
==== Front
Chin Med J (Engl)
Chin Med J (Engl)
CM9
Chinese Medical Journal
0366-6999
2542-5641
Lippincott Williams & Wilkins Hagerstown, MD

39075633
CMJ-2023-3162
10.1097/CM9.0000000000003199
00006
3
Original Article
Association and its population heterogeneities between low-density lipoprotein cholesterol and all-cause and cardiovascular mortality: A population-based cohort study
Lu Jiapeng 1
Zhang Haibo 1
Chen Bowang 1
Yang Yang 1
Cui Jianlan 1
Xu Wei 1
Song Lijuan 1
Yang Hao 1
He Wenyan 1
Zhang Yan 1
Peng Wenyao 1
Li Xi 1 2 3
Jia Rongman
1 National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China
2 Shenzhen Clinical Research Center for Cardiovascular Diseases, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, Guangdong 518057, China
3 Central China Sub-center of the National Center for Cardiovascular Diseases, Zhengzhou, Henan 451460, China
Correspondence to: Xi Li, National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Road, Beijing 100037, China E-Mail: xi.li@nccd.org.cn
30 7 2024
05 9 2024
137 17 20752083
08 3 2024
Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

Abstract

Background:

The association and its population heterogeneities between low-density lipoprotein cholesterol (LDL-C) and all-cause and cardiovascular mortality remain unknown. We aimed to examine the dose-dependent associations of LDL-C levels with specific types of cardiovascular disease (CVD) mortality and heterogeneities in the associations among different population subgroups.

Methods:

A total of 2,968,462 participants aged 35–75 years from China Health Evaluation And risk Reduction through nationwide Teamwork (ChinaHEART) (2014–2019) were included. Cox proportional hazard models and Fine–Gray subdistribution hazard models were used to estimate associations between LDL-C categories (<70.0, 70.0–99.9, 100.0–129.9 [reference group], 130.0–159.9, 160.0–189.9, and ≥190.0 mg/dL) and all-cause and cause-specific mortality.

Results:

During a median follow-up of 3.7 years, 57,391 and 23,241 deaths from all-cause and overall CVD were documented. We observed J-shaped associations between LDL-C and death from all-cause, overall CVD, coronary heart disease (CHD), and ischemic stroke, and an L-shaped association between LDL-C and hemorrhagic stroke (HS) mortality (P for non-linearity <0.001). Compared with the reference group (100.0–129.9 mg/dL), very low LDL-C levels (<70.0 mg/dL) were significantly associated with increased risk of overall CVD (hazard ratio [HR]: 1.10, 95% confidence interval [CI]: 1.06–1.14) and HS mortality (HR: 1.37, 95% CI: 1.29–1.45). Very high LDL-C levels (≥190.0 mg/dL) were associated with increased risk of overall CVD (HR: 1.51, 95% CI: 1.40–1.62) and CHD mortality (HR: 2.08, 95% CI: 1.92–2.24). The stronger associations of very low LDL-C with risk of CVD mortality were observed in individuals with older age, low or normal body mass index, low or moderate 10-year atherosclerotic CVD risk, and those without diagnosed CVD or taking statins. Stronger associations between very high LDL-C levels and all-cause and CVD mortality were observed in younger people.

Conclusions:

People with very low LDL-C had a higher risk of all-cause, CVD, and HS mortality; those with very high LDL-C had a higher risk of all-cause, CVD, and CHD mortality. On the basis of our findings, comprehensive health assessment is needed to evaluate cardiovascular risk and implement appropriate lipid-lowering therapy for people with very low LDL-C.

Keywords:

Low-density lipoprotein cholesterol
Mortality
Association study
Population heterogeneity
Prospective cohort study
OPEN-ACCESSTRUE
SDCT
==== Body
pmcIntroduction

High level of low-density lipoprotein cholesterol (LDL-C), the seventh highest-burden risk factor, which is widely perceived as a major contributor to the development of cardiovascular diseases (CVD), is a global health concern.[1] Evidence from clinical trials indicates that the reduction in CVD risk is proportional to the reduction in LDL-C levels, but no evidence shows a lower limit for the level of LDL-C.[2,3] Thus, the current guideline recommends a very low LDL-C treatment target (<70 mg/dL) for people with high CVD risk.[4,5]

Nevertheless, recent evidence indicates that there might not be a linear association between the full range of LDL-C and mortality. A meta-analysis of clinical trials stratified by baseline LDL-C level found no benefit of LDL-C lowering therapy on all-cause and cardiovascular mortality in people with LDL-C <100 mg/dL.[6] Population-based observational studies indicate that very low LDL-C (<70 mg/dL) at baseline is also significantly associated with an increased risk of CVD mortality.[789] At present, knowledge gaps remain in the following two major aspects. First, different associations of LDL-C with death owing to specific types of CVD need to be distinguished. Prior studies have revealed that low LDL-C levels, as well as intensive statin use, could be related to a high risk of hemorrhagic stroke (HS).[10,11] However, our understanding of the relationships between very low LDL-C levels with death owing to coronary heart disease (CHD) and ischemic stroke (IS) is still poor. Second, heterogeneities in the associations between LDL-C and mortality among population subgroups, particularly at the low end of the LDL-C range, have not been well elucidated. A study in a Korean cohort noted weaker associations between very low LDL-C and cardiovascular mortality in women and older adults.[9] However, potential differences in the association among subgroups by body weight, comorbidities, and statin use have not yet been investigated.

