria is a leading cause of progression to end‑stage kidney disease (ESKD) and is associated with cardiovascular morbidity and mortality. Two therapeutic axes have independently demonstrated renal‑protective effects: SGLT2 inhibitors (for example, dapagliflozin) reduce albuminuria and hard renal outcomes in people with CKD with and without diabetes, and non‑steroidal mineralocorticoid receptor antagonists (MRAs) such as finerenone lower albuminuria and reduce kidney and cardiovascular events in patients with type 2 diabetes and CKD. Combining complementary renoprotective mechanisms—SGLT2 inhibition to reduce intraglomerular hypertension and non‑steroidal MRA therapy to mitigate mineralocorticoid receptor‑mediated inflammation and fibrosis—could plausibly yield additive benefits, but safety concerns (especially hyperkalaemia) require careful assessment in randomized trials.
Study design
MIRO‑CKD was a multicentre, randomized, double‑blind, active‑controlled, dose‑finding phase 2b trial performed at 106 sites across 15 countries. Eligible adults had an estimated glomerular filtration rate (eGFR) of 25 to <60 mL/min/1.73 m2, urine albumin‑to‑creatinine ratio (UACR) >100 to ≤5000 mg/g, and serum potassium 3.5–5.0 mmol/L at baseline. Participants were randomized 1:1:1 to receive once‑daily balcinrenone 15 mg plus dapagliflozin 10 mg, balcinrenone 40 mg plus dapagliflozin 10 mg, or dapagliflozin 10 mg plus matched placebo (double‑dummy), as add‑on therapy to background renin–angiotensin system (RAS) blockade where tolerated. Treatment lasted 12 weeks followed by an 8‑week washout.
The primary efficacy endpoint was the relative change in UACR from baseline to week 12 in the intention‑to‑treat population of participants who received at least one dose of study medication. Missing UACR values were not imputed (assumed missing at random). Key secondary outcomes included safety and tolerability assessments, with special attention to hyperkalaemia, hypotension, and renal adverse events. The trial was registered at ClinicalTrials.gov (NCT06350123) and funded by AstraZeneca.
Key findings
Population: Between May and December 2024, 324 participants were randomized: 108 to balcinrenone 15 mg + dapagliflozin 10 mg, 110 to balcinrenone 40 mg + dapagliflozin 10 mg, and 106 to dapagliflozin 10 mg + placebo. Mean age was 64.6 years (SD 12.4), mean eGFR 42.2 mL/min/1.73 m2 (SD 10.5), and median baseline UACR 365 mg/g (IQR 157–825). Fifty‑six percent were already on an SGLT2 inhibitor prior to randomization. The cohort included 32% Asian, 7% Black/African American, and 56% White participants; 34% were female.
Primary efficacy: Both balcinrenone doses produced statistically significant and clinically meaningful reductions in albuminuria compared with dapagliflozin alone. At week 12 the percentage UACR difference versus dapagliflozin plus placebo was:
– −22.8% (90% CI −33.3 to −10.7; p = 0.0038) for balcinrenone 15 mg plus dapagliflozin 10 mg
– −32.8% (90% CI −42.0 to −22.1; p < 0.0001) for balcinrenone 40 mg plus dapagliflozin 10 mg.
These results indicate a dose‑dependent incremental anti‑albuminuric effect when adding balcinrenone to dapagliflozin. The reductions were observed throughout the 12‑week treatment period and partially reversed during the washout, consistent with a treatment effect rather than permanent structural change over the short study interval.
Safety: Investigator‑reported hyperkalaemia events were infrequent and relatively balanced across groups: 6% (7/108) for balcinrenone 15 mg + dapagliflozin, 7% (8/110) for balcinrenone 40 mg + dapagliflozin, and 5% (5/106) for dapagliflozin + placebo. Events of hypotension and renal adverse events were few and similarly distributed across arms; none were reported as serious. Two deaths occurred during the overall study period but both were >28 days after the last study dose; no deaths were considered related to study drug during treatment. Overall, the combination appeared well tolerated in this 12‑week window.
Context with prior evidence: The magnitude of albuminuria reduction with combined balcinrenone and dapagliflozin in MIRO‑CKD is comparable to or greater than reductions seen with non‑steroidal MRAs alone and builds on the renal benefits of SGLT2 inhibitors observed in larger outcome trials. For example, SGLT2 inhibition alone reduced kidney disease progression in DAPA‑CKD, and non‑steroidal MRAs such as finerenone have reduced albuminuria and improved renal outcomes in diabetes‑CKD populations. MIRO‑CKD provides randomized evidence supporting additive anti‑albuminuric effects from combining these two drug classes.
