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. 2022 Dec 2;101(48):e32003. doi: 10.1097/MD.0000000000032003

Association of low-density lipoprotein cholesterol levels with the risk of mortality and cardiovascular events: A meta-analysis of cohort studies with 1,232,694 participants

Ke Peng a, Xingyue Li b, Zhen Wang a, Meiling Li a, Yongjian Yang a,*
PMCID: PMC9726298  PMID: 36482567

Background:

Lowering elevated low-density lipoprotein cholesterol (LDL-C) is an important strategy to prevent cardiovascular disease (CVD), while some studies report low LDL-C increases all-cause mortality. Our study aimed to explore the appropriate low LDL-C level with the lower CVD risk but with no excess risk for all-cause mortality.

Methods:

PubMed, Embase, Cochrane Library, and Web of Science were searched until April 7, 2021. Twenty cohort studies with 1232,694 adults were obtained. Effect size index was evaluated using pooled relative risk (RR) with 95% confidence interval (CI). Heterogeneity was assessed using the Cochran’s Q test and I2 statistic, and heterogeneity sources was investigated using meta-regression. Publication bias was assessed and sensitivity analysis was performed.

Results:

The risks of all-cause mortality (RR: 1.34, 95%CI: 1.00–1.80), CVD death (RR: 1.79, 95%CI: 1.26–2.54), CHD death (RR: 2.03, 95%CI: 1.36–3.03) were higher in LDL-C ≥ 160 mg/dL than LDL-C of 70–129 mg/dL. Both LDL-C of 130–159 mg/dL and ≥ 160 mg/dL were associated with higher CVD risk than LDL-C of 70–129 mg/dL, with RR of 1.26 (95%CI: 1.08–1.47) and 1.70 (95%CI: 1.35–2.14), respectively. Compared to LDL-C of 70–129 mg/dL, no association was found between LDL < 70 mg/dL and all-cause mortality and CVD events.

Conclusion:

Our results found LDL-C ≥ 130 mg/dL was associated with the higher risk of all-cause mortality and CVD risk, indicating that adults with high LDL-C should take interventions to regulate the LDL-C level lower than 130 mg/dL.

Keywords: CVD event, LDL-C level, meta-analysis, mortality

1. Introduction

Low-density lipoprotein cholesterol (LDL-C) is converted from very LDL-C in plasma, mainly synthesized in the blood vessels and degraded in the liver.[1] In many populations, elevated LDL-C levels are associated with an increased risk of cardiovascular disease (CVD) development and death.[2,3] Also, several studies report that decreasing LDL-C levels by lipid-lowering treatment reduces the risk of CVD events and death.[4,5] It is well-known that CVD is the leading cause of death worldwide, and accounts for approximately 868,662 deaths in the United States annually; of these, coronary heart disease (CHD) accounts for nearly 365,744 (42%).[6] Therefore, it is important to focus on the changes of LDL-C levels to improve patients’ health and survival outcome.

Many studies have explored the association between LDL-C levels and mortality; however, the opposite result to previous studies on CVD sometimes found that the low level of LDL-C is associated with increased risk of all-cause mortality.[7–9] Ravnskov et al[10] also supported that LDL-C levels showed an inverse association with all-cause mortality. In some studies, both low and high LDL-C level have been strongly associated with all-cause mortality.[11,12] In a Korean study, low and high LDL-C level both resulted in the increased risk of all-cause mortality.[11] Also, a study in Denmark reported an U-shaped correlation between LDL-C level and all-cause mortality.[12] Although lowering the elevated LDL-C level is an important strategy to prevent CVD risk, it remains unclear in the appropriate low LDL-C level with the lower CVD risk but with no excess risk for all-cause mortality. This suggests that the appropriate LDL-C level for people needs to be further explored.

In this study, we performed a meta-analysis based on the currently available studies to explore the potential association of LDL-C levels with the risk of all-cause mortality. The main object of disease prevention is to extend the survival time, and all-cause mortality is the most important and easily determined outcome, and risk of deviation among all outcome indicators is minimal; therefore, we mainly focused on the association between LDL-C level and all-cause mortality. Also, we revealed the association between LDL-C level and CVD as a secondary analysis result.

