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The effect of fructose consumption on plasma cholesterol in adults: a meta-analysis of controlled feeding trials1,2,3

Tao 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, China
5 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 http://jn.nutrition.org

RUNNING TITLE: Fructose and cholesterol
WORD COUNT: 5618; NUMBER OF FIGUREA: 3; NUMBER OF TABLES: 2
SUPPLEMENTARY MATERIAL: Online Supporting Materials: 5
AUTHOR LIST FOR INDEXING: An, Zhang, Zhang, Zhou, Huang, Zhang

1 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: Fwzhangjian62@

PROSPERO REGISTRATION NUMBERS: CRD42012003351

ABSTRACT
Fructose 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-analysis

INTRODUCTION
Hyperlipidemia 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 Methods
This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria (10).
Search strategy. We searched PubMed (http://www.ncbi.nlm.nih.gov/pubmed; from 1966 to December 2012), Embase (; from 1966 to December 2012) and the Cochrane Library database (http://www.cochrane.org) 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 (MQS≥8).
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 means±SDs 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 Cochrane’s Q-test (P < 0.1), and was quantified by the I2 statistic, where I2 ≥ 50% was evidence of substantial heterogeneity. 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 for 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 plots and Egger’s linear regression test were conducted to detect publication bias.
RESULTS
Based on our search criteria, 1602 eligible studies were identified, and 1565 studies were excluded on review of the titles and abstracts. The remaining 37 studies were retrieved and fully reviewed. Fifteen of these did not meet the inclusion criteria and were excluded in the final analysis. A total of 22 studies (providing data for 24 trials) involving 4

74 subjects (15-36) were included in the meta-analysis (Supplemental Fig. 1, Table 1).
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, 10 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, 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), 3 trials in overweight/obese subjects (32, 33, 36), 2 trials in hyperinsulinemic subjects (16, 23), 1 trial in those who were impaired glucose-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% protein. 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, 32-35), and 15 trials in mixed form (15, 17, 22-31). The reported mean baseline serum TC ranged from 170 to 230.8 mg/dl, LDL-C ranged from 90.7 to 157 mg/dl, and HDL-C ranged from 35.1 to 57.1 mg/dl. Nineteen trials reported the fructose intake among background diet was not different between the fructose and control groups, in which 15 trials reported the background fructose intake account for ≤ 3% of total energy (9 to 24g) (15-23, 29, 32, 33, 35), while 4 trials did not report the proportion of it (24, 25, 26, 34). Four trials used background fructose ≤ 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 one trial reported less than 20g (4.3 % of total energy) fructose was consumed among basal diet (36). The baseline values were not provided 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), 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 no