Introduction The novel nonsteroidal mineralocorticoid receptor antagonist balcinrenone in combination with dapagliflozin reduced urinary albumin-to-creatinine ratio (UACR) over 12 weeks in the MIRO-CKD phase 2 trial in CKD and induced a modest acute eGFR reduction upon treatment initiation. This prespecified analysis explored the acute eGFR changes in response to balcinrenone/dapagliflozin and the association of these acute eGFR changes on safety and efficacy parameters. Methods Adults with CKD (N=324, eGFR >= 25-<60 ml/min per 1.73 m(2); UACR >= 100-<5000 mg/g) were randomized to balcinrenone/dapagliflozin 15/10 mg, balcinrenone/dapagliflozin 40/10 mg, or dapagliflozin 10 mg/placebo as adjunct to renin-angiotensin system therapy. The primary outcome was the relative change in UACR from baseline over 12 weeks. Acute eGFR changes 4 weeks post randomization and 4 weeks post treatment were assessed using mixed model repeated measures. We categorized participants according to relative eGFR changes: >= 10% reduction (eGFR dip); >0-<10% reduction; or an eGFR increase. We examined safety and concomitant changes in systolic BP (SBP) and UACR across categories of eGFR changes. Results Relative to dapagliflozin/placebo, the acute eGFR dip at week 4 with balcinrenone/dapagliflozin 15/10 mg was -0.6 ml/min per 1.73 m(2 )(95% confidence interval, -2.4 to 1.1) and with balcinrenone/dapagliflozin 40/10 mg -1.7 ml/min per 1.73 m2 (95% confidence interval, -3.5 to -0.01). The acute reduction in eGFR with balcinrenone/dapagliflozin was reversible 4 weeks after treatment discontinuation. This finding was consistent across subgroups. In the overall cohort, larger acute eGFR reductions were associated with larger reductions in UACR and SBP across treatment arms. Rates of serious adverse events and adverse events of special interest were low, similar in the balcinrenone/dapagliflozin versus placebo/dapagliflozin group, and unrelated to the acute eGFR change. Conclusion In adults with CKD, balcinrenone/dapagliflozin induced a modest acute eGFR reduction that was reversible after treatment discontinuation, did not lead to increased rates of adverse events, and was associated with greater SBP and UACR lowering.Clinical Trial registry name and registration number: .
Background Diabetes is the leading cause of kidney failure globally affecting 40% of people receiving peritoneal dialysis (PD). High-quality data on the potential impact of improving glycemic control is needed to inform the current recommendations to individualize HbA(1C) targets. Methods Data from 8 countries in the prospective cohort Peritoneal Dialysis Outcomes and Practice Patterns Study (2014-2022) were used to assess the association between baseline HbA(1C) and all-cause mortality in people with type 2 diabetes on PD for at least 90 days. Cox proportional hazards model adjusted for potential confounders was used to assess the relationship in the whole cohort and subgroups. Using inverse probability weighting, an average treatment effect in the treated analysis further investigated potential implications of improved glycemic control. Results HbA(1C) was measured at least once in 8436 patients during a mean follow-up of 16 months. Compared with HbA(1C) <= 8% (Diabetes Control and Complications Trial units), HbA(1C) >8% was associated with higher risk of all-cause mortality in the cohort as a whole (hazard ratio [HR] 1.18 P = 0.02 95% confidence interval [CI], 1.03 to 1.35) and within subgroups: age younger than 65 years (HR, 1.28; P = 0.01; 95% CI, 1.05 to 1.56), average albumin >3.0 g/dl (HR, 1.25; P = 0.004; 95% CI, 1.07 to 1.46), no preexisting coronary artery disease (CAD; HR, 1.24; P = 0.008; 95% CI, 1.06 to 1.46), hemoglobin <10 g/L (HR, 1.50; P = 0.01; 95% CI, 1.09 to 2.07), and PD vintage <1 year (HR, 1.22; P = 0.02; 95% CI, 1.03 to 1.45). The projected survival advantage at 3 years for those with HbA(1C) <= 8% compared with >8% was 7% overall, increasing to 12% in younger cohorts (age younger than 65 years). The largest predicted absolute survival advantage of 16% (78% versus 61%) was seen in those aged younger than 65 years, with a normal serum albumin level and no history of CAD. Conclusions Associations between HbA1C and mortality argue for tighter individualized targets for patient subgroups (younger, noninflamed, and without established CAD). Our weighted analysis suggests improved glycemic control (reducing HbA(1C) to <8%) may result in an absolute reduction in mortality at 3 years of up to 12% in younger cohorts.
