nutrients

Article
Association between Egg Consumption and
Cholesterol Concentration: A Systematic Review and
Meta-Analysis of Randomized Controlled Trials
Man-Yun Li 1,† , Jin-Hua Chen 2,3,4,† , Chiehfeng Chen 5,6,7,8, * and Yi-No Kang 7,8,9,10, *
1 School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan;
[email protected]
2 Graduate Institute of Data Science, College of Management, Taipei Medical University, Taipei 110, Taiwan;
[email protected]
3 Research Center of Biostatistics Center, College of Management, Taipei Medical University,
Taipei 110, Taiwan
4 Biostatistics Center, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
5 Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University,
Taipei 110, Taiwan
6 Division of Plastic Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University,
Taipei 116, Taiwan
7 Cochrane Taiwan, Taipei Medical University, Taipei 110, Taiwan
8 Evidence-Based Medicine Center, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
9 Research center of big data and meta-analysis, Wan Fang Hospital, Taipei Medical University,
Taipei 116, Taiwan
10 Institute of Health Behaviors and Community Sciences, College of Public Health, National Taiwan
University, Taipei 106, Taiwan
* Correspondence: [email protected] (C.C.); [email protected] (Y.-N.K.);
Tel.: +886-2-2930-7930 (Y.-N.K.)
† Man-Yun Li and Jin-Hua Chen contribute equally.




Received: 11 June 2020; Accepted: 1 July 2020; Published: 4 July 2020


Abstract: The association of egg consumption and serum cholesterol concentrations in healthy people
has been discussed for a long time. In this study, we aimed to explore association of egg consumption
with on low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c)
concentrations and the LDL-c/HDL-c ratio through meta-analysis. This systematic review only
included randomized controlled trials (RCTs) investigating egg consumption in healthy populations
without combination therapy. We extracted mean and standard deviation for LDL-c/HDL-c ratio,
LDL-c/HDL-c. The extracted data were pooled in a random-effects model and were presented
as mean difference (MD) with 95% confidence interval (CI). Moreover, subgroup analyses were
conducted for understanding effects of more egg consumption (MEC) on different intervention
periods, egg-consumption levels, classification of responders. Overall, 17 RCTs met the eligibility
criteria and pooled results showed MEC group had a higher LDL-c/HDL-c ratio than the control
group (MD = 0.14, p = 0.001, I2 = 25%). The MEC group also had higher LDL-c than the control
group (MD = 8.14, p < 0.0001, I2 = 18%). Moreover, for the subset of intervention over two months,
the MEC group seemed to have a larger effect size than the subset of intervention within two months.
This synthesis, the largest meta-analysis on this topic, shows the impact of egg consumption on lipid
profiles among healthy subjects. Notably, longer time with MEC may lead to higher LDL-c/HDL-c
ratio and LDL-c. However, RCTs with long tern follow-up are needed to guarantee the association
between egg consumption and human health.