2. Methods

This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.[13]

2.1. Literature search strategy

Two investigators (K.P. and X.Y.L.) performed the literature search in 4 databases (PubMed, Embase, Cochrane Library, and Web of Science) up to April 7, 2021. Supplementary Table 1, Supplemental Digital Content, http://links.lww.com/MD/I5 shows the search terms and number of articles from PubMed (n = 7496), Embase (n = 11,018), Cochrane Library (n = 15,740), and Web of Science (n = 2516), respectively. Ethical approval was waived because this meta-analysis was based on the published data. Informed consent was not given since individual patient data were not involved.

2.2. Inclusion and exclusion criteria

Inclusion criteria: participants reported with data on LDL-C level; the experimental group with LDL-C < 70 mg/dL, LDL-C of 130–159 mg/dL, and LDL-C ≥ 160 mg/dL, and the control group with LDL-C of 70 to 129 mg/dL; outcome: mortality and CVD event; studies published in English. The cut-points of LDL-C level were chosen according to the National Cholesterol Education Program’s (NCEP’s) updated clinical guidelines for cholesterol testing and management (Adult Treatment Panel Ⅲ)[14] and 2016 Chinese guidelines of dyslipidemia.[15]

Exclusion criteria: Topic not meeting the requirements; reviews, meta-analyses, abstracts, editorial materials, letters, protocols, corrections, retracted publications, and case reports; Animal experiments; studies with incomplete data; Data not available (data cannot be extracted for analysis due to unit discrepancy, outcome discrepancy, and so on).

2.3. Data extraction

The extraction and appraisal of data were conducted by 2 independent investigators (K.P. and X.Y.L.) who were not involved in the included studies. A third investigator (Z.W.) would resolve the discrepancies based on consensus after discussion. The data were extracted including name of the first author, publication year, country, study design, population, total number, sex, age, LDL-C level, follow-up time and outcomes. The population was classified as general group, high CVD risk group, and original disease group (acute heart failure, chronic kidney disease, acute coronary syndrome, etc.). The stratification of LDL-C level was adapted from the National Cholesterol Education Program guidelines.[16]

2.4. Types of outcome measures

The primary outcome was mortality, including all-cause mortality, CVD death, and CHD death. The secondary outcome was CVD event, including CHD event, myocardial infarction (MI), and stroke.

2.5. Methodological quality appraisal

The quality of cohort studies was assessed by 2 independent investigators (K.P. and X.Y.L.) based on revised Newcastle-Ottawa Scale.[17] The total score of this scale was 9, and the overall study quality was defined as poor (0–3), fair (4–6), and good (7–9).

2.6. Statistical analysis

The STATA 15.1 software (Stata Corporation, College Station, TX) was used for statistical analysis. The effect size index was expressed as relative risk (RR) with 95% confidence intervals (CIs). Heterogeneity was assessed by the Cochran’s Q test and quantified with I-squared (I2), with the greater I2 value representing the greater heterogeneity. Pooled RR was calculated using a random-effects model (I2 ≥ 50%) or a fixed-effects model (I2 < 50%). The sources of heterogeneity were searched by meta-regression analyses based on region, population, and accepting lipid-lowering medication. Subgroup analysis was performed to deep explore the association of region, population, and accepting lipid-lowering medication with the outcomes. The power analysis was performed to assess statistical power for results based on less than 5 articles using G*Power 3.1 software (Universität Düsseldorf, Düsseldorf, Germany). The robustness of results for each outcome was evaluated using sensitivity analysis, and Begg’s test and Egger’s regression test was used to evaluate the publication bias if more than 9 trials were included.[18] P < .05 was considered statistically significant.

3. Results

3.1. Study selection and population

After searching the 4 English databases according to retrieval strategy, a total of 36,770 studies were identified. Of these, 21,743 studies were retained after the removal of duplicates. Based on content from titles and abstracts, 21,225 studies were excluded. The eligible 518 full texts were further evaluated; among which, 498 texts were excluded because groups didn’t meet the requirements (n = 365) and data were not available (n = 133), and then 20 studies were finally included.[19–38] Figure 1 shows the flow chart of study selection. The included 20 studies were all cohort studies (16 for high quality, 4 for low quality), and a total of 1232,694 adult participants were enrolled. The characteristics and quality assessment score of each included study are shown in Table 1.

Figure 1.

Figure 1.

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The flow chart of study selection. The figure was created by Visio (v2013, Microsoft, WA).

Table 1.

Baseline characteristics of included studies.

