Blood pressure lowering effect of lactotripeptides assumed as functional foods: a meta-analysis of current available clinical trials

Abstract

The oral assumption of lactotripeptides Valine–Proline–Proline (VPP) and Isoleucine–Proline–Proline (IPP) as nutraceuticals or functional foods is supposed to improve blood pressure (BP) control by angiotensin-converting enzyme-inhibition. However, data derived from clinical trials have reached conflicting conclusions. To perform a meta-analysis of placebo-controlled clinical trials evaluating the anti-hypertensive effect of lactotripeptides assumed as nutraceuticals or functional foods. Trials identified using a defined search strategy in PubMed were included in the meta-analysis, and their pooled effect was estimated with a random effects model, weighting for the inverse of the variance. Heterogeneity, publication bias, subgroup and meta-regression analyses were performed. A total of 18 trials have been identified, the clinical data of which have been clearly reported. Pooled effect of peptides was a reduction of −3.73 mm Hg (95% CI: −6.70, −1.76) for systolic blood pressure (SBP) and 1.97 mm Hg (95% CI: −3.85, −0.64) for diastolic blood pressure (DBP). The effect was more evident in Asian patients (SBP=−6.93 mm Hg (95% CI: −10.95, −2.94); DBP=−3.98 mm Hg(95% CI: −5.38, −2.44)) than in Caucasian ones (SBP=−1.17 mm Hg (95% CI: −2.82, 0.72); DBP=−0.52 mm Hg (95% CI: −1.39, 0.13)), and apparently not related to age, baseline BP values, dose of lactotripeptides assumed or length of the treatment. VPP and IPP lactotripeptides assumed as functional foods may significantly reduce SBP particularly in Asian subjects. The relevance of this findings in other ethnicities or associated with different dietary pattern should to be further investigated.

Introduction

Despite the availability of many effective and well-tolerated pharmacological treatments, cardiovascular diseases remain the leading cause of death and disability in the developed countries.1

Arterial hypertension is one of the most relevant independent risk factors for cardiovascular diseases and its elevated prevalence is expected to increase all over the world over the next two decades.2 In particular the Framingham data indicate that the lifetime risk of developing hypertension is a staggering 90% and it is estimated that the global burden of hypertension will increase to 1.56 billion afflicted individuals by 2025.2 From a global perspective, suboptimal BP accounts annually for 7.6 million premature deaths and a loss of 92 million disability-adjusted life-years (one disability-adjusted life-year is equivalent to one lost year of healthy life).3 On the other side, recent studies have shown that the maintenance of a normal blood pressure (BP) levels reduces the incidence of cardiovascular complications both in the hypertensive population and in subjects whose BP values are only slightly elevated above the optimal range.4 This would imply the importance of improving BP control in the overall population of subjects. However, as it is not reasonable to actively treat all subjects with suboptimal BP control with anti-hypertensive drugs, the main international guidelines5, 6 stress the preventive impact of an adequate dietary and lifestyle intervention to reach and maintain optimal BP levels.

Beyond the well-known effects on BP of the DASH7 and the Mediterranean diets,8 a recent meta-analysis has suggested that some peptides derived from food proteins may lead to a significant reduction of systolic (−5.13 mm Hg; 95% CI: −7.1/−3.1) and diastolic BP (DBP) (−2.42 mm Hg; 95% CI: −3.8/−1.0).9 In particular, these peptides, that are encrypted within the primary structure of milk proteins and can be released by enzymatic hydrolysis either during gastrointestinal digestion or during food processing, have been reported to exert some angiotensin-converting enzyme inhibitory activity.10 A detailed description of the individual milk proteins displaying in vitro angiotensin-converting enzyme-inhibitory activity is outside the purposes of this review and is reviewed elsewhere.11 However, the best characterized peptides are those found in the fermented milk and bearing the amino-acid sequence isoleucine–proline–proline (IPP) and valine–proline–proline (VPP).