We leveraged a nationwide mega-population cohort with uniformly measured lipid profiles at baseline to examine the dose-dependent associations of LDL-C levels with the risk of all-cause mortality and cardiovascular mortality and to explore their relationships in different population subgroups stratified by age, sex, body weight, morbidities, CVD risk, and statin use.

Methods

Ethics

The protocol for the China Health Evaluation And risk Reduction through nationwide Teamwork (ChinaHEART) project was approved by the central ethics committee at Fuwai Hospital (Beijing, China) (No. 2014-574). All participants provided written informed consent.

Study design and population

The study cohort was established based on ChinaHEART (formerly named China Patient-centered Evaluative Assessment of Cardiac Events Million Persons Project, PEACE MPP), which is an ongoing government-funded public health program throughout China. Details of the project design have been described previously.[12] Briefly, from November 2014 to December 2019, 286 district/county-level regions in 31 provinces in China were selected as study sites to provide diversity in geographic distribution, population structure, and exposure to risk factors and disease patterns. In terms of study site selection, population size, population stability, and local capacity to support the project were considered. Local residents aged 35–75 years, who had lived in the community for at least 6 months of the prior 12 months, were invited to participate in this project, with an overall response rate of approximately 30%.

A total of 3,820,651 participants were recruited in the ChinaHEART cohort. We excluded participants with non-fasting blood lipid results (n = 476,171), and those with missing or implausible values (total cholesterol [TC] <100.2 mg/dL or TC >400.6 mg/dL, triglycerides [TG] <50.5 mg/dL or TG >500.4 mg/dL, high-density lipoprotein cholesterol [HDL-C] <15.1 mg/dL or HDL-C >100.2 mg/dL) for blood lipids at baseline (n = 314,675) owing to a limited measuring range or device issues in lipid measurement at site level. We also excluded those with non-statin lipid-lowering treatment (n = 48,645), diagnosed cancer (n = 5406), or missing values of covariates including education, annual household income, body mass index (BMI), and diabetes mellitus (n = 7292). Finally, 2,968,462 participants were included in the analysis [Supplementary Figure 1, http://links.lww.com/CM9/C62].

Data collection and variables

For each participant, standardized in-person interviews were conducted by trained personnel to collect information on socioeconomic status (i.e., educational attainment, annual household income, and marital status), lifestyle behaviors (i.e., tobacco smoking and alcohol drinking), medical history, and medication use. More specifically, in terms of tobacco smoking status, patients were categorized as never, former, or current smokers. Alcohol drinking frequency was categorized into never, once or less per month, 2–4 times per month, 2–3 times per week, or more than 4 times per week; the amount of alcohol consumed during a typical day of drinking was also estimated. All participants were queried about their medical history, including a history of diabetes mellitus, myocardial infarction, stroke, and cancer, or whether they received specific treatments such as coronary artery bypass graft surgery (CABG) and percutaneous coronary intervention (PCI). In this study, a previous history of CVD was derived based on self-reported myocardial infarction, CABG, PCI, or stroke. Medication use was determined by self-reported use of anti-diabetics or lipid-lowering drugs in the past 2 weeks. If participants were taking any kind of drugs, they were further asked to report the name, dose, and frequency of each drug.

For each participant, blood lipids, blood glucose, blood pressure, height, and weight were measured at baseline. TC, TG, and HDL-C were directly measured using a rapid lipid analyzer and fasting whole blood samples (CardioChek PA Analyzer; Polymer Technology Systems, Indiana, USA). Levels of LDL-C were calculated using the Friedewald equation. Values of LDL-C were converted to milligrams per deciliter. Blood glucose level was measured using a rapid blood glucose analyzer (BeneCheck BK6–20M Multi-Monitoring System, Suzhou Pu Chun Tang Biotechnology, Jiangsu, China). Participants were considered to be in a fasting state if they had eaten their last meal at least 8 hours before their visit. Diabetes mellitus was defined as self-reported previously diagnosed diabetes, taking anti-diabetics, or fasting glucose ≥7 mmol/L.[13]

Blood pressure was measured twice in the right upper arm, after a 5-minute rest, in a seated position and using a standardized electronic blood pressure monitor (Omron HEM-7430, Omron Corporation, Kyoto, Japan). If the difference between the two systolic blood pressure measurements was larger than 10 mmHg, a third measurement was obtained, and the average of the last two readings was used. Hypertension was defined as systolic blood pressure of 140 mmHg or higher, diastolic blood pressure of 90 mmHg or greater, or use of antihypertensive medications.[14] BMI was defined as weight in kilograms divided by the square of height in meters.

Ascertainment of outcomes

Participants’ vital status and cause of death were collected via a passive follow-up process, in which a data link was established between the cohort and the National Mortality Surveillance System and Vital Registration of China Center for Disease Control and Prevention (CDC), which covers urban and rural areas in 31 provinces in China. The death records in this system are reported by health care institutions in near real time. Then, the staff at the China CDC check these against local residential records and health insurance records annually. In the National Mortality Surveillance System and Vital Registration, the main cause of death is coded using the International Classification of Diseases, Tenth Revision (ICD-10) codes. All-cause mortality, cardiovascular mortality (codes I00–I99), mortality from CHD (codes I20–I25), stroke (codes I60–I63), IS (code I63), and HS (codes I60–I62) were included as study outcomes.