Author Year Country Study design population Total number Sex (M/F) Age (yr) LDL-C (mg/dL), number Lipid-lowering medication (number) Follow-up (yr) Quality assessment Outcomes
Curb 2004 USA Prospective cohort General 2424 M 77.8 <80 (391), 80–99 (511), 100–119 (623), 120–139 (474), 140–159 (235), ≥160 (134) 0 6 7 d, e
Psaty 2004 USA Prospective cohort General 4885 1954/2931 72.3 ± 5.5 ≤100 (924), 100–129 (1571), 130–159 (1436), ≥160 (901) 245 7.5 6 a, e, f, g
Kilpatrick 2007 USA retrospective cohort Disease 15859 8564/7295 61 ± 16 <40 (167), 40–69 (503), 70–99 (459), 100–129 (205), ≥130 (84) - 3 4 a, b, d
Cho 2010 Korea Prospective cohort Disease 9571 6967/2604 62.6 ± 12.5 <70 (840), 70–99 (2265), 100–129 (3182), 130–159 (2075), ≥160 (1209) 7327 1 5 a, b, d, e, f
Noda 2010 Japan Prospective cohort General 91219 30802/60417 40–79 <80 (8788), 80–99 (16776), 100–119 (22840), 120–139 (20357), ≥140 (22458) 2280 10.3* 6 a, b, c, e, d
Wong 2010 USA Prospective cohort General 4311 1674/2637 72.5 ± 5.45 <100 (846), 100–130 (1413), 130–160 (1259), ≥160 (793) 190 10.2 ± 4.5 7 d
Farrell 2012 USA Prospective cohort General 40718 M 44.8 ± 9.6 <100 (6575), 100–129 (13136), 130–159 (12468), 160–189 (5965), ≥190 (2574) - 16.7 ± 9.0 7 a, b, c, d, e
Kahn 2013 USA Retrospective cohort Disease 2428 1327/1101 Adults ≤70 (1048), 71–100 (801), 101–130 (381), >130 (198) statins 975, others 136 2.9 ± 2.2 4 d
Tonelli 2013 Canada Prospective cohort Disease 836060 418030/418030 49.4 ± 14.8 < 100 (234097), 100–130 (300981), 130–160 (192294), 160–190 (83606), ≥190 (25082) statin 142130, fibrate or ezetimibe 16721 4 4 d, e, f
Berard 2016 France Prospective cohort General 6915 3859/3056 35–44 1822, 45–54 2728, 55–64 2365 <100 (579), 100–129 (1371), 130–159 (2072), ≥160 (2705) - 10 6 a, b, d
Chinwong 2016 Thailand Cohort Disease 405 245/160 64.9 ± 11.5 <70 (110), 70–99 (155), ≥100 (140) all 1.94(0.92–2.64)* 5 a, e, g
Pletcher 2016 USA Prospective cohort General 4860 2331/2529 42.6 ± 4.4 ≤100 (846), 101–130 (2281), 131–160 (1421), >160 (312) 34 24.5 ± 8.5 7 d, e
Zhao 2016 USA Prospective cohort High CVD risk 3251 1873/1378 73.8 0–69 (109), 70–99 (519), 100–129 (1052), 130–159 (937), ≥160 (634) 176 22.5 4 a, d, e
Harari 2017 Israel Prospective cohort General 4832 M 42.1 ± 12.1 <100 (1116), 100–129 (1318), 130–159 (1250), ≥160 (917) - 22.1 ± 3.2 7 a, b, d
Tsujimoto 2017 Japan Prospective cohort High CVD risk 1500 830/670 20–39 116, 40–59 499, 60–79 720, ≥80 165 <70 (269), 70–120 (1013) 808 5.6 ± 3.1 5 a
Abdullah 2018 USA Prospective cohort General 36375 26190/10185 42(36–48)* <100 (6949), 100–129.9 (12426), 130–159.9 (10397), 160–189.9 (4689), ≥190(1914) - 26.8 (21.2–31.3)* 8 a, b, c, d, e
Zhang 2018 China Prospective cohort General 20954 10789/10165 47.4 ± 8.1 <70 (2948), 70–99 (6474), 100–129 (6842), 130–159 (3249), ≥160 (1441) 255 16.4 (8–20)* 6 d, g
Chamberlain 2019 USA Prospective cohort Disease 1854 1179/675 66 ± 13.3 <70 (743), 70–100 (644), ≥100 (467) all 5.9* 5 a, d
Zhang 2019 USA Prospective cohort General 36030 16035/19995 52.7 ± 16.6 <100 (5060), 100–129 (16052), 130–159 (12752), ≥160 (2165) 1856 17* 6 e, g
Johannesen 2020 Denmark Prospective cohort General 108243 48669/59574 58 (48–67)* <70 (6412), 70–92 (15681), 93–112 (21289), 113–131 (22207), 132–154 (21892), 155–189 (15999), >189 (4763) 13025 9.4* 6 a
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*Medians or medians (interquartile range). a, all-cause mortality; b, CVD death; c, coronary heart disease (CHD) death; d, CVD event; e, CHD event; f, myocardial Infarction (MI); g, stroke.

