Previous studies have suggested that whey supplementation may have beneficial effects on lipid profiles, although results were inconsistent. A literature search was performed in March 2015 for randomized controlled trials observing the effects of whey protein and its derivatives on circulating levels of triacylglycerol (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C). A meta-analysis was subsequently conducted. The meta-analysis results of 13 trials showed that whey supplementation significantly reduced the circulating TG level by 0.11 mmol/l (95% CI: −0.21, 0 mmol/l), whereas the whey protein had no effects on circulating TC (−0.11 mmol/l, 95% CI: −0.27, 0.05 mmol/l), LDL-C (−0.08 mmol/l, 95% CI: −0.23, 0.07 mmol/l) and HDL-C (0.01 mmol/l, 95% CI: −0.04, 0.05 mmol/l). Subgroup analysis showed that significant TG reduction disappeared in participants with low body mass index, low supplemental whey dose or under exercise training/energy restriction during the trial. No evidence of heterogeneity across studies and publication bias was observed. In conclusion, our findings demonstrated that the effects of whey protein supplementation were modest, with an overall lowering effect on TG but no effect on TC, LDL-C and HDL-C.
Cardiovascular disease (CVD) is one of the major causes of morbidity and mortality worldwide, imposing a large burden on public health systems. The World Health Organization (WHO) reported that 17.3 million individuals (~30% of global death) died from CVD in 2008.1 Hyperlipidemia and hyperlipoproteinemia are established risk factors for the development of CVD; specifically, high level of blood low-density lipoprotein cholesterol (LDL-C) is one of the major risk factors for CVD.2, 3, 4 Thus, CVD can be prevented or even treated through strategies that can beneficially regulate lipid profiles.
Whey, which has traditionally been considered a fairly useless liquid byproduct from the production of cheese, represents a newly emerging class of substances with an enormously wide spectrum of biological activities.5, 6, 7 The health benefits of whey protein and its fractions include immune-enhancing, antioxidative, antihypertensive and lipid-lowering properties. Our previous animal study demonstrated that the whey protein significantly increases plasma high-density lipoprotein cholesterol (HDL-C) and total antioxidative capacity, superoxide dismutase and glutathione in rats fed with a high-fat diet.8 Our previous meta-analysis also indicated that the intake of milk protein-derived tripeptides results in a significant decrease in blood pressure of prehypertensive and hypertensive patients.9 Recently, evidence from a number of clinical studies focused on the beneficial effects of whey proteins on circulating lipids and lipoproteins; however, the existing trials yielded inconsistent results.10, 11, 12, 13, 14, 15 This inconsistency may be attributed to the differences in study design, individual characteristics, protein dose and supplemental duration. Therefore, we conducted a meta-analysis of randomized controlled trials (RCTs) to examine whether the supplementation of whey and whey-related peptides has beneficial effects on lipid metabolism-related markers including triacylglycerol (TG), total cholesterol (TC), LDL-C and HDL-C.
Materials and methods
The preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines were followed as much as possible for this meta-analysis.16 A systematic literature search of the PubMed, Web of Science and Cochrane library up to the end of March 2015 was conducted using the following search terms ‘whey OR milk OR dairy’ in combination with ‘triacylglycerol OR triglyceride OR cholesterol OR lipoprotein OR lipid’. An additional manual search was followed by reference lists of review articles. No restriction was imposed, and authors of the original studies were not contacted for additional information.
Studies were considered and subsequently selected in this meta-analysis if (1) studies were RCTs of whey protein or its derivatives (whey fraction and whey peptides) in adults (age⩾18-year old), (2) participants were treated for over 4 weeks, (3) studies consisted of a control or a comparison group and (4) studies reported the net changes in lipid profiles (serum or plasma TG, TC, LDL-C or HDL-C) and their corresponding standard deviation or data to calculate these values.