Keywords: egg consumption; low-density lipoprotein; high-density lipoprotein

Nutrients 2020, 12, 1995; doi:10.3390/nu12071995 www.mdpi.com/journal/nutrients

Nutrients 2020, 12, 1995 2 of 14

1. Introduction
The American Heart Association recommends that total dietary cholesterol consumption should
be <300 mg/day [1]. A large egg yolk contains approximately 275 mg of cholesterol—near the
recommended daily limit of cholesterol intake [2]. The 2015–2020 Dietary Guidelines for Americans
removed the limitation of dietary egg consumption [3,4]. One study indicated that dietary cholesterol
contained in whole eggs is not well-absorbed and is not associated with longer-term plasma cholesterol
control [5], while other studies indicated that the concentration of low-density lipoprotein cholesterol
(LDL-c) and high-density lipoprotein cholesterol (HDL-c) significantly increased in an egg-consuming
group [6,7]. To clarify this controversy, some systematic reviews tried to determine whether egg
consumption influences cholesterol levels, but most of them only focused on LDL-c, HDL-c, total
cholesterol and triglycerides [8–11]. However, current evidence indicates that LDL-c/HDL-c ratio is
a better predictor of cardiovascular diseases than isolated parameters [12]. To our best knowledge,
only one of the previous systematic reviews investigated LDL-c/HDL-c ratio, and concluded that egg
consumption had insignificant effect on LDL-c/HDL-c ratio [9]. Unfortunately, the conclusion was not
based on all of the available data. There is still a need to reexamine this issue using a larger scale.
Eggs are an important food source because they contain many proteins, lipids and minerals [13].
A boiled egg (50 g) provides 6.29 g protein, 0.56 g carbohydrate, 1.6 g saturated fat, 2.0 g
monounsaturated fat and 0.7 g polyunsaturated fat. Moreover, eggs contain various minerals (calcium,
iron, magnesium and phosphorus) and many vitamins except vitamin C [14]. After consuming
eggs, the intestines are responsible for absorbing dietary cholesterol. Cholesterol absorption includes
dietary cholesterol and biliary cholesterol. Between dietary and biliary cholesterol, biliary cholesterol
accounts for most of the cholesterol in intestine. Biliary cholesterol is about two grams/day while
dietary cholesterol is 0.4 g/day according to the average American diet. The absorption rate varies in
population. The average rate is approximately 50% [15]. After absorption, free cholesterol is esterified
by enterocytes by action of acyl-coenzyme A cholesterol acyl-transferase [16]. Then, it is transported
inside chylomicrons into the peripheral circulation [17]. Next, chylomicrons form chylomicron
remnants under the action of lipoprotein lipase. The uptake of chylomicron remnants is mediated by
the LDL receptor, which recognizes apolipoprotein B 100 (Apo B 100) and apolipoprotein E (Apo E).
Through endocytosis, chylomicrons can be taken up in liver and most other tissues [18,19].
Hyperlipidemia is a phenomenon of increased levels of lipids or triglycerides [20]. It can
be classified as hypercholesterolemia, hypertriglyceridemia and elevation of both cholesterol and
triglycerides [21]. Higher amounts of LDL-c result in higher risks of cardiovascular diseases. There
are more than 100 million people in the United States with elevated LDL-c concentrations, so they
have higher risks of cardiovascular diseases [22]. The global prevalence of elevated total cholesterol
among adults are 39% [23]. The intake of dietary cholesterol is associated with increased LDL-c
concentration [11]. However, this is an oversimplification since the response of serum cholesterol to
dietary cholesterol intake is quite complicated. Humans can endogenously produce cholesterol, and
most of the cholesterol in the body comes from biosynthesis [24]. Due to this controversy, several
studies have examined the relationship between egg consumption and cholesterol levels. Some used
different doses of egg consumption while others combined different diets [25,26].
In the previous systematic review, they provided six randomized controlled trials to analyze
the effect of LDL-c/HDL-c ratio while we used more RCTs to strengthen the evidence [9]. Due to
incomplete information, we conducted a systematic review to examine the relationship between egg
consumption and lipid profiles, especially the association of egg consumption with LDL-c/HDL-c ratio.
Through this study, we would like to foster a better understanding of this controversy.

2. Methods
This comprehensive review was conducted according to the Cochrane handbook, and the
systematic review and meta-analysis were according to PRISMA guidelines [27]. Patient consent was
Nutrients 2020, 12, 1995 3 of 14

not required as this study used published data; therefore, it was also exempted from institutional
review board approval. The protocol was registered in PROSPERO (CRD42019138623).

2.1. Eligibility Criteria, Evidence Search and Study Selection

We only included randomized clinical trials (RCTs), while excluding case control studies and
cohort studies. Eligible trials only investigated healthy subjects; we excluded those trials that only
recruited patients with hypercholesterolemia, diabetes or hypertension because lipid levels would be
higher in patients with hypertension [28]. There was no limitation on the age of participants in eligible
trials. The intervention for the experimental group was consumption of eggs without accompanying
buttermilk drinks, because a previous study showed that consumption of buttermilk and skimmed
milk influences the effects of egg yolks on lipoprotein [29]. In addition, we excluded studies that used
palm oil in the diet because it has a hypercholesterolemic effect [30]. The control group in the previous
literature usually refers to regular egg consumption, a high-carbohydrate diet or the same amount of
an egg substitute. Regular egg consumption represented regular diet of every individual. Moreover,
there was no limitation on the method of cooking the eggs.
We screened the PubMed and EMBASE databases before May 2020. The primary search strategy
was (cholesterol OR lipoprotein OR LDL-c OR HDL-c) AND (egg OR eggs OR yolk OR yolks) with a
restriction of RCT. The search strategy had no publication date limitation.
After relevant references were identified from online databases, one investigator independently
did initial screening for eligible references according to the criteria, and another one double-checked
for the appropriateness of evidence selection. Then, we had a meeting to confirm eligible trials. A third
investigator participated in the meeting for making the final judgment of evidence selection.