CHD = coronary heart disease; CVD = cardiovascular disease; LDL-C = low-density lipoprotein cholesterol.

3.2. Association of LDL-C levels with mortality

Table 2 summarizes the analysis results on the association between LDL-C and mortality, including all-cause mortality, CVD death, and CHD death. When compared to participants with LDL-C levels of 70 to 129 mg/dL, those with levels < 70 mg/dL and 130 to 159 mg/dL had no greater risk of all-cause mortality, with RR value of 1.33 (95%CI: 0.94–1.89) and 1.05 (95%CI: 0.91–1.22), respectively. The pooled data showed that participants with LDL-C level ≥ 160 mg/dL presented a significant risk of all-cause mortality compared to those with LDL-C level of 70–129 mg/dL (RR: 1.34, 95%CI: 1.00–1.80). In region subgroups, we found no association between LDL-C level ≥ 160 mg/dL and all-cause mortality. In general participants, LDL-C level ≥ 160 mg/dL presented higher risk of all-cause mortality than LDL-C of 70 to 129 mg/dL, with RR value of 1.53 (95%CI: 1.13–2.07). Forest plots of the individual studies used in Table 2 can be found in Fig. 2A–C.

Table 2.

Association between LDL-C levels and mortality.

Outcomes Number of studies RR (95%CI) P I 2
All-cause mortality
 < 70 mg/dL (vs 70–129 mg/dL) 7 1.33 (0.94, 1.89) .109 98.0
 Sensitivity analysis 1.33 (0.94, 1.89)
 130–159 mg/dL (vs 70–129 mg/dL) 7 1.05 (0.91, 1.22) .467 89.5
 Sensitivity analysis 1.05 (0.91, 1.22)
 ≥ 160 mg/dL (vs 70–129 mg/dL) 8 1.34 (1.00, 1.80) .050 97.5
 Sensitivity analysis 1.34 (1.00, 1.80)
Region
 America 1.30 (0.88, 1.93) .194 98.7
 Asia 1.34 (0.92, 1.97) .132 85.7
 Europe 1.81 (0.79, 4.18) .164 NA
Population
 General 1.53 (1.13, 2.07) .007 93.3
 High CVD risk 0.92 (0.88, 0.95) <.001 NA
 Disease 0.97 (0.73, 1.28) .807 NA
CVD death
 < 70 mg/dL (vs 70–129 mg/dL) 2 1.72 (0.93, 3.19) .083 88.6
 Sensitivity analysis 1.72 (0.93, 3.19)
 130–159 mg/dL (vs 70–129 mg/dL) 5 1.19 (0.86, 1.67) .297 84.6
 Sensitivity analysis 1.19 (0.86, 1.67)
 ≥ 160 mg/dL (vs 70–129 mg/dL) 6 1.79 (1.26, 2.54) .001 89.4
 Sensitivity analysis 1.79 (1.26, 2.54)
Region
 America 2.15 (1.33, 3.47) .002 92.3
 Asia 1.58 (0.86, 2.91) .144 91.1
 Europe 1.81 (0.79, 4.18) .164 NA
Population
 General 2.05 (1.47, 2.86) <.001 85.5
 Disease 0.97 (0.73, 1.28) .807 NA
CHD death
 130159 mg/dL (vs 70–129 mg/dL) 2 1.41 (1.21, 1.64) <.001 44.9
 Sensitivity analysis 1.41 (1.21, 1.64)
 ≥160 mg/dL (vs 70–129 mg/dL) 3 2.03 (1.36, 3.03) .001 89.3
 Sensitivity analysis 2.03 (1.36, 3.03)
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CI = confidence interval; CVD = cardiovascular disease; CHD = coronary heart disease; I2 = I-squared; NA = not available; LDL-C = low-density lipoprotein cholesterol; RR = relative risk.

I2 reflected the degree of heterogeneity, with the greater I2 value representing the greater heterogeneity.

Figure 2.

Figure 2.

