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1、精选文库Theeffectoffructoseconsumptiononplasmacholesterolinadults:ameta-analysis of controlled feeding trials1,2,34,54,5444Tao An, Rong Cheng Zhang , Yu Hui Zhang , Qiong Zhou , Yan Huang , JianZhang4, *.4 State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular

2、 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 OnlineRUNNING TITLE: Fructose and cholesterolWORD COUNT: 5618; NUMBER OF

3、 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 Ch

4、ina to Dr Jian Zhang.-精选文库2 Author disclosures: T. An, R.C. Zhang, Y.H. Zhang, Q. Zhou, Y. Hung, J. Zhang have no conflicts of interest.PROSPERO REGISTRATION NUMBERS: CRD420120033511-精选文库234567ABSTRACTFructose is widely used as a sweetener in production of many foods, yet the relationbetween fructos

5、e intake and cholesterol remains uncertain. We performed a systematicreview and meta-analysis of human controlled feeding trials of isocaloric fructoseexchange forother carbohydrates to quantifythe effects offructose on totalcholesterol (TC), LDL cholesterol (LDL-C), and HDL cholesterol (HDL-C) in a

6、dult8humans. Weighted mean differences were calculated for changes from baseline9 cholesterol concentrations by using generic inverse variance random-effects models.10 The Heyland Methodological Quality was used to assessstudy quality. Subgroup11 analyses and meta-regression were conducted to explor

7、e possible influence of study12 characteristics. Twenty-four trials (with a total of 474 subjects) were included in our13 meta-analysis. In an overall pooled estimate, fructose exerted no effect on TC, LDL-C14 and HDL-C. Meta-regression analysis indicated that fructose dose was positively15 correlat

8、ed with the effect sizes of TC and LDL-C. Subgroup analyses showed that16isocaloric fructose exchange for carbohydrates could significantly increase TC by1712.97 mg/dL (95%CI: 4.66, 21.29; P = 0.002) and LDL-C by 11.59 mg/dL (95%CI:1819202122234.39, 18.78; P = 0.002) at >100g fructose/d but had n

9、o effect on TC and LDL-C whenfructose 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 andhigher-quality human controlled feeding trials are needed to confirm these results.Key words: fructose, choleste

10、rol, meta-analysis-精选文库24 INTRODUCTION25 Hyperlipidemia is a common risk factor for coronary heart disease (CHD), with2644.4% of adults in the United States having abnormal TC values and 32% having27 elevated LDL-C levels (1). Compared to subjects with normal blood lipid, those with28 hyperlipidemia

11、 have a 3-fold risk of heart attacks (2). Lifestyle modification should be29initiated in conjunction both primary and secondary prevention of CHD. More30 consideration exists as to what constitutes healthy eating.31 Fructose is the most naturally occurring monosaccharide, and has become a major32 co

12、nstituent of our modern diet. Fruit, vegetables, and other natural sources provide33 nearly one-third of dietary fructose, and two-thirds come from beverages and foods in34 the diets (eg, candies, jam, syrups, etc) (3). Fructose is preferred by many people,35 especially those with diabetes mellitus

13、because of its low glycemic index (23% versus36 glucose 100%) (4). After intestinal uptake, fructose is mainly removed from the blood37 stream by the liver in an insulin-independent manner, and is used for intrahepatic38 production of glucose, fatty acids or lactate. Cross-sectional studies in human

14、 suggest39 that excessive fructose consumption can lead to adverse metabolic effects, such as40 dyslipidemia and increased visceral adiposity (5-7). The Dietary Guidelines for41 Americans, 2010, point out that it is lack of sufficient evidence to set a tolerable upper42 intake of carbohydrates for a

15、dults (8). Although The Candian Diabetes Association43 suggests consumption of no more than 60g of added fructose per day by people with44 diabetes for its triglyceride-raising effect (9), the threshold dose of fructose at which45 the adverse influence on cholesterol is controversial.-精选文库46 To dete

16、rmine the effect of fructose on cholesterol, a substantial number of clinical47 trials have been performed on adult humans with different health status (diabetic,48 obese, overweight, hyperinsulinemic, impaired glucose-tolerant and healthy). These49 trials used various intake levels of fructose and

17、different protocols. Thus, it is difficult50 to reach a consistent conclusion across these studies. Therefore, we conducted a51 systematic review of the scientific literature and meta-analysis of controlled feeding52535455565758596061trials to evaluate the effect of isocaloric oral fructose exchange

18、 for carbohydrates oncholesterol and to clarify the active factors of fructose.Materials and MethodsThis meta-analysis followed the Preferred Reporting Items for Systematic Reviewsand Meta-analyses (PRISMA) criteria (10).following search terms: fructose and (lipemia or lipaemia or lipids or choleste

19、rol or“total cholesterol”or “LDL cholesterol”“HDLor cholesterol ) in”English. We also626364 search was restricted to reports of trials on humans.65 Study selection. All clinical trials using fructose and indexed within the above6667abstracts and titles for initial inclusion. If this was not sufficie

