Introduction
Stroke is a primary cause of disability and
mortality (1) and the medical
costs for stroke remain at a high level. Therefore, new approaches
are required to lower the incidence rate of this condition
globally. Accumulating evidence has shown that dietary habits
influence the incidence of stroke (2,3); for
instance, several studies have revealed that the intake of olive
oil, nuts and vegetables (all foods abundant in vitamin E) is
related to a lower incidence of stroke (4-6).
To date, eight isomers of vitamin E have been confirmed; among
these eight isomers, α-tocopherol, which is absorbed by the
digestive system and directly released into the blood circulation,
is regarded as the predominant form of vitamin E (7).
Vitamin E influences the process of low-density
lipoprotein (LDL) oxidation (8),
which is one of the notable initial steps in the pathogenesis of
atherosclerosis. However, prospective cohort studies have indicated
that the relationship between circulating α-tocopherol and stroke
is inconsistent (9-14).
Additionally, randomized controlled trials (RCTs) regarding vitamin
E supplementation and cardiovascular disease (CVD) have yielded
conflicting results (15,16). While some early trials suggested a
protective effect of vitamin E supplementation on CVD (17,18),
subsequent large-scale trials and meta-analyses failed to
demonstrate notable benefits for major cardiovascular events
(16,19,20).
Notably, some evidence even suggested potential risks, such as an
increased incidence of cerebral hemorrhage at high doses (21). These discrepancies underscore the
importance of evaluating circulating α-tocopherol, which accurately
reflects the net effect of dietary intake and individual
metabolism.
The primary aim of the present study was to
quantitatively evaluate the association between circulating
α-tocopherol levels and the risk of stroke. Specifically, the study
sought to determine whether this relationship varies across
different stroke types and populations. To achieve this, subgroup
analyses for circulating α-tocopherol and stroke risk according to
stroke subtypes (ischemic versus hemorrhagic), body mass index
(BMI), age, follow-up duration and physical activity were also
performed.
Materials and methods
Search strategy
The present meta-analysis was performed according to
the PRISMA guidelines. A literature search was conducted for all
cohort studies reporting the relationship between circulating
α-tocopherol levels and stroke. The electronic Web of Knowledge
(https://www.webofscience.com), Embase
(https://www.embase.com), Scopus (https://www.scopus.com), Cochrane Library (https://www.cochranelibrary.com) and PubMed
(https://pubmed.ncbi.nlm.nih.gov)
databases were searched through to January 2026. The following key
words and search strategies were used: ‘tocopherol’ or ‘vitamin E’;
and ‘stroke’ or ‘ischemic stroke’ or ‘hemorrhagic stroke’ or
‘cerebrovascular disease’ or ‘intracranial hemorrhage’ or ‘brain
hemorrhage’; and ‘serum’ or ‘circulating’ or ‘plasma’; and
‘cohort’. Additionally, any potential publications were retrieved
from the references of relevant reviews.
Study selection
The inclusion criteria were as follows: i) cohort
studies; ii) circulating α-tocopherol levels were measured; iii)
the outcome was stroke or its subtypes; and iv) risk ratio (RR) of
the incidence of stroke was reported. Estimates with maximum
adjustment for confounders were used. Experimental studies,
conference abstracts and studies that did not report stroke risk
estimates were excluded.
Data extraction
The following study characteristics and data were
extracted from the included articles: The first author, publication
year, area, participant age range, number of events and
participants, follow-up duration, quality score and the RRs and
corresponding confidence intervals (CIs). Data were independently
extracted in duplicate by two investigators. Any disagreement was
resolved by consultation with an arbitral author.
Evaluation of study quality
Publication quality was assessed according to the
scoring principles of the Newcastle-Ottawa Scale (NOS) (22). Studies awarded seven or more stars
were considered high quality.