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Forest plot for the association of all-cause mortality with LDL-C < 70 mg/dL (A), LDL-C level of 130 to 159 mg/dL (B), and LDL-C ≥ 160 mg/dL (C). The control group was LDL-C level of 70 to 129 mg/dL. I2 reflected the degree of heterogeneity, with the greater I2 value representing the greater heterogeneity. Figures are created by STATA software (v15.1, Stata Corporation, College Station, TX). LDL-C = low-density lipoprotein cholesterol.

The LDL-C < 70 mg/dL and LDL-C 130 to 159 mg/dL were not associated with the risk of CVD death (RR: 1.72, 95%CI: 0.93 to 3.19; RR: 1.19, 95%CI: 0.86–1.67) compared to LDL-C level of 70 to 129 mg/dL. The RR for CVD death in participants with LDL-C ≥ 160 mg/dL was 1.79 (95%CI: 1.26–2.54) with comparison of LDL-C from 70 to 129 mg/dL. Similarly, LDL-C ≥ 160 mg/dL was associated with an increased risk of CVD death in American participants (RR: 2.15, 95%CI: 1.33–3.47) and in general population (RR: 2.05, 95%CI: 1.46–2.86) compared to 70 to 129 mg/dL LDL-C. Forest plots of the individual studies used in Table 2 can be found in Fig. 3A–C.

Figure 3.

Figure 3.

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Forest plot for the association of CVD death with LDL-C < 70 mg/dL (A), LDL-C level of 130 to 159 mg/dL (B), and LDL-C ≥ 160 mg/dL (C). The control group was LDL-C level of 70 to 129 mg/dL. I2 reflected the degree of heterogeneity, with the greater I2 value representing the greater heterogeneity. Figures are created by STATA software (v15.1, Stata Corporation, College Station, TX). CVD = cardiovascular disease; LDL-C = low-density lipoprotein cholesterol.

For CHD death, compared to participants with LDL-C of 70 to 129 mg/dL, the risk was significantly high in 130–159 mg/dL group (RR: 1.41, 95%CI: 1.21–1.64) and ≥ 160 mg/dL group (RR: 2.03, 95%CI: 1.36–3.03). Forest plots of the individual studies used in Table 2 can be found in Fig. 4A and B. The statistical power was shown in Supplementary Table 2, Supplemental Digital Content, http://links.lww.com/MD/I6.

Figure 4.

Figure 4.

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Forest plot for the association of CHD death with LDL-C level of 130 to 159 mg/dL (A) and LDL-C ≥ 160 mg/dL (B). The control group was LDL-C level of 70 to 129 mg/dL. I2 reflected the degree of heterogeneity, with the greater I2 value representing the greater heterogeneity. Figures are created by STATA software (v15.1, Stata Corporation, College Station, TX). CHD = coronary heart disease; LDL-C = low-density lipoprotein cholesterol.

3.3. Association of LDL-C levels with CVD event

Table 3 displays the analysis results on the association between LDL-C and CVD event, CHD event, MI, and stroke. The control group was LDL-C level of 70 to 129 mg/dL. Compared to the control group, the risk of CVD event was significantly associated with LDL-C level of 130 to 159 mg/dL (RR: 1.26, 95%CI: 1.08–1.47) and LDL-C level ≥ 160 mg/dL (RR: 1.70, 95%CI: 1.35–2.14), but not associated with the LDL-C level < 70 mg/dL (RR: 1.01, 95%CI: 0.81–1.24). Moreover, American participants with LDL-C levels of 130 to 159 mg/dL had a higher risk to suffer CVD event (RR: 1.29, 95%CI: 1.07–1.57). The RR for participants with LDL-C level ≥ 160 mg/dL in America and Asia was 1.80 (95%CI: 1.31–2.47) and 1.50 (95%CI: 1.07–2.11), respectively. In general participants, both LDL-C of 130 to 159 mg/dL and ≥ 160 mg/dL were correlated with the high occurrence of CVD event with comparison of control group, and RR was 1.44 (95%CI: 1.09–1.91) and 1.96 (95%CI: 1.38–2.79), respectively.

Table 3.

Association between LDL-C levels and CVD event.

