Aldosterone-mineralocorticoid receptor signaling and residual cardiorenal risk in type 2 diabetes.

Abstract

Clinically important cardiorenal risk persists in type 2 diabetes mellitus (T2DM) despite major advances in metabolic and organ-protective therapy. This narrative review evaluates aldosterone-mineralocorticoid receptor (MR) signaling as one potential contributor and separates mechanistic plausibility from clinical-outcome evidence. PubMed, Embase, Web of Science Core Collection, and ClinicalTrials.gov searches, together with supplementary searches using the Foreign Medical Literature Retrieval Service (FMRS; Metstr), were updated through 22 September 2026; titles/abstracts and relevant full texts were independently screened by two authors. Experimental and observational evidence links MR signaling with inflammation, oxidative stress, fibrosis, endothelial dysfunction, and cardiorenal remodeling, but circulating aldosterone, renin, and the aldosterone-to-renin ratio have no validated thresholds for identifying clinically relevant tissue MR activation or predicting treatment response in unselected T2DM. In T2DM with chronic kidney disease (CKD) receiving maximum tolerated renin-angiotensin system blockade, finerenone reduces prespecified kidney and cardiovascular composite outcomes. By contrast, CONFIDENCE and phase 2 BI 690,517 mainly provide urinary albumin-to-creatinine ratio-based surrogate evidence, and FINEARTS-HF extends clinical-outcome evidence to heart failure with mildly reduced or preserved ejection fraction but was not restricted to diabetes. We therefore present four candidate domains for future MR-oriented phenotyping as a hypothesis-generating framework, not a diagnostic or treatment-selection algorithm. Overall, MR signaling is best regarded as a biologically plausible contributor within a multifactorial residual-risk model; prospective validation is required before biomarker-guided MR-targeted therapy can be recommended.