Expert commentary and interpretation
Biological plausibility: The observed additive reduction in UACR when combining a non‑steroidal MRA with an SGLT2 inhibitor is biologically plausible. SGLT2 inhibitors lower intraglomerular pressure via natriuresis and tubuloglomerular feedback, while MRAs antagonize mineralocorticoid receptor–driven inflammation, fibrosis, and sodium retention. Together, these mechanisms can act synergistically to reduce glomerular protein leakage and downstream progression signals.
Clinical significance: Albuminuria is an established surrogate for CKD progression and cardiovascular risk. A 20–30% relative reduction in UACR over 12 weeks is likely to be meaningful if sustained, and may translate into slower eGFR loss and fewer kidney events over time. However, MIRO‑CKD was not designed or powered to assess clinical outcomes (ESKD, doubling of serum creatinine, or major cardiovascular events), so phase 3 outcome trials will be required to confirm whether the observed albuminuria reductions translate into reductions in hard outcomes.
Safety considerations: Hyperkalaemia is a primary safety concern for MRAs. In MIRO‑CKD, hyperkalaemia rates were modest and similar across groups, suggesting that combining balcinrenone with dapagliflozin does not markedly increase short‑term hyperkalaemia risk compared with dapagliflozin alone in a selected population with baseline potassium ≤5.0 mmol/L and with background monitoring. That said, the short follow‑up, the trial’s sample size, and selection criteria (excluding patients with higher baseline potassium) limit conclusions about safety in higher‑risk populations. Longer trials with broader enrollment are needed to fully characterize hyperkalaemia risk and to define monitoring protocols and mitigation strategies (dietary guidance, potassium binders, dose modifications).
Limitations and generalisability: Key limitations include the short primary treatment duration (12 weeks), reliance on albuminuria as a surrogate endpoint, and incomplete uniformity of background therapy (56% were already on SGLT2 inhibitors before randomization). The trial excluded individuals with baseline potassium >5.0 mmol/L and may underrepresent frail patients and those with advanced CKD (eGFR <25 mL/min/1.73 m2). The ethnic mix was globally diverse but subgroup analyses for differential effects by race/ethnicity, diabetes status, baseline albuminuria category, or baseline SGLT2 use will be important to interpret applicability. Finally, missing UACR values were not imputed, which is acceptable if missingness is random but can bias results if not.
Implications for practice and research: MIRO‑CKD supplies promising phase 2 evidence that combining a non‑steroidal MRA with an SGLT2 inhibitor augments albuminuria reduction without clear short‑term safety penalties in a selected population. Clinically, this supports further development and phase 3 testing of balcinrenone plus SGLT2 inhibition to determine effects on eGFR trajectory, kidney failure, and cardiovascular outcomes. Trials should include longer follow‑up, predefined potassium management pathways, and evaluation in populations at higher hyperkalaemia risk.
Conclusion
MIRO‑CKD demonstrates that adding balcinrenone to dapagliflozin reduces albuminuria in people with CKD in a dose‑dependent manner over 12 weeks, with acceptable short‑term tolerability and modest hyperkalaemia event rates. These findings are hypothesis‑generating and justify larger, longer outcome trials to determine whether the combination reduces kidney and cardiovascular events and to fully characterize safety across a broader CKD population.
Practical takeaways for clinicians
- Combination therapy with a non‑steroidal MRA plus SGLT2 inhibitor produced clinically meaningful albuminuria reductions versus SGLT2 inhibition alone in MIRO‑CKD.
- Short‑term hyperkalaemia rates were low, but cautious use and serum potassium monitoring are prudent if the combination is used outside trials.
- Until phase 3 outcome data are available, clinicians should view these results as proof‑of‑concept rather than a mandate to combine therapies outside of controlled settings or guideline‑directed scenarios.
Funding and trial registration
MIRO‑CKD was funded by AstraZeneca. ClinicalTrials.gov identifier: NCT06350123.
References
1) Heerspink HJL, Cardona JF, Jolly S, Pergola PE, de Sousa‑Amorim E, Eriksson AL, Fredholm M, Gasparyan SB, Guzman NJ, Hartleib‑Geschwindner J, Jiang Y, Leonsson‑Zachrisson M, Mark PB; MIRO‑CKD study investigators. Balcinrenone in combination with dapagliflozin compared with dapagliflozin alone in patients with chronic kidney disease and albuminuria: a randomised, active‑controlled double‑blind, phase 2b clinical trial. Lancet. 2025 Nov 22;406(10518):2449‑2460. doi: 10.1016/S0140‑6736(25)02014‑8. PMID: 41218621.
2) Heerspink HJL, Stefánsson BV, Correa‑Rotter R, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383:1436‑1446.
3) Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019;380:2295‑2306. (CREDENCE trial)
4) Bakris GL, Agarwal R, Anker SD, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes (FIDELIO‑DKD). N Engl J Med. 2021;385:2173‑2184. (finerenone trials demonstrating benefits of non‑steroidal MRA therapy)
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