Statistical analyses

We described the participant characteristics according to LDL-C levels using percentages for categorical variables, mean ± standard deviation, or median (interquartile range), as appropriate, for continuous variables. To test the trends of participants’ characteristics among different levels of LDL-C, one-way analysis of variance or the Kruskal–Wallis test for continuous variables or χ2 test for categorical variables was conducted.

In the primary analysis, we used restricted cubic splines incorporated in the Cox models with three predefined knots at the 5th, 50th, and 95th centiles to evaluate the non-linear associations between LDL-C on a continuous scale and the risk of all-cause mortality and cause-specific mortality. These models were adjusted for age, sex (for the whole cohort), educational attainment, marital status, household income, tobacco smoking, alcohol drinking, BMI, hypertension, diabetes mellitus, history of CVD, and lipid-lowering treatment. The non-linear associations were tested using likelihood ratio tests. Additionally, Cox proportional hazard models and Fine–Gray subdistribution hazard models were fitted to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the LDL-C categories with the risk of all-cause and cause-specific mortality, in which LDL-C level was categorized into six groups (including <70.0, 70.0–99.9, 100.0–129.9 [reference group], 130.0–159.9, 160.0–189.9, and ≥190.0 mg/dL), according to Adult Treatment Panel III guidelines.[15] The following covariates were adjusted in these models: age, sex (for the whole cohort), education attainment, marital status, household income, tobacco smoking, alcohol drinking, BMI, hypertension, diabetes mellitus, history of CVD, and statin use. The proportional hazards assumption for the Cox models was checked using Schoenfeld residuals tests, and no violation was found. To further estimate the association of LDL-C categories with mortality in various population subgroups, a series of stratified analyses were performed in subgroups separated by age group (35–44, 45–54, 55–64, 65–75 years), sex (male and female), BMI (<18.5, 18.5–23.9, 24.0–27.9, ≥28.0 kg/m2), 10-year atherosclerotic cardiovascular disease (ASCVD) risk assessed according to the criteria in the 2016 Chinese Adult Dyslipidemia Prevention Guideline[16] (low, moderate, high, and extremely high), medical history (hypertension, diabetes mellitus, and CVD), and lipid-lowering treatment (yes or no).

In sensitivity analyses, we excluded participants whose outcomes occurred during the first year of follow-up to avoid reverse causality in checking the robustness of the primary results. We fitted regression models with adjustment for HDL-C levels as a covariate to control for the influence of HDL-C levels on the outcomes. Additionally, we fitted regression models for the LDL-C categories in a sub-cohort of participants with serial project ID numbers ending in 1, 3, 5, or 7 (n = 1,188,176), selected to provide detailed information on dietary patterns and physical activities so as to further adjust for these confounders.

A two-sided P <0.05 was considered statistically significant. All analyses were conducted with SAS 9.4 (SAS Institute Inc., Cary, NC, USA).

Results

Participant characteristics

Among 2,968,462 included participants, the mean age was 55.9 ± 9.9 years, and 1,799,134 (60.61%) were female [Table 1]. In this cohort, 24.66% (731,887), 35.90% (1,065,713), 25.97% (770,795), 9.85% (292,521), 2.71% (80,360), and 0.92% (27,186) of participants had LDL-C levels <70.0, 70.0–99.9, 100.0–129.9, 130.0–159.9, 160.0–189.9, and ≥190.0 mg/dL, respectively. Participants with very low levels of LDL-C (<70.0 mg/dL) tended to live in rural areas and had lower household income (P <0.05 for all). They were also more likely to smoke tobacco and drink alcohol frequently (P <0.05 for both) and had lower values for TC, HDL-C, and BMI (P <0.001).

Table 1 Baseline characteristics of all included study participants according to the level of LDL-C.

