Dietary saturated fat intake and risk of stroke: Systematic review and dose–response meta-analysis of prospective cohort studies

Journal Pre-proof Dietary saturated fat intake and risk of stroke: systematic review and dose-response meta-analysis of prospective cohort studies Zhou-Qing Kang, Ying Yang, Bo Xiao PII:

S0939-4753(19)30380-1

DOI:

https://doi.org/10.1016/j.numecd.2019.09.028

Reference:

NUMECD 2161

To appear in:

Nutrition, Metabolism and Cardiovascular Diseases

Received Date: 6 May 2019 Revised Date:

24 September 2019

Accepted Date: 25 September 2019

Please cite this article as: Kang Z-Q, Yang Y, Xiao B, Dietary saturated fat intake and risk of stroke: systematic review and dose-response meta-analysis of prospective cohort studies, Nutrition, Metabolism and Cardiovascular Diseases, https://doi.org/10.1016/j.numecd.2019.09.028. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V. on behalf of The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University.

Dietary saturated fat intake and risk of stroke: systematic review and dose-response meta-analysis of prospective cohort studies

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Zhou-Qing Kang1*, Ying Yang2, Bo Xiao2

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Department of Nursing, Jin Qiu Hospital of Liaoning Province (Geriatric Hospital of Liaoning Province), Shenyang, Liaoning province, China

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Department of Cardiovascular Medicine, Jin Qiu Hospital of Liaoning Province (Geriatric Hospital of Liaoning Province), Shenyang, Liaoning province, China

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* Correspondence: Zhou-Qing Kang [email protected]

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Keywords: stroke risk, dietary saturated fat intake, dose-response relation, meta-analysis.

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Abstract

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Background and Aims: Due to the conflicting research results, the association of saturated fatty acid (SFA) consumption and the risk of stroke remains controversial. We conducted a meta-analysis to evaluate potential dose-response relations between SFA intake and stroke.

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Methods and Results: PubMed, Embase, the Cochrane Library Central Register of Controlled Trials and Web of Science were searched. Summary relative risks (RRs) of the highest vs. the lowest category of SFA intake and their 95% confidence intervals (CIs) were pooled by random effect models. Linear or non-linear dose-response trend estimations were evaluated with data from categories of SFA consumption in each study.

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Fourteen studies involving a total of 598,435 participants were eligible for high vs. low metaanalysis, and 12 studies involving a total of 462,268 participants were eligible for the dose-response relation assessment. Higher dietary SFA intake was associated with a decreased overall stroke risk (RR, 0.87; 95% CI, 0.78– –0.96; I2 = 37.8%). A linear relation between SFA and stroke was explored (P = 0.01), the pooled RR of stroke per 10 grams/day increase in SFA intake was 0.94 (95%CI, 0.89– – 0.98; P = 0.01).

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Conclusion: This meta-analysis further demonstrated that a higher consumption of dietary SFA is associated with a lower risk of stroke, and every 10 grams/day increase in SFA intake is associated with a 6% relative risk reduction in the rate of stroke. Further research is needed to explore the influence of specific SFA types and different macronutrient replacement models of SFA on the stroke risk.

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Introduction

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Stroke is a global epidemic and a leading cause of long-term disability and death. The Global Burden of Disease, Injuries, and Risk Factors Study 2016 (GBD 2016) estimated that there were nearly 80 million stroke patients among 195 countries and territories, accounting for 10.11% of total deaths and 4.88% of total disability-adjusted life-years (DALYs) worldwide [1,2]. For the primary prevention of stroke, nutrition and dietary habits have been proved to be important controllable risk factors, and approximately 43% of stroke deaths and 51% of stroke DALYs were attributable to dietary risks in 2016 [2,3]. The health effects of dietary fats are influenced greatly by the types and proportions of the component fatty acids. Saturated fatty acids (SFA) contain only single carbon-tocarbon bonds, and foods rich in SFA include meat, cheese, butter, and whole milk. Unsaturated fatty acids contain one or more double carbon-to-carbon bonds, and foods rich in unsaturated fatty acids include olive oil, flaxseed oil, fish oil, walnuts, and peanuts [4]. In current dietary guidelines, a reduction in saturated fatty acid (SFA) consumption (less than 10% of energy intake per day) is recommended as a key part of a healthy diet for the prevention of cardiovascular diseases [5-7].

