A recent study published in Engineering has shed new light on the relationship between cholesterol levels and mortality risks. The research, conducted by a team of scientists from multiple institutions in China and the United Kingdom, suggests that low and decreasing cholesterol levels may be associated with higher risks of all-cause and cancer mortality.

The study involved a large-scale prospective and longitudinal cohort analysis, drawing participants from two Chinese cohorts—the Dongfeng–Tongji cohort and the Kailuan study—as well as the UK Biobank. A total of 163 115 Chinese and 317 305 UK adults were included in the analysis, with a mean age ranging from 49 to 61 years. The researchers excluded individuals using lipid-lowering medications, those with coronary heart disease, stroke, cancer, chronic obstructive pulmonary disease, or low body mass index (BMI < 18.5 kg/m²) at baseline, as well as deaths occurring within the first two years of follow-up to minimize reverse causality.
The study found that both high and low cholesterol levels were associated with different mortality risks. Specifically, high levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and non-high-density lipoprotein cholesterol (non-HDL-C) were primarily linked to coronary heart disease (CHD) mortality. Conversely, low levels of these cholesterol fractions were associated with increased risks of all-cause and cancer mortality. The optimal cholesterol levels for minimizing all-cause mortality risk were found to be TC: 200 mg/dL, LDL-C: 130 mg/dL, and non-HDL-C: 155 mg/dL in Chinese adults, which are consistent with guideline recommendations. [The study was approved by the Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology (approval number, [2008] 03), the Ethics Committee of Kailuan General Hospital (ChiCTR-TNRC-11001489), and the North West Multi-Centre Research Ethics Committee (application number, 88159).]

Interestingly, the study also examined the longitudinal changes in cholesterol levels over a period of four years. It revealed that a decrease of more than 20% in TC, LDL-C, and non-HDL-C levels was associated with a 14% to 26% higher risk of all-cause mortality compared to stable levels. This finding highlights the importance of monitoring cholesterol changes over time, as significant decreases may indicate underlying health issues.

The researchers used Cox proportional hazards models to estimate the risks, adjusting for various factors such as age, gender, BMI, education, smoking, drinking, physical activity, and histories of hypertension and diabetes. The study’s findings underscore the dual risk pattern of cholesterol levels, suggesting that both high and low levels can be harmful, depending on the cause of death.

The study’s strengths include its prospective design, large sample size, and rigorous participant selection. The inclusion of nearly 500 000 individuals from diverse populations enhances the generalizability of the findings. However, the authors acknowledge some limitations, such as the potential for residual confounding due to the observational nature of the study and the relatively short follow-up duration for some cohorts.

This study provides valuable insights into the complex relationship between cholesterol levels and mortality risks. It emphasizes the need for individualized lipid management strategies and suggests that low cholesterol levels and their longitudinal changes should be considered in future risk prediction models. Importantly, the study’s focus on untreated cholesterol levels does not contradict the efficacy of cholesterol-lowering therapies for cardiovascular disease prevention and treatment.

The paper “Low and Decreasing Cholesterol Levels and Risk of All-Cause and Cause-Specific Mortality: A Prospective and Longitudinal Cohort Study,” is authored by Qin Jiang, Jiachen Wu, Yu Yuan, Xingjie Hao, Pinpin Long, Kang Liu, Shihe Liu, Rong Peng, Kuai Yu, Rui Zeng, Shuohua Chen, Handong Yang, Xiulou Li, Xiaomin Zhang, Meian He, Lin Wang, Xiang Cheng, An Pan, Shouling Wu, Chaolong Wang, Tangchun Wu. Full text of the open access paper: https://doi.org/10.1016/j.eng.2025.06.032. For more information about Engineering, visit the website at https://www.sciencedirect.com/journal/engineering.