Non-HDL cholesterol:
an accessible marker of high residual risk
20 May 2024
| STUDY SUMMARY | |
| Objective | To investigate if non-HDL-C identifies residual risk of atherosclerotic cardiovascular disease (ASCVD) and death in statin-treated patients with ischaemic heart disease (IHD) and LDL-C ≤ 1.8 mmol/L. |
| Study design | Cohort study using data from regional and national health registries in Denmark. |
| Study population | 23,641 statin-treated patients with IHD and LDL-C ≤1.8 mmol/L within one year after coronary artery grafting. |
| Main study variables | Primary: Myocardial infarction (MI), ASCVD (MI or ischaemic stroke), and all-cause death occurring from one year after coronary artery grafting to end of follow-up. |
| Methods | Cox regression analyses were used to estimate adjusted hazard ratios (HR) for outcomes. The association of non-HDL-C and the outcomes was analysed with non-HDL-C as a continuous variable to provide an estimate of the HR per 1 mmol/L increase in non-HDL-C, as well as non-HDL-C divided in groups according to percentile. |
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Of the patients, 5922 (25.0%) had non-HDL-C <25th percentile (1.7 mmol/L), 10,950 (46.3%) between 25th–74th percentile (1.7–2.1 mmol/L), 5454 (23.1%) between 75th–94th percentile (2.2–2.6 mmol/L), and 1315 (5.6%) ≥95th percentile (≥2.7 mmol/L). Patients with high non-HDL-C (≥95th percentile) were younger, more likely to be active smokers, and had a higher prevalence of morbidities (diabetes, hypertension) and higher body mass index compared with those with non-HDL-C <25th percentile.
Over the median follow-up of 4.1 years (interquartile range 2.4–6.1 years), 893 (3.8%) patients had an MI, 1207 (5.1%) ASCVD, and 3054 (12.9%) patients died. Higher non-HDL-C was strongly associated with higher risk of MI, ASCVD, and all-cause death despite well-controlled LDL-C levels.
Table 1. Adjusted* Hazard ratios (HRs) for each non-HDL-C percentile group
* Adjusted for age, sex, smoking, hypertension, and LDL-C
Similar associations were shown in men and women, and in those patients aged <65 years and ≥65 years. |
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| Authors conclusion | 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. | ||||||||||||||||||||
COMMENT
Supported by an extensive evidence-base, LDL-C is indisputably causal for ASCVD and thus the focus of therapeutic targeting to prevent ASCVD (1-3). However, it is also recognised that a high residual cardiovascular risk persists among secondary prevention patients even if LDL-C levels are well managed (4). Attention has therefore been directed to other targets as markers of cholesterol-mediated residual cardiovascular risk.
Non-HDL-C, which is a measure of the cholesterol contained in all atherogenic particles (5), is indicated as a secondary target in clinical guidelines, and may therefore have practical value as a marker of residual risk. This hypothesis is supported by this robust study in over 23,000 patients with documented IHD and well controlled LDL-C levels on statin therapy. Consistent with an earlier analysis (6), higher non-HDL-C was strongly associated with higher risk for MI, ASCVD and all-cause death. These findings were consistent in men and women, and in younger and older patients. The authors therefore conclude that non-HDL-C should be included in lipid panels to guide clinical practice, given that it is readily calculated from lipid measures routinely tested (total cholesterol and HDL-C). Preferential use of non-HDL-C also avoids potential misinterpretation of the lipid profile resulting from limitations of equations used to estimate LDL-C (7). Whether non-HDL-C is the optimal target for cholesterol-mediated cardiovascular risk merits further study.
| References | 1. Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017;38:2459-72. 2. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111-88. 3. Visseren FLJ, Mach F, Smulders YM, et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2021;42:3227-337. 4. Boekholdt SM, Arsenault BJ, Mora S, et al. Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. JAMA 2012;307:1302–9. 5. Nordestgaard BG, Langlois MR, Langsted A, et al. Quantifying atherogenic lipoproteins for lipid-lowering strategies: consensus-based recommendations from EAS and EFLM. Atherosclerosis 2020;294:46–61. 6. Robinson J.G., Wang S., Smith B.J., Jacobson T.A. Meta-analysis of the relationship between non–high-density lipoprotein cholesterol reduction and coronary heart disease risk. J Am Coll Cardiol 2009;53:316–22. 7. Mancini GBJ, Ryomoto A, Iatan I, Hegele RA. LDL-C estimation equation performance characteristics highlight value of preferentially using non-HDL cholesterol or directly measured apolipoprotein B. Can J Cardiol 2023;39:963-6. |
| Key words | Non-HDL cholesterol; residual risk; cardiovascular events; marker |
