Low and Decreasing Cholesterol Levels and Risk of All-Cause and Cause-Specific Mortality: A Prospective and Longitudinal Cohort Study

Engineering ›› 2025, Vol. 54 ›› Issue (11) : 251 -260. DOI: 10.1016/j.eng.2025.06.032

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^aDepartment of Occupational and Environmental Health, Key Laboratory of Environment and Health, Ministry of Education & State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

^bDepartment of Scientific Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

^cDepartment of Epidemiology and Biostatistics, Key Laboratory of Environment and Health, Ministry of Education, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

^dSchool of Public Health, Guangzhou Medical University, Guangzhou 511495, China

^eGraduate School, North China University of Science and Technology, Tangshan 063210, China

^fKailuan General Hospital, Tangshan 063001, China

^gDepartment of Cardiovascular Diseases, Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Shiyan 442008, China

^hDepartment of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China

ⁱDepartment of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China

^jDepartment of Cardiology, Kailuan General Hospital, Tangshan 063001, China

* E-mail address: drwusl@163.com

* E-mail address: chaolong@hust.edu.cn

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Received	Accepted	Published
2025-03-03	2025-06-25	2025-07-08
Issue Date	Revised Date
2025-07-08	2025-04-22

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Abstract

This prospective study aimed to investigate the associations of untreated cholesterol levels and their longitudinal changes, especially low levels, with all-cause and cause-specific mortality in different populations. Participants were drawn from two Chinese cohorts and the UK Biobank, excluding those with lipid-lowering medications, coronary heart disease (CHD), stroke, cancer, clinically diagnosed chronic obstructive pulmonary disease, low body mass index (< 18.5 kg∙m^–2) at baseline, and deaths within the first two years to minimize reverse causality. Individual cholesterol changes were assessed in a subset who attended the resurvey after over four years. Mortality data were linked to registries, and risks were estimated using Cox proportional hazards models. A total of 163 115 Chinese and 317 305 UK adults were included (mean age, 49–61 years), with 43%, 81%, and 44% males in Dongfeng–Tongji, Kailuan, and UK Biobank cohorts, respectively. During a median follow-up of 9.7–12.9 years, 9553 and 15 760 deaths were documented in the Chinese cohorts and UK Biobank, respectively. After multivariate adjustments, nonlinear relationships were observed between total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and non-high-density lipoprotein cholesterol (non-HDL-C) levels and mortality. In both populations, high cholesterol was primarily associated with CHD mortality, while low cholesterol associated with all-cause and cancer mortality (P_nonlinear ≤ 0.0161). The optimal levels for all-cause mortality risk in Chinese adults (TC: 200 mg∙dL^–1; LDL-C: 130 mg∙dL^–1; non-HDL-C: 155 mg∙dL^–1) were lower than those in the UK Biobank but consistent with guideline recommendation. Additionally, decreasing cholesterol levels over four years were associated with higher all-cause and cancer mortality in the Chinese cohorts (P_nonlinear ≤ 0.0100). Participants with low TC, LDL-C, or non-HDL-C levels at both baseline and resurvey experienced elevated all-cause mortality risks in both populations, as did those with low/medium baseline levels and > 20% reductions over time in Chinese adults. In conclusion, higher TC, LDL-C, and non-HDL-C levels are associated with elevated CHD mortality. Importantly, low and/or longitudinally decreasing cholesterol levels are robustly associated with increased all-cause and cancer mortality, potentially serving as markers of premature death. Regular cholesterol monitoring, with attention to both high and low levels, is recommended to inform guideline updates and clinical strategies.

Keywords

Low cholesterol / Cancer mortality / Cardiovascular disease mortality / Longitudinal change / Prospective cohort study

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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. Low and Decreasing Cholesterol Levels and Risk of All-Cause and Cause-Specific Mortality: A Prospective and Longitudinal Cohort Study. Engineering, 2025, 54(11): 251-260 DOI:10.1016/j.eng.2025.06.032

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References

Publishing order | Descend order by publishing year | Descend order by cited within

[1]

Expert Panel on Detection, and Treatment of High Blood Cholesterol in Adults.Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAM A 2001;285(19):2486–97.

[2]	Joint Committee on the Chinese Guidelines for Lipid Management.Chinese guidelines for lipid management (2023). Chin Circ J 2023;51(3):221–55.