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However, some large cohort studies [8-10] from different countries and meta-analyses [11-12] show that higher SFA intake is not associated with stroke risk. Further more, several prospective studies [13-15] and meta-analyses [16,17] report inverse associations between dietary SFA intake and risk of stroke. For example, the Prospective Urban Rural Epidemiology (PURE) study [15] which included 135,335 individuals from 18 countries revealed a significant decreased stroke risk in relation to higher SFA intake. The variabilities refer to research regions, trial populations, research times, dietary assessment methods, and study durations; all of these may have caused inconsistencies in the results. These controversial results have challenged current diet recommendations and led to consumer confusion.

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To help further clarify the evidence, we performed this meta-analysis of cohort studies and conducted a more comprehensive and detailed assessment of dietary SFA intake and stroke risk, in which two recently published studies [15, 18] were included and more subgroups (stroke type, study region, gender, number of participants, method of dietary assessment, median or mean body mass index, duration of follow-up, quality of the literature) were analyzed. Most importantly, we quantified the dose-response relation between dietary SFA intake and stroke risk.

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Methods

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We performed this meta-analysis according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) [19]. The review was previously registered at the international prospective register of systematic reviews (PROSPERO, http://www.crd.york.ac.uk/prospero/, registration number: CRD42017076090).

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Search strategy and selection criteria

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A comprehensive literature search was conducted by using PubMed, Embase, the Cochrane Library Central Register of Controlled Trials and Web of Sscience (from January 1, 1946 to December 16, 2018). We combined the MeSH terms and key words and adapted for the four electronic databases. “Stroke,” “Cerebral Infarction,” “Cerebral Hemorrhage,” “Ischemic Attack Transient,” “Cerebrovascular Disorders,” “Saturated Fatty Acid,” “Dietary Fats,” “Fatty Acids,” “Saturated Fat,” “Dairy Consumption,” and their variants were carried out for search with species restriction of humans and limited to English articles. An example of search strategy from PubMed is provided in Supplemental Table 1. Moreover, we searched additional relevant studies by manually 2

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checking the reference lists of recent reviews and identified studies. Unpublished reports were not considered.

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A two-step selection process was used to identify eligible trials. Two independent authors (YY and XB) screened the relevant studies according to title or abstract. After that, the full- texts of all identified studies were retrieved for further assessment. Dissenting opinions were resolved by consensus after contacting a third author (KZQ). Inclusion criteria: (1) detected the association between dietary SFA intake and risk of stroke or stroke subtypes (ischemic stroke, intracranial hemorrhage, subarachnoid hemorrhage, etc.) among adult participants (aged 18 or older); (2) were prospective cohort studies; (3) collected and calculated SFA data from usual dietary intake based on reliable diet questionnaires; (4) defined stroke as or similar to the occurrence of rapidly developing clinical signs of focal or global disturbances of cerebral function that lasted more than 24 hours or resulted in death; (5) provided relative risk estimates—relative risks (RRs) or hazard ratios (HRs) and their 95% confidence intervals (CIs)—or provided interrelated data to calculate them; and (6) analyzed three or more categories of quantitative dietary SFA intake for the dose-response analyses, or a risk estimate of dietary SFA intake on a continuous scale. Exclusion criteria: studies (1) included participants who had suffered a stroke before recruitment; or (2) provided no relevant outcome or insufficient data (no response after sending a data request to the corresponding author). If studies were from the same cohort or shared an identical sample, only the study with the most comprehensive data or the longest duration of follow-up was included.

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Data extraction and quality assessment

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Two authors (KZQ and YY) independently extracted the variables from included studies using a standardized form that included first author, publication year, country, cohort name, duration of follow-up, the overall sample size, baseline age, mean or median body mass index, the proportion of men, method of dietary assessment, mean or median dietary SFA, relevant outcomes (stroke, ischemic stroke, intracranial hemorrhage, subarachnoid hemorrhage, etc), and adjusted variables of the multivariable analyses (age, sex, smoking, etc.). Normally, included studies analyze three or more categories of quantitative dietary SFA intake, but we extracted the max multivariable adjusted effect sizes of the highest vs. the lowest categories of SFA intake and their 95% CIs for the high vs. low meta-analyses. The Newcastle-Ottawa quality assessment scale (NOS) was applied to the quality assessment of eligible studies, which appraised observational studies from eight aspects (representation of nativeness of the exposed cohort, selection of the non-exposed cohort, ascertain ment of exposure, demonstration that outcome of interest was not present at start of study, comparability of cohorts on the basis of the design or analysis, assessment of outcome, duration of follow-up long enough for outcomes to occur, adequacy of follow-up of cohorts) and awarded 7 points or more for those that were considered high-quality studies [20]. Disagreements were settled by consensus reached after discussion.