Data extraction and quality assessment
According to the described selection criteria, two researchers (J-WZ, XT) extracted the data independently by using an electronic form. Any disagreement was resolved by discussion with the third researcher (L-QQ). The following characteristics were extracted from each selected study: first author’s name, year of publication, study design, sample size, study duration, type of whey protein and corresponding daily dose. A number of participant characteristics were also extracted as follows: gender, mean age, body mass index (BMI), health condition and baseline lipids of each study. The data for blood lipids were converted into the same unit (mmol/l). Study quality was assessed by a modified Jadad scale, in which the total score ranges from 0 to 7 points based on the description of randomization, concealment of allocation, double blinding, withdrawn or dropouts explanation.17 The analysis of intention-to-treat was also recorded as an additional factor for assessing study quality.
Data synthesis and statistical analysis
The difference between the baseline and final values of lipids was calculated as the net changes. Studies with no reported s.d. values had their values imputed from s.e.m., confidence interval (CI) or P-values using a standard formula.18 If only s.d. for the baseline and final values was provided, s.d. for the net changes was assigned based on the Follmann method using a correlation coefficient of 0.5.19
The heterogeneity among the studies was determined using the Q-test at the P<0.10 level of significance and further quantified by the I2 statistic, which describes the inconsistency across studies. In the presence of significant heterogeneity, the random-effects model was used to calculate the pooled effect size; otherwise, the fixed-effects model was applied.20
We further conducted pre-specified subgroup analysis stratified by main characteristics of participants (BMI, baseline LDL-C), supplemental dose and whether or not conducting exercise training or energy restriction during the intervention to assess the impact of these variables on outcomes. Among lipid profiles, baseline LDL-C levels were utilized for subgroup analysis. A sensitivity analysis was also performed where one single trial was omitted each time, and the effect size was recalculated to investigate its influence on the overall effect size. In addition, a meta-regression analysis was conducted to explore possible sources of heterogeneity across studies. A few covariates including BMI, baseline LDL-C and whey dose were critically selected in the analysis to minimize the likelihood of false-positive results. Potential publication bias was assessed using Begg’s funnel plots and Egger’s regression test.21 All analyses were conducted by using STATA version 12.0 (StataCorp, College Station, TX, USA). A P<0.05 was considered statistically significant, except where otherwise specified.
The initial search found a total of 902 records, of which 877 were excluded because they were reviews/letters, animal and cell experiments, observational studies or related to processing technology of dairy. After a full-text review of the remaining 25 potentially relevant articles, 12 articles were further excluded because they used milk and milk constituents rather than whey or its derivatives as the intervention products (five articles), measured acute effects (three articles), did not report lipid data (three articles) or had no appropriate control group (one articles). Finally, thirteen RCTs were selected for our meta-analysis (Figure 1).10, 11, 12, 13, 14, 15, 22, 23, 24, 25, 26, 27, 28
The characteristics of the included trials are presented in Table 1. Trials, published from 2007 to 2014, were conducted in USA (n=4), Germany (n=3), Australia (n=2), Sweden (n=1), Russia (n=1), Iran (n=1) and The Netherlands (n=1). A parallel design was used in all of the trials, and seven were double blinded. Sample sizes varied from 18 to 190, with a total of 390 in the intervention groups and 448 in the control groups. Three trials enrolled men only, and one had no information about gender. Mean ages ranged from 23.7 years to 54.5 years. Eight trials enrolled overweight/obese adults, and the others involved healthy male subjects and patients with metabolic syndrome, hypercholesterolemia, prehypertension, or mild hypertension. Seven trials claimed to exclude participants using lipid-lowering drugs or under-related treatments. The participants in four trials performed exercise training. Energy restriction was conducted before24 or during intervention26 in each trial. These approaches were conducted in both the intervention and control groups. Seven trials claimed no significant difference in energy intake between the intervention and control groups. However, energy intake was higher in the control group than in the intervention group by 20% in the study by Hambre et al.12 Nine trials did not observe the different changes in body weight between two groups. However, one study found an absolute treatment difference of 1.7 kg between two groups.11 Fasting plasma and serum were each used in six studies. The remaining one just indicated as blood sample and did not imply whether or not fasting sample was collected.26 The intervention duration lasted from 4 to 36 weeks, with 8 trials for 12 weeks. Intervention was heterogeneous in these trials. Four trials used the whey protein, whereas others used whey isolates or other whey products for intervention. The supplemental dose varied from 0.7 g to 90 g per day. The trials had relatively low Jadad scores, and the highest score was 5 in one trial. In brief, most trials did not appropriately describe the method of randomization. No trial described the use of allocation concealment method. The analysis of intention-to-treat was performed in four trials.