Characteristics	Aggregate	<70.0 mg/dL	70.0–99.9 mg/dL	100.0–129.9 mg/dL	130.0–159.9 mg/dL	160.0–189.9 mg/dL	≥190.0 mg/dL	F/χ2 values	P-value	
N (%)	2,968,462	731,887 (24.66)	1,065,713 (35.90)	770,795 (25.97)	292,521 (9.85)	80,360 (2.71)	27,186 (0.92)			
Mean age (years, mean±SD)	55.9 ± 9.9	54.7 ± 10.4	55.4 ± 10.0	56.6 ± 9.6	57.7 ± 9.1	58.4 ± 8.7	58.3 ± 8.7	6663.69*	<0.001	
Sex								40302.70†	<0.001	
Female	1,799,134 (60.61)	391,332 (53.47)	627,964 (58.92)	495,321 (64.26)	204,685 (69.97)	59,612 (74.18)	20,220 (74.38)			
Male	1,169,328 (39.39)	340,555 (46.53)	437,749 (41.08)	275,474 (35.74)	87,836 (30.03)	20,748 (25.82)	6966 (25.62)			
Urbanity								970.12†	<0.001	
Urban	1,183,785 (39.88)	282,388 (38.58)	423,306 (39.72)	314,765 (40.84)	119,648 (40.90)	32,643 (40.62)	11,035 (40.59)			
Rural	1,784,677 (60.12)	449,499 (61.42)	642,407 (60.28)	456,030 (59.16)	172,873 (59.10)	47,717 (59.38)	16,151 (59.41)			
Education levels								2975.90†	<0.001	
Primary school or below	1,268,513 (42.73)	311,100 (42.51)	450,665 (42.29)	327,879 (42.54)	129,625 (44.31)	36,452 (45.36)	12,792 (47.05)			
Middle school	969,586 (32.66)	245,892 (33.60)	352,564 (33.08)	248,391 (32.23)	90,866 (31.06)	24,074 (29.96)	7799 (28.69)			
High school	389,447 (13.12)	89,242 (12.19)	139,417 (13.08)	105,225 (13.65)	40,494 (13.84)	11,321 (14.09)	3748 (13.79)			
College or above	226,072 (7.62)	58,303 (7.97)	83,467 (7.83)	57,889 (7.51)	19,671 (6.72)	5087 (6.33)	1655 (6.09)			
Unknown	114,844 (3.87)	27,350 (3.74)	39,600 (3.72)	31,411 (4.08)	11,865 (4.06)	3426 (4.26)	1192 (4.38)			
Annual household income (RMB, Yuan)					2641.35†	<0.001	
<10,000	520,628 (17.54)	136,395 (18.64)	185,890 (17.44)	130,105 (16.88)	50,430 (17.24)	13,322 (16.58)	4486 (16.50)			
10,000–50,000	1,635,997 (55.11)	406,804 (55.58)	591,373 (55.49)	423,501 (54.94)	157,761 (53.93)	42,321 (52.66)	14,237 (52.37)			
>50,000	528,294 (17.80)	122,868 (16.79)	188,044 (17.64)	140,814 (18.27)	54,992 (18.80)	16,090 (20.02)	5486 (20.18)			
Unknown	283,543 (9.55)	65,820 (8.99)	100,406 (9.42)	76,375 (9.91)	29,338 (10.03)	8627 (10.74)	2977 (10.95)			
Married	2,757,309 (92.89)	684,370 (93.51)	992,773 (93.16)	713,064 (92.51)	268,711 (91.86)	73,516 (91.48)	24,875 (91.50)	1494.22†	<0.001	
Lifestyle										
Current smoking	579,593 (19.53)	168,247 (22.99)	215,100 (20.18)	135,905 (17.63)	45,490 (15.55)	11,038 (13.74)	3813 (14.03)	12816.26†	<0.001	
Alcohol drinking (≥2 times/week)	285,719 (9.63)	77,695 (10.62)	104,776 (9.83)	70,164 (9.10)	24,643 (8.42)	6351 (7.90)	2090 (7.69)	1995.63†	<0.001	
Medical history										
Hypertension	1,381,567 (46.54)	319,149 (43.61)	478,385 (44.89)	370,214 (48.03)	153,742 (52.56)	44,970 (55.96)	15,107 (55.57)	12402.22†	<0.001	
Diabetes mellitus	544,149 (18.33)	130,717 (17.86)	183,637 (17.23)	141,651 (18.38)	61,578 (21.05)	19,477 (24.24)	7,089 (26.08)	5377.31†	<0.001	
CVD	96,758 (3.26)	30,469 (4.16)	31,692 (2.97)	22,166 (2.88)	8,924 (3.05)	2,656 (3.31)	851 (3.13)	2573.31†	<0.001	
Statin use	35,069 (1.18)	17,598 (2.40)	10,097 (0.95)	4,655 (0.60)	1,803 (0.62)	648 (0.81)	268 (0.99)	12985.30†	<0.001	
Metabolic factors (mean±SD)									
TC (mg/dL)	176.5 ± 39.4	139.3 ± 24.5	166 ± 21.6	194.7 ± 22.3	226.2 ± 22.7	257.4 ± 24.8	300 ± 35.7	1163273.00*	<0.001	
TG (mg/dL)	138.3 ± 71.7	139.2 ± 80.3	132 ± 67.6	138.8 ± 66.3	148.4 ± 69.3	161.2 ± 78.6	174.6 ± 91.3	5942.57*	<0.001	
HDL-C (mg/dL)	55.4 ± 15.3	54.2 ± 16.2	54.9 ± 15.1	56.0 ± 14.6	57.6 ± 14.6	58.8 ± 15.1	60.0 ± 16.2	3806.66*	<0.001	
LDL-C (mg/dL)	93.9 ± 33.8	53.9 ± 12.4	85.2 ± 8.4	113.3 ± 8.5	142.3 ± 8.3	171.7 ± 8.4	213.6 ± 24.1	6466721.00*	<0.001	
BMI (kg/m2)	24.8 ± 3.4	24.5 ± 3.4	24.7 ± 3.4	25.0 ± 3.4	25.1 ± 3.3	25.2 ± 3.3	25.1 ± 3.3	2379.42*	<0.001	
Data are expressed as n, n (%), or mean±SD. * refers to F value tested by one-way analysis of variance, and † refers to χ2 value tested by χ2 test. BMI: Body mass index; CVD: Cardiovascular diseases; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; SD: Standard deviation; TC: Total cholesterol; TG: Triglyceride.

During the follow-up with a median duration of 3.7 years, a total of 57,391 (4.94/1000 person-years) deaths occurred. Among them, 23,241 (40.49%, 2.00/1000 person-years), 8652 (15.08%, 0.74/1000 person-years), 8108 (14.13%, 0.70/1000 person-years), 3008 (5.24%, 0.26/1000 person-years), 5100 (8.89%, 0.44/1000 person-years), and 19,863 (34.61%, 1.71/1000 person-years) were owing to overall CVD, CHD, stroke, IS, HS, and cancer, respectively.