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Statistical analysis

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One study [10] reported rate ratios separately by sex, and we pooled sex-specific relative risks using a fixed e ects model before inclusion in the subsequent high vs. low meta-analysis. The study by Gillman [13] reported RR and 95% CIs for a per-unit increase in SFA intake, and the relative risk of the highest vs. the lowest category was derived from the trend RR comparison of the 75th vs. 25th percentiles [21]. Most included studies used Cox regression analyses, and thus reported HRs extracted from the included studies were assumed to be approximately equal to RRs [17]. With a consideration of the clinical and methodological heterogeneity that could exist, we pooled the 3

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summary relative risks of stroke using random effects models, and used the max multivariable adjusted effect sizes of the highest vs. the lowest category of SFA intake and their 95% CIs, which were extracted from included studies or their supplemental files. We used I2 test to evaluate the magnitude of heterogeneity between studies, and a value of more than 50% was defined as significant heterogeneity [22]. Reasons for heterogeneity were explored through sensitivity analyses (omitted each study at a time using random-effects models). In addition, we carried out prespecified subgroup analyses by stroke type, study region, gender, number of participants, method of dietary assessment, median or mean body mass index, duration of follow-up, and NOS score. Potential publication bias was assessed visually by inspecting funnel plots, and the asymmetry of the funnel plot was assessed by using Egger’s or Begg’s regression test, with a p﹤0.1 indicating significance [23].

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Dose-response analyses were performed by using two-stage generalized least squares that were developed by Greenland and Longnecker [24]. First, linear trend estimation was conducted by using the natural logarithm of the stroke relative risks and 95% CIs across categories of SFA intake. Next, we assessed a potential non-linear trend estimation by using restricted cubic splines with three knots (at 10, 50, and 90 percentiles of the distribution) in the dose-response regression model [25]. The difference between the non-linear and linear models was compared by using a likelihood ratio test [26]. The median or mean intake of SFA, cases, person years or person, and relative risks with 95% confidence intervals from each category of included studies were extracted to apply this method. If medians or means were not available, approximate medians were calculated by using the midpoint of the lower and upper bounds of that category. If the highest or lowest category of SFA intake was open ended, we used the width of the adjacent category to calculate an upper or lower bound [27]. The study by Dehghan et al. [15] reported the median intake of SFA as percent of energy in each consumption category; no sufficient data (as grams per day) was available from the report or authors, so we did not include the study in the dose-response analyses. If the distribution of person years or person was not reported, group sizes of each category were assumed to be approximately equal. If the distribution of cases was not reported but the total number of cases was reported, we estimated the distribution of cases according to methods described in a previous paper [27]. We also examined the stroke type, comprising ischemic stroke, intracranial hemorrhage and subarachnoid hemorrhage; regional disparity, comprising which contains Asia, Europe, and North America; and gender gap, comprising specific effects on men and women, by conducting separate dose-response meta-analyses. All statistical analyses were executed by Stata software (version 12), and a P value less than 0.05 was considered statistically significant.

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Results

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Search results

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We initially identified 11,627 studies from four electronic databases, of which 11,518 studies were excluded by removing the duplicates and reviewing the title or abstract. Five records were added by manually checking the reference lists of recent reviews and identified studies. The full- texts of the remaining 114 studies were retrieved for further assessment. After that, 14 of eligible studies [8-10, 13-15, 18, 28-34] involving a total of 598,435 participants met our inclusion criteria for qualitative synthesis (high vs low meta-analysis). For the dose-response relation assessment, two studies [13, 15] were excluded for insufficient dose data or different measurement of dose unit. Finally, 12 eligible studies [8-10, 14, 18, 28-34] involving a total of 462,268 participants were included in the doseresponse meta-analysis. Fig. 1 displays the screening process.