2.2. Data Extraction

Baseline and outcome data were extracted. We extracted information on age, gender, intervention
time, the amount of egg consumption and outcomes. Moreover, we also extracted information on
absorption hypo-responders and hyper-responders to cholesterol. Because outcomes were continuous,
we extracted the mean and standard deviation (SD) for the meta-analysis.
As continuous outcomes were presented in different scales, we used a lipid conversion factor
(1 mmol/L = 38.67 mg/dL [31]) to convert mmol/L to mg/dL and used the mean difference (MD)
and 95% confidence interval (CI) in forest plots. When the value of the LDL-c/HDL-c ratio was not
available in the original report, we use Taylor approximation to estimate its value: E(x/y) ≈ {E(x)/E(y)
× (1+CVy×(CVy − Corr (x,y) × CVx))} and V(x/y) ≈ ((E(x))2 /(E(y))2 )(σ2 x/(E(x))2 − 2 × CV(x,y)/E(x) E(y)
+ σ2 y/(E(y))2 ) [32,33]; where x represents LDL-c and y represents HDL-c. E(x/y) is an exceptional value
of LDL-c/HDL-c. E(x) and E(y) populations are respective concentrations of LDL-c and HDL-c and we
estimated them from our collected studies. Corr(x,y) is the correlation coefficient between LDL-c and
HDL-c and we estimated the value to be 0.195 according to Weggemans et al. [11]. CVx and CVy are
coefficients of variation of LDL-c and HDL-c, respectively, and we estimated them from our collected
studies. σ2 x represents the variance of LDL-c, while σ2 y represents the variance of HDL-c. CV(x,y) is
the covariance of LDL-c and HDL-c.

2.3. Quality Assessment

The quality of the included trials was determined using the quality assessment tool for quantitative
studies, which was developed by the effective public health practice project [34]. There are six
components in the quality assessment tool: selection bias, study design, confounders, blinding, data
collection methods, withdrawals and dropouts. Each component was ranked as strong, moderate or
weak according to the guidelines of the quality assessment tool for quantitative studies [34].
Nutrients 2020, 12, 1995 4 of 14

2.4. Evidence Synthesis and Statistical Analysis

We used Review Manager 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration,
Copenhagen, Denmark) to analyze our extracted data and estimated pooled results in a random-effects
model. Because our outcomes were continuous data, we presented MDs and 95% CIs for pooled
estimates. We also did subgroup analysis according to the intervention times and the amount of eggs
consumed. Because the treatment of experimental groups varied widely, we subdivided experimental
groups into additional 1 egg, 1, 2 and ≥ 3 eggs/day according to egg-consumption levels. All the
experimental group are called MEC group. Intervention times were divided into ≤ 2 months and >
2 months. Then, we used I2 statistic to measure heterogeneity. A rough guide for heterogeneity is
that > 50% may indicate substantial heterogeneity [35]. We further conducted a sensitivity analysis
to confirm that the pooled results were not influenced by individual studies. Publication bias was
assessed by a funnel plot and Egger’s test.

3. Results
Our initial search included 213 studies from PubMed, EMBASE and hand searching. After
duplicates were removed, 148 references were screened by title and abstract and we excluded 120
non-relevant references. The full text of several remaining references was excluded because of using
other treatments (n = 4). Therefore, we included 24 references from 17 RCTs [6,7,36–57]. A flowchart
shows the screening and selection processes (Figure 1).
Nutrients 2020, 12, x FOR PEER REVIEW 5 of 16

Figure 1. Flowchart of the systematic review and meta-analysis according to PRISMA guidelines.
Figure 1. Flowchart of the systematic review and meta-analysis according to PRISMA guidelines.
3.1. Characteristics and Quality of Included Studies
3.1. Characteristics andWe
Quality ofrandomized
included 17 Includedclinical
Studiestrials [7,36,40–48,51,53–57]. Table below shows an overview
of the characteristics of the included studies. All subjects in the studies we included were healthy.
We included 17 randomized
Studies clinical
with subjects that trials [7,36,40–48,51,53–57].
had hypertension, diabetes or hypercholesterolemiaTable belowSixshows an overview
were excluded.
studies were RCTs [40,42,47,53,54,56]. Eleven studies were crossover studies [7,36,41,43–
of the characteristics of the included
46,48,51,55,57]. studies.
The intervention All
time ranged subjects
21–84 days (Tablein
1).the studies
The quality of allwe included
studies was were healthy.
acceptable
Studies with subjects that(Table
hadS1).hypertension, diabetes or hypercholesterolemia were excluded. Six
studies were RCTs [40,42,47,53,54,56]. Eleven studies were crossover studies [7,36,41,43–46,48,51,55,57].
The intervention time ranged 21–84 days (Table 1). The quality of all studies was acceptable (Table S1).

