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精品文档The effect of fructose consumption on plasma cholesterol in adults: a meta-analysis of controlled feeding trials1,2,3Tao An4,5, Rong Cheng Zhang4,5, Yu Hui Zhang4, Qiong Zhou4, Yan Huang4, Jian Zhang4, *.4 State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China5 Tao An and Rong Cheng Zhang contributed equally to this study.3 Supplemental Table 1 and supplemental Figures 1-4 are available as Online Supporting Material with the online posting of this paper at RUNNING TITLE: Fructose and cholesterolWORD COUNT: 5618; NUMBER OF FIGUREA: 3; NUMBER OF TABLES: 2SUPPLEMENTARY MATERIAL: Online Supporting Materials: 5AUTHOR LIST FOR INDEXING: An, Zhang, Zhang, Zhou, Huang, Zhang1 The study was supported by the Ministry of Science and Technology of China with grant of the National High-tech Research and Development Program of China to Dr Jian Zhang. 2 Author disclosures: T. An, R.C. Zhang, Y.H. Zhang, Q. Zhou, Y. Hung, J. Zhang have no conflicts of interest.* To whom correspondence should be addressed. Mailing address: Heart Failure Center, Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishilu, Beijing, China; Zip code: 100000; Telephone number: 86-10-88396180; Fax number: 86-10-88396180; E-mail: FPROSPERO REGISTRATION NUMBERS: CRD42012003351ABSTRACTFructose is widely used as a sweetener in production of many foods, yet the relation between fructose intake and cholesterol remains uncertain. We performed a systematic review and meta-analysis of human controlled feeding trials of isocaloric fructose exchange for other carbohydrates to quantify the effects of fructose on total cholesterol (TC), LDL cholesterol (LDL-C), and HDL cholesterol (HDL-C) in adult humans. Weighted mean differences were calculated for changes from baseline cholesterol concentrations by using generic inverse variance random-effects models. The Heyland Methodological Quality was used to assess study quality. Subgroup analyses and meta-regression were conducted to explore possible influence of study characteristics. Twenty-four trials (with a total of 474 subjects) were included in our meta-analysis. In an overall pooled estimate, fructose exerted no effect on TC, LDL-C and HDL-C. Meta-regression analysis indicated that fructose dose was positively correlated with the effect sizes of TC and LDL-C. Subgroup analyses showed that isocaloric fructose exchange for carbohydrates could significantly increase TC by 12.97 mg/dL (95%CI: 4.66, 21.29; P = 0.002) and LDL-C by 11.59 mg/dL (95%CI: 4.39, 18.78; P = 0.002) at 100g fructose/d but had no effect on TC and LDL-C when fructose intake was 100g/d. In conclusion, very high fructose intake (100g/d) could lead to significantly increase in serum LDL-C and TC. Larger, longer and higher-quality human controlled feeding trials are needed to confirm these results.Key words: fructose, cholesterol, meta-analysisINTRODUCTIONHyperlipidemia is a common risk factor for coronary heart disease (CHD), with 44.4% of adults in the United States having abnormal TC values and 32% having elevated LDL-C levels (1). Compared to subjects with normal blood lipid, those with hyperlipidemia have a 3-fold risk of heart attacks (2). Lifestyle modification should be initiated in conjunction both primary and secondary prevention of CHD. More consideration exists as to what constitutes healthy eating.Fructose is the most naturally occurring monosaccharide, and has become a major constituent of our modern diet. Fruit, vegetables, and other natural sources provide nearly one-third of dietary fructose, and two-thirds come from beverages and foods in the diets (eg, candies, jam, syrups, etc) (3). Fructose is preferred by many people, especially those with diabetes mellitus because of its low glycemic index (23% versus glucose 100%) (4). After intestinal uptake, fructose is mainly removed from the blood stream by the liver in an insulin-independent manner, and is used for intrahepatic production of glucose, fatty acids or lactate. Cross-sectional studies in human suggest that excessive fructose consumption can lead to adverse metabolic effects, such as dyslipidemia and increased visceral adiposity (5-7). The Dietary Guidelines for Americans, 2010, point out that it is lack of sufficient evidence to set a tolerable upper intake of carbohydrates for adults (8). Although The Candian Diabetes Association suggests consumption of no more than 60g of added fructose per day by people with diabetes for its triglyceride-raising effect (9), the threshold dose of fructose at which the adverse influence on cholesterol is controversial.To determine the effect of fructose on cholesterol, a substantial number of clinical trials have been performed on adult humans with different health status (diabetic, obese, overweight, hyperinsulinemic, impaired glucose-tolerant and healthy). These trials used various intake levels of fructose and different protocols. Thus, it is difficult to reach a consistent conclusion across these studies. Therefore, we conducted a systematic review of the scientific literature and meta-analysis of controlled feeding trials to evaluate the effect of isocaloric oral fructose exchange for carbohydrates on cholesterol and to clarify the active factors of fructose.Materials and MethodsThis meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria (10).Search strategy. We searched PubMed (/pubmed; from 1966 to December 2012), Embase (; from 1966 to December 2012) and the Cochrane Library database () by using the following search terms: fructose and (lipemia or lipaemia or lipids or cholesterol or “total cholesterol” or “LDL cholesterol” or “HDL cholesterol”) in English. We also searched China National Knowledge Infrastructure () and Wangfang database () in Chinese according to the search strategy. The search was restricted to reports of trials on humans.Study selection. All clinical trials using fructose and indexed within the above databases were collected. Two independent reviewers (T.A., R.C.Z) screened the abstracts and titles for initial inclusion. If this was not sufficient, full texts articles were obtained and reviewed by at least two independent reviewers (T.A., R.C.Z, Q.Z., Y.H.). The reference lists of retrieved articles also used to supplement the database. Any disagreements were resolved through discussion. We included controlled feeding trials investigating the chronic effect of fructose on blood cholesterol, from both randomized and nonrandomized studies, if they met the following criteria: subjects must have been administered fructose for at least 2 weeks; studies investigated the effect of oral free (unbound, monosaccharide) fructose when compared with isocaloric control diet with another carbohydrate in place of fructose; studies were performed in human adults with either a parallel or crossover design; subjects in both experimental groups and control groups were instructed to consume isocaloric diets. If the study reported any comparisons, we included all such comparisons in the meta-analysis.Data extraction and quality assessment. Two reviewers (T.A., R.C.Z) independently extracted relevant data from eligible studies. Disagreements were resolved by one of the two authors (Y.H.Z., J.Z.). These data included information on study features (author, year of publication, study design, randomization, blinding, sample size, comparator, fructose form, dose, follow-up and macronutrient profile of the background diet), participant characteristics (gender, age and healthy status) and baseline and final concentrations or net changes of total cholesterol, LDL-C and HDL-C. Data initially extracted were converted to system international unit (eg, TC: 1 mmol/L converted to 38.6 mg/dL). For multi-arm studies, only intervention groups that met inclusion criteria were used in this analysis. If blood lipid concentrations were measured several times at different stages of trials, only final records of lipid concentrations at the end of the trials were extracted for this meta-analysis.The quality of each study was assessed with the Heyland Methodological Quality Score (MQS) (11), generalized as follows: randomization; analysis; blinding; patient selection; comparability of groups at baseline; extent of follow up; treatment protocol; co-intervention; outcomes. The highest score for each area was two points. Higher numbers represented a better quality (MQS8).Data synthesis. Statistical analyses were performed with Stata software (version 11.0; StataCorporation, TX, USA) and REVMAN software (version 5.2; Cochrane Collaboration, Oxford, United Kingdom). Separate pooled analyses were conducted by using the generic inverse variance random-effects