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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, China5Tao 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: 2 SUPPLEMENTARY 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. Zhanghave no conflicts of interest.* To whom correspondence should be addressed. Mailing address: Heart FailureCenter, 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: CRD1ABSTRACT2Fructose is widely used as a sweetener in production of many foods, yet the relation 3between fructose intake and cholesterol remains uncertain. We performed a systematic 4review and meta-analysis of human controlled feeding trials of isocaloric fructose 5exchange for other carbohydrates to quantify the effects of fructose on total 6cholesterol (TC), LDL cholesterol (LDL-C), and HDL cholesterol (HDL-C) in adult 7humans. Weighted mean differences were calculated for changes from baseline 8cholesterol concentrations by using generic inverse variance random-effects models. 9The Heyland Methodological Quality was used to assess study quality. Subgroup 10analyses and meta-regression were conducted to explore possible influence of study 11characteristics. Twenty-four trials (with a total of 474 subjects) were included in our 12meta-analysis. In an overall pooled estimate, fructose exerted no effect on TC, LDL-C 13and HDL-C. Meta-regression analysis indicated that fructose dose was positively 14correlated with the effect sizes of TC and LDL-C. Subgroup analyses showed that 15isocaloric fructose exchange for carbohydrates could significantly increase TC by 1612.97 mg/dL (95%CI: 4.66, 21.29; P = 0.002) and LDL-C by 11.59 mg/dL (95%CI: 174.39, 18.78; P = 0.002) at >100g fructose/d but had no effect on TC and LDL-C when 18fructose intake was ≤100g/d. In conclusion, very high fructose intake (>100g/d) 19could lead to significantly increase in serum LDL-C and TC. Larger, longer and 20higher-quality human controlled feeding trials are needed to confirm these results.21Key words: fructose, cholesterol, meta-analysis2223INTRODUCTION24Hyperlipidemia is a common risk factor for coronary heart disease (CHD), with 2544.4% of adults in the United States having abnormal TC values and 32% having 26elevated LDL-C levels (1). Compared to subjects with normal blood lipid, those with 27hyperlipidemia have a 3-fold risk of heart attacks (2). Lifestyle modification should be 28initiated in conjunction both primary and secondary prevention of CHD. More 29consideration exists as to what constitutes healthy eating.30Fructose is the most naturally occurring monosaccharide, and has become a major 31constituent of our modern diet. Fruit, vegetables, and other natural sources provide 32nearly one-third of dietary fructose, and two-thirds come from beverages and foods in 33the diets (eg, candies, jam, syrups, etc) (3). Fructose is preferred by many people, 34especially those with diabetes mellitus because of its low glycemic index (23% versus 35glucose 100%) (4). After intestinal uptake, fructose is mainly removed from the blood 36stream by the liver in an insulin-independent manner, and is used for intrahepatic 37production of glucose, fatty acids or lactate. Cross-sectional studies in human suggest 38that excessive fructose consumption can lead to adverse metabolic effects, such as 39dyslipidemia and increased visceral adiposity (5-7). The Dietary Guidelines for 40Americans, 2010, point out that it is lack of sufficient evidence to set a tolerable upper 41intake of carbohydrates for adults (8). Although The Candian Diabetes Association 42suggests consumption of no more than 60g of added fructose per day by people with 43diabetes for its triglyceride-raising effect (9), the threshold dose of fructose at which 44the adverse influence on cholesterol is controversial.45To determine the effect of fructose on cholesterol, a substantial number of clinical 46trials have been performed on adult humans with different health status (diabetic, 47obese, overweight, hyperinsulinemic, impaired glucose-tolerant and healthy). These 48trials used various intake levels of fructose and different protocols. Thus, it is difficult 49to reach a consistent conclusion across these studies. Therefore, we conducted