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Study characteristics 4

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The main characteristics of the 14 included cohort studies are described in Table 1. The studies came from various countries. Five cohorts were from Asia, four were from Europe, four were from North America, and one was produced by 18 countries across five continents. The studies recruited community-based samples, and the sample size of the cohorts ranged from 832 to 135,335 participants. All the included studies used reliable methods to diagnose and define stroke and stroke subtypes, and the outcomes did not contain transient ischemic attack. Ten cohorts used validated food frequency questionnaires (FFQs, questionnaires for assessment of meal patterns, consumption frequencies and portion sizes of regularly eaten foods) for dietary assessment, and the remaining four cohorts used diet history method or 24-hour dietary recall. The duration of follow-up ranged from 7.4 years to 20 years.

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Risk of bias

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According to the NOS Scale, most eligible studies were evaluated as high-quality ranging from seven to nine points. Three studies acquired six points (Supplemental Table 2).

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As described in the methodology section, a systematic and comprehensive literature search was conducted. Two investigators independently performed study selection, data extraction, and study quality assessment. Disagreements were resolved by consensus. Moreover, the protocol previously registered in the PROSPERO and the MOOSE statement was followed when reporting this metaanalysis. These all reduced the risk of sampling bias, selection bias, and within-study biases to some extent.

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High vs. low meta-analysis

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The pooled results of all the 14 cohort studies showed that higher dietary SFA intake was associated with a decreased overall stroke risk (RR = 0.87; 95% CI, 0.78–0.96; I2 = 37.8%; Fig. 2). And no study noticeably affected the pooled results through sensitivity analyses (omitted each study at a time; Supplemental Figure 1).

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Subgroup analyses were conducted by stroke type, study region, gender, number of participants, method of dietary assessment, median or mean body mass index, median or mean duration of followup, NOS score (Fig. 3). Reduced stroke risks related to high SFA intake were found in the majority of subgroups: the intracranial hemorrhage subgroup (RR = 0.55; 95% CI, 0.41–0.73; I2 = 0%; Fig. 3), the Asia region subgroup (RR = 0.69; 95% CI, 0.54–0.88; I2 = 34.1%; Fig. 3), the men subgroup (RR = 0.83; 95% CI, 0.73–0.94; I2 = 0%; Fig. 3), the mixed (men and women) subgroup (RR = 0.77; 95% CI, 0.67–0.89; I2 = 18.7%; Fig. 3), the number of participants less than10,000 participants subgroup (RR = 0.73; 95% CI, 0.55–0.96; I2 = 29.5%; Fig. 3), the FFQ dietary assessment method subgroup (RR = 0.87; 95% CI, 0.76–0.99; I2 = 46.3%; Fig. 3), the median or mean body mass index less than 25 kg/m2 subgroup (RR = 0.77; 95% CI, 0.66–0.90; I2 = 24.4%; Fig. 3) , the median or mean duration of follow-up greater than or equal to 14 years subgroup (RR = 0.80; 95% CI, 0.71– 0.90; I2 = 10.7%; Fig. 3), and the NOS score greater than or equal to seven points subgroup (RR = 0.84; 95% CI, 0.76–0.93; I2 = 34.6%; Fig. 3).

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No significant association was found between higher SFA intake and stroke risks in the ischemic stroke subgroup, the subarachnoid hemorrhage subgroup, the Europe region subgroup, the North America region subgroup, women subgroup, the number of participants greater than or equal to 10,000 participants subgroup, the other dietary assessment methods subgroup, the median or mean 5

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body mass index greater than or equal to 25 kg/m2 subgroup, the median or mean duration of followup less than 14 years subgroup, and the NOS score less than seven points subgroup.

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For publication bias assessments, we did not find obvious asymmetry by visually assessing the shape of funnel plot (Fig. 4). The P value of Begg’s test was 0.66; of Egger’s test, 0.36.