5
Nutrients 2020, 12, 1995 5 of 14

Table 1. Characteristics of patients in the included studies.

Intervention Result (↑: increased concentration;

Trial Male/Female Age Range Duration
Egg Group Control ↓: decreased concentration)

Missimer et al. (2017) [7] 24/26 18–30 2 eggs/day Oatmeal 28 days LDL-c↑; HDL-c↑
Baumgartner et al. (2013) [40] 34/63 18–65 One extra egg Regular diet 84 days TC↑; LDL-c↑
Rueda et al. (2013) [54] 27/46 17–20 1 egg/day No egg 28 days Statistically insignificant change
Harman et al. (2008) [47] 14/31 18–55 2 eggs/day No egg 84 days Statistically insignificant change
Mutungi et al. (2008) [53] 28/0 40–70 3 eggs/day No egg 84 days HDL-c↑
Wal et al. (2008) [56] 10/63 25–60 2 eggs/day Regular diet 56 days Statistically insignificant change
Waters et al. (2007) [57] 0/22 50–77 3 eggs/day No egg 30 days TC↑; HDL-c↑; LDL-c↑
Herron et al. (2006) [48] 40/51 21–43 3 eggs/day Egg substitute 30 days TC↑; HDL-c↑; LDL-c↑
Greene et al. (2006) [46] 13/29 50–80 3 eggs/day Egg substitute 30 days HDL-c↑; LDL-c↑
Goodrow et al. (2006 [45]) 7/26 60–96 1 egg/day Egg substitute 35 days Statistically insignificant change
Katz et al. (2005) [51] 30/19 36–73 2 eggs/day Oatmeal 42 days Statistically insignificant change
Ballesteros et al. (2004) [36] 25/29 8–12 2 eggs/day Egg white 30 days LDL-c↑; HDL-c↑
Chakrabarty et al. (2004) [41] 22/12 19–32 1 egg/day No egg 56 days TC↑; LDL-c↑; TC/HDL-c↑
Ginsberg et al. (1995) [43] 0/13 22–31 3 eggs/day1 egg/day No egg 56 days TC↑; HDL-c↑; LDL-c↑
1 egg/day2 eggs/day4
Ginsberg et al. (1994) [44] 24/0 22–31 No egg 56 days TC↑; LDL-c↑
eggs/day
Garwin et al. (1992) [42] 42/56 41–48 12 eggs/week No egg 42 days TC↓; HDL-c↓; LDL-c↓
Sacks et al. (1984) [55] 4/13 18–24 1 egg/day No egg 21 days LDL-c↑
Nutrients 2020, 12, 1995 6 of 14

3.2. LDL-c/HDL-c Ratio

Our primary outcome was the LDL-c/HDL-c ratio and relevant data were available from 12 trials
(Figure 2). We excluded data from the trial by Rueda et al. [54] because the data had different included
participants between measurements of LDL-c and HDL-c. Therefore, we could not estimate the
LDL-c/HDL-c ratio by Taylor’s approximation [32,33]. Overall, more egg consumption (MEC) group
exhibited significant elevation in the ratio than did control groups (MD = 0.14; 95% CI: 0.05 to 0.22;
I2 = 25%). Based on the intervention time, we divided the included studies into subgroups of within
2 months and over 2 months. The MEC group presented significant higher LDL-c/HDL-c ratio than
control group in both subgroups of intervention within 2 months (MD = 0.11; 95% CI: 0.01 to 0.21;
I2 = 20%) 2020,
Nutrients and12,
over 2 months
x FOR (MD = 0.17; 95% CI: 0.03 to 0.32; I2 = 34%). The result of LDL-c/HDL-c
PEER REVIEW 7 of 16
ratio may not be affected by any single study (Figure S1) and publication bias (Figure S2).

Figure
Figure2. 2.Forest
Forestplot
plotof
ofLDL-c/HDL-c
LDL-c/HDL-c ratio.ratio.For
Forstudies
studies that
that thethe lipid
lipid levels
levels werewere reported
reported separately,
separately,
wewe presented
presentedinindifferent
differentrows
rows inin forest plots.
plots.(a)
(a)hypo-responder
hypo-responder group;
group; (b) (b) hyper-responder
hyper-responder group;
group;
(c) men group; (d) women
(c) men group; (d) women group; group; (e) one-egg group; (f) two-eggs group; (g) ≥ three-eggs group;
one-egg group; (f) two-eggs group; (g) ≥ three-eggs group; blue: blue:
p <P 0.05.
< 0.05.Blue
Bluerefers
refersto
tostatistical
statistical significance
significanceininpooled
pooledanalysis.
analysis.