a 50systematic review of the scientific literature and meta-analysis of controlled feeding 51trials to evaluate the effect of isocaloric oral fructose exchange for carbohydrates on 52cholesterol and to clarify the active factors of fructose.53Materials and Methods54This meta-analysis followed the Preferred Reporting Items for Systematic Reviews 55and Meta-analyses (PRISMA) criteria (10).56Search strategy.We searched PubMed (/pubmed; from 1966 to 57December 2012), Embase (.embase.; from 1966 to December 2012) and the Cochrane 58Library database () by using the following search terms: fructose and 59(lipemia or lipaemia or lipids or cholesterol or “total cholesterol”or “LDL 60cholesterol” or “HDL cholesterol”) in English. We also searched China National 61Knowledge Infrastructure () and Wangfang database () in 62Chinese according to the search strategy. The search was restricted to reports of trials 63on humans.64Study selection.All clinical trials using fructose and indexed within the above 65databases were collected. Two independent reviewers (T.A., R.C.Z) screened the 66abstracts and titles for initial inclusion. If this was not sufficient, full texts articles 67were obtained and reviewed by at least two independent reviewers (T.A., R.C.Z, Q.Z., 68Y.H.). The reference lists of retrieved articles also used to supplement the database.69Any disagreements were resolved through discussion. We included controlled feeding 70trials investigating the chronic effect of fructose on blood cholesterol, from both 71randomized and nonrandomized studies, if they met the following criteria: subjects 72must have been administered fructose for at least 2 weeks; studies investigated the 73effect of oral free (unbound, monosaccharide) fructose when compared with isocaloric 74control diet with another carbohydrate in place of fructose; studies were performed in 75human adults with either a parallel or crossover design; subjects in both experimental 76groups and control groups were instructed to consume isocaloric diets. If the study 77reported any comparisons, we included all such comparisons in the meta-analysis.78Data extraction and quality assessment.Two reviewers (T.A., R.C.Z) independently 79extracted relevant data from eligible studies. Disagreements were resolved by one of 80the two authors (Y.H.Z., J.Z.). These data included information on study features 81(author, year of publication, study design, randomization, blinding, sample size, 82comparator, fructose form, dose, follow-up and macronutrient profile of the 83background diet), participant characteristics (gender, age and healthy status) and 84baseline and final concentrations or net changes of total cholesterol, LDL-C and 85HDL-C. Data initially extracted were converted to system international unit (eg, TC: 1 86mmol/L converted to 38.6 mg/dL). For multi-arm studies, only intervention groups 87that met inclusion criteria were used in this analysis. If blood lipid concentrations 88were measured several times at different stages of trials, only final records of lipid 89concentrations at the end of the trials were extracted for this meta-analysis.90The quality of each study was assessed with the Heyland Methodological Quality 91Score (MQS) (11), generalized as follows: randomization; analysis; blinding; patient 92selection; comparability of groups at baseline; extent of follow up; treatment protocol;93co-intervention; outcomes. The highest score for each area was two points. Higher 94numbers represented a better quality (MQS≥8).95Data synthesis.Statistical analyses were performed with Stata software (version 11.0;96StataCorporation, TX, USA) and REVMAN software (version 5.2; Cochrane 97Collaboration, Oxford, United Kingdom). Separate pooled analyses were conducted 98by using the generic inverse variance random-effects models even where there was no 99evidence of between-study heterogeneity because these models give more 100conservative summary effect estimates in the presence of undetected residual 101heterogeneity than fixed-effects models. The different changes from baseline between 102fructose and carbohydrate comparators for total cholesterol, LDL cholesterol and 103HDL cholesterol were used to estimate the principle effect. We