Lipid Biomarkers: Non-HDL Cholesterol

Optimal Takeaways

Non-HDL cholesterol, calculated by subtracting HDL-C from total cholesterol, includes all circulating cholesterol except HDL-C and is closely linked with cardiovascular disease (CVD) risk. Higher levels of non-HDL-C are associated with arterial stiffness, ischemic heart disease, stroke, and major adverse cardiovascular events. Non-HDL-C can be a more reliable predictor of risk than LDL-C, even for patients undergoing statin treatment. Additionally, a non-HDL-C to HDL-C ratio might be an indicator of non-alcoholic fatty liver disease. However, non-HDL cholesterol assessments do not provide information about particle size and number or oxidation status, which are relevant to evaluating CVD risk.

Standard Range: 0 - 130 mg/dL (0 - 3.37 mmol/L)

The ODX Range: 70 – 99 mg/dL (1.18 – 2.56 mmol/L)

Low non-HDL-C suggests reduced cardiovascular risk, although it may also be associated with malnutrition.

High non-HDL-C is associated with increased cardiovascular risk, ischemic heart disease, ischemic stroke (NCD-RisC 2020), and increased intima-media thickness (Acevedo 2012). Elevated non-HDL-C is associated with vitamin D insufficiency (Lupton 2016). Non-HDL cholesterol above 190 mg/dL (4.9 mmol/L) is associated with primary hypercholesterolemia (Arnett 2019).      

Overview

Non-HDL cholesterol is calculated by subtracting HDL-C from total cholesterol. Assessing fasting non-HDL-C [comprising VLDL-C, VLDL remnants, IDL-C, LDL-C, and lipoprotein(a)] in the fasting state may provide important information about the atherogenicity of circulating cholesterol.

Meta-analyses suggest that atherosclerotic CVD correlates more closely with non-HDL-C than with LDL-C and is preferable to measuring total cholesterol alone (Adhyaru 2016). Researchers estimate that the risk of cardiovascular disease increases 22-28% for every 42 mg/dL (1.09 mmol/L) increase in non-HDL-C (Sniderman 2010).

Even in statin-treated subjects, non-HDL-C was a better indicator of MI and all-cause mortality than LDL-C. Risk for all-cause mortality increased with LDL-C below 82 mg/dL (2.1 mmol/L), non-HDL-C above 120 mg/dL (3.1 mmol/L), and Apo B above 73 mg/dL (0.73 g/L). The risk for MI was higher with elevated non-HDL-C and Apo B but not with elevated LDL-C) (Johannesen 2021).

A review of data from high CVD-risk subjects found that every 10 mg/dL (0.26 mmol/L) increase in non-HDL-C was associated with a 5% greater risk of MACEs. When examined further, every 10 mg/dL increase in remnant cholesterol (total cholesterol minus HDL-C and LDL-C) represented a 21% increased risk of MACEs (Castaner 2020).

In one large cross-sectional study of 16,733 Chinese adults, a non-HDL-C of 100 mg/dL (2.59 mmol/L) or higher was associated with increased arterial stiffness (a marker of atherosclerosis), even when LDL-C was below 70 mg/dL (1.81 mmol/L) (Wen 2019).

A retrospective study of 868 acute MI patients found that MACEs during follow-up were significantly associated with a non-HDL-C above 130 mg/dL (3.37 mmol/L) compared to below 100 mg/dL (2.59 mmol/L). A non-HDL-C of 100-130 (2.59-3.37 mmol/L) was associated with a non-significant increase in MACEs. Researchers also note that MACEs were significantly associated with a low LDL-C (below 70 mg/dL) versus LDL-C above 100 mg/dL and that 93% of the study population was on statin drugs (Wongcharoen 2017).    

A pooled evaluation of 1,127 population-based studies comprising 102.6 million adults globally suggests an optimal non-HDL-C cholesterol of 70-85 mg/dL (1.8-2.2 mmol/L) to minimize the risk of ischemic heart disease and stroke (NCD-RisC 2020).

Although non-HDL represents the potentially more atherogenic lipoproteins in circulation, it does not provide information about particle size and number or oxidation status, factors relevant to the clinical assessment of CVD risk (Schade 2020).

Evaluating non-HDL-C status further indicates that the non-HDL-C to HDL-C ratio may be a strong predictor of non-alcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH) (Wang D 2018, Wang K 2018).

