Large data analysis links cholesterol levels to heart disease and stroke risk

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An observational and modelling study which used individual-level data from almost 400,000 people extends existing research because it suggests that increasing levels of non-HDL cholesterol may predict long-term cardiovascular risk by the age of 75 years. Past risk estimates of this kind are based on 10-year follow-up data.

For example, women with non-HDL cholesterol levels between 3.7-4.8 mmol/litre, who were younger than 45 years, and had at least two additional cardiovascular risk factors, had a 16% probability of experiencing a cardiovascular disease event by the age of 75 years (16 in 100 women with these characteristics were predicted to have a cardiovascular event by the age of 75 years). For women aged 60 or over with the same characteristics, the estimated risk was 12%.

For men with the same characteristics, the estimated risk for those aged under 45 years was 29%, and was 21% for those aged 60 years or more.

“This increased risk in younger people could be due to the longer exposure to harmful lipids in the blood. The risk may also appear larger compared to older ages because people aged 60 years and older in our study had not developed cardiovascular disease up to this age, so they may be healthier than others of their age who were excluded from the study because they had had cardiovascular disease,” says Professor Barbara Thorand, German Research Centre for Environmental Health, Germany.

The amount of non-HDL cholesterol and low-density lipoproteins (LDL) in the blood are accepted as causal risk factors for cardiovascular disease, and play a significant part in predicting a person’s risk of developing cardiovascular disease.

The authors say that intervening early and intensively to reduce non-HDL cholesterol levels during the lifespan could potentially reverse early signs of atherosclerosis.

However, considerable uncertainty exists about the extent to which slightly increased or apparently normal cholesterol levels affect lifetime cardiovascular risk, and about which levels should be used to make treatment recommendations, particularly in young people. In the study, the authors used individual-level data from almost 400,000 people from 38 studies from Europe, Australia and North America. The participants had no cardiovascular disease at the start of the study and were followed for up to 43.5 years (median 13.5 years follow-up) for the occurrence of a fatal or non-fatal coronary heart disease event or ischaemic stroke.

Using their data, the authors assessed and confirmed the long-term association between cholesterol levels and cardiovascular event risk. They then used this data in a model to estimate the probability of a cardiovascular event by the age of 75 years for people aged 35-70 years, according to a person’s gender, non-HDL cholesterol levels, age, and cardiovascular disease risk factors (such as smoking status, diabetes, BMI, systolic blood pressure, and antihypertensive medication). The model also estimated how much risk could be reduced if non-HDL cholesterol levels were halved (the authors note that the 50% reduction was hypothetical and not based on specific estimates or treatments).

During follow-up, there were 54,542 fatal or non-fatal cases of heart disease and stroke. Looking at data for all age groups and both sexes, the authors found that the risk for a cardiovascular event decreased continuously with decreasing non-HDL levels and the risk was lowest for those individuals with the lowest non-HDL levels (classified as below 2.6 mmol non-HDL cholesterol per litre in the study).

Using the model to estimate the risk of a cardiovascular event by the age of 75 years for different age groups, the authors found that the highest long-term risks of cardiovascular disease were seen in individuals younger than 45 years of age.

For example, women with non-HDL cholesterol levels between 3.7-4.8 mmol/litre, who were younger than 45 years, and had at least two additional cardiovascular risk factors, had an estimated 16% probability of experiencing a cardiovascular disease event by the age of 75 years (ie, 16 in 100 women with these characteristics were predicted to have a cardiovascular event by the age of 75 years). For women aged 60 or over with the same characteristics, the estimated risk was 12%. For men with the same characteristics, the estimated risk for those aged under 45 years was 29%, and was 21% for those aged 60 years or more.

Using the model to estimate how much cardiovascular disease could be reduced if a person halved their non-HDL cholesterol levels, the authors found that for all non-HDL cholesterol levels, the greatest reductions were seen in the youngest age group compared with older age groups.

For example, in people younger than 45 years with levels of 3.7-4.8 mmol/litre and with at least two risk factors, they estimated that the long-term risk of cardiovascular disease could hypothetically be reduced from 16% to 4% in women, and from 29% to 6% in men. For people with the same characteristics aged 60 years or over, risk could potentially be reduced from 12% to 6% in women and from 21% to 10% in men.

“Our estimates suggest that halving non-HDL cholesterol levels may be associated with reduced risk of cardiovascular events by the age of 75 years, and that this reduction in risk is larger the sooner cholesterol levels are reduced. The risk scores currently used in the clinic to decide whether a person should have lipid-lowering treatment only assess the risk of cardiovascular disease over 10 years, and so may underestimate lifetime risk, particularly in young people,” says Professor Stefan Blankenberg, German Centre for Cardiovascular Research, Germany.

