Prognostic stratification of cardiovascular risk and cardiac remodeling in prediabetes: a multimodal analysis comparing ADA and WHO/IEC diagnostic criteria.
Level 3 - non-randomized controlled study
Prospective observational cohort study with Mendelian randomization analysis
PubMed 41776566 · doi:10.1186/s12933-026-03123-1
What was done
A prospective cohort of 278,697 individuals without baseline cardiovascular disease was stratified by glycemic status into normoglycemia, prediabetes, and type 2 diabetes. Prediabetes was defined according to American Diabetes Association criteria (ADA: fasting plasma glucose 5.6–6.9 mmol/L and/or HbA1c 5.7–6.4%) and World Health Organization/International Expert Committee criteria (WHO/IEC: fasting plasma glucose 6.1–6.9 mmol/L and/or HbA1c 6.0–6.4%). Over a 13.5-year follow-up, multivariable-adjusted models assessed incident cardiovascular disease (CVD), mortality, and cardiac magnetic resonance (CMR) markers in an exploratory substudy (n = 2,512). Mendelian randomization was conducted to assess the causality of prediabetes on cardiovascular outcomes.
What was found
Over 13.5 years, prediabetes increased CVD risk under both definitions, with higher risk estimates under WHO/IEC criteria (HR = 1.23, 95% CI 1.19–1.27) than ADA criteria (HR = 1.14, 95% CI 1.12–1.16), as well as stronger mortality associations. Mendelian randomization showed causal associations between prediabetes and 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). CMR imaging suggested early concentric left ventricular remodeling, particularly under WHO/IEC criteria.
Why it matters
This study demonstrates that prediabetes criteria capture different risk strata, with the stricter WHO/IEC definition identifying higher-risk individuals. It provides genetic and observational evidence supporting a causal relationship between intermediate dysglycemia and adverse cardiovascular outcomes.
Limits
The CMR remodeling analysis was restricted to an exploratory substudy of only 2,512 participants. Causal effect sizes from Mendelian randomization for overall CVD and hypertension were very small (OR 1.01). The lack of significant interaction across genetic susceptibility strata limits conclusions about effect modification, and specific population demographic characteristics were not detailed in the abstract.
Cited by
- supports A hemoglobin A1c of 5.7% is the diagnostic threshold for prediabetes.