The most comprehensive analysis of long term risk for cardiovascular disease related to non-high-density lipoprotein (non-HDL) cholesterol published in the journal The Lancet (December 2, 2019) suggests a link between cholesterol levels and risk of heart disease and stroke. The study covered almost 400,000 people from 19 countries who were followed for up to 43.5 years (median 13.5 years follow-up) between1970 to 2013. The most notable value of this study is their long- term follow up.

Researchers noted that this long-term evidence may be particularly important in people aged less than 45 years. Depending on cholesterol level and number of cardiovascular risk factors, men and women aged less than 45 years have a 12 to 43% or 6 to 24% risk (respectively) of having fatal or non-fatal heart disease or stroke by the age of 75.

Numerous studies have provided consistent evidence for a causal relationship between blood cholesterol concentrations and cardiovascular disease.

Aim of the study

In this study, the researchers evaluated long-term risk for cardiovascular disease in the population related to non-HDL cholesterol on the basis of existing thresholds of blood lipid concentrations. They established an easily applicable tool to assess the long-term probabilities for cardiovascular disease events associated with non-HDL cholesterol, using a derivation and validation approach; and provided a model indicating the potential benefit of an early lipid-lowering strategy in individuals without prevalent cardiovascular disease.

In a press release, Professor Barbara Thorand, German Research Center for Environmental Health, Germany and a co-author suggested that 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.

- Prof. Barbara Thorand

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

Key insights 

The investigators collected data of 400,000 people from 38 studies across Europe, Australia and North America They had no cardiovascular disease to begin with. They were followed up for 43.5 years (50% percent had a follow up period of 13.5 years) for the occurrence of a fatal or non-fatal coronary heart disease event or stroke.

From their data, the researchers 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.

The risk factors considered were 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).

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.

Limitations of the study

1. According to the researchers, one of the limitations of the study is 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.
2. The second limitation is that they 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. They noted that non-HDL cholesterol levels in young people are generally stable over the 30-year life course.
3. The researchers 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. Their modelled 50% reduction considers that the effects of treatment apply over a longer period (30 years) than has been studied in clinical trials (around seven years). However, the real-world benefits of lipid-lowering therapies like statins are probably lower than the cholesterol reductions seen in trials as the patients’ adherence may very well be suboptimal.

In a press release from the Science Media Centre, UK, Professor Colin Baigent, Director of the MRC Population Health Research Unit, and Professor of Epidemiology, Clinical Trial Service Unit & Epidemiological Studies Unit, University of Oxford, stated that this is an important paper because it shows what could be achieved if, starting early in their 40s, healthy people were to start taking a statin so that their bad cholesterol is halved for the rest of their lives.

It shows that, if they did this, their risk of having a heart attack or stroke by the time they are 75 would fall dramatically, and the earlier they start the larger the reduction in risk would be. The benefit of taking a statin to achieve a 50% reduction in bad cholesterol would be very much greater than any modest reduction in cholesterol that can be achieved by dietary change and that is why the impact of taking a statin lifelong would add substantially to healthy eating on its own.

- Prof. Colin Baigent

It is difficult to predict how long it will take for the peers and the learned societies to accept the conclusions from this study.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

Dr K S Parthasarathy is a freelance science journalist and a former Secretary of the Atomic Energy Regulatory Board. He is available at ksparth@yahoo.co.uk