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Dose-respone meta-analysis

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Figure 5 shows the results of non-linear dose-response analysis. A linear dose-response relation (P=0.01) between dietary SFA intake and the risk of stroke was explored. The pooled RR of stroke per 10 grams/day increase in SFA intake was 0.94 (95% CI, 0.89–0.98; P = 0.01); that is, every 10 grams/day increase in SFA intake was associated with a 6% decrease in the rate of stroke,whereas no evidence of a non-linear association was noted (P = 0.96). Similar linear relations were detected between dietary SFA intake and the risk of intracranial hemorrhage (P ＜ 0.001 for linear trend, and P = 0.91 for non-linear trend) and for stroke among Asians (P ＜ 0.001 for linear trend, and P = 0.49 for non-linear trend). The pooled RR per 10 grams/day increase in SFA intake was 0.71 for intracranial hemorrhage (95% CI, 0.61–0.82; P ＜ 0.001; Supplemental Figure 2) and 0.82 for stroke among Asians (95% CI, 0.76–0.89; P ＜ 0.001; Supplemental Figure 3). The pooled RR of stroke per 10 grams/day increase in SFA intake for each study included in the dose-response metaanalysis were summarized in the Supplemental Table 3. No evidence of linear or non-linear association was noted between dietary SFA intake and the risk of ischemic stroke subgroup or subarachnoid hemorrhage subgroup, the stroke risk among the Europe subgroup or North America subgroup, and the stroke risk among men subgroup or women subgroup.

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Discussion

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This meta-analysis identified 14 prospective cohort studies, including 598,435 individuals and 12,074 stroke events. By comparing the highest vs. the lowest category of SFA exposure, the pooled results showed a significant inverse association between dietary SFA intake and the risk of stroke, and similarly for most stroke subgroups (the intracranial hemorrhage subgroup, the Asia region subgroup, the men subgroup, the mixed people subgroup, the number of participants less than10,000 participants subgroup, the FFQ dietary assessment method subgroup, the median or mean body mass index less than 25 kg/m2 subgroup, the median or mean duration of follow-up greater than or equal to 14 years subgroup, and the NOS score greater than or equal to seven points subgroup). More importantly, this is the first meta-analysis to assess the dose-response association between dietary SFA intake and stroke. A linear dose-response relation was found, with every 10 grams/day increase in SFA intake associated with a 6% decrease in the rate of stroke. Similar linear relations were also detected between dietary SFA intake and the risk of intracranial hemorrhage, the risk of stroke among Asians. The reductions in the relative risk per 10 grams/day increase were 29% for the risk of intracranial hemorrhage, and 18% for the risk of stroke among Asians.

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The popular belief is that high SFA intake is detrimental to arterial health, and a reduction in SFA consumption is recommended by current dietary guidelines, probably because of the lower risk of arterial disease events (especially coronary heart disease) that were detected when replacing part of the SFA intake with PUFA [35]. As one of the important manifestations of arterial disease, stroke and its relation to dietary SFA intake have attracted much attention. In general, our study revealed a significant reduction of overall stroke risk in relation to higher SFA intake. The result was similar to a recent meta-analysis [16] but different from a previous meta-analysis [11], largely because of the limited number of included literatures and the inability to cover recently published literatures of the 6

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earlier meta-analysis. Although the evidence of these biological mechanisms was insufficient and complicated, some findings possibly explained the inverse relationship between SFA consumption and the risk of stroke. For instance, the concentration of high-density lipoprotein cholesterol (HDL C) and ApoA1 increased with higher SFA intake, the concentration of total cholesterol and lowdensity lipoprotein cholesterol (LDL - C) decreased with specific type of SFA intake (stearic acid) [36], the concentration of triglycerides and ApoB-to-ApoA1 ratio decreased with higher SFA intake, and the risk of atrial fibrillation decreased with high levels of long-chain SFAs (stearic acid, arachidic acid, behenic acid, and lignoceric acid) [15, 37]. These changes associated with higher SFA intake may play a role in reducing the risk of stroke. Moreover, we further classified stroke into ischemic stroke, intracranial hemorrhage, and subarachnoid hemorrhage, rather than ischemic stroke and hemorrhagic stroke, because the confusing term hemorrhagic stroke could mean not only primary intracranial hemorrhage or subarachnoid hemorrhage but also hemorrhage after infarction [38]. Then we explored specific relationships regarding high SFA intake and its association with a reduction in intracranial hemorrhage risk, rather than the risks of ischemic stroke or subarachnoid hemorrhage. For ischemic stroke, the finding was similar to a previous meta-analysis [12] but different from another previous meta-analysis [16]. For intracranial hemorrhage, the finding was similar to the previous meta-analysis [17]: SFA was a major determinant of total and LDL- C, which were strongly inversely associated with intracranial hemorrhage [39-41]. Although no significant association was found, this was the first meta-analysis to explore the associations between saturated fat intake and subarachnoid hemorrhage. Additionally, consistent with previous studies, we found reduced stroke risks in relation to people from Asia rather than Europe or North America. The regional differences probably are due to the lower levels of background SFA intake among Asians [16, 17]. Excess weight and obesity are thought to be risk factors of stroke, so we used 25 kg/m2 as a boundary value for body mass index according to WHO standards. The pooled results from studies with a mean or median body mass index more than 25 kg/m2 showed no association between dietary saturated fat intake and risk of stroke. This was similar to previous meta-analyses [16, 17]. Lower risks of stroke were found when subgroup studies were high-quality (NOS score no less than seven points), had long follow-up time (mean or median duration of follow-up no less than 14 years), used validated food frequency questionnaire (FFQ), and had male or mixed samples. These findings, too, were consistent with previous meta-analyses [15]. In addition, we further considered the effects of study sample size on the results. The reduction in stroke risks associated with high SFA intake was found in the number of participants less than 10,000 subgroup rather than the number of participants greater than or equal to 10,000 subgroup. This was probably because studies with a sample size of less than 10,000 mostly came from Asia. Moreover, considering some controversies about influence factors such as poverty diet and regional heterogeneity of the large sample size PURE study, we performed some analyses that removed the PURE’ data, but the results were not significantly different (Supplemental Table 4) [42-45].