applied paired 104analyses to all crossover trials according to the methods of Elbourne and colleagues 105(12). Weighted mean differences of fructose consumption on cholesterol 106concentrations and corresponding 95% CIs were calculated. A 2-sided P value <0.05 107was set as the level of significance for an effect. The variances for net changes in 108serum cholesterol were only reported directly in two trials (29, 31). We calculate net 109changes for other studies by using the means±SDs cholesterol concentrations at 110baseline and at the end of intervention period (13). SDs were calculated from SEs 111when they were not directly given. If these data were unavailable, we extrapolated 112missing SDs by borrowing SDs derived from other trials in this meta-analysis (14). In 113addition, we assumed a conservative degree of correlation of 0.5 to impute the 114change-from-baseline SDs, with sensitivity analyses performed across a range of 115possible correlation coefficients (0.25 and 0.75) (13). For crossover trials in which 116only final measurements were included, the differences in mean final measurements 117were assumed on average to be the same as the differences in mean change scores 118(13). Inter-study heterogeneity was tested by the Cochrane’s Q-test (P < 0.1), and was 119quantified by the I2statistic, where I2 ≥ 50% was evidence of substantial heterogeneity. 120To explore the potential effects of factors on the primary outcomes and investigate the 121possible sources of heterogeneity, we performed meta-regressions and predefined 122subgroup analyses stratified by comparator, dose, study duration, randomization, 123health status, study design and study quality. As for studies used a range of fructose 124doses, the average doses calculated on the basis of the average reported energy intake 125or weight of participants (28.5 calories per kilogram of body weight). Sensitivity 126analyses were also performed according to the Cochrane Handbook for Systemic 127Review. Funnel plots and Egger’s linear regression test were conducted to detect 128publication bias.129RESULTS130Based on our search criteria, 1602 eligible studies were identified, and 1565 131studies were excluded on review of the titles and abstracts. The remaining 37 studies 132were retrieved and fully reviewed. Fifteen of these did not meet the inclusion criteria 133and were excluded in the final analysis. A total of 22 studies (providing data for 24 134trials) involving 474 subjects (15-36) were included in the meta-analysis 135(Supplemental Fig. 1, Table 1).136The reports of Koh and Reiser (22, 23) included two trials (bringing the total 137number of trials to 24). Eleven trials were randomized (17, 18, 20, 21, 25, 27-29, 31, 13834, 36). Nineteen trials used crossover (15-19, 21-32), and five used parallel designs 139(20, 33-36). As for the 19 cross-over trials, 10 trials have reported the washout period 140(16, 18, 22, 25, 27-31), 9 trials did not have washout period (15, 17, 19, 21, 23, 24, 26, 14132). The trials varied in size, from 8 to131 subjects. The mean age of trial participants 142ranged from 26.7 to 64.4 years. Seventeen trials (15, 17-23, 25, 27, 28, 30, 31, 34, 36) 143were performed in outpatient settings, 3 trials (26, 29, 32) in inpatient settings, and 4 144trials in both outpatient and inpatient settings (16, 24, 33, 35). Nine trials were 145conducted on diabetic subjects (19-21, 24-27, 29, 30), 8 trials in healthy subjects (17, 14618, 22, 23, 28, 31, 34, 35), 3 trials in overweight/obese subjects (32, 33, 36), 2 trials in 147hyperinsulinemic subjects (16, 23), 1 trial in those who were impaired 148glucose-tolerant (22), and 1 trial in subjects with type IV hyperlipoproteinaemia (HLP) 149(15). Background diets were 42-55% carbohydrate, 25-38% fat, and 13-20% protein. 