LDL-C levels and mortality risk in the overall population

A J-shaped association between LDL-C levels and all-cause mortality was observed (P for non-linearity <0.001) [Figure 1]. In the analysis of LDL-C categories, compared with participants who had LDL-C 100.0–129.9 mg/dL, those with LDL-C <70.0 mg/dL (HR: 1.16, 95% CI: 1.14–1.18) and LDL-C ≥190.0 mg/dL (HR: 1.31, 95% CI: 1.23–1.39) had an increased risk of all-cause mortality [Table 2].

Figure 1 Association between LDL-C and risk of all-cause and cause-specific mortality. We used RCS incorporated in the Cox models with three predefined knots at the 5th, 50th, and 95th centiles to evaluate the non-linearity associations between LDL-C and risk of mortality. CHD: Coronary heart disease; CI: Confidence interval; CVD: Cardiovascular disease; HR: Hazard ratio; HS: Hemorrhagic stroke; IS: Ischemic stroke; LDL-C: Low-density lipoprotein cholesterol; RCS: Restricted cubic splines.

Table 2 HRs and 95% CIs for the association between LDL-C categories and risk of mortality among all participants.

Outcomes	<70.0 mg/dL	70.0–99.9 mg/dL	100.0–129.9 mg/dL	130.0–159.9 mg/dL	160.0–189.9 mg/dL	≥190.0 mg/dL	
All-cause mortality	1.16 (1.14–1.18)	1.02 (1.00–1.04)	1.00 (ref)	1.01 (0.98–1.04)	1.05 (1.00–1.10)	1.31 (1.23–1.39)	
CVD mortality	1.10 (1.06–1.14)	0.98 (0.95–1.01)	1.00 (ref)	1.03 (0.98–1.08)	1.08 (1.00–1.16)	1.51 (1.40–1.62)	
Mortality from CHD	0.98 (0.92–1.04)	0.95 (0.89–1.01)	1.00 (ref)	1.07 (0.99–1.15)	1.22 (1.10–1.34)	2.08 (1.92–2.24)	
Mortality from IS	1.03 (0.93–1.13)	0.93 (0.84–1.02)	1.00 (ref)	1.04 (0.91–1.17)	0.89 (0.65–1.13)	1.16 (0.81–1.51)	
Mortality from HS	1.37 (1.29–1.45)	1.11 (1.04–1.18)	1.00 (ref)	1.06 (0.95–1.17)	0.97 (0.78–1.16)	1.04 (0.74–1.34)	
Cox proportional hazard models were fitted to calculate HRs and 95% CI for the LDL-C categories with risk of all-cause and cause-specific mortality. All models were adjusted for age, sex, education attainment, marital status, household income, tobacco smoking, alcohol drinking, BMI, self-reported hypertension, self-reported diabetes, self-reported CVD, and statin use. BMI: Body mass index; CHD: Coronary heart disease; CI: Confidence interval; CVD: Cardiovascular disease; HR: Hazard ratio; HS: Hemorrhagic stroke; IS: Ischemic stroke; LDL-C: Low-density lipoprotein cholesterol; ref: Reference.

With respect to cause-specific mortality, we observed J-shaped associations between LDL-C levels and overall CVD, CHD, and IS mortality, V-shaped associations between LDL-C levels and stroke mortality, and L-shaped associations between LDL-C levels and HS mortality (P for non-linearity <0.001) [Figure 1]. In the regression models of LDL-C categories, very low LDL-C levels (<70.0 mg/dL) were significantly associated with an increased risk of overall CVD (HR: 1.10, 95% CI: 1.06–1.14) and HS mortality (HR: 1.37, 95% CI: 1.29–1.45). Very high LDL-C levels (≥190.0 mg/dL) were associated with an increased risk of overall CVD (HR: 1.51, 95% CI: 1.40–1.62) and CHD mortality (HR: 2.08, 95% CI: 1.92–2.24) [Table 2]. In the sensitivity analyses, the associations between LDL-C and risk of all-cause and CVD mortality, and the estimated risk were similar to the main results [Supplementary Tables 1–3, http://links.lww.com/CM9/C62].

LDL-C levels and mortality risk in population subgroups

In the analysis by age group, stronger associations between very high LDL-C levels and all-cause and CVD mortality were observed in younger people (P for interaction <0.05) [Table 3 and Supplementary Table 4, http://links.lww.com/CM9/C62]. A similar magnitude of association between very low LDL-C levels and all-cause mortality was found among different age groups. Furthermore, very low LDL-C was associated with an increased risk of CVD and HS mortality in people aged 55 years or above but not in younger groups (P for interaction <0.001) [Table 3 and Supplementary Table 5, http://links.lww.com/CM9/C62].

Table 3 Subgroup analysis for the association between LDL-C categories and CVD mortality among all participants.