Primary and subgroup analyses
The relationship between circulating α-tocopherol
levels and the total stroke risk was investigated. Subgroup
analyses according to stroke subtype (ischemic versus hemorrhagic),
BMI, age (≥65 vs. <65 years), follow-up duration (>10 vs. ≤10
years) and physical activity (adjusted or not) were conducted. The
cut-offs for the specific subgroup analyses (such as a BMI of 25,
an age of 65 and a follow-up of 10 years) were based on the median
values from the included studies.
Dose-response analysis
A dose-response meta-analysis was performed
according to previously reported methods (23,24).
For each study, the mean level of circulating α-tocopherol for each
category and its corresponding RR were extracted for analysis. When
the mean circulating α-tocopherol level was unavailable, the
midpoint of the lower and upper boundaries was used as the average
level for that category. For the upper exposure category, 1.2-fold
of its lower limit was used.
Meta-regression and sensitivity
analyses
To explore potential sources of heterogeneity,
meta-regression analyses were performed for follow-up duration and
age (both as continuous variables), as well as physical activity
adjustment status (adjusted vs. not adjusted). Additionally, a
leave-one-out sensitivity analysis was conducted to evaluate the
stability of the pooled results.
Statistical analysis
The summary RRs were obtained by the
inverse-variance method using the random-effects model (25,26).
Between-study heterogeneity was assessed by I2
statistics (26); heterogeneity
between studies was defined as I2>50% or a
significance level of P<0.10. Publication bias was determined
using Egger's test and the risk of publication bias was ascertained
when P<0.05. The present meta-analysis was conducted using
Review Manager (RevMan) software, version 5.4 (The Cochrane
Collaboration). To further explore potential sources of
heterogeneity and assess the stability of the results,
meta-regression and leave-one-out sensitivity analysis were
performed using R Project for Statistical Computing, version 4.5.2
(RStudio, Inc.) with the ‘meta’ (https://CRAN.R-project.org/package=meta) and ‘metafor’
(https://CRAN.R-project.org/package=metafor)
packages.
Results
Results of the literature search
In total, 856 potential studies were retrieved by
the initial literature search. A flow chart summarizing the study
selection is shown in Fig. 1. At
first, 132 duplicated articles were excluded, then 668 studies were
excluded after a review of the abstract and title. Subsequently, 56
potentially relevant studies underwent full-text evaluation.
Finally, 6 studies (9-14)
on circulating α-tocopherol were included in the present
meta-analysis. These studies involved 104,209 individuals and 2,194
stroke outcomes. In total, 2 studies (9,11)
were awarded 7 stars and 4 studies (10,12-14)
were awarded 8 stars according to the NOS. Additionally, 4 included
studies (9,10,12,13)
contained relevant data for dose-response analysis.
Study characteristics
The characteristics of the 6 cohort studies are
shown in Table I. The publication
year ranged from 1999 to 2020. In total, 3 studies (9,11,12)
were from Finland, 1(10) was from
the United States, 1(14) was from
Sweden and 1(13) was from Japan.
All 6 prospective studies reported the risk estimates for
circulating α-tocopherol with maximum-adjusted confounders.
 | Table ICharacteristics of the studies on
circulating α-tocopherol and stroke. |
Table I
Characteristics of the studies on
circulating α-tocopherol and stroke.
