Diabetes mellitus increases the risk of incident aortic stenosis by 1.3 to 1.7-fold and promotes denser valvular calcification through interconnected immunometabolic and inflammatory pathways.
This review delineates the immunometabolic pathways linking diabetes to accelerated calcific aortic valve disease, identifying actionable nodes for future targeted therapies.
This review synthesizes the immunometabolic mechanisms linking diabetes mellitus to accelerated calcific aortic valve disease (CAVD) and evaluates their therapeutic implications. Despite the absence of disease-modifying pharmacotherapy for CAVD, diabetes consistently increases incident aortic stenosis risk (HR 1.3–1.7), calcification burden, and disease severity, independent of traditional cardiovascular risk factors. Epidemiological, imaging, and histological evidence demonstrate that dysglycemia promotes earlier onset, denser valvular calcium deposits, and worse post-intervention outcomes. We delineate seven interconnected and partially overlapping pathways through which diabetes remodels the aortic valve: hyperglycemia-driven valvular interstitial cell (VIC) phenotypic switching and insulin resistance; advanced glycation end-product–RAGE signaling; oxidative stress and mitochondrial dysfunction; macrophage NLRP3–IL-1β inflammasome activation; endothelial barrier compromise; BMP–Runx2–Wnt–Notch osteogenic reprogramming; and CKD–mineralocorticoid receptor cross-talk. These processes convert metabolic stress into sustained valvular inflammation, matrix remodeling, and ectopic ossification. Mechanistic and observational data provide a rationale for evaluating metformin, SGLT2 inhibitors, IL-1β/NLRP3 inhibitors, and Lp(a)-lowering strategies as candidate approaches to modulate calcification progression. Integrated metabolic–inflammatory–imaging biomarkers offer potential for risk stratification and trial enrichment. This immunometabolic framework identifies actionable nodes and underscores the urgent need for dedicated, valve-focused randomized trials in diabetic CAVD to translate mechanistic insights into clinical benefit. Graphical abstract
Zhang et al. (2026) conducted a review in Calcific aortic valve disease and diabetes mellitus. Diabetes mellitus increases the risk of incident aortic stenosis by 1.3 to 1.7-fold and promotes denser valvular calcification through interconnected immunometabolic and inflammatory pathways.