3.3.3.3.
Low-Density
Low-densityLipoprotein Cholesterol
Lipoprotein Cholesterol
The
The1313RCTs
RCTswe weincluded
included in in this
this study showedthat
study showed thatthe
theMEC
MEC group
group had
had a significantly
a significantly higher
higher
concentration
concentration ofof LDL-c
LDL-c thanthe
than thecontrol
controlgroup (MD==8.14;
group(MD 8.14;95%
95%CI:CI:4.46
4.46to 11.82; II22 =
to11.82; = 18%)
18%) Based
Basedonon the
the intervention time, we discovered that the MEC group exhibited higher LDL-c
intervention time, we discovered that the MEC group exhibited higher LDL-c than the control group in than the control
group
both in both subgroups
subgroups of intervention
of intervention within 2 within
months2 months
(MD = 8.09 (MDmg/dL;
= 8.09 mg/dl; 95%3.04
95% CI: CI: to
3.04 to 13.14,
13.14, I2 =I30%)
2

and= 30%)
over and over 2 (MD
2 months months (MDmg/dL;
= 8.48 = 8.48 mg/dl; 95%
95% CI: CI: to
2.77 2.77 to 14.18,
14.18, I2 =I9%).
2 = 9%). Longer
Longer interventionperiod
intervention periodmay
lead to greater LDL-c concentration (Figure 3). The result of LDL-c may not be affected by anyany
may lead to greater LDL-c concentration (Figure 3). The result of LDL-c may not be affected by single
single study (Figure S3) and publication bias (Figure S4).
study (Figure S3) and publication bias (Figure S4).
Nutrients 2020, 12, 1995 7 of 14
Nutrients 2020, 12, x FOR PEER REVIEW 8 of 16

Figure 3. Forest
Figure plotplot
3. Forest of low-density
of low-densitylipoprotein cholesterol
lipoprotein cholesterol (mg/dL).
(mg/dl). For For studies
studies that
that the thelevels
lipid lipid levels
werewere reported
reported separately,
separately, wewepresented
presented in different
differentrows
rows inin
forest plots.
forest (a) hypo-responder
plots. group; group;
(a) hypo-responder
(b) hyper-responder
(b) hyper-responder group;
group; (c)(c)men
mengroup;
group; (d)
(d)women
women group;
group;(e) (e)
one-egg
one-egggroup; (f) two-eggs
group; group; group;
(f) two-eggs
(g) ≥ (g) ≥ three-eggs
three-eggs group;
group; blue:pP<<0.05.
blue: 0.05. Blue
Bluerefers
referstoto
statistical significance
statistical in pooled
significance analysis.
in pooled analysis.

3.4. High.-density
3.4. High-Density LipoproteinCholesterol
Lipoprotein Cholesterol
We divided
We divided 13 RCTs
13 RCTs into
into twogroups
two groups according
according totothe intervention
the time.
intervention Based
time. on theon
Based included
the included
studies, the MEC group did not show significant difference with the control group (MD = 1.27; 95%
studies, the MEC group did not show significant difference with the control group (MD = 1.27;
CI: −0.28 to 2.83; I2 =2 0%) when pooled together. Similar results also showed in the subgroup by
95% CI: −0.28 to 2.83; I = 0%) when pooled together. Similar results also showed in the subgroup
intervention duration (Figure 4). The result of HDL-c may not be affected by any single study (Figure
by intervention duration
S5) and publication bias(Figure 4). The result of HDL-c may not be affected by any single study
(Figure S6).
(Figure S5) and publication bias (Figure S6).

