Non-HDL Cholesterol for Cardiovascular Risk Stratification

Study Questions:

How does the full spectrum of bloodstream non–high-density lipoprotein (HDL) cholesterol concentrations affect cardiovascular disease (CVD) risk?


Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America were used in this risk-evaluation and risk-modeling study. People without known CVD at baseline and with robust available data on CVD outcomes were included. The primary composite endpoint of atherosclerotic CVD was defined as the occurrence of a coronary heart disease event or ischemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds; adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, a tool was created to estimate the probabilities of a CVD event by the age of 75 years, dependent on age, sex, and risk factors; and the associated modeled risk reduction, assuming a 50% reduction of non-HDL cholesterol.


Of the 524,444 people in the 44 cohorts in the Consortium database, 398,846 belonging to 38 cohorts were identified for study inclusion (184,055 [48.7%] women; median age, 51.0 years [interquartile range (IQR), 40.7-59.7 years]). Of these, 199,415 were included in a derivation cohort (91,786 [48.4%] women) and 199,431 (92,269 [49.1%] women) in a validation cohort. During a maximum follow-up of 43.6 years (median, 13.5 years; IQR, 7.0–20.1), 54,542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year CVD event rates for increasing non-HDL cholesterol categories (from 7.7% for non-HDL cholesterol <2.6 mmol/L to 33.7% for ≥5.7 mmol/L in women, and from 12.8% to 43.6% in men; p < 0.0001). Multivariable adjusted Cox models with non-HDL cholesterol <2.6 mmol/L as a reference showed an increase in the association between non-HDL cholesterol concentration and CVD for both sexes (from hazard ratio, 1.1; 95% confidence interval [CI], 1.0-1.3 for non-HDL cholesterol 2.6 to <3.7 mmol/L to 1.9; 95% CI, 1.6-2.2 for ≥5.7 mmol/L in women, and from 1.1, 95% CI, 1.0-1.3 to 2.3, 95% CI, 2.0-2.5 in men). The derived tool allowed the estimation of CVD event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of a CVD event by the age of 75 years, and this risk reduction was greater the earlier cholesterol concentrations were reduced.


Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic CVD. This study provides a simple tool for individual long-term risk assessment and the potential benefit of early lipid-lowering intervention. The authors concluded that these data could be useful for physician–patient communication about primary prevention strategies.


The blood concentrations of non-HDL and low-density lipoprotein (LDL) cholesterol are accepted as causal cardiovascular risk factors, and are an important part of CVD risk prediction in the general population. This study provides a comprehensive analysis of long-term cardiovascular risk related to non-HDL cholesterol, and creates a tool to easily assess the long-term probabilities for CVD events and the effect on risk associated with the modification of non-HDL cholesterol. The use of an up-to-date, multinational, population-based, pooled cohort data set creates a model that should be pertinent across a broad range of patient populations. The portrayal of the risk model in a format suggestive of a roulette wheel may help with physician–patient discussions in the consideration of a risk factor as just that: a probability-weighted risk.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Lipid Metabolism, Nonstatins

Keywords: Atherosclerosis, Brain Ischemia, Cardiovascular Diseases, Cholesterol, Cholesterol, HDL, Cholesterol, LDL, Coronary Disease, Dyslipidemias, Primary Prevention, Risk Assessment, Risk Factors, Risk Reduction Behavior, Stroke, Vascular Diseases

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