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1、精选文库1,2,3The effect of fructose consumption on plasma cholesterol in adults: ameta-analysis of controlled feeding trials4,54,5444Tao An , Rong Cheng Zhang , Yu Hui Zhang , Qiong Zhou , Yan Huang , JianZhang The study was supported by the Ministry of Science and Technology of China with grant of the

2、National High-tech Research and Development Program of China to Dr Jian Zhang. *4State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, NationalCenter for Cardiovascular Diseases, Chinese Academy of Medical Sciences andPeking Union Medical College, Beijing, China5 FTao An and Rong Cheng Zha

3、ng contributed equally to this study.3 ,Supplemental Table 1 and supplemental Figures 1-4 are available as OnlineSupporting Material with the online posting of this paper at :/RUNNING TITLE: Fructose and cholesterolWORD COUNT: 5618; NUMBER OF FIGUREA: 3; NUMBER OF TABLES: 2SUPPLEMENT

4、ARY MATERIAL: Online Supporting Materials: 5AUTHOR LIST FOR INDEXING: An, Zhang, Zhang, Zhou, Huang, Zhang精选文库2Author 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 FailureCenter

5、, Cardiovascular Institute and Fuwai Hospital, Chinese Academy of MedicalSciences and Peking Union Medical College, 167 Beilishilu, Beijing, China; Zip code: 100000; Telephone number: 86-10-88396180; Fax number: 86-10-88396180; E-mail:Fwzhangjian62163 PROSPERO REGISTRATION NUMBERS: CRD42022022351精选文

6、库2 ABSTRACT3 Fructose is widely used as a sweetener in production of many foods, yet the relation4 between fructose intake and cholesterol remains uncertain. We performed a systematic5 review and meta-analysis of human controlled feeding trials of isocaloric fructose6 exchange for other carbohydrate

7、s to quantify the effects of fructose on total7 cholesterol (TC), LDL cholesterol (LDL-C), and HDL cholesterol (HDL-C) in adult8 humans. Weighted mean differences were calculated for changes from baseline9 cholesterol concentrations by using generic inverse variance random-effects models.10 The Heyl

8、and Methodological Quality was used to assessstudy quality. Subgroup11 analyses and meta-regression were conducted to explore 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

9、 exerted no effect on TC, LDL-C14 and HDL-C. Meta-regression analysis indicated that fructose dose was positively15 correlated with the effect sizes of TC and LDL-C. Subgroup analyses showed that16 isocaloric fructose exchange for carbohydrates could significantly increase TC by17 12.97 mg/dL (95%CI

10、: 4.66, 21.29; P = 0.002) and LDL-C by 11.59 mg/dL (95%CI:18 4.39, 18.78; P = 0.002) at >100g fructose/d but had no effect on TC and LDL-C when19 fructose intake was w 100g/d. In conclusion, very high fructose intake (>100g/d)20 could lead to significantly increase in serum LDL-C and TC. Large

11、r, longer and21 higher-quality human controlled feeding trials are needed to confirm these results.22 Key words: fructose, cholesterol, meta-analysis2324252627282930313233343536373839404142434445精选文库INTRODUCTIONHyperlipidemia is a common risk factor for coronary heart disease (CHD), with 44.4% of ad

12、ults 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 preventi

13、on 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 fr

14、om 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 liv

15、er 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 Dietar

16、y Guidelines for Americans, 2022, 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 triglycerid

17、e-raising effect (9), the threshold dose of fructose at which the adverse influence on cholesterol is controversial.46474849505152535455565758596061626364656667精选文库To determine the effect of fructose on cholesterol, a substantial number of clinical trials have been performed on adult humans with dif

18、ferent 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

19、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 Item

20、s for Systematic Reviews and Meta-analyses (PRISMA) criteria (10).Search strategy. We searched PubMed ( :/ /pubmed; from 1966 to December 2022), Embase ( :/ embase ; from 1966 to December 2022) and the Cochrane Library database ( :/ ) by using the following search terms:

21、fructose and (lipemia or lipaemia or lipids or cholesterol or total cholesterol or LDL cholesterol HDLor cholesterol ) in ,English. We also searched China National Knowledge Infrastructure () and Wangfang database ( wanfangdata ) in Chinese according to the search strategy. The search was restricted

22、 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精选文库68 were obtai

23、ned and reviewed by at least two independent reviewers (T.A., R.C.Z, Q.Z.,69 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 fructo

24、se on blood cholesterol, from both72 randomized 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 contr

25、ol diet with another carbohydrate in place of 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

26、 such comparisons in the meta-analysis.79 Data extraction and quality assessment. Two reviewers (T.A., R.C.Z) independently80 extracted relevant data from eligible studies. Disagreements were resolved by one of81 the two authors (Y.H.Z., J.Z.). These data included information on study features82 (au

27、thor, year of publication, study design, randomization, blinding, sample size,83 comparator, fructose form, dose, follow-up and macronutrient profile of the84 background diet), participant characteristics (gender, age and healthy status) and85 baseline and final concentrations or net changes of tota

28、l 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 groups88 that met inclusion criteria were used in this analysis. Ifblood lipid concentrations89 were measured s

29、everal times at different stages of trials,only final records of lipid精选文库90919293949596979899100101102103104105106107108109110111concentrations 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) (

30、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(MQS>8).Data synth

31、esis. 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 the

32、re 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 cholester

33、ol, 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 w

34、ere calculated. A 2-sidedP 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 means=!SDs cholesterol concentrations atbaselin

35、e and at the end of intervention period (13). SDs were calculated from SEs112113114115116117118119120121122123124125126127128129130131132133精选文库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-analy

36、sis (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

37、 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 Cochrane Qs-test (P < 0.1), and was quantified by the I 2 statistic, where I 2 550% was evidence of substantial heterogeneity.

