Increased Lifetime Exposure to High LDL Cholesterol Predicts ASCVD

The notion that lower is better for longer raises provocative questions about when to start risk reduction, experts say.

Increased Lifetime Exposure to High LDL Cholesterol Predicts ASCVD

Measuring the number of years an individual is exposed to high LDL-cholesterol levels can better predict cardiovascular events than a static measure of LDL cholesterol levels in early middle age, according to the results of a new study.  

Moreover, increased exposure to a high level of LDL cholesterol early in life was associated with a greater risk of future cardiovascular events than exposure to a similarly high LDL cholesterol level in later years. In other words, say investigators, high cholesterol levels are never safe, not even in young people, and physicians should aim for optimal LDL-cholesterol levels early in adulthood if they want to reduce the risk of cardiovascular disease.

“If we’re going to make a real dent in coronary heart disease, we need to start early and we’re going to have to go low,” said lead investigator Michael Domanski, MD (University of Maryland School of Medicine, Baltimore). “I’m not even sure how many clinical trials we need to tell us that. I think if we put the data together, we need to really lower cholesterol at a young age.”

The new study, published online September 21, 2020, in the Journal of the American College of Cardiology, provides support for assessing risk based on cumulative lifetime exposure to LDL cholesterol, which is not unlike “pack-years” when assessing risk in cigarette smokers, say experts.  

If we’re going to make a real dent in coronary heart disease, we need to start early and we’re going to have to go low. Michael Domanski

Kausik Ray, MD (Imperial College London, England), is a proponent of shifting to a cumulative-exposure model for the assessment of LDL cholesterol and cardiovascular risk. Ray, who wasn’t involved in the new analysis, said it adds yet more data to the evolving field of primary prevention. “We know from genetic studies that cumulative exposure is important,” he told TCTMD. “For example, small changes maintained over a long period of time produce the same benefits as large changes over a short time horizon. Conversely, . . . small excess elevated cholesterol levels maintained over a longer time horizon carry a greater risk than much higher levels [that] may arise later in life and have only been present for a short period of time.”

The implication of cumulative exposure is that physicians need to consider long-term or lifetime risk, added Ray.

Visualising the long-term trajectory moves prevention earlier into the life course, where it may be most effective before more advanced atherosclerosis is present. This may well be feasible with diet and lifestyle started earlier where the compound benefits, if maintained, are greatest,” he explained. For patients who don’t see sufficient improvement in their lipid parameters, then a pharmacological intervention could be considered earlier than it is typical, said Ray.

Risk Based on Lifetime LDL Cholesterol Exposure

Speaking with TCTMD, Domanski said one approach to quantify the risk burden of LDL cholesterol over time is to calculate the area under the curve (AUC) of LDL cholesterol versus age. While the AUC metric of cumulative risk is based on exposure to LDL cholesterol over time, they also calculated the trajectory of that exposure and whether the time course played a part in modulating the risk of incident cardiovascular events.  

“The question is: how do we best quantify the risk of somebody that comes into clinic that takes into account their entire life and not just as they sit in your office with a particular [LDL] level?” said Domanski. “We’d like to have some metric of risk that takes into account not only high LDL cholesterol at a given moment, but what the trajectory has been over time.”

Using data from CARDIA, the researchers sought to determine if cumulative exposure between 18 and 40 years in 4,958 asymptomatic adults was related to subsequent risk of incident cardiovascular events. Cumulative exposure was calculated as the area under the LDL cholesterol versus age curve and expressed in mg/dL x years (AUC18-40 years). Subjects were followed for a median of 16 years after age 40.

During follow-up, 275 individuals free from cardiovascular disease before age 40 had an event, including 134 who developed CHD. When stratified into quartiles, those with greater cumulative LDL cholesterol exposure from age 18 to 40 years had significantly more cardiovascular events. Overall, the event rate was 8.6% for those in the upper AUC18-40 years quartile versus 5.5%, 4.4%, and 2.6% for those in quartiles three, two, and one (P < 0.0001 for trend).

“It makes sense,” said Domanski about the results. “If you have long-term exposure, you’d expect to have more [AUC] and more risk.”

The more interesting finding, he said, relates to time course, which they assessed by measuring the risk of incident of cardiovascular disease based on the AUC of LDL cholesterol from age 18 to 30 years (early) and 31 to 40 years (late). The AUC18-30 years was associated with a greater risk of cardiovascular disease compared with the same area accumulated later in life. For example, for two individuals with the same LDL cholesterol level at age 40, those with greater cumulative LDL cholesterol exposure during early adulthood had a higher risk of cardiovascular events than those exposed to the same amount of LDL cholesterol between 31 and 40 years.

