Abstract 4363637: Different Criteria of Prediabetes and Cardiovascular Risk and Mortality: A Prospective Cohort and Mendelian Randomization and Imaging Study in the UK Biobank

Background: Prediabetes, an intermediate metabolic state preceding diabetes, independently accelerates cardiovascular pathology through dysglycemia-driven mechanisms. This study evaluates its heterogeneous risk stratification by diagnostic criteria (ADA vs. WHO/IEC) and causal cardiovascular consequences. Methods: In 278,697 UK Biobank participants without baseline cardiovascular disease, prediabetes was classified by ADA (fasting glucose 5.6–6.9 mmol/L/HbA1c 5.7–6.4%) and WHO/IEC (fasting glucose 6.1–6.9 mmol/L/HbA1c 6.0–6.4%) criteria. Associations with incident CVD, mortality, and cardiac remodeling (via cardiac magnetic resonance, CMR) were assessed. Mendelian randomization (MR) tested causality of prediabetes on outcomes. 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, 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. CMR revealed early concentric left ventricular remodeling in prediabetes (mass-to-volume ratio: β=1.95%), accentuated in stricter diagnostic groups. Risks persisted across genetic susceptibility strata, underscoring dysglycemia’s universal impact. Conclusion: Early identification of prediabetes—a critical metabolic threshold—is vital to intercept disease progression before irreversible complications develop.