TY - JOUR

T1 - Application of non-HDL cholesterol for population-based cardiovascular risk stratification

T2 - results from the Multinational Cardiovascular Risk Consortium

AU - Brunner, Fabian J.

AU - Waldeyer, Christoph

AU - Ojeda, Francisco

AU - Salomaa, Veikko

AU - Kee, Frank

AU - Sans, Susana

AU - Thorand, Barbara

AU - Giampaoli, Simona

AU - Brambilla, Paolo

AU - Tunstall-Pedoe, Hugh

AU - Moitry, Marie

AU - Iacoviello, Licia

AU - Veronesi, Giovanni

AU - Grassi, Guido

AU - Mathiesen, Ellisiv B.

AU - Söderberg, Stefan

AU - Linneberg, Allan

AU - Brenner, Hermann

AU - Amouyel, Philippe

AU - Ferrières, Jean

AU - Tamosiunas, Abdonas

AU - Nikitin, Yuriy P.

AU - Drygas, Wojciech

AU - Melander, Olle

AU - Jöckel, Karl Heinz

AU - Leistner, David M.

AU - Shaw, Jonathan E.

AU - Panagiotakos, Demosthenes B.

AU - Simons, Leon A.

AU - Kavousi, Maryam

AU - Vasan, Ramachandran S.

AU - Dullaart, Robin P.F.

AU - Wannamethee, S. Goya

AU - Risérus, Ulf

AU - Shea, Steven

AU - de Lemos, James A.

AU - Omland, Torbjørn

AU - Kuulasmaa, Kari

AU - Landmesser, Ulf

AU - Blankenberg, Stefan

AU - Zeller, Tanja

AU - Kontto, Jukka

AU - Männistö, Satu

AU - Metspalu, Andres

AU - Lackner, Karl

AU - Wild, Philipp

AU - Peters, Annette

AU - Meisinger, Christa

AU - Donfrancesco, Chiara

AU - Signorini, Stefano G.

AU - Alver, Maris

AU - Woodward, Mark

AU - Gianfagna, Francesco

AU - Costanzo, Simona

AU - Wilsgaard, Tom

AU - Eliasson, Mats

AU - Jørgensen, Torben

AU - Völzke, Henry

AU - Dörr, Marcus

AU - Nauck, Matthias

AU - Schöttker, Ben

AU - Lorenz, Thiess

AU - Makarova, Nataliya

AU - Twerenbold, Raphael

AU - Dallongeville, Jean

AU - Dobson, Annette

AU - Malyutina, Sofia

AU - Pajak, Andrzej

AU - Engström, Gunnar

AU - Bobak, Martin

AU - Schmidt, Börge

AU - Jääskeläinen, Tuija

AU - Niiranen, Teemu

AU - Jousilahti, Pekka

AU - Giles, Graham

AU - Hodge, Allison

AU - Klotsche, Jens

AU - Magliano, Dianna J.

AU - Lyngbakken, Magnus N.

AU - Hveem, Kristian

AU - Pitsavos, Christos

AU - Benjamin, Emelia J.

AU - Bakker, Stephan J.L.

AU - Whincup, Peter

AU - Ikram, M. Kamran

AU - Ingelsson, Martin

AU - Koenig, Wolfgang

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

U2 - 10.1016/S0140-6736(19)32519-X

DO - 10.1016/S0140-6736(19)32519-X

M3 - Journal article

C2 - 31810609

AN - SCOPUS:85076158283

VL - 394

SP - 2173

EP - 2183

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 10215

ER -