150The carbohydrate comparators choose starch in 13 trials (15, 16, 21, 23-25, 27-30, 32, 15136), glucose in 6 trials (22, 31, 33-35), sucrose in 3 trials (17, 18, 26), and mixed 152carbohydrates in two trials (19, 20). Four trials used fructose in crystalline (16, 18, 20, 15321), 5 trials in liquid (19, 32-35), and 15 trials in mixed form (15, 17, 22-31). The 154reported mean baseline serum TC ranged from 170 to 230.8 mg/dl, LDL-C ranged 155from 90.7 to 157 mg/dl, and HDL-C ranged from 35.1 to 57.1 mg/dl. Nineteen trials 156reported the fructose intake among background diet was not different between the 157fructose and control groups, in which 15 trials reported the background fructose intake 158account for ≤3% of total energy (9 to 24g) (15-23, 29, 32, 33, 35), while 4 trials did 159not report the proportion of it (24, 25, 26, 34). Four trials used background fructose ≤3% 160(3.2 to 18g) of total energy in the control groups, but put total fructose into 161consideration in the fructose group (27, 28, 30-31). Only o ne trial reported less than 16220g (4.3 % of total energy) fructose was consumed among basal diet (36). The baseline 163values were not provided in 5 trials (19, 22, 23). The median fructose dose in the 164available trials included in our meta-analysis was 79.25 g/d (range: 30-182 g/d), and 165the duration varied from 2 to 26 weeks.166The quality scores of each study ranged from 6 to 9. Fifteen trials were classified 167as high quality (MQS≥8),and 8 trials were of low quality (17, 19, 26, 30, 32-35). 168Only three trials were blinded, one single-blinded (34) and 2 double-blinded (29, 35). 169Eight trials (19, 21, 24, 26-30) received industry funding. Three studies with four 170trials (15, 16, 22) did not report any information about financial conflicts of interest. 171Effect of fructose on cholesterol172Total cholesterol.Twenty-two trials (16-34, 36) reported the value of TC, and the 173pooled estimate was 2.47 mg/dL (95% CI: -3.04, 7.98; P = 0.38) without statistically 174heterogeneity (heterogeneity Chi2 = 28.14, I2= 25%, P = 0.14) (Fig. 1). The residual 175sources of heterogeneity were investigated by meta-regression models. Univariate 176meta-regression showed that the fructose dose was positively related to TC, even after 177adjusted for study duration and health status(regression coefficient = 0.18; 95% CI: 1780.06, 0.31, P = 0.008)(Table 2). The dose-response relation between fructose 179consumption and TC largely explained the residual heterogeneity of the effect. 180Subsequently, we stratified fructose dose ≤60, >60 to 100, and >100 as moderate, 181high, and very high, respectively, according to Candian Diabetes Association and 182reference ranges for fructose (9, 37, 38). Fructose could significantly increase TC by 18312.97 mg/dL (95%CI: 4.66, 21.29; P= 0.002) when fructose intakes were >100g/d 184but had no effect on TC if fructose was given lower than 100g. Predefined subgroup 185analyses were conducted by study characteristics (Supplemental Table 1). Sensitivity 186analyses according to possible correlation coefficients (0.25 and 0.75) and 187systematically removal of each individual trial did not alter the overall analysis and 188analyses stratified by dose.189LDL cholesterol.The mean change for LDL cholesterol in nineteen trials (15, 16, 18, 19020, 22, 23, 25-35) was 3.76 mg/dL (95% CI: -1.07, 8.6; P = 0.13) without statistically 191heterogeneity (heterogeneity Chi2 = 19.85, I2= 9%, P = 0.34) (Fig. 2). The residual 192sources of heterogeneity were investigated by meta-regression models. Univariate 193meta-regression showed that the fructose dose was positively related to LDL-C, even 194after adjusted for comparators, study duration and health status(regression coefficient 195= 0.15; 95% CI: 0.03, 0.28, P = 0.02)(Table 2). The dose-response relation between 196fructose consumption and LDL-C largely explained the residual heterogeneity of the 197effect. We stratified fructose dose according to CDA and reference ranges for fructose 198(9, 37, 38). Fructose intake >100g/d could significantly increase LDL-C by 11.59 199mg/dL (95%CI: 4.39, 18.78; P= 0.002). Predefined subgroup analyses were 200conducted by other study characteristics (Supplemental Table 1). Sensitivity analyses 201across possible correlation coefficients (0.25 and 0.75) did not alter the overall 202analysis and analyses stratified by dose. The removal of Cybulska et al resulted in a 203significant LDL-C-raising effect in the overall analysis (P = 0.03).204HDL cholesterol.The result of HDL cholesterol was calculated based on 24 trials 205(15-36), the mean difference was -0.56 mg/dL (95% CI: -2.05, 0.93; P = 0.46) without 206heterogeneity (heterogeneity Chi2 = 21.85, I2= 0%, P= 0.53) (Fig. 3). 