Prognostic stratification of cardiovascular risk and cardiac remodeling in prediabetes: a multimodal analysis comparing ADA and WHO/IEC diagnostic criteria

Prediabetes, an intermediate metabolic state preceding diabetes, independently accelerates cardiovascular pathology through dysglycemia-driven mechanisms. This study evaluates the heterogeneous cardiovascular risk stratification by directly comparing two major diagnostic criteria (ADA vs. WHO/IEC) and assesses the causal cardiovascular consequences of prediabetes, an area requiring further elucidation. After excluding participants with baseline cardiovascular disease, the remaining cohort with complete glycemic and relevant assessment data (n = 278,697) was stratified into normoglycemia, prediabetes, and type 2 diabetes mellitus (T2DM). Prediabetes was subsequently classified according to both ADA (fasting plasma glucose, FPG 5.6–6.9 mmol/L and/or glycosylated hemoglobin A1c, HbA1c 5.7–6.4%) and WHO/IEC (FPG 6.1–6.9 mmol/L and/or HbA1c 6.0–6.4%) criteria. Associations with incident cardiovascular disease (CVD), mortality, and cardiac remodeling (via cardiac magnetic resonance, CMR) were assessed using multivariable-adjusted models. Mendelian randomization (MR) tested causality of prediabetes on outcomes. All observational analyses were adjusted for key demographic, lifestyle, and clinical covariates. Over 13.5 years, prediabetes—irrespective of criteria—elevated CVD risk (ADA: HR = 1.14, 95% CI 1.12–1.16; WHO/IEC: HR = 1.23, 95% CI 1.19–1.27), with stronger mortality associations in WHO/IEC-defined individuals. MR analyses confirmed that prediabetes was causally associated with increased CVD (OR 1.01, 95% CI 1.01–1.02), coronary heart disease (OR 1.09, 95% CI 1.02–1.17), myocardial infarction (OR 1.12, 95% CI 1.06–1.19), stroke (OR 1.06, 95% CI 1.02–1.10), and primary hypertension (OR 1.01, 95% CI 1.01–1.02) risks. In an exploratory CMR substudy (n = 2512), early concentric left ventricular remodeling was suggested, particularly under WHO/IEC criteria. Risks were consistently observed across genetic susceptibility strata, though the lack of significant interaction warrants cautious interpretation and further investigation into potential effect modifications. These findings highlight the differential prognostic utility of ADA and WHO/IEC criteria for cardiovascular risk stratification in prediabetes.