Outcomes Number of studies RR (95%CI) P I 2
CVD event
< 70 mg/dL (vs 70–129 mg/dL) 6 1.01 (0.81, 1.24) .958 89.1
Sensitivity analysis 1.01 (0.81, 1.24)
130–159 mg/dL (vs 70–129 mg/dL) 10 1.26 (1.08, 1.47) .003 93.8
Sensitivity analysis 1.26 (1.08,1.47)
Region
America 1.29 (1.07, 1.57) .009 96.1
Asia 1.21 (0.85, 1.71) .297 89.6
Europe 1.42 (0.58, 3.47) .444 NA
Population
 General 1.44 (1.09, 1.91) .011 94.1
 High CVD risk 1.00 (0.95, 1.05) .951 NA
 Disease 1.04 (0.76, 1.40) .826 93.0
 ≥160 mg/dL (vs 70–129 mg/dL) 12 1.70 (1.35, 2.14) <.001 96.9
 Sensitivity analysis 1.70 (1.35, 2.14)
Region
 America 1.80 (1.31, 2.47) <.001 98.2
 Asia 1.50 (1.07, 2.11) .019 88
 Europe 1.81 (0.79, 4.18) .164 NA
Population
 General 1.96 (1.38, 2.79) <.001 95.9
 High CVD risk 1.01 (0.95, 1.07) .820 NA
 Disease 1.32 (0.85, 2.04) .221 95.6
Lipid-lowering medication
 No 2.05 (1.20, 3.50) .009 NA
CHD event
 < 70 mg/dL (vs 70–129 mg/dL) 3 0.80 (0.63, 1.01) .062 29.8
 Sensitivity analysis 0.80 (0.63, 1.01)
 130–159 mg/dL (vs 70–129 mg/dL) 8 1.43 (1.12, 1.82) .004 97.0
 Sensitivity analysis 1.43 (1.12, 1.82)
Region
 America 1.44 (1.12, 1.85) .004 97.4
 Asia 1.26 (0.67, 2.39) .470 NA
Population
 General 1.61 (1.23, 2.11) .001 92.7
 High CVD risk 1.05 (0.96, 1.14) .314 NA
 Disease 1.20 (1.13, 1.28) <.001 0.0
 ≥160 mg/dL (vs 70–129 mg/dL) 10 1.87 (1.44, 2.44) <.001 96.6
 Sensitivity analysis 1.87 (1.44, 2.44)
Region
 America 2.01 (1.50, 2.70) <.001 97.3
 Asia 1.30 (1.02, 1.68) .038 0.0
Population
 General 2.16 (1.61, 2. 90) <.001 92.7
 High CVD risk 1.08 (0.98, 1.18) .140 NA
 Disease 1.63 (1.53, 1.74) <.001 0.0
Lipid-lowering medication
 No 2.05 (1.20, 3.50) .009 NA
MI
 130–159 mg/dL (vs 70–129 mg/dL) 3 1.19 (1.12, 1.26) <.001 0.0
 Sensitivity analysis 1.19 (1.12, 1.26)
 ≥160 mg/dL (vs 70–129 mg/dL) 3 1.39 (1.03, 1.87) .031 73.3
 Sensitivity analysis 1.39 (1.03,1.87)
Region
 America 1.40 (0.99,1.98) .057 85.9
 Asia 1.25 (0.57, 2.72) .576 NA
Population
 General 1.15 (0.89, 1.48) .293 NA
 Disease 1.63 (1.53, 1.74) <.001 0.0
Stroke
 < 70 mg/dL (vs 70–129 mg/dL) 2 1.15 (0.82, 1.62) .431 0.0
 Sensitivity analysis 1.15 (0.82,1.62)
 130–159 mg/dL (vs 70–129 mg/dL) 4 1.22 (0.93, 1.61) .150 77.3
 Sensitivity analysis 1.22 (0.93, 1.61)
 ≥160 mg/dL (vs 70–129 mg/dL) 4 1.21 (0.83, 1.75) .321 79.8
 Sensitivity analysis 1.21 (0.83, 1.75)
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CI = confidence interval; CVD = cardiovascular disease; CHD = coronary heart disease; I2 = I-squared; LDL-C = low-density lipoprotein cholesterol; MI = myocardial Infarction; NA = not available; RR = relative risk.

I2 reflected the degree of heterogeneity, with the greater I2 value representing the greater heterogeneity.