3.5. Further Analysis

Concerning egg-consumption level, we divided studies into three groups: one egg, two eggs and
three or more eggs (Table 2). With one-egg-consumption and three-or-more-eggs-consumption,
the MEC group did not have significant difference from control group, while MEC group of
two-eggs-consumption showed significantly higher LDL-c/HDL-c ratio (MD = 0.13; 95% CI: 0.01 to
0.26; I2 = 13%). Interestingly, we found that two included studies [46,48] in the three-or-more-eggs
subgroup had a shorter intervention time of within 2 months, which accounted for 53.7% of participants.
Therefore, length of intervention period may be the main reason for the increased LDL-c/HDL-c ratio.
In the subgroup analysis for LDL-c, one-egg group (MD = 8.37; 95% CI: 1.06 to 15.69; I2 = 22%),
two-egg group (MD = 7.32; 95% CI: 2.20 to 12.44; I2 = 0%) and three-or-more-eggs group (MD = 9.87;
95% CI: 2.09 to 17.65; I2 = 42%) resulted in significantly higher LDL-c than control group.
About the subgroup analysis for HDL-c, one-egg (MD = 0.28; 95% CI: −2.85 to 3.42; I2 = 0%) and
two-eggs (MD = 0.35; 95% CI: −2.35 to 3.04; I2 =8 0%) showed no significant lower elevations than
control group. Interestingly, in the subgroup of three-or-more-eggs, MEC had higher HDL-c than
control group (MD = 2.55 mg/dL; 95% CI: 0.16 to 4.94; I2 = 0%). Therefore, egg consumption only
slightly influenced the HDL-c.
Nutrients 2020, 12, 1995 8 of 14
Nutrients 2020, 12, x FOR PEER REVIEW 9 of 16

Figure 4. Forest
Figure plot
4. Forest plotofofhigh-density
high-density lipoprotein cholesterol(mg/dl)
lipoprotein cholesterol (mg/dL) forfor studies
studies thatthat the lipid
the lipid levelslevels
werewere reported
reported separately,we
separately, wepresented
presented in different
differentrows
rowsininforest
forestplots.
plots.(a) (a)
hypo-responder
hypo-responder group;
group;
(b) (b) hyper-respondergroup;
hyper-responder group;(c)
(c)men
men group;
group; (d)
(d)women
womengroup;
group; (e)(e)
one-egg
one-egg group; (f) two-eggs
group; group;
(f) two-eggs group;
(g) (g) ≥ three-eggs
≥ three-eggs group.Black
group. Blackdiamond
diamond refers
referstotono
nostatistical
statisticalsignificance
significance in pooled
in pooledanalysis.
analysis.

3.5. Further Analysis

Table 2. Subgroup analysis.
Concerning egg-consumption level, we divided studies into three groups: one egg, two eggs and
Outcome/
three or more eggs (Table 2). With one-egg-consumption and three-or-more-eggs-consumption, the
Subgroup
MEC group Studies
did not have Patients from control
significant difference MD group, while95% CI MEC groupI-Square
of two-eggs-
consumption showed significantly higherLDL-c/HDL-c
LDL-c/HDL-c ratio
ratio (MD = 0.13; 95% CI: 0.01 to 0.26; I2 =
13%). Interestingly,
1 egg we found
5 that two included
226 studies0.20
[46,48] in the three-or-more-eggs59%
−0.01–0.42 subgroup
2 eggs intervention5 time of within
had a shorter 3202 months, which
0.13 accounted0.01–0.26 13%
for 53.7% of participants.
≥ 3 eggs
Therefore, 5
length of intervention 339 be the main0.09
period may −0.02–0.20
reason for the increased LDL-c/HDL-c0% ratio.
LDL-c
1 egg 6 2662. Subgroup analysis.
Table 8.37 1.06–15.69 22%
2 eggs 5 320 7.32 2.20–12.44 0%
Outcome/
≥ 3 eggs 5 339 9.87 2.09–17.65 42%
Subgroup Studies Patients HDL-c MD 95% CI I-square
1 egg 6 276
LDL-c/HDL-c 0.28
ratio −2.85–3.42 0%
2 eggs
1 egg 55 320
226 0.35
0.20 −2.35–3.04
−0.01–0.42 0%59%
≥ 3 eggs 5 339 2.55 0.16–4.94 0%
2 eggs 5 320 0.13 0.01–0.26 13%
≥ 3 eggs 5 339 0.09 −0.02–0.20 0%
4. Discussion LDL-c
1 egg 6 266 8.37 1.06–15.69 22%
4.1. Summary
2 eggsof Main Results
5 320 7.32 2.20–12.44 0%
≥ 3study
Our eggs provides strong
5 evidence339
on the topic 9.87 2.09–17.65 42%
of the impact of egg consumption on lipid
profiles through synthesizing more than 10 trials. 9Compared to Rouhani et al. [9], we included studies
that were published before 2000. The results indicated that egg consumption significantly increases
Nutrients 2020, 12, 1995 9 of 14

the LDL-c/HDL-c ratio and LDL-c levels, especially with a longer intervention duration. Yet, egg
consumption did not effectively increase the HDL-c level. Our pooled results revealed some significant
findings among subgroups of egg-consumption levels, but the results did not show a clear trend of
increment with the egg-consumption level.