The aim of the present study was to perform a meta-analysis of the available data on the effect of lactotripeptides on BP control in subjects with a wide range of baseline BP levels. We also evaluated the possible interactions between the effects of lactotripeptides and some of the variables influencing BP control in the general population.

Methods

Selection of studies

As part of finding a defined search string in PubMed for relevant clinical trials, literature reviews and selected clinical trials on bioactive peptides derived from food proteins were studied. Several searches of databases and the internet were also carried out, providing an overview of the subject. It was also discovered that some reports have only been published in Japanese. To avoid problems and limitations with the translation of these reports, it was decided to perform this meta-analysis by including only studies published in English. The strategy was to develop a defined search string that would find all relevant clinical trials registered in PubMed. The reference list of the selected trials has been carefully examined to identify any additional study not registered in the PubMed database. The defined search string in PubMed with generated translations of expressions is shown in Figure 1.

Figure 1
figure1

Search string in PubMed with generated translations to find clinical trials on the effect of peptides derived from food proteins on BP.

By 1 January 2010, 26 studies have been listed in the PubMed and 14 of them have been considered relevant according to selection criteria and included in the meta-analysis (Figure 2). Other four trials have been selected after references cross matching. Studies describing data for pre-specified categories of patients (normotensive, high-normal BP and hypertension) have been evaluated as multiple studies and the data have been analyzed as independent trials.

Figure 2
figure2

Selection of randomized placebo-controlled trials for meta-analysis.

Data abstraction

Number, age- and sex-ratio of participants, duration of intervention, baseline systolic (SBP) and DBP, change at end of intervention and daily amount of active component or placebo product were obtained from each trail (Tables 1 and 2 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29). In a trial by Mizuno et al.,22 participants were given different amounts of active product. Only data from the group of participants given the highest amount were abstracted for use in the meta-analysis.

Table 1 Baseline characteristics of clinical trials included for meta-analysis with mean and standard deviation values
Table 2 Daily intervention of bioactive components and duration of clinical trials included for meta-analysis

Statistical analysis

The effect of intervention was estimated with a within subject comparison of the participants' BP at the start and end of trial. Statistically, let Xij be the BP for the intervention group, in which i=1 or 2 that is at start or end of the trial, respectively, and j=1, 2,…, n is the participants with active intervention. The mean effect of intervention is defined as

and for placebo

Estimates of the mean effect of intervention and placebo with standard deviations (s.d.I and s.d.P) were obtained from the studies. For meta-analysis, the trial effect could then be estimated by

with standard error of trial effect given by

Both fixed and random effects models were examined to calculate the mean pooled effect size with confidence intervals.

The pooled relative risk (and 95% confidence interval) was estimated with a random effect model, weighting for the inverse of the variance.30 The heterogeneity among studies was tested by Q statistic and quantified by H statistic and I2 statistic.31 The influence of individual studies, from which the meta-analysis estimates are derived, was examined by omitting one study at a time to see the extent to which inferences depend on a particular study or group of studies (sensitivity analysis).

Publication bias was visually examined after construction of a funnel plot, in which standard error is plotted against net changes in BP. In addition, Egger regression and its corresponding test for publication bias were performed.32 The effect and quality of individual trials were examined by making cumulative and exclusion sensitivity forest plots.33 Meta-regression with trial effects as dependent variable and combined amounts of tripeptides VPP and IPP in trials as independent variable weighted by the inverse variance from the random effect model was performed. The meta-analysis was also repeated dividing the available trials on the basis of the ethnicity of the enrolled patients (Asians vs Europeans), of the age of the patients (divided on the basis of the fifth percentile of the age distribution), of the study duration (divided on the basis of the median of the study duration distribution) and of the baseline BP (normal/high-normal BP vs hypertension).

Statistical calculations for meta-analysis and generation of plots were performed using the MIX software, version 1.54,34 and weighted least square regression for meta-regression was preformed using SPSS 15.0.1 for Windows (Chicago, IL, USA).