20、nt, full texts articles-精选文库6869 Y.H.). The reference lists of retrieved articles also used to supplement the database.70 Any disagreements were resolved through discussion. We included controlled feeding71 trials investigating the chronic effect of fructose on blood cholesterol, from both72 randomi

21、zed and nonrandomized studies, if they met the following criteria: subjects73 must have been administered fructose for at least 2 weeks; studies investigated the74 effect of oral free (unbound, monosaccharide) fructose when compared with isocaloric75 control diet with another carbohydrate in place o

22、f fructose; studies were performed in76 human adults with either a parallel or crossover design; subjects in both experimental77 groups and control groups were instructed to consume isocaloric diets. If the study78 reported any comparisons, we included all such comparisons in the meta-analysis.7980

23、extracted relevant data from eligible studies. Disagreements were resolved by one of8182 (author, year of publication, study design, randomization, blinding, sample size,83comparator, fructoseform,dose, follow-upand macronutrient profileofthe84 background diet), participant characteristics (gender,

24、age and healthy status) and85baseline and final concentrations or net changes of total cholesterol, LDL-Cand86 HDL-C. Data initially extracted were converted to system international unit (eg, TC: 187 mmol/L converted to 38.6 mg/dL). For multi-arm studies, only intervention groups88that met inclusion

25、 criteria were used in this analysis. Ifblood lipidconcentrations89were measured several times at different stages of trials,only finalrecords of lipid-精选文库90 concentrations at the end of the trials were extracted for this meta-analysis.9192939495The quality of each study was assessed with the Heyla

26、nd Methodological QualityScore (MQS) (11), generalized as follows: randomization; analysis; blinding; patientselection; comparability of groups at baseline; extent of follow up; treatment protocol;co-intervention; outcomes. The highest score for each area was two points. Highernumbers represented a

27、better quality(MQS 8).96 Data synthesis. Statistical analyses were performed with Stata software (version 11.0;97StataCorporation, TX,USA)and REVMANsoftware (version5.2;Cochrane98 Collaboration, Oxford, United Kingdom). Separate pooled analyses were conducted99 by using the generic inverse variance

28、random-effects models even where there was no100 evidence of between-study heterogeneity because these models give more101 conservative summary effect estimates in the presence of undetected residual102 heterogeneity than fixed-effects models. The different changes from baseline between103 fructose

29、and carbohydrate comparators for total cholesterol, LDL cholesterol and104 HDL cholesterol were used to estimate the principle effect. We applied paired105 analyses to all crossover trials according to the methods of Elbourne and colleagues106107108109110111(12).Weightedmeandifferencesoffructosecons

30、umptiononcholesterolconcentrations and corresponding 95% CIs were calculated. A 2-sidedP value <0.05was set as the level of significance for an effect. The variances for net changes inserum cholesterol were only reported directly in two trials (29, 31). We calculate netchanges for other studies b

31、y using the means±SDs cholesterol concentrations atbaseline and at the end of intervention period (13). SDs were calculated from SEs-精选文库112 when they were not directly given. If these data were unavailable, we extrapolated113 missing SDs by borrowing SDs derived from other trials in this meta-

32、analysis (14). In114addition, we assumed a conservative degree of correlation of 0.5 to impute the115 change-from-baseline SDs, with sensitivity analyses performed across a range of116 possible correlation coefficients (0.25 and 0.75) (13). For crossover trials in which117 only final measurements we

33、re included, the differences in mean final measurements118 were assumed on average to be the same as the differences in mean change scores119 (13). Inter-study heterogeneity was tested by the CochraneQs-test (P < 0.1), and was120 quantified by the I2 statistic, where I2 50% was evidence of substa

34、ntial heterogeneity.121 To explore the potential effects of factors on the primary outcomes and investigate the122 possible sources of heterogeneity, we performed meta-regressions and predefined123 subgroup analyses stratified by comparator, dose, study duration, randomization,124 health status, stu

35、dy design and study quality. As for studies used a range of fructose125 doses, the average doses calculated on the basis of the average reported energy intake126 or weight of participants (28.5 calories per kilogram of body weight). Sensitivity127 analyses were also performed according to the Cochra

36、ne Handbook for Systemic128 Review. Funnel plots and Egger linears regression test were conducted to detect129 publication bias.130 RESULTS131 Based on our search criteria, 1602 eligible studies were identified, and 1565132 studies were excluded on review of the titles and abstracts. The remaining 3

37、7 studies133 were retrieved and fully reviewed. Fifteen of these did not meet the inclusion criteria-精选文库134 and were excluded in the final analysis. A total of 22 studies (providing data for 24135136137138139trials)involving474subjects (15-36)wereincludedinthemeta-analysis(Supplemental Fig. 1, Tabl

38、e 1 ).The reports of Koh and Reiser (22, 23) included two trials (bringing the totalnumber of trials to 24). Eleven trials were randomized (17, 18, 20, 21, 25, 27-29, 31,34, 36). Nineteen trials used crossover (15-19, 21-32), and five used parallel designs140 (20, 33-36). As for the 19 cross-over tr

