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Early LDL-C Exposure and Cumulative Burden Increase CHD Risk in Middle Age


Clinical decisions on LDL-C management currently rely on a measure at one time point, typically middle age. A new study suggests burden begins early and so should assessment.

Cumulative LDL-C exposure during early adulthood and middle age was associated with risk of incident coronary heart disease (CHD) events, independent of midlife LDL-C level, according to results of a recent pooled cohort analysis that included >18 000 participants.

"The findings suggest that maintaining an optimal level of LDL-C throughout young adulthood and middle age can minimize the lifetime risk for atherosclerotic cardiovascular disease," concluded the researchers, writing in JAMA Cardiology.

Implications of the findings go even further, according to editorial writers Ann Marie Navar, MD, PhD, University of Texas Southwestern Medical Center in Dallas, and Gregg Fonarow, MD, University of California Los Angeles, who state that “…the current guideline-endorsed paradigm of deferring the treatment of mild and moderate elevations of LDL-C levels in young adults not only misses a critical opportunity for prevention but also unnecessarily allows lipid-related risk to accumulate for decades."

As context for their research, investigators led by Yiyi Zhang, PhD, of Columbia University Medical Center in New York City, point to the limited number of studies that have examined long-term exposure to LDL-C and the impact over time on cardiovascular disease (CVD) risk. The current body of evidence, they say, reflects observation of the association of LDL-C level and CVD at a single point in time, eg, middle or older age.

Zhang and colleagues drew data for the analysis from 4 large, US community-based prospective cohort studies: The Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Framingham Heart Study Offspring Cohort, and Multi-Ethnic Study of Atherosclerosis.

“…the current guideline-endorsed paradigm of deferring the treatment of mild and moderate elevations of LDL-C levels in young adults not only misses a critical opportunity for prevention but also unnecessarily allows lipid-related risk to accumulate for decades."

Study inclusion was limited to participants aged 18 to 60 years with data for ≥ 2 LDL-C measures taken at least 2 years apart with at least 1 of the LDL-C measures occurring during middle age at 40 to 60 years. Excluded from the final analysis were individuals with existing CVD before the index visit (last study visit between ages 40 and 60 with an observed LDL-C measure) and those with missing covariate data.

The final study population comprised 18 288 individuals with a mean age of 56.4 years at index visit; 10 309 were women and 12 980 identified as non-Hispanic White.

The primary exposures of interest to Zhang et al were cumulative exposure to LDL-C, time-weighted average (TWA) LDL-C, and LDL-C slope change from age 18 to 60 years and their association with incident CHD, ischemic stroke, and heart failure


The median follow up was 16 years during which there were 1165 CHD, 599 ischemic stroke, and 1145 heart failure events.

In the multivariable Cox proportional hazards regression model that adjusted for the most recent LDL-C level measured during middle age and for other CVD risk factors, hazard ratios (HR) for CHD were:

  • Cumulative LDL-C level: HR 1.57 (95% confidence interval [CI], 1.10-2.23; Ptrend = .01)
  • TWA LDL-C level: HR 1.69 (95% CI, 1.23-2.31; Ptrend <.001)
  • LDL-C slope: HR 0.88 (95% CI, 0.69-1.12; Ptrend = .28)

Investigators found no association between any of the LDL-C variables and ischemic stroke or heart failure.

They found that associations were similar in women HR 1.82 (95% CI, 1.07 - 3.10) and men HR 1.67 (95% CI, 1.06 - 2.64).

In participants who never used lipid-lowering medication (n = 15 626), investigators found that TWA LDL-C level remained significantly associated with incident CHD (HR 1.54; 95% CI, 1.08 - 2.18).


“We found that higher levels of exposure to cumulative LDL-C and TWA LDL-C during young adulthood and middle age were associated with an increased risk of incident CHD events, even after adjusting for the most recent LDL-C level during middle age,” wrote authors in the study’s Discussion.

Given that no association was found between LDL-C slope and CHD after adjusting for midlife LDL-C level or measures of cumulative LDL-C level and other cardiovascular events (ie, ischemic stroke, heart failure), Zhang and colleagues suggest that “current LDL-C level and cumulative LDL-C burden are independently associated with CHD risk.”

In the authors' discussion of the clinical implications of their findings they note that incorporating serial LDL-C measures and cumulative LDL-C burden into clinical practice could help refine CVD risk assessment and improve clinical decisions that are now based on contemporary LDL-C values.

"Moreover, given that the risk of developing atherosclerotic plaques and CHD events is associated with the cumulative exposure to LDL-C, it is plausible that achieving optimal lipid levels early in life and maintaining those optimal levels throughout adulthood may prevent incident CHD events better than the current paradigm of deferring lowering LDL-C levels to later in life when atherosclerosis is likely already advanced."

Reference: Zhang Y, Pletcher MJ, Vittinghoff E, et al. Association between cumulative low-density lipoprotein cholesterol exposure during young adulthood and middle age and risk of cardiovascular events. JAMA Cardiol. Published online September 22, 2021. doi:10.1001/jamacardio.2021.3508

Editorial: Navar AM, Fonarow GC. Transforming the paradigm for lipid lowering. JAMA Cardiol. Published online September 22, 2021. doi:10.1001/jamacardio.2021.3517

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