Long-Term Cholesterol Risk Points to Need for Earlier Testing

December 04, 2019

New data from almost 400,000 individuals who were followed for up to 43 years have shown that the link between raised non-HDL cholesterol and future risk of cardiovascular disease is strongest in younger people.

The researchers also simulated what effect a 50% reduction in cholesterol levels would have over a lifetime, and found that although this was effective at reducing cardiovascular risk at all ages, the largest relative risk reductions were in younger individuals — probably because they would have lowered their cholesterol exposure for a longer period of their lives.

The data raise questions about testing for increased cholesterol earlier in a person's life than currently recommended.

"At present, most people don't think about getting a cholesterol test until they are in their 50s or 60s. By this time, they could have been living with high cholesterol levels for 40-plus years and a lot of the damage has already been done," senior author Stefan Blankenberg, MD, of the University Heart & Vascular Center Hamburg in Germany, told Medscape Medical News.

"Our data suggest that we shouldn't wait until middle age to think about this," he said. "The younger you are when you find out that you have high cholesterol, the more can be done to minimize the damage." 

"We are not recommending that everyone takes a statin for the whole of their lives, but our results do suggest that having a cholesterol test as a young adult is a good idea," Blankenberg added. "That way it will be possible for each individual to determine their risk and make a decision about whether to take a statin or not."

The study was published online yesterday in The Lancet.   

The results provide more information than has been available about the link between cholesterol levels and the lifetime risk of cardiovascular disease, particularly in younger adults, the authors say.  

Statin trials have generally involved older people and those with — or at high risk of — heart disease, with relatively short follow up of around 5 to 7 years, Blankenberg said. "Our main objective was to see how lipid levels predicted cardiovascular risk over a lifetime — not just the next few years."

For the study, the researchers identified 398,846 individuals (median age 51 years) without cardiovascular disease at baseline from 38 different cohort studies. They had been followed for a median of 13.5 years (maximum 43 years) for cardiovascular events.

Results showed that 30-year cardiovascular disease event rates were progressively higher for increasing non-HDL cholesterol categories, and were approximately three-to-four times higher in the highest non-HDL cholesterol category (≥ 5.7 mmol/L/220 mg/dL) than those in the lowest category (< 2.6 mmol/L/100 mg/dL) at 33.7% vs 7.7% in women, and 43.6% vs 12.8% in men. 

"We found a very strong relationship between non-HDL cholesterol levels and future cardiovascular risk — not only for 10 years, but for up to 30 years," Blankenberg said. "And the link becomes stronger as the follow-up time increases. Cholesterol level at age 40 was very strongly related to cardiovascular risk at age 70."

"What really stood out for me from our data was the incredible strength of the increase in long-term risk with raised cholesterol," he added. "It is very impressive to see how the Kaplan-Meier curves diverge from 15 years onward even with small differences in cholesterol levels. Over the long-term, this can translate into a large risk."

The steepest increase of the relative hazard associated with non-HDL cholesterol was found in individuals younger than age 45 years at baseline (hazard ratio [HR] 4.3 in women and 4.6 men, for non-HDL cholesterol ≥ 5.7 mmol/L vs the reference value of 2.6 mmol/L).

Within the older groups, the association of non-HDL cholesterol with incident cardiovascular disease was attenuated but still detectable in individuals aged 60 years and older (HR 1.4 in women and 1.8 in men, for non-HDL cholesterol ≥ 5.7 mmol/L vs the reference of 2.6 mmol/L).

Tool to Assess Lifetime Risk and Lipid-Lowering Benefit  

The researchers also developed a tool to calculate the potential benefit of an early lipid-lowering strategy in individuals without prevalent cardiovascular disease across a range of non-HDL cholesterol categories.

The tool is specific for age, sex, and cardiovascular risk factors and assesses the individual long-term probability of cardiovascular disease by the age of 75 years associated with non-HDL cholesterol.

"The risk scores currently used for decision making about lipid-lowering intervention assess only the 10-year cardiovascular risk and therefore underestimate lifetime risk, particularly in young individuals," the authors state.

They say their risk tool provides "an opportunity to estimate lifetime risks based on non-HDL cholesterol in an accessible and easily understood way that can improve physician–patient communication about preventive strategies in clinical practice."

It also predicts the potentially achievable long-term cardiovascular disease risk, assuming a 50% reduction of non-HDL cholesterol, which they say "provides unique insights into the benefits of a potential early intervention in primary prevention."

The researchers give an example of the population with non-HDL cholesterol of 3.7 to 4.8 mmol/L, younger than 45 years, and with at least two other cardiovascular risk factors, in whom the long-term risk of cardiovascular disease could hypothetically be reduced from 15.6% to 3.6% in women and from 28.8% to 6.4% in men.

This translates into a number needed to treat (to reduce one cardiovascular disease event over the lifespan by the age of 75 years) of 8.3 in women and 4.5 in men.

"Our data is a step toward a more personalized approach and suggests that identifying younger people with high cholesterol levels has a great potential for future benefit," Blankenberg concluded

In an accompanying commentary, Jennifer G. Robinson, MD, of the University of Iowa in Iowa City, says the tool described in the paper "could facilitate shared decision making in primary prevention by estimating lifetime risk of atherosclerotic cardiovascular disease up to 75 years of age, as well as the potential for individualized benefit from lowering non-HDL cholesterol or LDL cholesterol concentrations over a lifetime."

In praising the research team's risk tool for calculating the net benefit of lipid-lowering interventions early in life, Robinson says the team should even go a step further.

"The investigators should develop an online calculator in addition to the risk tool that could facilitate the widespread incorporation of their recommendations into future guidelines for cholesterol lowering," she writes.

The Lancet. Published online December 3, 2019. Abstract, Editorial

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