Physicians' Academy for Cardiovascular Education

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


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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