Net changes in lipid profiles
Figure 2 shows the effects of whey protein and its derivatives on blood lipid profiles. Compared with the control group, whey was associated with an average net change in TG ranging from −0.64 mmol/l to 0 mmol/l, with two trials reaching statistical significance. Although most trials demonstrated a reduction in TC and LDL-C after whey intervention, no studies reached statistical significance. After the meta-analysis, the pooled effect indicated that whey supplementation significantly reduced the circulating TG level (0.11 mmol/l, 95% CI: −0.21, 0; P=0.05). The pooled effect of whey protein on TC, LDL-C and HDL-C was −0.11 mmol/l (95% CI: −0.27, 0.05, P=0.19), −0.08 mmol/l (95% CI: −0.23, 0.07, P=0.29) and 0.01 mmol/l (95% CI: −0.04, 0.05, P=0.93), respectively. No evidence of heterogeneity was observed for these outcomes (P-values ranged from 0.83 to 0.99 and all I2=0%).
Table 2 presents the results of subgroup analyses for circulating TG. A significant reduction in the TG level after whey supplementation was not observed in participants with BMI <30 kg/m2 (−0.05 mmol/l, 95% CI: −0.19, 0.08), or with whey supplementation <30 g/day (−0.11 mmol/l, 95% CI: −0.21, 0.01), or conducting exercise training/energy restriction (−0.06 mmol/l, 95% CI: −0.21, 0.08). The beneficial effect of whey on TG was not observed stratified by the baseline LDL-C level. For circulating TC, LDL-C and HDL-C, no beneficial effects were consistently observed in the subgroup analyses stratified by pre-defined factors (data not shown).
Sensitivity analysis and meta-regression analysis
The sensitivity analysis for TG showed a range from −0.15 mmol/l (−0.29, −0.02; P=0.03) to −0.19 mmol/l (−0.20, 0.02; P=0.09) by omitting one study at each turn. Sensitivity analysis yielded a narrow range for TC ((−0.13 mmol/l (95% CI: −0.30, 0.03; P=0.12) to (−0.08 mmol/l, 95% CI: −0.24, 0.09; P=0.35)), LDL-C ((−0.11 mmol/l, 95% CI: −0.27, 0.05; P=0.17) to (−0.05 mmol/l, 95% CI: −0.21, 0.12; P=0.58)) and HDL-C ((0 mmol/l, 95% CI: −0.05, 0.05; P=0.09) to (−0.01 mmol/l, 95% CI: −0.04, 0.06; P=0.74)). Meta-regression analysis was subsequently conducted to assess whether lipid changes are related to BMI, baseline LDL-C and the whey dose. The results revealed that none of these covariates had significant effects on the pooled effect (data not shown).
Begg’s test suggested no evidence of publication bias for the outcomes (P=0.25, 0.90, 0.89, 0.89). Similarly, Egger’s test did not indicate any evidence of publication bias (P=0.62, 0.30, 0.42, 0.43).
The present study, to the best of our knowledge, is the first meta-analysis examining the effects of whey supplementation on lipid profiles in RCTs. Our results showed that whey protein supplementation reduced the circulating TG level by 0.11 mmol/l but had no effects on TC, LDL-C and HDL-C. In addition, there was no evidence of heterogeneity across studies, and publication bias was not observed.
Comparison of the present results with those in the literature
Recent meta-analyses of RCTs focused on the effects of high-protein diets on biomarkers of obesity. Santesso et al.29 found that higher protein intakes significantly decrease TG and increased HDL-C. However, the effect on HDL-C disappeared after restricting studies with lower risk of bias.29 In our previous meta-analysis of 9 trials among obese type 2 diabetes, high-protein diets borderline significantly reduced TG by 0.17 mmol/l (95% CI −0.36, 0.02).30 Thus, not only protein type (whey protein vs. control) but also the protein amount (high vs. low protein) are critical factors affecting the beneficial effects of whey protein supplementation on the TG level.
