Abstract
BACKGROUND: Traditional management of low-density lipoprotein cholesterol (LDL-C) relies on single-point measurements, neglecting long-term magnitude and the duration of exposure to elevated LDL-C over time. This study aimed to evaluate the association between LDL-C time in target range (TTR) and the risk of major adverse cardiovascular events (MACE) in two US cohorts. METHODS: This study was a secondary analysis of the Atherosclerosis Risk in Communities (ARIC) study and the Multi-Ethnic Study of Atherosclerosis (MESA) cohorts. LDL-C TTR was defined as the percentage of the area under curve for LDL-C values below 100 mg/dL relative to the total area over the first 4 visits. Association between LDL-C TTR and MACE was estimated using adjusted Cox models and Fine-Gray competing risk models. RESULTS: Over a mean follow-up of 21.2 ± 8.1 years, 3306 MACE occurred among 16,310 participants. The highest LDL-C TTR quartile was associated with a 25 % reduction in MACE (HR: 0.75, 95 % CI: 0.68 to 0.83), 42 % reduction in myocardial infarction (HR: 0.58, 95 % CI: 0.49 to 0.68), 24 % reduction in stroke (HR: 0.76, 95 % CI: 0.64 to 0.91), and 13 % reduction in CVD death (HR: 0.87, 95 % CI: 0.76 to 1.00; borderline significance). TTR remained significantly associated with MACE after adjusting for mean LDL-C or LDL-C variability, and were robust in competing risk analyses. TTR also outperformed mean LDL-C and LDL-C variability in prognostic value (Akaike information criterion, C-statistics). CONCLUSIONS: LDL-C TTR independently predicts MACE and may offer a more comprehensive assessment of long-term LDL-C control than mean levels or variability, supporting its potential clinical utility.