| Author, year | Location | Age, years | Stroke events | Participants | Follow-up duration,
years | RR (95% CI), high
vs. low | Maximum
adjustment | Quality score | (Refs.) |
|---|
| Leppälä et
al, 1999 | Finland | Range, 50-69 | 1057 TS 85 SAH 112
ICH 807 IS | 28,519 M | 8 | SAH: 1.10
(0.53-2.31) ICH: 0.47 (0.23-0.93) IS: 0.70 (0.55-0.89) | Age, BMI, SBP,
serum total and HDL cholesterol, smoking, alcohol consumption,
diabetes, heart disease, education, physical activity, and
α-tocopherol and β-carotene supplementation. | 7 | (9) |
| Hak et al,
2004 | USA | Range, 40-84 | 297 IS | 22,071 M | 13 | IS: 0.67
(0.36-1.26) | Age, smoking, BMI,
total and HDL cholesterol, triglycerides, levels of other
tocopherols, history of hypertension, diabetes mellitus, and
parental history of MI before the age 60; frequency of vigorous
exercise, alcohol and assignment to aspirin or β-carotene treatment
or placebo. | 8 | (10) |
| Marniemi et
al, 2005 | Finland | Range, 65-99 | 70 TS | 755 M and F | 10 | TS: 0.60
(0.31-1.18) | Age, sex, smoking,
functional capacity and weight-adjusted energy intake. | 7 | (11) |
| Nagao et al,
2012 | Japan | Range, 40-79 | 530 TS 302 IS 210
ICH | 39,242 M and F | 13 | M: TS: 0.81
(0.41-1.60) IS: 0.83 (0.35-2.00) HS: 0.97 (0.25-3.77) F: TS: 0.35
(0.16-0.77) IS: 0.47 (0.14-1.52) HS: 0.26 (0.07-0.97) | BMI, smoking,
alcohol drinking, history of hypertension and diabetes mellitus,
walking, sports, total cholesterol and high-density lipoprotein
cholesterol. | 8 | (13) |
| Karppi et
al, 2012 | Finland | Range, 46-65 | 67 TS 50 IS | 1,031 M | 12.1 | TS: 1.08
(0.48-2.44) IS: 1.09 (0.44-2.73) | Age, examination
year BMI, SBP, smoking, serum LDL cholesterol, diabetes and history
of stroke | 8 | (12) |
| Lind et al,
2020 | Sweden | PIVUS: mean ± SD,
70.1±0.1 ULSAM: mean ± SD, 71.2±0.6 TwinGene: mean ± SD,
68.3±8.2 | 173 IS | 12,591 M and F | 4.3 | IS: 0.83
(0.73-0.95) | Age, sex, systolic
blood pressure, diabetes, smoking, LDL- and HDL-cholesterol, BMI
and atrial fibrillation | 8 | (14) |
Circulating α-tocopherol and stroke
risk
A meta-analysis of the 6 studies showed that a
higher level of circulating α-tocopherol was related to a 22% lower
stroke risk (RR, 0.78; 95% CI, 0.70-0.87; I2=0;
P<0.01; Fig. 2). Furthermore,
circulating α-tocopherol was associated with ischemic stroke risk
reduction (RR, 0.80; 95% CI, 0.72-0.90; P<0.01) but not
hemorrhagic stroke risk reduction (RR, 0.65; 95% CI, 0.41-1.01;
P=0.06).
Subgroup analyses for the association
of circulating α-tocopherol with stroke risk
Subgroup analyses according to BMI and age are shown
in Fig. 3. Subgroup analyses
according to follow-up duration and physical activity are shown in
Fig. 4. A high circulating
α-tocopherol level was associated with a reduced stroke risk in the
BMI <25 (RR, 0.57; 95% CI, 0.34-0.95; P=0.03), BMI >25 (RR,
0.80; 95% CI, 0.72-0.89; P<0.01), age ≥65 years (RR, 0.75; 95%
CI, 0.59-0.95; P=0.02), age <65 years (RR, 0.73; 95% CI,
0.60-0.90; P<0.01), follow up duration ≤10 years (RR, 0.78; 95%
CI, 0.68-0.89; P<0.01), physical activity adjusted (RR, 0.69;
95% CI, 0.57-0.84; P<0.01) and physical activity not adjusted
(RR, 0.83; 95% CI, 0.73-0.94; P<0.01) subgroups. However,
circulating α-tocopherol was not associated with a reduced stroke
risk in the follow-up duration of >10 years subgroup (RR, 0.73;
95% CI, 0.49-1.09; P>0.05). The I2 values were 15, 4
and 25% for the follow-up duration ≤10 years, follow-up duration
>10 years and age >65 years subgroups, respectively. The
I2 values were 0 in the remaining subgroups.