For CHD event, the RR was 1.43 (95%CI: 1.12–1.82) and 1.87 (95%CI: 1.44–2.44) in participants with LDL-C level of 130 to 159 mg/dL and ≥ 160 mg/dL, respectively. There was no statistical difference between LDL-C < 70 mg/dL and CHD risk. In American participants, general population, and disease population, LDL-C level of 130 to 159 mg/dL was associated with an increased risk of CHD, with RR of 1.44 (95%CI: 1.12–1.85), 1.61 (95%CI: 1.23–2.11), and 1.20 (95%CI: 1.13–1.28), respectively. For participants in America and Asia, LDL-C ≥ 160 mg/dL was associated with a higher CHD risk (RR: 2.01, 95%CI: 1.50–2.70; RR: 1.30, 95%CI: 1.02–1.68). The similar result was shown in general population, disease population, and participants not accepting lipid-lowering medication, with RR of 2.16 (95%CI: 1.61–2.90), 1.63 (95%CI: 1.53–1.74), and 2.05 (95%CI: 1.20–3.50), respectively.

The occurrence of MI was high in LDL-C level of 130 to 159 mg/dL (RR: 1.19, 95%CI: 1.12–1.26) and ≥ 160 mg/dL (RR: 1.39, 95%CI: 1.03–1.87). The similar result was found in disease population, with RR of 1.63 (95%CI: 1.53–1.74). The association of LDL-C with stroke was not significant in < 70 mg/dL group, 130 to 159 mg/dL group, and ≥ 160 mg/dL group. Supplementary Table 2, Supplemental Digital Content, http://links.lww.com/MD/I6 displays the statistical power.

3.4. Sensitivity analysis and publication bias

The sensitivity analysis was performed by sequentially removing the trial to estimate the robustness of the overall results. The results of our study were stable by that no significant change of the results happened after eliminating a trial (Tables 2 and 3). Also, no obvious publication bias was detected using Begg’s test and Egger’s regression test regarding LDL-C of 130 to 159 mg/dL on CVD event (Z = 1.07, T = 1.52), LDL-C ≥ 160 mg/dL on CVD event (Z = 1.17, T = 1.80), and LDL-C ≥ 160 mg/dL on CHD event (Z = 0.18, T = 0.66) (Table 4).

Table 4.

Publication bias of outcomes by Begg’s test and Egger’s regression test.

Outcomes Begg’s test Egger’s regression test
Z P T P
LDL-C of 130–159 mg/dL on CVD event 1.07 .283 1.52 .168
LDL-C ≥ 160 mg/dL on CVD event 1.17 .244 1.80 .102
LDL-C ≥ 160 mg/dL on CHD event 0.18 .858 0.66 .526
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CVD = cardiovascular disease; CHD = coronary heart disease; LDL-C = low-density lipoprotein cholesterol.

4. Discussion

Our meta-analysis included 20 cohort studies containing a total of 1232,694 adult participants to explore the association between LDL-C level and mortality and CVD events. According to the overall results, the risk of all-cause mortality, CVD death, and CHD death was higher in participants with LDL-C level ≥ 160 mg/dL compared to those with LDL-C level of 70 to 129 mg/dL. CHD death risk was also higher in LDL-C level of 130 to 159 mg/dL group than in LDL-C level of 70 to 129 mg/dL group. Both LDL-C level of 130 to 159 mg/dL and LDL-C level ≥ 160 mg/dL increased the risk of CVD event, CHD event, and MI compared to LDL-C level of 70 to 129 mg/dL. LDL-C < 70 mg/dL was not found to associate with the all-cause mortality and CVD event.

LDL-C is a main atherogenic lipoprotein and has been identified as the causal risk factor for atherosclerosis and CVD.[4] Since CVD is the main reason for mortality worldwide and accounts for approximately 31% of all deaths,[39] it is logically reasonable that high level of LDL-C may increase CVD mortality, even all-cause mortality. Consistently, our study found that high LDL-C level (≥ 160 mg/dL) indicated an increased risk of all-cause mortality. In line with our findings, Harari et al[32] found the association of increased LDL-C level with the high risk of all-cause mortality. Also, Schubert et al[40] reported that elevation of LDL-C level increased the hazard of all-cause mortality. Some former epidemiological studies have reported a continuous and graded correlation of LDL-C level to CVD death and CHD death.[6,41] A study from Abdullah et al[34] demonstrated that LDL-C level ≥ 130 mg/dL increased the CHD death by 50%, and LDL-C level ≥ 160 mg/dL presented a significant association with CVD death and CHD death. Similarly, our study showed the high CVD and CHD death when LDL-C level ≥ 160 mg/dL, and CHD death was also high in LDL-C level of 130 to 159 mg/dL. In addition, LDL-C < 70 mg/dL was not found to associate with the risk of all-cause mortality and CVD death when comparing to LDL-C level of 70 to 129 mg/dL. These findings suggested that people should maintain the LDL-C level less than 130 mg/dL. An Israel study has reported that LDL-C < 130 mg/dL was not significantly associated with all-cause mortality and CVD death.[32] The study performed by Yu et al[42] also supported that the target prevention value for all-cause mortality should be 130 mg/dL.