Groups	HR (95% CI)	P for interaction	
<70.0 mg/dL	70.0–99.9 mg/dL	100.0–129.9 mg/dL	130.0–159.9 mg/dL	160.0–189.9 mg/dL	≥190.0 mg/dL	
Age (years)							<0.001	
35–44	0.94 (0.71–1.18)	0.83 (0.60–1.06)	1.00 (ref)	0.89 (0.51–1.28)	0.63 (–0.27 to 1.52)	2.12 (1.30–2.94)		
45–54	0.99 (0.88–1.10)	0.93 (0.83–1.03)	1.00 (ref)	1.08 (0.93–1.22)	1.11 (0.86–1.37)	1.39 (1.01–1.77)		
55–64	1.14 (1.07–1.21)	1.02 (0.96–1.08)	1.00 (ref)	1.02 (0.93–1.11)	1.15 (1.00–1.29)	1.72 (1.52–1.92)		
65–75	1.12 (1.07–1.16)	0.98 (0.94–1.03)	1.00 (ref)	1.03 (0.97–1.09)	1.05 (0.94–1.15)	1.40 (1.25–1.55)		
Sex							<0.001	
Male	1.04 (1.00–1.09)	0.96 (0.91–1.00)	1.00 (ref)	1.09 (1.02–1.16)	1.12 (1.00–1.24)	1.69 (1.52–1.86)		
Female	1.24 (1.18–1.29)	1.03 (0.97–1.08)	1.00 (ref)	0.98 (0.91–1.04)	1.05 (0.94–1.16)	1.39 (1.24–1.54)		
BMI group (kg/m2)						<0.001	
<18.5	1.17 (0.97–1.37)	1.03 (0.84–1.23)	1.00 (ref)	0.95 (0.61–1.29)	1.03 (0.41–1.64)	1.14 (0.25–2.04)		
18.5–23.9	1.24 (1.18–1.29)	1.05 (1.00–1.10)	1.00 (ref)	1.06 (0.99–1.14)	1.19 (1.07–1.32)	1.65 (1.47–1.83)		
24.0–27.9	0.99 (0.93–1.05)	0.93 (0.88–0.99)	1.00 (ref)	0.98 (0.90–1.05)	1.06 (0.94–1.19)	1.46 (1.28–1.64)		
≥28.0	0.99 (0.90–1.08)	0.92 (0.84–1.01)	1.00 (ref)	1.08 (0.97–1.18)	0.92 (0.73–1.11)	1.40 (1.14–1.67)		
Current smoking							<0.001	
Yes	1.03 (0.96–1.10)	0.94 (0.87–1.00)	1.00 (ref)	1.14 (1.04–1.23)	1.27 (1.10–1.43)	1.95 (1.72–2.18)		
No	1.14 (1.10–1.18)	1.00 (0.96–1.04)	1.00 (ref)	1.00 (0.94–1.05)	1.03 (0.94–1.12)	1.40 (1.27–1.54)		
Alcohol drinking							0.070	
Yes	1.07 (0.96–1.19)	0.95 (0.84–1.06)	1.00 (ref)	1.10 (0.94–1.26)	1.41 (1.16–1.66)	2.12 (1.77–2.48)		
No	1.11 (1.07–1.15)	0.99 (0.95–1.02)	1.00 (ref)	1.02 (0.97–1.07)	1.05 (0.96–1.13)	1.46 (1.34–1.58)		
Self-reported diabetes						<0.001	
Yes	0.95 (0.89–1.02)	0.91 (0.85–0.97)	1.00 (ref)	1.12 (1.04–1.20)	1.09 (0.96–1.22)	1.59 (1.41–1.76)		
No	1.18 (1.14–1.23)	1.02 (0.98–1.06)	1.00 (ref)	0.97 (0.91–1.03)	1.06 (0.96–1.16)	1.44 (1.29–1.59)		
Self-reported hypertension						0.090	
Yes	1.09 (1.05–1.13)	0.97 (0.93–1.01)	1.00 (ref)	1.04 (0.99–1.10)	1.13 (1.03–1.22)	1.49 (1.36–1.63)		
No	1.16 (1.09–1.22)	1.01 (0.95–1.08)	1.00 (ref)	0.99 (0.90–1.08)	0.93 (0.76–1.10)	1.55 (1.33–1.77)		
10-year ASCVD risk						<0.001	
Extreme high	0.90 (0.78–1.02)	0.95 (0.84–1.07)	1.00 (ref)	1.16 (1.00–1.32)	1.23 (0.98–1.49)	1.64 (1.27–2.02)		
High	0.93 (0.84–1.02)	0.90 (0.84–0.97)	1.00 (ref)	1.15 (1.06–1.23)	1.13 (1.01–1.25)	1.28 (1.16–1.41)		
Moderate	1.23 (1.15–1.32)	1.05 (0.99–1.11)	1.00 (ref)	0.95 (0.88–1.03)	0.97 (0.82–1.11)	NA		
Low	1.20 (1.14–1.27)	1.02 (0.96–1.08)	1.00 (ref)	0.92 (0.81–1.04)	0.85 (0.63–1.08)	NA		
Self-reported CVD						<0.001	
Yes	0.93 (0.82–1.04)	0.94 (0.83–1.04)	1.00 (ref)	1.15 (1.01–1.29)	1.18 (0.95–1.41)	1.60 (1.27–1.93)		
No	1.14 (1.10–1.18)	0.99 (0.95–1.03)	1.00 (ref)	1.01 (0.96–1.06)	1.06 (0.98–1.15)	1.50 (1.38–1.62)		
Statin use							0.290	
Yes	0.86 (0.54–1.17)	0.92 (0.58–1.26)	1.00 (ref)	1.11 (0.58–1.64)	0.94 (0.02–1.86)	1.49 (0.32–2.66)		
No	1.11 (1.08–1.15)	0.98 (0.95–1.02)	1.00 (ref)	1.03 (0.98–1.08)	1.08 (1.00–1.16)	1.51 (1.39–1.62)		
Cox proportional hazard models were fitted to calculate HRs and 95% CI for the LDL-C categories with risk of all-cause and cause-specific mortality. All models were adjusted for age, sex, education attainment, marital status, household income, tobacco smoking, alcohol drinking, BMI, self-reported hypertension, self-reported diabetes, self-reported CVD, and statin use. ASCVD: Atherosclerotic cardiovascular disease; BMI: Body mass index; CI: Confidence interval; CVD: Cardiovascular disease; HR: Hazard ratio; LDL-C: Low-density lipoprotein cholesterol; NA: Not available; ref: Reference.

