Prediabetes, obesity and risk for incident atherosclerotic cardiovascular disease: A large-scale contemporary cohort study

Prediabetes is a highly prevalent metabolic state associated with the development of type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD). Early identification and management of prediabetes and obesity are critical to mitigate this risk, particularly in younger adults. However, contemporary large-scale data on the interplay of prediabetes, obesity, and cardiovascular outcomes across the adult lifespan remains limited. We conducted a retrospective cohort study of adults aged 18-90 years old within Kaiser Permanente Northern California (KPNC) from 2015-2018, excluding those with a prior history of diabetes or ASCVD. Individuals with prediabetes (HbA1c 5.7-6.4% or fasting glucose 100-125 mg/dL) were compared with those with normoglycemia. Obesity was classified based on body mass index (BMI) ≥ 30kg/m 2 at baseline. The primary outcome was incident ASCVD, a composite of myocardial infarction, stroke, or revascularization procedures. Outcomes were tracked over 5 years and analyzed using multivariable Cox proportional hazards models, adjusted for demographic and clinical covariates and stratified by age group. The final cohort comprised 1,358,882 individuals (mean age of 52.5 years; 55.8% women) of whom 688,575 (50.7%) had prediabetes at baseline. In the cohort19.2% had both prediabetes and obesity, 31.5% had prediabetes without obesity, 12.2% did not have prediabetes but had obesity, and 37.1% had neither. Over a mean follow-up period of 4.1 years, prediabetes was independently associated with a 21% increased risk of ASCVD after full adjustment (Hazard Ratio HR 1.21; 95% CI, 1.18-1.25). This association was strongest among younger adults (ages 18-34: HR 1.54; 95% CI, 1.18-2.02). Fully adjusted, HRs for 5-year ASCVD risk were 1.32 (95% CI 1.28-1.37) for individuals with prediabetes and obesity, and 1.22 (95% CI 1.18-1.26) for those with prediabetes without obesity, compared to the reference group without prediabetes or obesity. In a large, contemporary cohort study, prediabetes was independently associated with a significantly increased 5-year risk of ASCVD. The relative risk was most pronounced among young adults and those with obesity. These findings underscore a critical window for implementing targeted strategies to mitigate cardiovascular risk early during metabolic dysregulation.