[3]	Johannesen CDL, Langsted A, Mortensen MB, Nordestgaard BG.Association between low density lipoprotein and all cause and cause specific mortality in Denmark: prospective cohort study.BMJ 2020; 371:m4266.

[4]	Sung KC, Huh JH, Ryu S, Lee JY, Scorletti E, Byrne CD, et al.Low levels of low-density lipoprotein cholesterol and mortality outcomes in non-statin users.J Clin Med 2019; 8(10):1571.

[5]	Chen L, Chen S, Bai X, Su M, He L, Li G, et al.Low-density lipoprotein cholesterol, cardiovascular disease risk, and mortality in China.JAMA Netw Open 2024; 7(7):e2422558.

[6]	Abdullah SM, Defina LF, Leonard D, Barlow CE, Radford NB, Willis BL, et al.Long-term association of low-density lipoprotein cholesterol with cardiovascular mortality in individuals at low 10-year risk of atherosclerotic cardiovascular disease.Circulation 2018; 138(21):2315-2325.

[7]	Noda H, Iso H, Irie F, Sairenchi T, Ohtaka E, Ohta H.Association between non-high-density lipoprotein cholesterol concentrations and mortality from coronary heart disease among Japanese men and women: the Ibaraki Prefectural Health Study.J Atheroscler Thromb 2010; 17(1):30-36.

[8]	Zeng RX, Xu JP, Kong YJ, Tan JW, Guo LH, Zhang MZ.U-shaped relationship of non-HDL cholesterol with all-cause and cardiovascular mortality in men without statin therapy.Front Cardiovasc Med 2022; 9:903481.

[9]	Madsen CM, Varbo A, Nordestgaard BG.Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies.Eur Heart J 2017; 38(32):2478-2486.

[10]	Ko DT, Alter DA, Guo H, Koh M, Lau G, Austin PC, et al.High-density lipoprotein cholesterol and cause-specific mortality in individuals without previous cardiovascular conditions: the CANHEART study.J Am Coll Cardiol 2016; 68(19):2073-2083.

[11]	Schatz IJ, Masaki K, Yano K, Chen R, Rodriguez BL, Curb JD.Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study.Lancet 2001; 358(9279):351-355.

[12]	Jacobs DR Jr, Blackburn H, Higgins M, Reed D, Iso H, McMillan G, et al.Report of the conference on low blood cholesterol: mortality associations.Circulation 1992; 86(3):1046-1060.

[13]	Risk NCD Factor Collaboration.Repositioning of the global epicentre of non-optimal cholesterol.Nature 2020; 582(7810):73-77.

[14]

Stone NJ, Robinson JG, Lichtenstein AH, Bairey CNMerz, Blum CB, Eckel RH, et al.2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.Circulation 2014; 129(25 Suppl 2):S1-S45.

[15]	Anderson KM, Castelli WP, Levy D.Cholesterol and mortality. 30 years of follow-up from the Framingham study.JAMA 1987; 257(16):2176-2180.

[16]	Jeong SM, Choi S, Kim K, Kim SM, Lee G, Son JS, et al.Association of change in total cholesterol level with mortality: a population-based study.PLoS One 2018; 13(4):11.

[17]	Wang F, Zhu J, Yao P, Li X, He M, Liu Y, et al.Cohort profile: the Dongfeng–Tongji cohort study of retired workers.Int J Epidemiol 2013; 42(3):731-740.

[18]	Yuan Y, Liu K, Zheng MY, Chen S, Wang H, Jiang Q, et al.Analysis of changes in weight, waist circumference, or both, and all-cause mortality in Chinese adults.JAMA Netw Open 2022; 5(8):e2225876.

[19]	Sudlow C, Gallacher J, Allen N, Beral V, Burton P, Danesh J, et al.UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age.PLoS Med 2015; 12(3):e1001779.

[20]	Nitika N, Mishra SS, Lohani P.Lexis Expansion: a prerequisite for analyzing time changing variables in a cohort study.Nepal J Epidemiol 2017; 7(2):681-684.

[21]	Greenland S, Longnecker MP.Methods for trend estimation from summarized dose–response data, with applications to meta-analysis.Am J Epidemiol 1992; 135(11):1301-1309.

[22]	He GD, Liu XC, Liu L, Yu Y, Chen C, Huang J, et al.A nonlinear association of total cholesterol with all-cause and cause-specific mortality.Nutr Metab 2021; 18(1):25.

