Composition of non-HDL cholesterol and residual cardiovascular risk in secondary prevention

Abstract Background Non-high-density lipoprotein cholesterol (non-HDL-C) is associated with atherosclerotic cardiovascular disease (ASCVD) and is a recommended secondary prevention treatment target. However, the composition of non-HDL-C, that is, the relative contribution of remnant cholesterol (remnant-C) and low-density-lipoprotein cholesterol (LDL-C), is not considered for cardiovascular risk prediction. Purpose To examine ASCVD risk by composition of non-HDL-C. Methods Based on the Western Denmark Heart Registry, we established a cohort of patients with ischemic heart disease, including patients with acute coronary syndrome or stable angina pectoris, undergoing coronary angiography for evaluation of coronary artery disease between 2011 and 2020. A complete lipid panel within 1 year after coronary angiography on statin treatment was required. Patients with triglycerides >4.5 mmol/L were excluded. Exposures were remnant-C, LDL-C, non-HDL-C, and composition of non-HDL-C. The latter was defined as remnant-C of non-HDL-C, and LDL-C of non-HDL-C, in percentages. Cox regression analyses obtained adjusted hazard ratios (aHR) for myocardial infarction, ASCVD (myocardial infarction, ischemic stroke, and cardiovascular death), and all-cause death occurring from 1 year after coronary angiography to end of follow-up November 1, 2022. Results The secondary prevention cohort included 42,341 statin-treated patients (67.7% were men; median [IQR] age 66 [58-73] years). During median 4.1 years of follow-up, 3,846 patients developed ASCVD. Per 1 mmol/L increase in remnant-C, LDL-C, and non-HDL-C, the aHR for ASCVD was 1.41 (95% CI 1.28-1.55), 1.12 (95% CI 1.08-1.17), and 1.17 (95% CI 1.13-1.21), respectively (Figure 1). The relative contribution of remnant-C and LDL-C was median (IQR) 24.6% (18.5-33.1) and 75.4% (66.9-81.5) of non-HDL-C, respectively. When remnant-C constituted a larger percentage of non-HDL-C (and LDL-C a lower percentage), the aHR for ASCVD showed a linear increase in risk whereas the opposite trend was observed for LDL-C (Figure 2). Thus, per 10% increase in remnant-C of non-HDL-C, the aHR of ASCVD was 1.06 (95% CI 1.03-1.09) compared to 0.94 (95% CI 0.91-0.97) per 10% increase in LDL-C of non-HDL-C. Results were comparable for myocardial infarction and all-cause death, and by age, sex, and other clinically relevant subgroups. Conclusions The composition of non-HDL-C is strongly associated with ASCVD risk, with the risk escalating as remnant-C constitutes a larger percentage, and LDL-C a smaller percentage, of non-HDL-C. These findings challenge current guidelines and demonstrate the value of considering composition of non-HDL-C in clinical practice for more accurate risk assessment.Figure 1Figure 2