Multi-National Evaluation of Low-Density Lipoprotein Cholesterol Equations in Young Adulthood for Long-Term Risk of Atherosclerotic Cardiovascular Disease

BACKGROUND: Accurate low-density lipoprotein cholesterol (LDL-C) assessment in young adulthood is critical for atherosclerotic cardiovascular disease (ASCVD) prevention, yet the optimal estimation equation remains uncertain. We compared the Friedewald, Martin-Hopkins, and Sampson equations for evaluating long-term ASCVD risks. METHODS: We included participants from 7 population-based cohorts within the International Childhood Cardiovascular Cohort Consortium who had LDL-C measurements in young adulthood (aged 20-39 years) and follow-up data for incident ASCVD. LDL-C levels were estimated using the Friedewald, Martin-Hopkins, and Sampson equations. For each pair of equations, participants were categorized into concordant (normal/normal, elevated/elevated) and discordant (normal/elevated, elevated/normal) groups based on LDL-C classifications (normal <130 mg/dL versus elevated ≥130 mg/dL). ASCVD events (myocardial infarction, stroke, transient ischemic attack, ischemic heart failure, angina, peripheral artery disease, carotid intervention, abdominal aortic aneurysm, coronary revascularization) were adjudicated from medical records. Associations between discordance and incident ASCVD were estimated using Fine-Gray regressions. RESULTS: Among 10 550 participants (56.8% females; mean baseline age [SD], 29.8 [4.3] years), 376 ASCVD events occurred over a mean follow-up of 22.7 years. Elevated LDL-C by all equations was associated with ASCVD events (subdistribution hazards ratio [95% CI]: Martin-Hopkins, 1.69 [1.35-2.12]; Sampson, 1.52 [1.22-1.90]; Friedewald, 1.47 [1.17-1.84]). Total discordance ranged from 2.3% to 2.9%. Compared with the concordant normal LDL-C group, normal LDL-C by Friedewald but elevated by Martin-Hopkins had higher ASCVD risks (3.32 [1.94-5.66]), with no excess risk in the reverse discordance (1.19 [0.47-3.05]). Normal Friedewald but elevated Sampson LDL-C had higher ASCVD risks (1.69 [0.93-3.05]); no participants had the reverse discordance. Normal Sampson LDL-C but elevated Martin-Hopkins LDL-C had higher ASCVD risks (3.94 [1.80-8.64]), whereas the reverse discordance showed no increased risk (0.86 [0.39-1.91]). CONCLUSIONS: The Martin-Hopkins equation provides more accurate LDL-C-based risk classification, identifying high-risk young adults missed by other equations and minimizing misclassification of those at normal risk.