Non-HDL cholesterol and residual risk of cardiovascular events in patients with ischemic heart disease and well-controlled LDL cholesterol: a cohort study

Background: Identifying patients at high residual risk of atherosclerotic cardiovascular disease (ASCVD) despite statin-treatment is of paramount clinical importance. We aim to investigate if non-high-density lipoprotein cholesterol (non-HDL-C) identifies residual risk of ASCVD and death in statin-treated patients with ischemic heart disease and low-density lipoprotein cholesterol (LDL-C) ≤ 1.8 mmol/L. Methods: Leveraging Danish regional and national registries, we identified statin-treated patients with ischemic heart disease who underwent coronary angiography (CAG) and attained LDL-C ≤ 1.8 mmol/L within a year post-CAG. Outcomes were myocardial infarction (MI), ASCVD (MI or ischemic stroke), and all-cause death occurring from one year after CAG to end of follow-up. Cox regression analyses obtained adjusted hazard ratios (HR). Findings: Between January 1, 2011, and December 31, 2020, we included 23,641 statin-treated patients with ischemic heart disease and LDL-C ≤ 1.8 mmol/L. During median follow-up of 4.1 years (IQR 2.4-6.1), 893 (3.8%) patients developed MI, 1207 (5.1%) ASCVD, and 3054 (12.9%) patients died. For ASCVD the adjusted HRs (95% confidence interval) for non-HDL-C < 25th percentile (<1.7 mmol/L) versus 25th-74th (1.7-2.1 mmol/L), 75th-94th (2.2-2.6 mmol/L), and ≥95th (≥2.7 mmol/L) percentile were 1.1 (0.9-1.3), 1.4 (1.1-1.7), and 1.8 (1.4-2.4), and for all-cause death 1.0 (0.9-1.1), 1.2 (1.1-1.4), and 1.4 (1.2-1.7), respectively. Interpretation: In a contemporary secondary prevention cohort of patients with well-managed LDL-C, non-HDL-C emerges as an easily accessible marker to detect patients facing high residual risk of ASCVD and death. These findings are important for preventive strategies extending beyond LDL-C targets. Funding: Research grant from the Novo Nordisk Foundation.