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Compared to the previous four meta-analysis [11, 12, 16, 17] on this topic, this meta-analysis was based on many prospective cohorts from various populations, and incorporated a much larger number of individuals, and the inclusion of the PURE study [15] including 135,335 individuals from 18 countries made the conclusions more convincing. More subgroups were analyzed in this study, which could partly reduce the heterogeneity between studies and gain more detailed and significative results under different conditions. In addition, we conducted dose-response analysis to explore the linear and non-linear relations. It is helpful to quantify the relations and test the shape of the possible associations. To our knowledge, it was the first time the dose-response association between dietary SFA intake and risk of stroke has been assessed.

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However, our meta-analyses have some limitations. Firstly, because the authors did not analyze and report the data of specific SFA types, we could not explore the associations between specific types of SFA intake and stroke risk, let alone in a dose-response manner. Secondly, for the doseresponse analyses, the PURE study [15] with large sample was excluded because we could not obtain the dose data of SFA intake as grams per day from the published reports or the authors. Thirdly, different studies do have different definitions of "highest" and "lowest" categories of dietary saturated fat intake. Because of the limited number of published articles, we could not conduct a more detailed stratification analysis. With the deepening and expansion of research, we advocated stratification analysis according to different levels of dietary SFA intake or obtained individual patient data for analyses to deal with heterogeneity. More accurate results of the dose-response relation and smaller influence of potential confounders would be achievable, if we could conduct this meta-analysis using individual data rather than summary statistics. Finally, because of to the limitations of observational studies and dietary assessment tools, with the addition of the difficulty to obtain more detailed data from published studies or authors, we did not examine the influence of different macronutrient replacement models of saturated fat on the results.

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In conclusion, the results of this study provide further evidence for the protective e ects of diets high in SFA on the reduction of stroke risk. Every 10 grams/day increase in SFA intake is associated with a 6% decrease in the rate of stroke. These findings could provide scientific evidence to reevaluate the restrictions on SFA intake for future dietary guidelines, but it is also important to consider the impact of relaxing restrictions on the risk of other chronic diseases (especially for the cardiovascular diseases). Moreover, in order to systematically and comprehensively explore the relationship between saturated fat intake and human health in the future, more well-designed trials of this topic should focus on specific stroke types and saturated fat types, different macronutrient replacement models of saturated fat, and use of fatty acid biomarkers are recommended.

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Conflict of Interest

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None.

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Author Contributions

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ZQK designed this research, searched the lecture, evaluated the quality of evidence, extracted data, performed the analyses, wrote the paper. YY screened and evaluated the quality of evidence, extracted data. BX screened the data.

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Funding

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None.