References

Acevedo, Mónica et al. [Total/HDL cholesterol ratio and non HDL cholesterol as predictors for increased intima media thickness]. Revista medica de Chile vol. 140,8 (2012): 969-76. doi:10.4067/S0034-98872012000800001

Adhyaru, Bhavin B, and Terry A Jacobson. “New Cholesterol Guidelines for the Management of Atherosclerotic Cardiovascular Disease Risk: A Comparison of the 2013 American College of Cardiology/American Heart Association Cholesterol Guidelines with the 2014 National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia.” Endocrinology and metabolism clinics of North America vol. 45,1 (2016): 17-37. doi:10.1016/j.ecl.2015.09.002

Arnett, Donna K et al. “2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.” Journal of the American College of Cardiology vol. 74,10 (2019): 1376-1414. doi:10.1016/j.jacc.2019.03.009

Castaner, Olga et al. “Remnant Cholesterol, Not LDL Cholesterol, Is Associated With Incident Cardiovascular Disease.” Journal of the American College of Cardiology vol. 76,23 (2020): 2712-2724. doi:10.1016/j.jacc.2020.10.008

Heidemann, Britt E et al. “The relation between VLDL-cholesterol and risk of cardiovascular events in patients with manifest cardiovascular disease.” International journal of cardiology vol. 322 (2021): 251-257. doi:10.1016/j.ijcard.2020.08.030

Johannesen, Camilla Ditlev Lindhardt et al. “Apolipoprotein B and Non-HDL Cholesterol Better Reflect Residual Risk Than LDL Cholesterol in Statin-Treated Patients.” Journal of the American College of Cardiology vol. 77,11 (2021): 1439-1450. doi:10.1016/j.jacc.2021.01.027

Lupton, Joshua R et al. “Deficient serum 25-hydroxyvitamin D is associated with an atherogenic lipid profile: The Very Large Database of Lipids (VLDL-3) study.” Journal of clinical lipidology vol. 10,1 (2016): 72-81.e1. doi:10.1016/j.jacl.2015.09.006

NCD Risk Factor Collaboration (NCD-RisC). “Repositioning of the global epicentre of non-optimal cholesterol.” Nature vol. 582,7810 (2020): 73-77. doi:10.1038/s41586-020-2338-1

Pagana, Kathleen Deska; Pagana, Timothy J.; Pagana, Theresa N. Mosby's Diagnostic and Laboratory Test Reference. Elsevier Health Sciences. 2019.

Schade, David S et al. “Cholesterol Review: A Metabolically Important Molecule.” Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists vol. 26,12 (2020): 1514-1523. doi:10.4158/EP-2020-0347

Sniderman, Allan et al. “Why is non-high-density lipoprotein cholesterol a better marker of the risk of vascular disease than low-density lipoprotein cholesterol?.” Journal of clinical lipidology vol. 4,3 (2010): 152-5. doi:10.1016/j.jacl.2010.03.005

Wang, Dianhui et al. “Higher non-HDL-cholesterol to HDL-cholesterol ratio linked with increased nonalcoholic steatohepatitis.” Lipids in health and disease vol. 17,1 67. 3 Apr. 2018, doi:10.1186/s12944-018-0720-x

Wang, Kun et al. “Non-HDL-cholesterol to HDL-cholesterol ratio is a better predictor of new-onset non-alcoholic fatty liver disease than non-HDL-cholesterol: a cohort study.” Lipids in health and disease vol. 17,1 196. 21 Aug. 2018, doi:10.1186/s12944-018-0848-8

Wen, Jia et al. “Associations of non-high-density lipoprotein cholesterol, triglycerides and the total cholesterol/HDL-c ratio with arterial stiffness independent of low-density lipoprotein cholesterol in a Chinese population.” Hypertension research : official journal of the Japanese Society of Hypertension vol. 42,8 (2019): 1223-1230. doi:10.1038/s41440-019-0251-5

Wongcharoen, Wanwarang et al. “Is non-HDL-cholesterol a better predictor of long-term outcome in patients after acute myocardial infarction compared to LDL-cholesterol? : a retrospective study.” BMC cardiovascular disorders vol. 17,1 10. 5 Jan. 2017, doi:10.1186/s12872-016-0450-9