38、To explore the potential effects of factors on the primary outcomes and investigate the possible sources of heterogeneity, we performed meta-regressions and predefined subgroup analyses stratified by comparator, dose, study duration, randomization, health status, study design and study quality. As f

39、or studies used a range of fructose doses, the average doses calculated on the basis of the average reported energy intake or weight of participants (28.5 calories per kilogram of body weight). Sensitivity analyses were also performed according to the Cochrane Handbook for Systemic Review. Funnel pl

40、ots and Egger'linears regression test were conducted to detectpublication bias.RESULTSBased on our search criteria, 1602 eligible studies were identified, and 1565studies were excluded on review of the titles and abstracts. The remaining 37 studieswere retrieved and fully reviewed. Fifteen of th

41、ese did not meet the inclusion criteria134135136137138139140141142143144145146147148149150151152153154155精选文库and were excluded in the final analysis. A total of 22 studies (providing data for 24 trials) involving 474 subjects (15-36) were included in the meta-analysis (Supplemental Fig. 1, Table 1 )

42、.The reports of Koh and Reiser (22, 23) included two trials (bringing the total number 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 designs (20, 33-36). As for the 19 cross-over trials, 1

43、0 trials have reported the washout period (16, 18, 22, 25, 27-31), 9 trials did not have washout period (15, 17, 19, 21, 23, 24, 26, 32). The trials varied in size, from 8 to131 subjects. The mean age of trial participants ranged from 26.7 to 64.4 years. Seventeen trials (15, 17-23, 25, 27, 28, 30,

44、31,34, 36) were performed in outpatient settings, 3 trials (26, 29, 32) in inpatient settings, and 4 trials in both outpatient and inpatient settings (16, 24, 33, 35). Nine trials were conducted on diabetic subjects (19-21,24-27, 29, 30), 8 trials in healthy subjects (17, 18, 22, 23, 28, 31, 34, 35)

45、, 3 trials in overweight/obese subjects (32, 33, 36), 2 trials in hyperinsulinemic subjects (16,23), 1 trial in those who were impairedglucose-tolerant (22), and 1 trial in subjects with type IV hyperlipoproteinaemia (HLP) (15). Background diets were 42-55% carbohydrate, 25-38% fat, and 13-20% prote

46、in. The carbohydrate comparators choose starch in 13 trials (15, 16, 21,23-25, 27-30, 32, 36), glucose in 6 trials (22, 31, 33-35), sucrose in 3 trials (17, 18, 26), and mixed carbohydrates in two trials (19, 20). Four trials used fructose in crystalline (16, 18, 20, 21), 5 trials in liquid (19, 32-

47、35), and 15 trials in mixed form (15, 17, 22-31). Thereported mean baseline serum TC ranged from 170 to 230.8 mg/dl, LDL-C ranged精选文库156157158159160161162163164165166167168169170171172173174175176177from 90.7 to 157 mg/dl, and HDL-C ranged from 35.1 to 57.1 mg/dl. Nineteen trials reported the fructo

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

49、sed background fructoseW 3%(3.2 to 18g) of total energy in the control groups, but put total fructose into consideration in the fructose group (27, 28, 30-31). Only o ne trial reported less than 20g (4.3 % of total energy) fructose was consumed among basal diet (36).The baselinevalues were not provi

50、ded in 5 trials (19, 22, 23). The median fructose dose in the available trials included in our meta-analysis was 79.25 g/d (range: 30-182 g/d), and the duration varied from 2 to 26 weeks.The quality scores of each study ranged from 6 to 9. Fifteen trials were classified as high quality (MQS > 8),

51、 and 8 trials were of low quality (17, 19, 26, 30, 32-35). Only three trials were blinded, one single-blinded (34) and 2 double-blinded (29, 35). Eight trials (19, 21,24, 26-30) received industry funding. Three studies with four trials (15, 16, 22) did not report any information about financial conf

52、licts of interest. Effect of fructose on cholesterolTotal cholesterol. Twenty-two trials (16-34, 36) reported the value of TC, and the pooled estimate was 2.47 mg/dL (95% CI: -3.04, 7.98; P = 0.38) without statistically heterogeneity (heterogeneity Chi 2 = 28.14, I 2 = 25%, P = 0.14) ( Fig. 1). The

53、residual sources of heterogeneity were investigated by meta-regression models. Univariatemeta-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 coefficient = 0.18; 95% CI:1790.06, 0.31, P = 0.008) (Table

54、 2 ). The dose-response relation between fructose180 consumption and TC largely explained the residual heterogeneity of the effect.181 Subsequently, we stratified fructose dose w 60, >60 to 100, and >100 as moderate,182 high, and very high, respectively, according to Candian Diabetes Associati

55、on 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. Predefined subgroup186 analyses were conducted by st

56、udy characteristicsSupplemental( Table 1 ). Sensitivity187 analyses according to possible correlation coefficients (0.25 and 0.75) and188 systematically removal of each individual trial did not alter the overall analysis and189 analyses stratified by dose.190 LDL cholesterol. The mean change for LDL

57、 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 Chi 2 = 19.85, I 2 = 9%, P = 0.34) ( Fig. 2 ). The residual193 sources of heterogeneity were investigated by meta-regression models. Univariate194 meta-regression showed that the fructose dose was positively related to LDL-C, even195 after adjusted for comparators, study duration and health status(regression coefficient196 = 0.15; 95% CI: 0.03, 0.28, P = 0.02) (Table 2). The dose-response relation between197 fructose consumptio