Key Points We assessed whether baseline urine albumin-creatinine ratio (UACR) and eGFR modify treatment effects on UACR reduction and safety in the CONFIDENCE trial. Higher baseline eGFR or UACR, age, female sex, and atherosclerotic cardiovascular disease were associated with greater albuminuria lowering at 6 months (180 days). Treatment effects on efficacy and safety were consistent, with no significant heterogeneity across baseline UACR or eGFR groups. Background In the CONFIDENCE trial, simultaneous initiation of finerenone (10 or 20 mg) and empagliflozin (10 mg) was superior to either monotherapy in reducing albuminuria at 180 days in participants with type 2 diabetes and CKD. In this analysis, we evaluated whether baseline urine albumin-creatinine ratio (UACR) and eGFR were associated with the magnitude of UACR reduction, and whether baseline UACR and eGFR modify the effect of combination treatment. Methods In this post hoc analysis of the CONFIDENCE trial ( n =796), linear mixed-effects models were used to evaluate the effects of baseline UACR and eGFR on the change in UACR from baseline using subgroups on the basis of clinically relevant thresholds of UACR (<300 versus ≥300 mg/g) and eGFR (<60 versus ≥60 ml/min per 1.73 m 2 ). Logistic regression models were used to assess the odds of achieving UACR reductions at day 180. Results At day 180, higher baseline eGFR (per 10 ml/min per 1.73 m 2 ) was independently associated with a −7% (95% confidence interval [CI], −11 to −4) greater reduction in UACR ( P < 0.001), and higher baseline UACR (per log change of UACR) was independently associated with a −9% (95% CI, −14 to −3) greater reduction in UACR ( P < 0.001). However, the treatment effect of finerenone, empagliflozin, or their combination on changes in UACR levels was not modified by baseline levels of eGFR or UACR. Besides the use of combination therapy, independent predictors of >30% reduction in UACR were age (odds ratio [OR], 1.23 per 10 years [95% CI, 1.05 to 1.45]), female sex (OR, 1.95 [95% CI, 1.32 to 2.86]), and atherosclerotic cardiovascular disease (OR, 1.63 [1.13 to 2.35]). The safety end points showed no significant heterogeneity across UACR or eGFR. Conclusions Overall, greater albuminuria lowering was seen with a higher baseline eGFR or UACR, older age, in female patients, and those with atherosclerotic cardiovascular disease, irrespective of the treatment. Albuminuria-lowering with combination therapy, finerenone, or empagliflozin treatment effects were independent of baseline eGFR or UACR. Clinical Trial registry name and registration number: ClinicalTrials.gov, NCT05254002; European Union Drug Regulating Authorities Clinical Trials Database 2021-003037-11.