Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: These findings highlight the differential prognostic utility of ADA and WHO/IEC criteria for cardiovascular risk stratification in prediabetes.