“In lieu of needed clinical trial results investigating the benefits of long-term lipid-lowering therapy in people younger than 45, this study may provide helpful insights on the benefits of lipid-lowering therapy as primary prevention from an earlier age. However, future research is needed to understand whether intervention in young people with a high lifetime risk, but low 10-year risk, would have more benefits than later intervention,” he concludes.

Professor Frank Kee, Queens University Belfast, UK, adds: “Further research is also needed on how useful lifetime absolute risk estimates are for motivating behaviour change among otherwise healthy young people, and whether titrating any intervention dose according to a non-HDL target would be more effective than to a target of overall life-time risk.”

The authors note some limitations within their study, including that their study results may not be generalisable to other regions or racial and ethnic groups as the study was based on data from people of European ancestry from high-income countries. The authors used data about the participants’ non-HDL cholesterol levels when they entered the study only, and so could not account for changes in cholesterol levels.

However, they note that non-HDL cholesterol levels in young people are generally stable over the 30-year life course. They also could not account for participants beginning to take lipid-lowering therapy during the study, but adjusted cholesterol levels for people who were already taking lipid-lowering therapy at the start of the study.

Lastly, they note that their modelled 50% reduction posits that the effects of treatment apply over a longer period (30 years) than has been studied in clinical trials (around seven years), and note that real-world benefits of lipid-lowering therapies like statins are probably lower than the cholesterol reductions seen in trials because of sub-optimal adherence and side effects.

Writing in a linked Comment, Professor Jennifer G Robinson, University of Iowa, also says that the size of this reduction is the main limitation of the analysis, as only long-term lipid-lowering treatment is likely to achieve a reduction of this size, but the existing evidence for these drugs does not assess decades-long treatment, meaning that the risk of adverse events – which would alter the benefit-to-risk ratio – are unclear.

She writes: “The novelty of Brunner and colleagues’ findings arises from projecting the effect of beginning cholesterol-lowering therapy early in life. Such therapy could reduce the lifetime risk of atherosclerotic cardiovascular disease in patients with increased concentrations of non-HDL and LDL cholesterol, especially when risk is further amplified by the presence of comorbid factors. These individuals could be at much lower 10-year risk thresholds of atherosclerotic cardiovascular disease than are currently recommended for consideration of statin therapy. Lowering cholesterol with more intensive therapy is also supported by findings that generic statins are cost-saving or highly cost-effective even for primary prevention in patients at low risk of cardiovascular disease.”

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.

Authors
Fabian J Brunner, Christoph Waldeyer, Francisco Ojeda, Veikko Salomaa, Frank Kee, Susana Sans, Barbara Thorand, Simona Giampaoli, Paolo Brambilla, Hugh Tunstall-Pedoe, Marie Moitry, Licia Iacoviello, Giovanni Veronesi, Guido Grassi, Ellisiv B Mathiesen, Stefan Söderberg, Allan Linneberg, Hermann Brenner, Philippe Amouyel, Jean Ferrières, Abdonas Tamosiunas, Yuriy P Nikitin, Wojciech Drygas, Olle Melander, Karl-Heinz Jöckel, David M Leistner, Jonathan E Shaw, Demosthenes B Panagiotakos, Leon A Simons, Maryam Kavousi, Ramachandran S Vasan, Robin PF Dullaart, S Goya Wannamethee, Ulf Risérus, Steven Shea, James A de Lemos, Torbjørn Omland, Kari Kuulasmaa, Ulf Landmesser, Stefan Blankenberg, Tanja Zeller, Jukka Kontto, Satu Männistö, Andres Metspalu, Karl Lackner, Philipp Wild, Annette Peters, Christa Meisinger, Chiara Donfrancesco, Stefano G Signorini, Maris Alver, Mark Woodward, Francesco Gianfagna, Simona Costanzo, Tom Wilsgaard, Mats Eliasson, Torben Jørgensen, Henry Völzke, Marcus Dörr, Matthias Nauck, Ben Schöttker, Thiess Lorenz, Nataliya Makarova, Raphael Twerenbold, Jean Dallongeville, Annette Dobson, Sofia Malyutina, Andrzej Pajak, Gunnar Engström, Martin Bobak, Börge Schmidt, Tuija Jääskeläinen, Teemu Niiranen, Pekka Jousilahti, Graham Giles, Allison Hodge, Jens Klotsche, Dianna J Magliano, Magnus N Lyngbakken, Kristian Hveem, Christos Pitsavos, Emelia J Benjamin, Stephan JL Bakker, Peter Whincup, M Kamran Ikram, Martin Ingelsson, Wolfgang Koenig

The Lancet material

The Lancet abstract

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