[23]	Lewington S, Whitlock G, Clarke R, Sherliker P, Emberson J, Halsey J, et al.Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55000 vascular deaths.Lancet 2007; 370(9602):1829-1839.

[24]	Fry A, Littlejohns TJ, Sudlow C, Doherty N, Adamska L, Sprosen T, et al.Comparison of sociodemographic and health-related characteristics of UK Biobank participants with those of the general population.Am J Epidemiol 2017; 186(9):1026-1034.

[25]	Li X, Guan B, Wang Y, Tse G, Zou F, Khalid BW, et al.Association between high-density lipoprotein cholesterol and all-cause mortality in the general population of northern China.Sci Rep 2019; 9(1):14426.

[26]	Yang ZM, Wu MY, Lu JM, Zhu Y, Li D, Yu ZB, et al.HDL-C, longitudinal change and risk of mortality in a Chinese cohort study.Nutr Metab Cardiovasc Dis 2021; 31(9):2669-2677.

[27]	Li J, Liu M, Liu F, Chen S, Huang K, Cao J, et al.Age and genetic risk score and rates of blood lipid changes in China.JAMA Netw Open 2023; 6(3):e235565.

[28]

Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, et al.Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.Eur Heart J 2017; 38(32):2459-2472.

[29]	Navarese EP, Robinson JG, Kowalewski M, Kolodziejczak M, Andreotti F, Bliden K, et al.Association between baseline LDL-C level and total and cardiovascular mortality after LDL-C lowering: a systematic review and meta-analysis.JAMA 2018; 319(15):1566-1579.

[30]	Benn M, Tybj Aærg-Hansen, Stender S, Frikke-Schmidt R, Nordestgaard BG.Low-density lipoprotein cholesterol and the risk of cancer: a Mendelian randomization study.J Natl Cancer Inst 2011; 103(6):508-519.

[31]	Yang G, Mason AM, Wood AM, Schooling CM, Burgess S.Dose–response associations of lipid traits with coronary artery disease and mortality.JAMA Netw Open 2024; 7(1):e2352572.

[32]	Jayanama K, Theou O, Blodgett JM, Cahill L, Rockwood K.Frailty, nutrition-related parameters, and mortality across the adult age spectrum.BMC Med 2018; 16(1):188.

[33]	Tall AR, Yvan-Charvet L.Cholesterol, inflammation and innate immunity.Nat Rev Immunol 2015; 15(2):104-116.

[34]	Read TE, Harris HW, Grunfeld C, Feingold KR, Kane JP, Rapp JH.The protective effect of serum lipoproteins against bacterial lipopolysaccharide.Eur Heart J, 14 Suppl K 1993; 125-129.

[35]	Feingold KR, Funk JL, Moser AH, Shigenaga JK, Rapp JH, Grunfeld C.Role for circulating lipoproteins in protection from endotoxin toxicity.Infect Immun 1995; 63(5):2041-2046.

[36]	Gluchowski NL, Becuwe M, Walther TC, Farese RVJr.Lipid droplets and liver disease: from basic biology to clinical implications.Nat Rev Gastroenterol Hepatol 2017; 14(6):343-355.

[37]	Qin WH, Yang ZS, Li M, Chen Y, Zhao XF, Qin YY, et al.High serum levels of cholesterol increase antitumor functions of nature killer cells and reduce growth of liver tumors in mice.Gastroenterology 2020; 158(6):1713-1727.

[38]	Heravi G, Yazdanpanah O, Podgorski I, Matherly LH, Liu W.Lipid metabolism reprogramming in renal cell carcinoma.Cancer Metastasis Rev 2022; 41(1):17-31.

[39]

Penson PE, Long DL, Howard G, Toth PP, Muntner P, Howard VJ, et al.Associations between very low concentrations of low density lipoprotein cholesterol, high sensitivity C-reactive protein, and health outcomes in the Reasons for Geographical and Racial Differences in Stroke (REGARDS) study.Eur Heart J 2018; 39(40):3641-3653.

[40]	Gaba P, O ML’Donoghue, Park JG, Wiviott SD, Atar D, Kuder JF, et al.Association between achieved low-density lipoprotein cholesterol levels and long-term cardiovascular and safety outcomes: an analysis of FOURIER-OLE.Circulation 2023; 147(16):1192-1203.

[41]	von A Eckardstein, Nordestgaard BG, Remaley AT, Catapano AL.High-density lipoprotein revisited: biological functions and clinical relevance.Eur Heart J 2023; 44(16):1394-1407.