models even where there was no evidence of between-study heterogeneity because these models give more conservative summary effect estimates in the presence of undetected residual heterogeneity than fixed-effects models. The different changes from baseline between fructose and carbohydrate comparators for total cholesterol, LDL cholesterol and HDL cholesterol were used to estimate the principle effect. We applied paired analyses to all crossover trials according to the methods of Elbourne and colleagues (12). Weighted mean differences of fructose consumption on cholesterol concentrations and corresponding 95% CIs were calculated. A 2-sided P value 0.05 was set as the level of significance for an effect. The variances for net changes in serum cholesterol were only reported directly in two trials (29, 31). We calculate net changes for other studies by using the meansSDs cholesterol concentrations at baseline and at the end of intervention period (13). SDs were calculated from SEs when they were not directly given. If these data were unavailable, we extrapolated missing SDs by borrowing SDs derived from other trials in this meta-analysis (14). In addition, we assumed a conservative degree of correlation of 0.5 to impute the change-from-baseline SDs, with sensitivity analyses performed across a range of possible correlation coefficients (0.25 and 0.75) (13). For crossover trials in which only final measurements were included, the differences in mean final measurements were assumed on average to be the same as the differences in mean change scores (13). Inter-study heterogeneity was tested by the Cochranes Q-test (P 60 to 100, and 100 as moderate, high, and very high, respectively, according to Candian Diabetes Association and reference ranges for fructose (9, 37, 38). Fructose could significantly increase TC by 12.97 mg/dL (95%CI: 4.66, 21.29; P = 0.002) when fructose intakes were 100g/d but had no effect on TC if fructose was given lower than 100g. Predefined subgroup analyses were conducted by study characteristics (Supplemental Table 1). Sensitivity analyses according to possible correlation coefficients (0.25 and 0.75) and systematically removal of each individual trial did not alter the overall analysis and analyses stratified by dose. LDL cholesterol. The mean change for LDL cholesterol in nineteen trials (15, 16, 18, 20, 22, 23, 25-35) was 3.76 mg/dL (95% CI: -1.07, 8.6; P = 0.13) without statistically heterogeneity (heterogeneity Chi2 = 19.85, I2 = 9%, P = 0.34) (Fig. 2). The residual sources of heterogeneity were investigated by meta-regression models. Univariate meta-regression showed that the fructose dose was positively related to LDL-C, even after adjusted for comparators, study duration and health status (regression coefficient = 0.15; 95% CI: 0.03, 0.28, P = 0.02) (Table 2). The dose-response relation between fructose consumption and LDL-C largely explained the residual heterogeneity of the effect. We stratified fructose dose according to CDA and reference ranges for fructose (9, 37, 38). Fructose intake 100g/d could significantly increase LDL-C by 11.59 mg/dL (95%CI: 4.39, 18.78; P = 0.002). Predefined subgroup analyses were conducted by other study characteristics (Supplemental Table 1). Sensitivity analyses across possible correlation coefficients (0.25 and 0.75) did not alter the overall analysis and analyses stratified by dose. The removal of Cybulska et al resulted in a significant LDL-C-raising effect in the overall analysis (P = 0.03).HDL cholesterol. The result of HDL cholesterol was calculated based on 24 trials (15-36), the mean difference was -0.56 mg/dL (95% CI: -2.05, 0.93; P = 0.46) without heterogeneity (heterogeneity Chi2 = 21.85, I2 = 0%, P = 0.53) (Fig. 3). Meta-regression analysis did not show significant effect modifier of HDL-C. Predefined subgroup analyses were conducted by study characteristics (Supplemental Table 1). Sensitivity analyses according to possible correlation coefficients (0.25 and 0.75) and systematically removal of each individual trial did not alter the overall analysis. Publication bias Funnel plots and Eggers test indicated no significant publication bias in the meta-analyses of TC, LDL cholesterol, and HDL cholesterol (TC Eggers test: P = 0.881; LDL cholesterol Eggers test: P = 0.815; HDL cholesterol Eggers test: P = 0.484) (