207Meta-regression analysis did not show significant effect modifier of HDL-C. 208Predefined subgroup analyses were conducted by study characteristics (Supplemental 209Table 1). Sensitivity analyses according to possible correlation coefficients (0.25 and 2100.75) and systematically removal of each individual trial did not alter the overall 211analysis.212Publication bias213Funnel plots and Egger’s test indicated no significant publication bi as in the 214meta-analyses of TC, LDL cholesterol, and HDL cholesterol (TC Egger’s test: P= 2150.881; LDL cholesterol Egger’s test: P= 0.815; HDL cholesterol Egger’s test: P= 2160.484) (Supplemental Figs. 2-4).217DISCUSSION218This meta-analysis of 24 controlled feeding trials with 477 subjects found no 219effect on TC, LDL-C and HDL-C when fructose was substituted for other 220carbohydrates. Residual heterogeneity was detected by meta-regression for this 221outcome that fructose dose was positively correlated with the effect sizes of TC and 222LDL-C.223The present meta-analysis is consistent with a prospective 2-year trial on chronic 224effect of fructose from Turku sugar studies XI, which did not report any change in 225cholesterol for those individuals who consumed more than 100g fructose/d (39). 226Aeberli et al reported another prospective, randomized, 3-week controlled crossover 227trial in which healthy young men were fed 80 g/d free fructose, and found a 228significant atherogenic LDL subclass distribution (40). However, there was an average 229of 34g combined fructose consumed among basal foods in this study, which meant 230subjects consumed fructose over 110g/d. The median dose of fructose available in our 231meta-analysis was ≈79.25 g/d, it was higher than 90th percentile (78 g/d) and lower 232than 95th percentile (87 g/d) in the United States, reported by the National and Health 233and Nutrition Examination Survey III (41). As for subjects with diabetic mellitus, 234Sievenpiper et al did not report cholesterol-raising effect if the fructose dose was >60 235g/d (median: 97.5 g/d) in their meta-analysis (42). The result of our study and 236intervention trials may be supported the idea that fructose did not increase cholesterol 237for the subjects with generalizable levels of exposure.238The results of subgroup analyses showed that the effects of fructose intake on TC 239and LDL-C were significant as the fructose dose > 100g/d. An intake of 100g/d is 240approximately equal to 400kcal/d or 20% of energy intake for a sedentary person with 241an energy requirement of 2000 kcal/d. The doses for cholesterol-raising effect account 242for less than 10 percent of intake in males and females aged 19 to 22 years, the group 243with the highest level of exposure in the United States (41). Another study found that 244the upper quintile of Americans consume more than 110g fructose daily as added 245sugar or as high-fructose corn syrup (43). Although a small number of people 246consume fructose at very high dose, it is necessary to advise them to change their 247lifestyle.248The dose-dependent effect on triglyceride was also reported in a recent 249meta-analysis that concluded the same dose threshold of 100g/d for a 250triglyceride-increasing effect of fructose on fasting triglyceride level in adult humans 251(38). For healthy subjects who consumed 150g of fructose/day, endogenous 252cholesterol synthesis and the fat content of viscera and liver have been shown to 253increase (44). All evidences have proved that fructose is proposed to have adverse 254effects at very high or excessive doses. The mechanism of the cholesterol increase by 255fructose might be due to increased levels of advanced glycation end products, which 256cause damage to LDL and make it poorly recognized by lipoprotein receptors and 257scavenger receptors (45). Furthermore, excess exposure to fructose can damage the 258function of adipocytes and may reduce the recycling of cholesterol extracted from 259serum LDL. Studies have shown that elevated uric acid might contribute to LDL-C 260increases, and this effect can be reduced by allopurinol (46).261Based on the composition of added sugars in the