Our meta-analysis was in accordance with several intervention studies, which were not included in the present meta-analysis because of the acute study design or the lack of a control group. In overweight and obese postmenopausal women, a single oral dose of 45 g of whey protein isolate significantly reduced postprandial TG after a high-fat meal compared with 45 g of casein or glucose.31 Similarly, 45 g of whey added to a fat-rich meal produced a lower TG response compared with 45 g of casein, cod or gluten protein, respectively, in patients with type 2 diabetes.32 In these two acute trials, no effect of whey protein on TC, LDL-C and HDL-C was observed. In another clinical trial, 11 obese women received 60 g of whey protein supplement daily for 4 weeks. Compared with baseline levels, fasting TG and TC significantly decreased by 15 and 7.4%, respectively.33 Our meta-analysis was also supported by findings from animal studies. In the study by Hamad et al.,34 whey protein isolate or whey protein hydrolysate could significantly reduce high-carbohydrate fat-free diet-induced elevation in hepatic TG in rats. However, the lowering effect of whey on serum TC was not statistically significant.34
Possible underlying mechanisms
Although TG is measured more precisely than cholesterol, circulating TG is influenced by numerous factors such as eating behavior, hepatic and intestinal metabolism for lipids.35 All trials in this meta-analysis, except one,26 indicated that overnight fasting blood samples were used to measure circulating lipids. The TG reduction effects induced by whey supplementation in our findings are biologically plausible. Such effects might be related to the effect of whey protein on the promotion of hepatic lipid metabolism, the inhibition of absorption of fatty acid and cholesterol in the intestine and the increase in excretion of fecal sterols.7 In the meta-analysis by Miller et al.36 with 14 RCTs, whey protein was found to decrease body weight and body fat, which could possibly improve lipid profiles.
The TG reduction effects by whey protein supplementation might also be attributed to the functional components in whey protein. For instance, beta-lactoglobulin accounts for 45–57% of whey protein. As a member of the lipocalin family, it may capture hydrophobic molecules and thus may decrease the intestinal lipid absorption.37 It has also been suggested that sphingolipids, present in whey protein isolates, may block lipid absorption.38 In the study by Duivenvoorden et al.,39 APOE*3Leiden mice were fed a Western-type diet supplemented with different sphingolipids for 9 weeks, in which sphingolipids decreased the absorption of dietary cholesterol and free fatty acids and reduced plasma TG by 58%. In addition, an in vitro study reported that leucine, isoleucine, valine, skim milk, casein and whey may downregulate gene expression related to cholesterol metabolism and lipogenesis, whereas isoleucine and whey also downregulated gene expression involved in fatty acid transport and cholesterol absorption.40 Thus, high contents of branched-chain amino acids in whey protein could also account for the differential effect on TG levels.
Findings in subgroup analysis
In subgroup analysis, significant TG reduction after whey intervention in obese participants was clinically relevant, suggesting that whey intervention was especially efficacious in this group of individuals who mostly need to lower TG. Moreover, our subgroup analysis indicated that the effect of TG reduction disappeared when supplemental whey was less than 30 g/day, suggesting the importance of a certain amount of whey protein to elicit measurable beneficial effects in humans. Weinheimer et al.15 reported that at least 35 g of whey protein per day is necessary to improve metabolic health responses. Although habitual whey intake was not reported, most of these trials considered the balance of habitual diet in the control and intervention groups. In addition, in the subgroup analysis, we found that the TG-lowering effect disappeared when exercise training or energy restriction was applied during the trial. As important approaches for the prevention and treatment of hyperlipidemia, exercise training or energy restriction probably masked the effects of whey protein on lipid profiles. Furthermore, the frequency, intensity and duration of these additional approaches varied considerably. All of these factors could influence lipid profiles regardless of whey supplementation, and interrelated effects might even occur between whey proteins and other lifestyle strategies, including exercise and energy restriction.