39、ials, 10 trials have reported the washout period141 (16, 18, 22, 25, 27-31), 9 trials did not have washout period (15, 17, 19, 21, 23, 24, 26,142 32). The trials varied in size, from 8 to131 subjects. The mean age of trial participants143 ranged from 26.7 to 64.4 years. Seventeen trials (15, 17-23,

40、25, 27, 28, 30, 31, 34, 36)144 were performed in outpatient settings, 3 trials (26, 29, 32) in inpatient settings, and 4145 trials in both outpatient and inpatient settings (16, 24, 33, 35). Nine trials were146 conducted on diabetic subjects (19-21, 24-27, 29, 30), 8 trials in healthy subjects (17,1

41、47 18, 22, 23, 28, 31, 34, 35), 3 trials in overweight/obese subjects (32, 33, 36), 2 trials in148hyperinsulinemicsubjects (16,23),1trialinthosewhowereimpaired149 glucose-tolerant (22), and 1 trial in subjects with type IV hyperlipoproteinaemia (HLP)150 (15). Background diets were 42-55% carbohydrat

42、e, 25-38% fat, and 13-20% protein.151 The carbohydrate comparators choose starch in 13 trials (15, 16, 21, 23-25, 27-30, 32,152 36), glucose in 6 trials (22, 31, 33-35), sucrose in 3 trials (17, 18, 26), and mixed153 carbohydrates in two trials (19, 20). Four trials used fructose in crystalline (16,

43、 18, 20,154 21), 5 trials in liquid (19, 32-35), and 15 trials in mixed form (15, 17, 22-31). The155 reported mean baseline serum TC ranged from 170 to 230.8 mg/dl, LDL-C ranged-精选文库156 from 90.7 to 157 mg/dl, and HDL-C ranged from 35.1 to 57.1 mg/dl. Nineteen trials157 reported the fructose intake

44、among background diet was not different between the158 fructose and control groups, in which 15 trials reported the background fructose intake159 account for 3% of total energy (9 to 24g) (15-23, 29, 32, 33, 35), while 4 trials did160not report the proportion of it (24, 25, 26, 34). Four trials used

45、 background fructose 3%161 (3.2 to 18g) of total energy in the control groups, but put total fructose into162 consideration in the fructose group (27, 28, 30-31). Only o ne trial reported less than163 20g (4.3 % of total energy) fructose was consumed among basal diet (36). The baseline164 values wer

46、e not provided in 5 trials (19, 22, 23). The median fructose dose in the165 available trials included in our meta-analysis was 79.25 g/d (range: 30-182 g/d), and166 the duration varied from 2 to 26 weeks.167 The quality scores of each study ranged from 6 to 9. Fifteen trials were classified168 as hi

47、gh quality (MQS 8), and 8 trials were of low quality (17, 19, 26, 30, 32-35).169 Only three trials were blinded, one single-blinded (34) and 2 double-blinded (29, 35).170 Eight trials (19, 21, 24, 26-30) received industry funding. Three studies with four171 trials (15, 16, 22) did not report any inf

48、ormation about financial conflicts of interest.172 Effect of fructose on cholesterol173 Total cholesterol. Twenty-two trials (16-34, 36) reported the value of TC, and the174 pooled estimate was 2.47 mg/dL (95% CI: -3.04, 7.98; P = 0.38) without statistically175 heterogeneity (heterogeneity Chi2 = 28

49、.14, I 2 = 25%, P = 0.14) ( Fig. 1). The residual176 sources of heterogeneity were investigated by meta-regression models. Univariate177 meta-regression showed that the fructose dose was positively related to TC, even after-精选文库178 adjusted for study duration and health status (regression coefficien

50、t = 0.18; 95% CI:1790.06, 0.31, P = 0.008) (Table 2). The dose-response relation between fructose180 consumption and TC largely explained the residual heterogeneity of the effect.181 Subsequently, we stratified fructose dose 60, >60 to 100, and >100 as moderate,182 high, and very high, respect

51、ively, according to Candian Diabetes Association and183 reference ranges for fructose (9, 37, 38). Fructose could significantly increase TC by184 12.97 mg/dL (95%CI: 4.66, 21.29; P = 0.002) when fructose intakes were >100g/d185 but had no effect on TC if fructose was given lower than 100g. Predef

52、ined subgroup186 analyses were conducted by study characteristicsSupplemental( Table 1 ). Sensitivity187analyses according to possible correlation coefficients (0.25 and 0.75) and188systematically removal of each individual trial did not alter the overall analysis and189 analyses stratified by dose.190 LDL cholesterol. The mean change for LDL cholesterol in nineteen trials (15, 16, 18,191 20, 22, 23, 25-35) was 3.76 mg/dL (95% CI: -1.07, 8.6; P = 0.13) without statistically192 heterogeneity (heterogeneity Chi2 = 19.85, I 2 = 9%, P = 0.34) ( Fig.