Cumulative LDL-c exposure associated with future CHD risk

Association Between Cumulative Low-Density Lipoprotein Cholesterol Exposure During Young Adulthood and Middle Age and Risk of Cardiovascular Events

Literature - Zhang Y, Pletcher MJ, Vittinghoff E, et al., - JAMA Cardiol. 2021;6(12):1406-1413. doi:10.1001/jamacardio.2021.3508

Cumulative LDL-c and time-weighted average LDL-c during young adulthood and middle age (18-60 years) are associated with risk of incident CHD, independent of midlife LDL-c, in a cohort study of 18,288 participants.

Introduction and methods


There are only few studies on the association of long-term exposure to LDL-c with CV risk [1-4]. This may be due to a restricted enrollment age range and limited studies with repeated measurements of LDL-c in both early and later life.

It is still unknown whether LDL-c slope or cumulative LDL-c is a stronger risk factor of future CVD risk. Time-weighted average (TWA) LDL-c, calculated as the cumulative exposure to LDL-c divided by the duration of exposure, is a measure of the cumulative burden of LDL-c and is associated with CVD risk [2,5]. It is not clear whether cumulative LDL-c and TWA LDL-c have a similar association with CVD events.

This study examined the associations of cumulative exposure to LDL-c, TWA LDL-c, and the LDL-c slope change during young adulthood and middle age with incident CVD in later life.

Study design

This study used pooled data from 4 large, community-based prospective cohort studies in the US. 18,288 Participants with 2 or more LDL-c measures that were >2 years apart between 18 and 60 years, with at least 1 of the LDL-c measures at middle age at 40-60 years were included. Data from 1971 to 2017 were collected. Median follow-up was 16 years. LDL-c trajectories from 18 years to the end of follow-up were modeled, and using these trajectories the cumulative exposure to LDL-c, TWA LDL-c and LDL-c slope change from age 18 to 60 years were estimated. Then, the independent associations between these LDL-c exposures with subsequent risks of CVD were assessed.


Outcomes were coronary heart disease (CHD), ischemic stroke, and heart failure (HF).

Main results

  • In multivariable Cox proportional hazard regression models that also adjusted for LDL-c at the most recent measurement during middle age, HRs for CHD that compared the top with bottom quartiles of the LDL-c variables were: 1.57 (95%CI:1.10-2.23, Ptrend=0.01) for cumulative LDL-c, 1.69 (95%CI:1.23-2.31, Ptrend<0.001) for TWA LDL-c and 0.88 (95%CI: 0.69-1.12, Ptrend=0.28) for LDL-c slope.
  • No association was seen between any of the LDL-c variables and risk of ischemic stroke or HF.


This pooled cohort study showed that greater cumulative exposure to LDL-c and TWA LDL-c during young adulthood and middle age were associated with an increased risk of CHD, even after correction for the most recent LDL-c level measured during middle age. These results highlight that maintaining an optimal LDL-c level from age 18 to 60 years reduces lifetime risk of CVD.

Find this article online at JAMA Cardiol

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