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References

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10.1016/S0140-6736(18)30774-8

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Figure and Table List in the Manuscript

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Figure 1. Flow diagram of the systematic review process

481 482

Figure 2. Random effects meta-analysis on the relations between saturated fatty acids intake and risk of stroke

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Figure 3. Forest plot of subgroup analyses for stroke

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Figure 4. Begg’s funnel plot with 95% confidence intervals (CIs) of publication bias test

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Figure 5. Dose-response relation between saturated fatty acids intake and risk of stroke

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Table 1. Characteristics of studies included in meta-analysis of dietary saturated fat intake and risk of stroke

488 489

Figure and Table List in the Supplemental Material

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Supplemental Table 1. Example search strategy (PubMed)

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Supplemental Table 2. Scores of Newcastle-Ottawa Scale assigned to cohort studies included in the meta-analysis

493 494

Supplemental Table 3. Pooled RR of stroke per 10 grams/day increase in SFA intake for each study included in the dose-response meta-analysis

495 496

Supplemental Table 4. Pooled results of the relations between saturated fatty acids intake and risk of stroke including and excluding the PURE study in the meta-analysis

497 498

Supplemental Figure 1. Sensitivity analyses for the primary outcome (omitted each study at a time using random-effects models)

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Supplemental Figure 2. Dose-response relation between saturated fatty acids intake and risk of intracerebral hemorrhage

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Supplemental Figure 3. Dose-response relation between saturated fatty acids intake and risk of stroke among Asians

12

Table 1. Characteristics of studies included in meta-analysis of dietary saturated fat intake and risk of stroke Study (publication year)

Cohort name (country)

Outcomes NO. of Age at Median Median or Method of Median or Median or mean Participant baseline or SFA of the extracted for Mean dietary mean s (men%) (years) mean duration of assessment dietary highest and the analyses BMI follow-up SFA intake lowest categories (NO. of cases) (g/d) * (g/d) (years)

Gillman (1997)13

Framingham Heart Study (USA)

832 (100%)

45-65

≥25

20

24-hour dietary recall

43.8

NA

IS:61

Seino (1997)28

Shibata Study (Japan)

2,283 (41.8%)

40-89

＜25

15.5

FFQ

Q2:9.8 Q3:12.1

Q1:7.2 Q4:15.4

IS:75

Iso (2001)8

Nurses’ Health Study (USA)

85,764 (0%)

34-59

＜25

14

FFQ

28

Q1:20 Q5:36

Stroke:690 IS:386 ICH:64 SAH:129

He (2003)29

Health professional follow up study (USA)

43,732 (100%)

40-75

＜25

14

FFQ

24

Q1:17 Q5:31

Stroke:580 IS:455

Iso (2003)30

Cardiovascular risk surveys (Japan)

4,775 (47.5%)

40-69

＜25

14.3

24-hour dietary recall

Q2:8.4 Q3:11.9

Q1:5.2 Q4:17.1

ICH:67

Sauvaget Adult Health Study (Japan) (2004)9

3,731 (38.5%)

35-89

＜25

14

12

Q1:7 Q3:21

IS:60

Yamagishi Japan Collaborative (2010)31 Cohort Study for Evaluation of Cancer Risk (Japan)

58,453 (39.4%)

40-79

＜25

14.1

24-hour dietary recall FFQ

14.4

Q1:9.2(Men) Q5:20.3(Men) Q1:9.4(Women) Q5:19.8(Women)

Stroke:976 IS:321 ICH:224 SAH:153

Atkinson Caerphilly Prospective (2011)32 Study (UK)

2,710 (100%)

45-59

≥25

18

FFQ

32.8

Q1:26.8 Q5:50.4

Stroke:176

Adjusted variables

NOS score

Age, systolic blood pressure, cigarettes smoked, glucose intolerance, left ventricular hypertrophy, BMI, intake of energy, fruits and vegetables, alcohol Age, sex, diastolic blood pressure, atrial

7

fibrillation，intake of a specific type of lipid Age, smoking, time interval, BMI, alcohol intake, menopausal status, postmenopausal hormone use, vigorous exercise, usual aspirin use, multivitamin use, vitamin E use, n-3 fatty acid intake, calcium intake, hypertension, diabetes, high cholesterol levels, total energy intake BMI, physical activity, hypertension, smoking, aspirin use, multivitamin use, consumption of alcohol, potassium, fibre, vitamin E, fruit and vegetables, total energy intake, hypercholesterolaemia, unsaturated fatty acids (poly, mono), trans fatty acids Age, sex, total energy intake, BMI, hypertension category, diabetes, serum total cholesterol, smoking, ethanol intake, menopausal status Age, sex, radiation dose, city, BMI, smoking, alcohol, hypertension, diabetes Age, sex, hypertension, diabetes, smoking, alcohol consumption, BMI, mental stress, walking, sports, educational level, dietary intakes of total energy, cholesterol, n-3 and n-6 polyunsaturated fatty acids, vegetables, fruit, animal protein Age, total energy, smoking, adult social class, marital status, alcohol intake, vitamin C intake, vegetable fibre intake, blood pressure, cholesterol, BMI, fasting glucose, diabetes, atrial fibrillation