Dose-response analysis
In total, 4 studies and 90,863 participants were
included in the random-effects linear dose-response analysis. The
results of this analysis showed that circulating α-tocopherol was
associated with a reduced stroke risk (P-value for
heterogeneity=0.55; P=0.015). Furthermore, each 5 mg/l increment of
circulating α-tocopherol was related to an average 8% lower risk of
stroke (RR=0.92; 95% CI, 0.85-0.98) (Fig. 5). Additionally, the models were
checked for non-linearity; however, the results demonstrated no
significant non-linearity (P>0.05).
Meta-regression, sensitivity and
publication bias analyses
The meta-regression showed that follow-up duration
(P=0.185), age (P=0.942) and physical activity (P=0.133) were not
significant sources of heterogeneity (Fig. 6). Subgroup analyses revealed
low-to-moderate heterogeneity in specific groups (I2 was
15, 4 and 25% for duration ≤10-year, duration >10-year and age
≥65-year subgroups, respectively). The sensitivity analysis showed
that the summary results for circulating α-tocopherol and stroke
risk remained robust when leaving any single study out; the summary
RRs ranged between 0.70 and 0.81 (Fig.
7). Symmetrical characteristics were confirmed through visual
inspection of the funnel plot, and no publication bias was detected
(P>0.05) following Egger's test (Fig. 8).
Discussion
The novelty of the present study lies not in the
general association between vitamin E and stroke, which has been
previously documented (27,28),
but rather in the specific analysis of circulating α-tocopherol
levels and the implementation of comprehensive subgroup and
dose-response analyses. Unlike prior research detailed
stratifications by stroke type, BMI, age, follow-up duration and
physical activity were conducted to identify specific susceptible
populations. Furthermore, a rigorous dose-response analysis of
circulating α-tocopherol was performed to clarify its physiological
threshold. While a recent meta-analysis of RCTs suggested that
vitamin E supplementation may help prevent ischemic stroke
(28), it is notable that
consumption at non-recommended doses might increase the risk of
intracerebral hemorrhage (21). By
focusing on circulating levels, the present study provides a more
precise perspective to reconcile these conflicting findings.
Circulating α-tocopherol is the primary fat-soluble
antioxidant; its abilities involve scavenging free radicals,
protecting lipids from peroxidation and inhibiting LDL cholesterol
oxidation; these abilities contribute to inhibiting atherosclerosis
(29). Accumulating evidence also
shows that tocopherols inhibit platelet aggregation and
atherothrombosis (30,31).
All of the six studies (9-14)
included in the present study reported associations between
circulating α-tocopherol and overall stroke risk. Notably, three
studies (9,13,14)
showed that circulating α-tocopherol was associated with a lower
overall stroke risk, whereas the remaining studies (10-12)
showed that circulating α-tocopherol was not associated with
overall stroke risk. Additionally, four included studies (9,10,12,13)
examined ischemic stroke risk, whereas two included studies
(9,13) examined hemorrhagic stroke risk. In
the present study, the subgroup analysis results showed that a high
circulating α-tocopherol level was related to a 43% lower stroke
risk in the BMI-adjusted subgroup and a 20% lower stroke risk in
the BMI-not-adjusted subgroup. A previous antioxidant study showed
that a concoction of antioxidants (containing 800 IU of vitamin E,
10 mg of carotene and 500 mg of vitamin C) could lower
exercise-induced lipid hydroperoxide levels in overweight adults
compared with the placebo-treated overweight group (32). Oxidative stress can result in the
excessive production of reactive oxygen species, which play
essential roles in stroke-related neuronal injury (33).
