Application of non-HDL cholesterol for population-based cardiovascular risk stratification: results from the Multinational Cardiovascular Risk Consortium

Abstract

Background: The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment.

Methods: In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic 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, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol.

Findings: Of the 524 444 individuals in the 44 cohorts in the Consortium database, we identified 398 846 individuals belonging to 38 cohorts (184 055 [48·7%] women; median age 51·0 years [IQR 40·7-59·7]). 199 415 individuals were included in the derivation cohort (91 786 [48·4%] women) and 199 431 (92 269 [49·1%] women) in the 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 cardiovascular disease 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 lower than 2·6 mmol/L as reference showed an increase in the association between non-HDL cholesterol concentration and cardiovascular disease for both sexes (from hazard ratio 1·1, 95% CI 1·0-1·3 for non-HDL cholesterol 2·6 to <3·7 mmol/L to 1·9, 1·6-2·2 for ≥5·7 mmol/L in women and from 1·1, 1·0-1·3 to 2·3, 2·0-2·5 in men). The derived tool allowed the estimation of cardiovascular disease event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts as reflected by smooth calibration curves analyses and a root mean square error lower than 1% for the estimated probabilities of cardiovascular disease. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of a cardiovascular disease event by the age of 75 years, and this risk reduction was greater the earlier cholesterol concentrations were reduced.

Interpretation: Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic cardiovascular disease. We provide a simple tool for individual long-term risk assessment and the potential benefit of early lipid-lowering intervention. These data could be useful for physician-patient communication about primary prevention strategies.

Funding: EU Framework Programme, UK Medical Research Council, and German Centre for Cardiovascular Research.

Figure 1

Incidence of cardiovascular disease across non-HDL cholesterol thresholds Cumulative incidence curves and numbers at risk for incident fatal and non-fatal cardiovascular disease according to non-HDL cholesterol concentration categories in women and men. Death from non-cardiovascular-disease causes was used as competing risk. p values are given for Gray's test comparing cumulative incidence curves.

Figure 2

Sex-specific continuous association of non-HDL cholesterol and cardiovascular disease Sex-specific linear association of non-HDL cholesterol and cardiovascular disease risk (winsorised at 1·6 and 8·5 mmol/L). The Cox model used is adjusted for age, sex, study cohort, smoking, diabetes, body-mass index, systolic blood pressure, and antihypertensive medication. Non-HDL cholesterol was modelled using cubic splines. An interaction between sex and non-HDL cholesterol was included in the model. Median follow-up was 12·8 (IQR 7·5–18·4) years.

Figure 3

Age-specific and sex-specific association of non-HDL cholesterol and cardiovascular disease Lifetime sex-specific HRs for fatal and non-fatal cardiovascular disease (reference non-HDL cholesterol <2·6 mmol/L) in the overall cohort and according to three age categories (p<0·001 for the interaction of age and non-HDL cholesterol categories in women and in men). The Cox regression models were adjusted for age at baseline, sex, study cohort, smoking, diabetes, body-mass index, systolic blood pressure, and antihypertensive medication. HR=hazard ratio.

Figure 4

Model of long-term cardiovascular disease risk prediction and the benefit of lipid reduction Individual risk of fatal or non-fatal cardiovascular disease in women (A) and men (B) according to age, non-HDL cholesterol concentration, and the number of additional cardiovascular risk factors (daily smoking, arterial hypertension, diabetes, and obesity; white circle). The red circle represents the probability (%) of cardiovascular disease by the age of 75 years. The hypothetically achievable probability (%) for cardiovascular disease by the age of 75 years after 50% reduction of non-HDL cholesterol is given in the green circle. Corresponding 95% CIs are provided in the appendix (p 37).