In the analysis of all-cause mortality by sex, a slightly stronger association was identified in female participants (HR: 1.26, 95% CI: 1.22–1.30 in female individuals vs. HR: 1.11, 95% CI: 1.08–1.14 in male participants; P for interaction <0.001) among those with very low LDL-C. A weaker association was identified in female participants (HR: 1.24, 95% CI: 1.13–1.34 in female individuals vs. HR: 1.41, 95% CI: 1.29–1.53 in male participants) among those with very high LDL-C [Supplementary Table 4, http://links.lww.com/CM9/C62]. Similar results were found in the stratified analysis by sex for CVD and CHD mortality [Table 3, Supplementary Table 6, http://links.lww.com/CM9/C62, and Figure 2].

Figure 2 Association between LDL-C and risk of mortality from specific types of CVD by age, sex, BMI, and 10-year ASCVD risk. We used RCS incorporated in the Cox models with three predefined knots at the 5th, 50th, and 95th centiles to evaluate the non-linearity associations between LDL-C and risk of mortality from specific types of CVD. ASCVD: Atherosclerotic cardiovascular disease; BMI: Body mass index; CHD: Coronary heart disease; CI: Confidence interval; CVD: Cardiovascular disease; HR: Hazard ratio; HS: Hemorrhagic stroke; LDL-C: Low-density lipoprotein cholesterol; RCS: Restricted cubic splines.

In the analysis by BMI, stronger associations between very low LDL-C and all-cause and CVD mortality were found in people with low or normal weight (BMI <24.0 kg/m2) (P for interaction <0.001) [Table 3 and Supplementary Table 4, http://links.lww.com/CM9/C62]. Additionally, slightly stronger associations between very low LDL-C and all-cause and CVD mortality were found in those without risk factors, including current smoking as well as self-reported diabetes and hypertension. Similarly, stronger associations between very low LDL-C and all-cause and CVD mortality were observed in participants with a low or moderate 10-year ASCVD risk. In the analysis by BMI, risk factors, and 10-year ASCVD risk, no significant differences in the association were found for IS mortality [Supplementary Table 7, http://links.lww.com/CM9/C62]. For HS mortality, a significant association was only found in participants with low 10-year ASCVD risk [Supplementary Table 5, http://links.lww.com/CM9/C62].

Among participants without diagnosed CVD or statin use, very low LDL-C levels were associated with increased risks of all-cause, CVD, and HS mortality [Table 3 and Supplementary Tables 4 and 5, http://links.lww.com/CM9/C62]. To further explore the variation in the associations, we tested the association between LDL-C categories and mortality in population groups combined with diagnosed CVD and statin use. Very low LDL-C levels were associated with increased risks of all-cause, CVD, and HS mortality in participants without either diagnosed CVD or statin use, whereas very low LDL-C levels were associated with a decreased risk of IS mortality in those with diagnosed CVD but not taking statins [Supplementary Table 8, http://links.lww.com/CM9/C62].

Discussion

In this nationwide population-based prospective study, we found that very low LDL-C levels (<70.0 mg/dL) were associated with an increased risk of all-cause, overall CVD, and HS mortality, whereas very high LDL-C levels (≥190.0 mg/dL) were associated with an increased risk of all-cause, overall CVD, and CHD mortality in the whole cohort, after adjusting for comprehensive demographic, socioeconomic, and behavioral factors. In stratified analyses, significant associations of very low LDL-C levels with increased risks of all-cause and CVD mortality were observed in individuals with older age, low or normal BMI, low or moderate 10-year ASCVD risk, and those without diagnosed CVD or taking statins.

Our study extends the existing evidence in the following respects. First, we found different non-linear associations of LDL-C levels with different types of CVD mortality (i.e., ischemic vs. hemorrhagic diseases). Specifically, J-shaped associations were observed between LDL-C levels and CHD and IS mortality whereas an L-shaped association was observed for HS mortality. This is supported by previous studies of the pathogenic mechanism,[17,18] and jointly confirm the J-shaped association between LDL-C levels and CVD mortality observed in previous cohort studies.[789] A recent Chinese cohort study reported that lower LDL-C levels were associated with an increased risk of incident intracerebral hemorrhage (ICH) when LDL-C was <70.0 mg/dL.[19] To validate the causal relationship between LDL-C and incident CVD, previous Mendelian randomization analyses have reported that lower genetically predicted LDL-C levels are associated with a reduced risk of CHD and IS and an increased risk of ICH.[10,20,21] However, these analyses were performed based on the assumption that LDL-C levels are linearly associated with the risk of cardiovascular events. Further non-linear Mendelian randomization studies are needed to clarify whether very low LDL-C levels have a causal effect on the morbidity and mortality risk of CVD and its subtypes.