In the present study, the subgroup analysis results
also showed that a high circulating α-tocopherol level was related
to a 31% lower stroke risk in the physical activity-adjusted
subgroup and a 17% lower stroke risk in the physical
activity-not-adjusted subgroup. Previous evidence shows that
physical activity is a modifiable risk factor for stroke risk and
that moderate physical activity helps reduce stroke risk (34). Moreover, the subgroup analysis
results indicated that follow-up duration affected the association
of circulating α-tocopherol with stroke risk. As such, there may be
a critical period for circulating α-tocopherol to achieve stroke
risk reduction. However, the subgroup analysis results showed that
the association between a high circulating α-tocopherol level and
stroke risk was not markedly affected by age; a high circulating
α-tocopherol level was related to a 25% lower stroke risk in the
age ≥65 years subgroup and a 27% lower stroke risk in the age
<65 years subgroup; the subgroup analysis results for follow-up
duration >10 years were not significant. It is notable that the
point estimate (RR=0.73) was similar to that of the other
subgroups, but the CI was wide, likely due to reduced power.
The studies included in the present study reported
that the vitamin E consumption was mainly derived from foods such
as olive oils, nuts and vegetables. No adverse effects were
reported for high or low dietary vitamin E intake. In total, two
included studies (11,13) reported that an individual's average
vitamin E intake was <10 mg/day. Previous evidence has
demonstrated that the methods of cooking foods typically influence
the absorption of vitamin E (27).
Several limitations of the present study should be
acknowledged. Firstly, the subgroup analysis results should be
interpreted cautiously due to the limited sample size and the
number of cases. Secondly, the interpretation of the BMI subgroup
results should be approached with caution as only one included
study (13) provided an RR for
individuals with a mean BMI <25; a meaningful summary RR for
these individuals could not be calculated from a single study.
Thirdly, only one included study (9) reported the relationship between
circulating α-tocopherol and subarachnoid stroke; thus, the summary
RRs for subarachnoid stroke could not be estimated. The results of
the meta-regression analyses showed that follow-up duration, age,
and physical activity adjustment status were not the sources of
heterogeneity between studies. Given the relatively small number of
studies included (n=6) the power of the meta-regression to detect
true moderators was low. The I2 statistic value for the
primary analysis (total stroke) was 0. However, the I2
values were 15, 4 and 15% for the follow-up duration ≤10 years,
follow-up duration >10 years and age >65 years subgroups,
respectively. Thus, low heterogeneity may exist due to the varied
follow-up durations and ages of the patients. Finally, besides the
subgroups, the limitation of the overall small number of included
studies may have influenced the outcomes. In the present study,
meta-regression and sensitivity analysis were utilized to assess
the robustness of the findings. Although the overall heterogeneity
was negligible (I2=0.00%), the fluctuations observed in
subgroup analyses (ranging from 4-25%) suggest that varied
follow-up durations and patient ages may influence outcomes. Given
the small number of studies (n=6), the statistical power of the
meta-regression should be interpreted with caution. However, the
consistent results across the leave-one-out analysis (RR range:
0.70-0.81; all P<0.05) further confirm the reliability and
robustness of the observed effect.
In conclusion, the results of the present
meta-analysis indicate that a higher circulating α-tocopherol level
may be related to lower ischemic but not hemorrhagic stroke risk.
Notably, while physical activity is a critical determinant of
stroke risk, the protective association of α-tocopherol remains
significant and is further strengthened after accounting for this
factor. This suggests that α-tocopherol may play a vital role in
stroke prevention, particularly within the context of active
lifestyle management.
Acknowledgements
Not applicable.
Funding
Funding: No funding was received.
Availability of data and materials
The data generated in the present study may be
requested from the corresponding author.
Authors' contributions
PX conceived and designed the study, analyzed and
interpreted the data and performed the primary meta-analysis. PC
performed the meta-regression and sensitivity analysis, wrote the
initial draft, and edited the manuscript. Both PX and PC
participated in the proofreading and verification of the final
manuscript. PX and PC confirm the authenticity of all the raw data.
All authors read and approved the final version of the
manuscript.
Ethics approval and consent to
participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing
interests.
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