In a defined population, reducing elevated LDL-C level is a crucial strategy in primary and secondary prevention for CVD event.[43,44] Many clinical trials have demonstrated an increased risk of CVD-relevant morbidity correlated with elevation of LDL-C level.[45–47] Additionally, LDL-C has been identified as the primary target to prevent CHD by the NCEP Expert Panel.[16] Previous studies have reported that high LDL-C level increased the risk of an CHD event.[48] A clinical trial of cholesterol lowering in high-risk patients (162 mg/dL) also suggested high LDL-C concentration was associated with the increased risk of CHD.[49] In our meta-analysis, the elevated LDL-C level (130–159 mg/dL or ≥ 160 mg/dL) showed high occurrence of CVD event and CHD event. Navarese et al[5] suggested that LDL-C-lowering therapy was beneficial to patients with higher baseline LDL-C level, with a large reduction in CVD morbidity. They also reported that the overall risk of MI was reduced with the decrease in LDL-C level.[5] A previous cohort study in Japan showed the increased risk of MI in higher concentration of LDL-C.[50] Herein, population with LDL-C level of 130 to 159 mg/dL or ≥ 160 mg/dL had a higher risk of MI. A similar finding was reported in the study of Kim et al[51]

Although our meta-analysis explored the reasonable LDL-C level to prevent both all-cause mortality and CVD event based on a large number of participants, some limitations existed. First, the predictive value of LDL-C level for death risk may be magnified because the included populations were relatively older and some of them may die of increasing age during the long follow-up time. Second, health-related behaviors may be one of the sources of heterogeneity; however, we have no access to the data on this aspect for further analysis. Third, the articles included in our meta-analysis take LDL-C as a classified variable, so that we cannot analyze LDL-C as a continuous variable to explore its linear association with mortality. Fourth, some relevant studies that LDL-C level cannot be grouped as we did may be missed.

5. Conclusion

In conclusion, our results showed that high LDL-C level (≥ 130 mg/dL) was associated with the high risk of all-cause mortality and CVD events. This finding may suggest that adults with high LDL-C level should take interventions and lipid-lowering treatment to regulate the LDL-C level less than 130 mg/dL. Our results need to be cautiously interpretated and need to be verified by clinical studies in the future.

Author contributions

KP and YY designed the study. KP wrote the manuscript. XL, ZW, and ML collected, analyzed and interpreted the data. YY critically reviewed, edited and approved the manuscript. All authors read and approved the final manuscript.

Conceptualization: Ke Peng, Yongjian Yang.

Data curation: Xingyue Li, Zhen Wang, Meiling Li.

Formal analysis: Xingyue Li, Zhen Wang, Meiling Li.

Investigation: Xingyue Li, Zhen Wang, Meiling Li.

Methodology: Xingyue Li, Zhen Wang, Meiling Li.

Writing—original draft: Ke Peng, Yongjian Yang.

Writing—review and editing: Ke Peng, Yongjian Yang.

Supplementary Material

medi-101-e32003-s001.pdf (234.4KB, pdf)

Abbreviations:

CHD =
coronary heart disease
CIs =
confidence intervals
CVD =
cardiovascular disease
I2 =
I-squared
LDL-C =
low-density lipoprotein cholesterol
MI =
myocardial infarction
NCEP =
National Cholesterol Education Program
PRISMA =
Preferred Reporting Items for Systematic Reviews and Meta-Analyses
RR =
relative risk

Supplemental Digital Content is available for this article.

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

This study was supported by National Science Foundation of China (No.81873477).

The authors of this work have nothing to disclose.

How to cite this article: Peng K, Li X, Wang Z, Li M, Yang Y. Association of low-density lipoprotein cholesterol levels with the risk of mortality and cardiovascular events: A meta-analysis of cohort studies with 1,232,694 participants. Medicine 2022;101:48(e32003).

Contributor Information

Ke Peng, Email: drpeng209@126.com.

Xingyue Li, Email: Bluesnow140@126.com.

Zhen Wang, Email: ruotian-1025@163.com.

Meiling Li, Email: Bluesnow140@126.com.

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Supplementary Materials

medi-101-e32003-s001.pdf (234.4KB, pdf)
medi-101-e32003-s002.pdf (203KB, pdf)

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