7

7

6

7

7

7

6

Study (publication year)

Cohort name (country)

NO. of Age at Median Median or Method of Median or Participant baseline or Mean dietary mean s (men%) (years) mean duration of assessment dietary BMI follow-up SFA intake (years) (g/d) * Wallstrom Malmo Diet and Cancer 20,674 ≥25 13.5 Diet history 16.8(Men) 44-73 (2012)10 Cohort (Sweden) method 16.7(Wome (39.4%) n)

Swedish Mammography Cohort (Sweden)

34,670 (0%)

49-83

≥25

10.4

FFQ

26.9

Yaemsiri Women’s Health (2012)34 Initiative Observational Study (USA)

87,025 (0%)

50-79

≥25

7.6

FFQ

14.5

Yamagishi Japan Public Health (2013)14 Center-based prospective Study (Japan)

81,931 (46.5%)

45-74

＜25

11.1

FFQ

16.3

Dehghan Prospective Urban (2017)15 Rural Epidemiology study (18 countries) Sluijs EPIC-Netherlands (2017)18 cohort study (The Netherlands)

135,335 (41.7%)

35-70

NA

7.4

FFQ

8%

36,520 (25%)

20-70

≥25

15

FFQ

Q2:27 Q3:30

Larsson (2012)33

Median or mean Adjusted variables NOS Outcomes SFA of the extracted for score highest and the analyses lowest categories (NO. of cases) (g/d) IS:401(Men) Age, method version, total energy intake, 7 Q1:13(Men) Q5:22.7(Men) IS:354(Women) season, BMI, smoking, education, alcohol Q1:12.9(Women) category, systolic blood pressure, Q5:22.1(Women) antihypertensive treatment, antihyperlipidemic treatment, leisure time physical activity, energy-adjusted dietary fiber Q1:19.5 Age, smoking, education, BMI, total 8 Stroke:1,680 Q5:35.5 physical activity, hypertension, diabetes, IS:1,310 aspirin use, family history of myocardial infarction, intakes of alcohol, protein, dietary fiber, cholesterol 6 Q1:12.9 Age, race, education, income, smoking, IS:1,049 Q5:26.1 hormone use, total metabolic equivalent task hours per week, alcohol, coronary heart disease, atrial fibrillation, diabetes, aspirin use, antihypertensive medication use, cholesterol-lowering medication use, BMI, systolic blood pressure, total energy intake, dietary vitamin E, fruits, vegetable, fiber intake Q1:9.6 7 Stroke:3,192 Age, sex, energy intake, cohort, smoking, Q5:24.9 alcohol intake, BMI, sports at leisure time, IS:1,939 walking and standing time, perceived ICH:894 mental stress, energy-adjusted dietary SAH:348 intakes of carbohydrate, protein, cholesterol, vegetables, fruit, and calcium Q1:2.8% 7 Stroke:2,234 Age, sex, education, smoking, physical Q5:13.2% activity, diabetes, urban/rural, energy intake, waist-to-hip ratio Q1:23 IS:479 Age, sex, smoking, physical activity index, 9 Q4:34 BMI, education, systolic blood pressure, hypertension, diabetes, dietary intakes of energy, cholesterol, carbohydrates and alcohol

Abbreviations: BMI, body mass index; SFA, saturated fatty acids; NA, not available; FFQ, food frequency questionnaire; IS, ischemic stroke; ICH, intracranial hemorrhage; SAH, subarachnoid hemorrhage. * We listed the median or mean dietary SFA intake values of the intermediate category if the authors did not report the population mean or median values. 14

Highlights Higher dietary saturated fat intake is associated with a decreased overall stroke risk There is a linear dose-response relation between dietary saturated fat intake and the risk of stroke It is necessary to re-evaluate the restrictions on saturated fat intake for future dietary guidelines