Strengths and limitations
In the present study, we increased the sample size using a meta-analysis approach, and consequently the statistical power improved. More reliable results could be concluded based on comprehensive analyses according to multiple study characteristics. In addition, the identification of the current studies from various global regions supported the generalizability of our findings. However, our study also had limitations. First, although no evidence of heterogeneity across studies was observed, the study characteristics varied and may complicate the interpretation of findings. For example, the included RCTs mostly enrolled overweight/obese participants and patients with hypertension, hyperlipidemia or metabolic syndrome. The health status of the body may also influence the effect of whey protein on lipid changes. For the only trial with healthy male, sensitivity analysis showed that whey supplementation had no influence on the pooled effect.11 Second, heterogeneous type of whey and control treatments was another limitation of the present study. Intervention in individual RCTs included whey protein, hydrolyzed whey protein and whey peptides from different food processing methods. Similarly, control diets included baseline diet, placebo, milk and several types of carbohydrates. Each specific component may function differently in terms of the lipid response. Macronutrient contents, especially protein intake, varied between two groups in most trials. This variation may also affect blood lipid profiles rather than whey protein per se.41 Energy intake affects the circulating lipid profile. Except for one trial that described a 20% different energy intake, other studies reported no differences in energy intake between control and intervention groups. Third, the validity of meta-analysis relies on the quality of primary studies. The included trials had relatively low Jadad scores, which ranged from 2 to 5. Although the trials were stated as RCTs, only a few studies described the method of randomization appropriately, and no trial described the use of allocation concealment method. Finally, the lack of baseline lipids in two trials and the whey dose in one trial possibly affected subgroup analysis.
Publication bias is always a concern for meta-analyses. Thus, in this meta-analysis, we carefully followed a well-designed search strategy to minimize the possibility of missing relevant studies. Moreover, both Begg’s test and Egger’s test detected no significant publication bias. Therefore, the potential influence of publication bias was not an issue affecting the results in our present meta-analysis.
Clinical effect of circulating TG reduction by high whey supplementation
A meta-analysis in the 1990s showed that circulating TG levels are inversely associated with the risk of CVDs, even after adjustment for the HDL-C level.42 Although randomized trials showing cardiovascular benefits of TG reduction are still lacking, new triglyceride-lowering drugs are being developed. For example, meta-regression in large controlled trials demonstrated that fibrates can lead to ~54% (95% CI: 5–78%) reduction in major CVD events per 1 mmol/l TG reduction.35 Thus, 0.11 mmol/l TG reduction by whey might not be clinically important. Exploring whether whey supplementation possibly potentiates the effects of other lipid-lowering drugs on TG reduction may be necessary.
Our findings demonstrated the modestly favorable effects of whey protein supplementation on circulating TG levels. No effects of whey protein on TC, LDL-C and HDL-C levels were found. Considering the limited studies and possible heterogeneity of trials, additional well-designed RCTs are needed to further clarify the effect of supplemental whey protein on TC and lipoprotein cholesterol.
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This study was funded by Yili Innovation Center, Inner Mongolia Yili Industrial Group Co., Ltd.
L-QQ and IMYS designed the study; L-QQ developed search strategies and drafted the manuscript; J-WZ and XT completed the literature search and data extraction. ZW, YW and IMYS critically reviewed the manuscript and contributed to the discussion. All authors assisted in the interpretation of the analyses and the revision of the manuscript.
The funder had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
L-QQ received grant support from Yili Innovation Center, Inner Mongolia Yili Industrial Group Co., Ltd., to conduct the review. YW and IMYS are employees of Inner Mongolia Yili Industrial Group Co., Ltd. The remaining authors declare no conflict of interest.
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Zhang, JW., Tong, X., Wan, Z. et al. Effect of whey protein on blood lipid profiles: a meta-analysis of randomized controlled trials. Eur J Clin Nutr 70, 879–885 (2016). https://doi.org/10.1038/ejcn.2016.39
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