Second, our analysis implied that the elevated risk of CVD mortality observed in people with very low LDL-C levels may be attributed to poor nutritional or health status. In our study, individuals who had very low LDL-C levels were more likely to have lower BMI, annual income less than RMB 50,000 Yuan, and live in less-developed areas (i.e., western and rural areas) than those with higher LDL-C levels. Even though the association between very low LDL-C and CVD mortality remained after adjusting for BMI, income, and urbanity, the results of stratified analysis were significant only among those with low and normal weight, but not in overweight or obese people. Moreover, stronger associations between very low LDL-C and HS mortality were found in people with relatively low BMI. Previous studies also have reported that lower BMI and cholesterol levels, which represent malnutrition status, are associated with an increased risk of all-cause and CVD mortality.[22232425] This is plausible because, on the one hand, malnutrition status might lead to a higher risk of CVD, such as higher risk of hemorrhagic transformation among patients with acute IS;[26,27] on the other hand, malnutrition status is a risk factor of poorer prognosis in patients with CVD.[28] These findings indicate that greater attention should be paid to this vulnerable population in clinical practice in terms of risk assessment and lipid-lowering treatment.

Third, we reported significant discrepancies in the associations between very low LDL-C and mortality across 10-year ASCVD risk levels, diagnosed CVD, and statin use. Among the high CVD-risk population, defined based on either the risk prediction algorithm or medical history, there was no significant association between very low LDL-C levels and all-cause and CVD mortality. This was similar in participants taking statins, who were speculated to have a high baseline CVD risk. These findings indicate that untreated or treated very low LDL-C levels would not bring about adverse health effects among individuals with a high CVD risk. Furthermore, compared with individuals who had very low baseline LDL-C levels, it is speculated that those achieving lower LDL-C levels through intensive lipid-lowering treatment could have an even smaller excess CVD mortality risk because the latter might have better nutrition status. Nevertheless, in the high CVD-risk groups, although full-spectrum monotonic associations between LDL-C and CVD mortality were observed, and the HR point estimates of very low LDL-C were less than 1.00, we failed to observe a significant protective effect on CVD mortality, as indicated in recent clinical trials;[29,30] this may be owing to the limited number of CVD deaths in our cohort.

Lipid-lowering therapy should be widely applied to control dyslipidemia in Chinese population.[31] Our findings have potential clinical implications for the prevention and treatment of CVD. First, the risk of HS should be assessed before and after initiating lipid-lowering treatment, especially for those with lower baseline LDL-C levels, considering that very low LDL-C levels were consistently associated with an increased HS mortality in our study and with the HS incidence rate in previous studies,[9,19] including intensive lipid-lowering trials.[30,32] Second, for those with poor health or nutritional status, very low LDL-C levels should receive greater attention in clinical practice. Improving health status might be the first priority, and LDL-C levels and cardiovascular risk should be monitored closely.

This study had several limitations. First, this was an observational study; therefore, causality between LDL-C and mortality could not be confirmed; however, we conducted sensitivity analyses by removing death within the first year of follow-up or in participants without diagnosed CVD to robustly assess their epidemiological relationship. Second, although various confounders were adjusted in the Cox models, we could not eliminate residual confounding bias caused by unmeasured confounders, such as physical activity and dietary control. Third, owing to the short follow-up time, our study was underpowered to estimate the association of LDL-C with the risk of some specific CVD deaths or in some specific population subgroups. However, baseline LDL-C level could reflect exposure during the short follow-up period, which makes the association between LDL-C level and the risk of mortality closer.

In conclusion, in this population-based prospective study, we observed that people with very low LDL-C levels had a greater risk of all-cause and CVD mortality, particularly HS, and people with very high LDL-C levels had a greater risk of all-cause, CVD, and CHD mortality. Greater attention is needed to comprehensively assess individuals’ cardiovascular risk, based on medical history and overall health status, to implement appropriate lipid-lowering therapy in those with low LDL-C levels. Future studies on the causal relationship between very low LDL-C levels and overall or subtypes of cardiovascular events and mortality are warranted.

Acknowledgement

We appreciate the multiple contributions made by study teams at the National Center for Cardiovascular Diseases and the local sites in the collaborative network in the realms of study design and operations, particularly data collection by Hao Dai, Binbin Jin, and Hui Zhong. We thank Analisa Avila, MPH, ELS, of Liwen Bianji (Edanz) (www.liwenbianji.cn) for editing the language of a draft of this manuscript.

Funding

This project was supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Science (No. 2021-I2M-1-011), the National High Level Hospital Clinical Research Funding (Nos. 2022-GSP-GG-4, 2023-GSP-RC-20), the Ministry of Finance of China and National Health Commission of China, and the 111 Project from the Ministry of Education of China (No. B16005).

Conflicts of interest

None.

Supplementary Material

SUPPLEMENTARY MATERIAL

How to cite this article: Lu JP, Zhang HB, Chen BW, Yang Y, Cui JL, Xu W, Song LJ, Yang H, He WY, Zhang Y, Peng WY, Li X. Association and its population heterogeneities between low-density lipoprotein cholesterol and all-cause and cardiovascular mortality: A population-based cohort study. Chin Med J 2024;137:2075–2083. doi: 10.1097/CM9.0000000000003199
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