Longer Exposure to Elevated LDL Tied to Higher CHD Risk

Higher exposure to LDL cholesterol (LDL-C) during young adulthood and middle age is associated with a significantly higher risk of coronary heart disease (CHD), regardless of midlife lipid levels, new research suggests.

Investigators analyzed pooled data from four prospective studies, encompassing over 18,000 participants with an average age of 56 years, to assess a potential association between cumulative LDL-C exposure, time-weighted average (TWA)-LDL cholesterol, and change in LDL-C slope from young adulthood to middle age and incident cardiovascular disease (CVD). The median follow-up period was 16 years.

They found that, after adjusting for covariates, individuals with the greatest cumulative exposure and highest TWA-LDL cholesterol levels had, respectively, a 1.6- and 1.7-fold higher risk of CHD compared with those with the lowest cumulative exposure and lowest TWA-LDL levels.

“Understanding young adult levels of LDL-C may help inform management decision-making in middle age,” lead author Yiyi Zhang, PhD, an investigator at Columbia University Irving Medical Center, New York City, told theheart.org | Medscape Cardiology.

“It is plausible that achieving optimal lipid levels early in life and maintaining those optimal levels throughout adulthood may more effectively prevent CVD as opposed to the current paradigm of deferring LDL-C-lowering to later ages when atherosclerosis is likely already advanced,” Zhang said.

The study was published online September 22 in JAMA Cardiology.

Different Metrics

“Some evidence from Mendelian randomization studies suggests that the effect of LDL-C on the risk of CVD is determined by both the current level and the cumulative burden of LDL-C exposure over time,” Zhang said. “However, the majority of prior observational studies assessing the association between LDL-C and CVD risk focused on LDL-C measured at a single timepoint — usually in middle or older age.”

TWA-LDL cholesterol, which is the cumulative exposure to LDL-C divided by the duration of exposure, “captures the cumulative burden of LDL-C and has been associated with incident CVD risk,” the researchers note.

A high LDL-C level measured once in middle age “might reflect a rapidly increasing LDL-C (ie, a greater slope of change in LDL-C) level or an LDL-C level that has been persistently high (ie, a greater cumulative exposure to LDL-C),” the authors state.

Few studies have looked at long-term exposures to LDL-C and their influence on CVD risk. Moreover, “there are different metrics to measure LDL-C levels such as cumulative LDL-C, TWA LDL-C, and LDL-C slope, but it is unclear whether these measures share similar or exhibit different associations with CVD,” said Zhang.

To investigate the question, the researchers pooled data from four prospective cohort studies: Atherosclerosis Risk in Communities Study (ARIC), Coronary Artery Risk Development in Young Adults Study (CARDIA), Framingham Heart Study Offspring Cohort, and Multi-Ethnic Study of Atherosclerosis (MESA).

Participants (n = 18,288; mean [SD] age, 56.4 [3.7] years; 56.4% female; 71.0% non-Hispanic white) had ≥ 2 LDL-C measures ≥ 2 years apart between ages 18 and 60 years, with ≥ 1 measure occurring during middle age (40 – 60 years). Participants were required to have no history of CVD before the index visit, and to have available covariate data.

Each LDL-C variable was categorized into quartiles, based on their sample size, with the lowest quartile consisting of the lowest LDL-C measurement.

The researchers conducted two multivariable analyses, one of which adjusted for demographic and health status and medication factors, and the other further adjusting for LDL-C levels at the index visit.

At the time of the index visit, the overall mean LDL level was 123.0 mg/dL, the cumulative LDL level was 4837 mg/dL, the TWA-LDL level was 125.6 mg/dL, and the slope of the LDL-C curve was 0.7 mg/dL/year.

Refining Risk Assessment

During the 16-year median follow-up period, a total of 1165 incident CHD, 599 ischemic stroke, and 1145 heart failure (HF) events were identified.

The multivariable analysis that adjusted for demographic and clinical risk factors found significantly higher risk for CHD in the highest vs the lowest quartile, both in cumulative LDL-C and TWA LDL-C, but not slope.

Table 1. CHD for Highest vs Lowest Quartile Adjusted for Demographic and Clinical Risk Factors


Hazard Ratio (95% CI)

P for Trend

Cumulative LDL-C

1.97 (1.50 – 2.58)

< .001


1.95 (1.54 – 2.46)

< .001

LDL-C slope

1.26 (1.03 – 1.55)


LDL-C levels at index visit

1.79 (1.49 – 2.14)

< .001

In the models that further adjusted for LDL levels at the index visit, CHD remained associated with cumulative as well as TWA-LDL-C levels in the top quartile, compared with the lowest quartile, but not with slope.

Table 2. CHD Risk for Top vs Bottom Quartile Further Adjusted for LDL Levels at Index Visit


Hazard Ratio (95% CI)

P for Trend

Cumulative LDL-C

1.57 (1.10 – 2.23)

< .01


1.69 (1.23 – 2.31)

< .001

LDL-C slope

0.88 (0.69 – 1.12)


“No association was observed between any of the LDL-C variables and the risk of ischemic stroke or HF,” the authors note.

These patterns were similar among men and women; however, the associations of cumulative LDL-C and TWA-LDL-C levels with CHD “appeared to be stronger in participants who self-identified as non-Hispanic white, compared to those who self-identified as non-Hispanic Black individuals.” On the other hand, the test for interaction did not show evidence of difference by race and ethnicity, the authors note.

Among the participants who never used lipid-lowering medication (n = 15,626), TWA-LDL-C level remained significantly associated with incident CHD.

“Clinical decisions are currently guided by contemporary LDL-C values, whereas our findings suggest that incorporating serial LDL-C measures and cumulative LDL-C burden over years into clinical practice may further refine CVD risk assessment and help inform strategies for primary prevention,” Zhang commented.

Missed Opportunity

Commenting on the study for theheart.org | Medscape Cardiology, Ann Marie Navar, MD, PhD, associate professor of medicine (cardiology), UT Southwestern Medical Center, Dallas, Texas, said she thinks current guidelines are “missing a huge opportunity to lower CVD risk by under-treating high LDL-C in young people.”

As of now, “those with elevated LDL are only recommended for treatment if they have extremely high LDL-C or other risk factors — this is despite our knowledge that leaving LDL-C untreated even if it’s mildly elevated (ie, over 100 mg/dL) early in life allows potentially decades of exposure to atherogenic lipoproteins,” said Navar, who is the coauthor of an accompanying editorial and was not involved with the study.

“We should not allow lipid-related risk to accumulate untreated when we have safe and effective therapies available,” she stated.

Zhang added, “It is important to maintain an optimal level of LDL-C throughout young and middle age to minimize the cumulative exposure to LDL-C to reduce the lifetime risk of developing atherosclerotic cardiovascular disease.”

The study was supported by grants from the National Institutes of Health (NIH). Zhang has disclosed no relevant financial relationships. Navar reported grants from Bristol Myers Squibb, Esperion, Amgen, and Janssen; personal fees from Amarin, Amgen, Astra Zeneca, Boehringer Ingelheim, CSL, Esperion, Janssen, Lilly, Sanofi, Regeneron, NovoNordisk, Novartis, The Medicines Company, New Amsterdam, Cerner, 89Bio, and Pfizer outside the submitted work; and being the associate editor of JAMA Cardiology.

JAMA Cardiology. Published online September 22, 2021. Abstract, Editorial

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