4.2. Overall, Completeness and Applicability of the Evidence

As to the primary outcome, pooled results of the LDL-c/HDL-c ratio, we found significantly
higher value in the MEC group than in the control group (MD = 0.14). For the primary prevention of
cardiovascular diseases, the target value of LDL-c/HDL-c for men is < 3.0, while for women it is < 2.5.
The risk level for men is > 3.5, while for women it is > 3.0 [12]. Moreover, LDL-c/HDL-c ratio is associated
with increased risk of sudden cardiac death and cardiovascular diseases, which includes coronary
artery disease, cerebrovascular disease, peripheral artery disease and aortic atherosclerosis [12,58,59].
Thus, those with a borderline LDL-c/HDL-c ratio should restrict their egg consumption because
higher egg consumption increased LDL-c/HDL-c ratio by 0.14. According to our evidence, we found
potential reasoning for this phenomenon from the pooled estimates of differences in LDL-c and HDL-c
concentrations. Results showed that egg consumption did not increase HDL-c, but increased LDL-c.
Therefore, egg consumption affects the LDL-c/HDL-c ratio.
HDL-c plays an important role in reverse cholesterol transport. HDL-c takes cholesterol from
peripheral tissue and transports to liver for excretion into the feces [60]. For HDL-c, our evidence
only showed a very little effect size with non-significance, especially in the subgroup with over two
months of treatment. LDL-c is a fat that circulates in vessels, moving to the tissue that is needed
for cell repair. It also accumulates inside of arterial wall [19]. The target value of LDL-c is less than
100 mg/dL. When the concentration reaches 130 mg/dL to 159 mg/dL, it means borderline high [61].
For LDL-c, a non-extreme short-term intervention (16 weeks) of daily cholesterol consumption led to
increased LDL-c. This result was consistent with another study [30]. Thus, people with borderline
high LDL-c level should restrict their egg consumption. A further study revealed that MEC resulted in
increased LDL-c and HDL-c concentrations more than oatmeal breakfast and breakfast [52]. Egg white
had an effect of decreasing total cholesterol and increasing HDL-c compared to tofu and cheese [62].
Moreover, different cooking methods resulted in different amounts of cholesterol. For example, there
are three common types of egg products in China. All of them are cooked eggs, but with different
amounts of cholesterol per 100 g [63]. As to egg consumption with additional food or drinks, one of the
included studies indicated that consuming eggs with buttermilk caused increases in LDL-c and total
cholesterol to become statistically insignificant [40]. When consuming choline bitartrate supplement as
control group, the study revealed that LDL-c/HDL-c ratio did not show significant elevation in MEC
group while our results showed a slight elevation in LDL-c/HDL-c ratio with significance. Therefore,
we consider choline bitartrate supplement to be a factor that slightly increase LDL-c/HDL-c ratio,
making the elevation of LDL-c/HDL-c ratio in MEC group become insignificance [26]. When it comes
to different amount of egg consumption, our study cannot determine dose effect. Most of our findings
echo to a study by Dimarco et al., in which the effects of different amount of egg consumption on
cholesterol level were evaluated [25]. Increasing dose of egg intake seems to associate with higher
HDL-c level. However, it is still unclear in association of increasing dose of egg consumption and
LDL-c or LDL-c/HDL-c ratio. On the basis of previous synthesis, we also notice that the results of
LDL-c and LDL-c /HDL-c ratio may be driven by responders [9]. However, random-effects model was
applied for all of our analyses. In the statistical model, variances of samples among trials are taken in
to consideration; and thus, the results are close to the effects in the entire population in the synthesis.
The results may not be seriously biased by the responders.

4.3. Comparison to Previous Syntheses

Before our synthesis, there were three important meta-analyses on the topic of egg consumption
and lipoprotein levels [9–11]. Most meta-analyses indicated that egg consumption will increase LDL-c
Nutrients 2020, 12, 1995 10 of 14