United States where the fructose: 262glucose ratio is close to 0.43, and the NHANES 1999–2004 estimates (41), the 263increase of fructose consumption is always accompanied with an increase in total 264energy intake. Persons consuming >100g/d of sugars are potentially eating in excess 265of their energy requirement (47), and then overweight and obesity could result. So we 266can not suggest that it is safe to only limit fructose to <100g/d in coronary heart 267disease management and prevention. It may need to take into account the other 268components of foods that accompany the fructose. This dose threshold effects on TG 269and LDL-C can only help better inform nutritional guidance and avoid inappropriate 270marketing of carbohydrates.271Our meta-analysis did not show significant effect of fructose on HDL-C. 272However, Perez-Pozo et al (46) reported a significant HDL-C-lowing effect in 74 273adult men fed with 200g fructose/d in a randomized, 2-week crossover trial, 274suggesting that excessive fructose dose intake can also affect HDL-C. Further trials 275are needed to find the threshold of fructose on HDL-C.276There are several limitations to our work. First, many trials had a relatively small 277sample size, and most of them were funded by industry which can affect the quality of 278studies. Second, the change of fructose in the background diet can affect the practical 279utility of the outcomes of meta-analyses. However, most of trials used the background 280diet with ≤ 3% of total energy derived from fructose (15-23, 27-33, 35), others trials 281did not report the proportion of fructose in the background (24, 25, 26, 34). It was 282hard to make sure the dose of background fructose in every trial. Third, the data 283provided by Reiser et al (23) must be interpreted with caution. Although this study 284met all of our inclusion criteria, they choose a low P:S (polyunsaturated : saturated) 285rate of the fat as the background diet, which might change the metabolism of fructose 286as diets high in saturated fatty acids can enhance intestinal fructose absorption (48). 287Fourth, some of included trials lack test statistics, baseline values and SDs. We 288overcame these problems according to the methods proposed by Cochrane Handbook 289for Systematic Reviews of Interventions. Finally, it is difficult to differentiate effects of 290other modifiers, such as exercise and age, from those included trials. These factors can 291also influence the final result. Fructose can indeed be metabolized during exercise, 292and the rate of metabolism is different between exercise and sedentary lifestyle. Most 293of participants were requested to follow a designed regiment at home, but it is not 294easy to maintain the activity intensity. On the plus size, the age of participants in our 295meta-analysis ranged from 18 to 72 years old. Evidence from animal experiments 296shows that fructose absorption may affected by age, as older rats showed decreased 297fructose absorption (49). However, no human trial has been done to assess the 298difference in fructose effect among different age groups. Therefore, further studies 299should attempt to limit or isolate the degree of heterogeneity present in the study 300population to better assess the effect of age.301In conclusion, our meta-analysis shows that fructose used as a sweetener in 302isocaloric exchange for other carbohydrates has significant increasing effects on TC 303and LDL-C in individuals with very high fructose (>100g). This effect seems not to be 304dose-dependent when fructose is given at moderate or high dose of fructose (<100g). 305Further studies should concentrate on larger, longer and higher-quality human 306controlled feeding trials, which provide a better assessment of the effect of fructose on 307cholesterol.308Acknowledgements309Tao An, Rong Cheng Zhang and Jian Zhang designed the research; Tao An, Rong 310Cheng Zhang, Yu Hui Zhang and Jian Zhang preformed the research; Tao An and 311Rong Cheng Zhang summarized the data and had primary responsibility for the 312accuracy of the analysis; Rong Cheng Zhang wrote the manuscript. All the authors 313had full access to the data. None of the authors declared a conflict of interest.314。