This approach tells a more complete story than a snapshot of LDL cholesterol at a single point in time. Seth Martin

“In effect, what happens is that for the same area increase when you’re younger, you acquire more late risk than you would if you accumulated the same area when you’re older,” said Domanski. “It tells us that if we’re going to prevent coronary heart disease, the time to start is early. It really makes a difference. This is a clear demonstration of that, with real data in real people followed for many, many years.”

Another clinical implication is that physicians need to understand the patient’s accumulated exposure to LDL cholesterol—and the course of that exposure—if they are to fully grasp their risk of cardiovascular disease. “If you’re sitting in your office and two people have the same LDL cholesterol, they could have very different risk of a subsequent event depending on their prior history of LDL cholesterol,” said Domanski. “It’s the whole trajectory. In other words, the risk you accumulate for a given LDL cholesterol elevation is different at different ages and is higher with younger people.”

The adage ‘I played around when I was 20, but now that I’m 40 I have to start taking care of myself,’ is not true, said Domanski. While lowering LDL cholesterol at any time is a good idea, it’s best not to do damage early.

Seth Martin, MD (Johns Hopkins Medical Institute, Baltimore, MD), called the new research an elegant confirmation that risk relates to cumulative LDL cholesterol exposure and the time course of that exposure.

“This approach tells a more complete story than a snapshot of LDL cholesterol at a single point in time and is an opportunity to get more out of our electronic medical records,” he said in an email. “It seems feasible clinically, and to do so will take more regular surveillance of LDL cholesterol than typically happens in clinical practice from age 18 to 40, paired with automation in the medical record to present the cumulative results to clinicians and patients in an intuitive manner.”

Like Domanski, Martin said when it comes to treatment, the data are signaling not only that lower is better, but also that earlier is better, too.

Appetite for Very Early Primary Prevention

In an editorial, Michael Shapiro, DO (Wake Forest University School of Medicine, Winston Salem, NC), and Deepak Bhatt, MD (Brigham and Women’s Hospital, Boston, MA), also say the findings “allow us to imagine that an earlier risk factor treatment approach may be a more effective primary prevention strategy than waiting until middle age to initiate serious risk factor modification.”

The “unresolved tension,” say the editorialists, is whether it is necessary to formally test the premise with an intervention study. The annualized event rate in young adults with elevated LDL cholesterol is very low, however, making such a trial prohibitive given the large number of patients and extensive follow-up required, they say. Shapiro and Bhatt also question whether society has the “appetite to start low-intensity therapy in large swaths of young, healthy individuals even if randomized trial evidence does not support this approach.”  

For Domanski, the present paper makes the case strongly that lower is better and it’s best to start young.

“If we could keep LDL cholesterol in the neonatal range throughout the lifespan, there might be other problems, but I suspect we’d see a lot less coronary heart disease,” he said. “You’ll pay a price. You’ll need to give people medication. But you know what, coronary heart disease is the number one killer in the world. It’ll kill more people in the lifetime of a child today than all the wars of history combined. It might be worth accepting more medication than we’d like to get rid of this disease.”     

Michael O’Riordan is the Managing Editor for TCTMD. He completed his undergraduate degrees at Queen’s University in Kingston, ON, and…

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  • Domanski reports no conflicts of interest.
  • Shapiro reports serving on the advisory board of Amgen, Alexion, Esperion, and Regeneron; consulting for Amgen and Novartis; and serving on board of directors of the American Society of Preventive Cardiology and Familial Hypercholesterolemia Foundation.
  • Bhatt reports receiving research funding or unfunded research support from Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi, Synaptic, The Medicines Company, FlowCo, Merck, Novo Nordisk, PLx Pharma, and Takeda; being a site co-investigator for Biotronik, Boston Scientific, St. Jude Medical, and Svelte; being a trustee for ACC; serving as an advisory board member, director, or chair for Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; the Boston VA Research Institute, the Society of Cardiovascular Patient Care, TobeSoft; the American Heart Association Quality Oversight Committee; serving on a range of data safety monitoring committees; receiving honoraria for editorial or committee activities for a range of publications and organizations; and receiving royalties from Elsevier.
  • Ray reports receiving personal fees for consultancy from Abbvie, Amgen, Astra Zeneca, Sanofi, Regeneron MSD, Pfizer, Resverlogix, Akcea, Boehringer Ingelheim, Novo Nordisk, Takeda, Kowa, Algorithm, Cipla, Cerenis, Dr Reddys, Lilly, Zuellig Pharma, Bayer, Daiichi Sankyo, The Medicines Company, and Esperion and research grant support from Pfizer, Amgen, Sanofi, Regeneron and MSD.
  • Martin reports serving on scientific advisory boards for Amgen, Esperion, Regeneron, and Sanofi. He is a co-inventor of a method for LDL cholesterol calculation for which Johns Hopkins University has a pending patent.