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Higher LDL-cholesterol levels linked to higher CVD mortality risk in the elderly

Presented by
Dr Zhen Zhou, University of Tasmania, Australia
AHA 2022
In healthy older adults not taking any lipid-lowering agents, higher low-density lipoprotein-cholesterol (LDL-C) concentrations were associated with a decreased mortality risk from non-cardiovascular causes and an increased mortality risk due to cardiovascular disease (CVD); however, the reduced risk for non-CVD mortality was likely driven by reverse causality. 

The prognostic implications of cholesterol levels in older persons remain uncertain. In the absence of consistent evidence, there is a perception that low levels of total cholesterol and LDL-C might be linked to a high mortality risk in this population, as they are indicators of serious disease.

Dr Zhen Zhou (University of Tasmania, Australia) presented the results of a cohort study, which explored the longitudinal associations of LDL-C levels with all-cause mortality, CVD mortality, cancer mortality, and the combined non-CVD/non-cancer mortality in healthy, older adults. It included 12,334 participants from the ASPREE (NCT01038583) trial, a double-blind, randomised, placebo-controlled trial of aspirin in the elderly. These participants had no prior CVD events, dementia, or physical disabilities at enrolment and were not taking any lipid-lowering agents. The mean age was 75 years and 54% were women. They were followed up for a median duration of 6.9 years.

Of the 12,334 participants, 1,250 (10%) died during the study period (24% due to CVD, 43% cancer, and 33% from non-CVD/non-cancer causes). The researchers calculated adjusted hazard ratios for each outcome per 1 mmol/L increment in LDL-C. To check for reverse causality (i.e. the direction of cause-and-effect contrary to a common presumption), the analysis was repeated by excluding participants who died in the 5 years after baseline. In addition, the researchers adjusted their analyses for age, sex, race/country, high-density lipoprotein-cholesterol (HDL-C), triglycerides, body mass index, smoking, alcohol use, education, hypertension, diabetes, chronic kidney disease, and frailty status.

“We noted a U-shaped relation linking LDL-C and all-cause mortality, with the lowest mortality at 3.3 mmol/L) and a curvilinear relation for other mortality outcomes,” Dr Zhou described. Each 1 mmol/L higher LDL-C was associated with a lower risk of all-cause mortality (HR 0.91; 95% CI 0.84–0.98), cancer mortality (HR 0.84; 95% CI 0.74–0.94), and the combined non-CVD/non-cancer mortality (HR 0.82; 95% CI 0.72–0.93) but a higher risk of CVD mortality (HR 1.19; 95% CI 1.03–1.39). However, the reduced risks of all-cause and non-CVD/non-cancer mortality were significant only in men (P sex interaction<0.05). After excluding the deaths in the first 5 years, the HRs were increased for all-cause mortality, cancer mortality, and combined non-CVD/non-cancer mortality (1.03 vs. 1.05 vs 0.91, respectively), but the HR was stable for CVD mortality (1.21, all P>0.10).

The researchers concluded that these counterintuitive findings regarding non-CVD mortality suggest reverse causality.

    1. Zhou Z, et al. Low-density-lipoprotein cholesterol and mortality outcomes among healthy older adults not taking lipid-lowering agents: A cohort study with 12,334 participants. EP.APS.P327. AHA Scientific Sessions 2022, 05–07 November, Chicago, USA.


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