Cumulative LDL-C Burden and Incident Acute Coronary Syndrome in Type 2 Diabetes

Background: Low-density lipoprotein cholesterol (LDL-C) is a central modifiable driver of atherosclerotic cardiovascular disease, yet cardiovascular risk in type 2 diabetes mellitus (T2DM) may be better captured by longitudinal LDL-C exposure than by a single LDL-C measurement. We examined the association of current LDL-C, cumulative LDL-C burden, and prior time below LDL-C targets with incident acute coronary syndrome (ACS) in patients with T2DM. Methods: We conducted a retrospective longitudinal cohort study using routinely collected electronic health-record data. Patients with T2DM and at least one valid LDL-C measurement between 1 January 2018 and 31 December 2023 were followed from the first eligible LDL-C measurement until incident ACS or administrative censoring on 31 March 2024. LDL-C was modeled using time-updated start–stop Cox regression. The primary exposure was current LDL-C category: <1.4, 1.4 to <1.8, 1.8 to <2.6, 2.6 to <3.4, 3.4 to <4.9, and ≥4.9 mmol/L. Secondary exposure metrics were cumulative LDL-C burden above prespecified thresholds and prior percentage of follow-up time below LDL-C targets. Models were adjusted for age, sex, hypertension, chronic kidney disease, HbA1c, T2DM duration, and calendar year of baseline LDL-C measurement; HbA1c and T2DM duration were multiply imputed. Results: The analytic cohort included 106,185 patients, 426,965 LDL-C intervals, and 5416 incident ACS events over 419,251.0 person-years. Compared with current LDL-C <1.4 mmol/L, adjusted ACS risk was higher for current LDL-C 3.4 to <4.9 mmol/L (HR 1.35, 95% CI 1.21–1.50) and ≥4.9 mmol/L (HR 1.94, 95% CI 1.63–2.32), whereas lower LDL-C categories were not clearly different from the reference category after adjustment. Each 1 mmol/L-year higher cumulative LDL-C burden was associated with higher ACS risk across evaluated thresholds, with HRs ranging from 1.04 to 1.13. Greater prior time below LDL-C targets was associated with lower ACS risk, with HRs of 0.97–0.98 per 10% higher time below target. Findings were consistent in sensitivity analyses restricted to patients with at least three LDL-C measurements, landmark analyses, and complete-case analysis. Conclusions: In patients with T2DM, incident ACS risk was associated with very high current LDL-C and with longitudinal LDL-C exposure captured by cumulative burden and time below target. These findings support sustained, target-oriented LDL-C control and suggest that longitudinal LDL-C metrics may complement single LDL-C values in cardiovascular risk assessment.