and HDL-c [9–11]. An earlier one in 2001 used limited studies and mainly analyzed LDL-c and
HDL-c [11]. The other two previous syntheses had insufficient evidence for identifying the impact
of egg consumption on the LDL-c/HDL-c ratio, although they found significant findings in separate
pooled LDL-c and HDL-c concentrations [9,10]. One of the recent syntheses included 27 references
on this topic, but only pooled seven of them from six RCTs in the meta-analysis of LDL-c/HDL-c
ratio. Then, they found highly heterogenous estimate even in some subgroup analysis [9]. Another
one synthesis by Wang et al. in 2019 focused on middle-age and older population and analyzed
LDL-c/HDL-c ratio only two RCTs [10]. Those syntheses noted the importance of the LDL-c/HDL-c
ratio with some significant findings in some subgroup analyses, while they were prevented from
making a perfect quantitative synthesis because of statistical techniques. Our study overcame the
statistical barrier of estimating the LDL-c/HDL-c ratio according to a relevant formula [32,33]. That is
to say, our evidence provides more-powerful results for understanding the impact of egg consumption
on the LDL-c/HDL-c ratio.
In the previous syntheses, moreover, they mixed health subjects and patients. On the contrary, our
study tried to avoid bias from conceptual heterogeneity by focusing on healthy subjects. For instance,
the best synthesis in recent years included trials by Bautista et al. [30] and Schwab et al. [64], but we did
not include those trials because they recruited patients with diabetes or hypercholesterolemia [9]. Thus,
pooled results in the present study may be more precise and our findings may be more appropriate
for healthy population. Furthermore, we carefully reviewed all trials to avoid overestimating. For
example, in a previous meta-analysis, the synthesis double-counted results from the same trial by
the study team of Herron et al. [38,39,48–50]. Similarly, a trial by the study team of Greene et al. was
also double-counted [6,46,57]. The double-counted results may have resulted in overestimates and
inaccuracies. That is why our pooled results of HDL-c differed from previous syntheses because of
the differences in conceptual heterogeneities and data sources between our synthesis and previous
meta-analyses as described in this paragraph.

4.4. Limitations
There were some limitations to this study because of potential biases in the synthesis.
The intervention duration of the included studies were all within a year. We could not conclude results
for longer intervention times. Next, we could not determine the foods accompanying the eggs in every
included study. Different background diets may have influenced the results. However, we excluded
the intervention that may influence the cholesterol level, we could not tell whether there is other factors
due to insufficient information [26]. Then, due to the variation between included studies, MEC group
have different amount of egg consumption. However, we used subgroup analysis to explain the result,
≥ three-egg group still had variation. Finally, the LDL-c/HDL-c ratio was the main estimation used to
assess the risk of cardiovascular diseases [12]. Not every included study reported the LDL-c/HDL-c
value. Thus, we had to estimate the LDL-c/HDL-c value in several studies.

5. Conclusions
Based on available evidence, this is the largest meta-analysis in exploring the impact of egg
consumption on LDL-c/HDL-c ratio among healthy subjects and reveals that more eggs consumed per
day may influence cardiovascular disease risks by increasing LDL-c and the LDL-c/HDL-c ratio. Notably,
longer-term high egg-consumption may lead to higher LDL-c/HDL-c ratio and LDL-c. However,
RCTs with long tern follow-up are needed to guarantee the association between egg consumption and
human health.

Supplementary Materials: The following are available online at http://www.mdpi.com/2072-6643/12/7/1995/s1.

Table S1: Risk of bias; Figure S1: Sensitivity analysis of LDL-c/HDL-c ratio; Figure S2: Small study effects in
LDL-c/HDL-c ratio; Figure S3: Sensitivity analysis of LDL-c; Figure S4: Small study effects in LDL-c; Figure S5:
Sensitivity analysis of LDL-c; Figure S6: Small study effects in LDL-c.
Nutrients 2020, 12, 1995 11 of 14

Author Contributions: M.-Y.L., C.C. Data curation: M.-Y.L. formal analysis: M.-Y.L., C.C. funding acquisition:
C.C. investigation: C.C. methodology: J.-H.C., C.C., Y.-N.K. project administration: M.-Y.L., C.C. software: J.-H.C.,
C.C. supervision: C.C., Y.-N.K. validation: M.-Y.L.: J.-H.C., C.C. visualization: Y.-N.K. writing—original draft:
M.-Y.L. writing—review & editing: J.-H.C., C.C., Y.-N.K. All authors have read and agreed to the published
version of the manuscript.
Funding: This research received a grant from Wan Fang Hospital, Taipei Medical University (108-wf-eva-01).
The sponsor had no role during our study.
Conflicts of Interest: The authors declare that they have nothing to disclose regarding financial or nonfinancial
conflicts of interest with respect to this manuscript.

Abbreviations
CI Confidence interval
HDL-c high-density lipoprotein cholesterol
LDL-c low-density lipoprotein cholesterol
MEC more egg consumption
MD mean difference
NSR nonspecific responders
PRISMA preferred reporting items for systematic reviews and meta-analyses
RCT randomized clinical trial
SD standard deviation

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