Results

Study characteristics

The main characteristics of the trials included in the meta-analysis are summarized in Tables 1, 2, 3 and all of them have been published in international peer-reviewed journals. A total of the enrolled 1691 participants completed the trials. The mean duration of intervention was 6.8±2.5 weeks with a range from 4 to 21 weeks of treatment. The mean lactotripeptide daily dose was 9.4±13.3 mg (median value=21.6 mg). In most of the trials participants were older than 50 years of age (mean age: 52.8±8.6 years), with a higher proportion of males than females.

Table 3 Calculating the effect of trials on the basis of within or between subject comparison of intervention and placebo control treatment

Quantitative analysis

The results of the pooled analysis with respect to SBP and DBP are reported in Figures 3 and 4, respectively. The treatment with lactotripeptides was associated with a significant reduction of both SBP (−3.73 mm Hg (95% CI: −6.70, −1.76), P=0.011) and DBP (−1.97 mm Hg (95% CI: −3.85, −0.64), P=0.038). As expected there was significant heterogeneity between the different studies (SBP: P=0.03; DBP: P=0.04), even whether the Funnel plot analysis did not show a significant asymmetry, thereby excluding a publication bias (SBP: Egger's test P=0.38; DBP: Egger's test: P=0.29). Sensitivity analysis showed that the cumulative estimate of the effect of lactotripeptides on BP did not vary substantially with the exclusion of any one of the studies.

Figure 3
figure3

Standard forest plot from meta-analysis on SBP (heterogeneity: P=0.03, Egger's test: P=0.38). *Data from participants with high-normal BP. **Data from participants with mild hypertension. °Lactotripeptides added with potassium. +Data from participants with normal BP. ++Data from participants with high-normal BP. LD, low dose; MD, medium dose; HD, high dose.

Figure 4
figure4

Standard forest plot from meta-analysis on DBP (heterogeneity: P=0.04, Egger's test: P=0.29). *Data from participants with high-normal BP. **Data from participants with mild hypertension. °Lactotripeptides added with potassium. +Data from participants with normal BP. ++Data from participants with high-normal BP. LD, Low dose; MD, medium dose; HD, high dose.

The meta-regression approach suggested that the ethnicity of the subjects could be a remarkable cause of heterogeneity across the studies. For this reason we have repeated the meta-analysis according to subject ethnicity (Figures 5, 6, 7, 8) and we observed that the effect of lactotripeptides on BP was much more evident in Asian subjects (SBP: −6.93 mm Hg (95% CI: −10.95, −2.94), P<0.001; DBP=−3.98 mm Hg (95% CI: −5.38, −2.44), P=0.009) than in Caucasian population (SBP=−1.17 mm Hg (95% CI: −2.82, 0.72), P=0.07; DBP=−0.52 mm Hg (95% CI: −1.39, 0.13), P=0.06).

Figure 5
figure5

Standard forest plot from meta-analysis on SBP in Asian studies. (Heterogeneity: P=0.03, Egger's test: P=0.42). *Data from participants with high-normal BP. **Data from participants with mild hypertension.

Figure 6
figure6

Standard forest plot from meta-analysis on SBP in European studies. (Heterogeneity: P=0.33, Egger's test: P=0.62). °Lactotripeptides added with potassium. +Data from participants with normal BP. ++Data from participants with high-normal BP. LD, low dose; MD, medium dose; HD, high dose.

Figure 7
figure7

Standard forest plot from meta-analysis on DBP in Asian studies. (Heterogeneity: P=0.14, Egger's test: P=0.48). *Data from participants with high-normal BP. **Data from participants with mild hypertension.

Figure 8
figure8

Standard forest plot from meta-analysis on DBP in European studies. (Heterogeneity: P=0.53, Egger's test: P=0.49). °Lactotripeptides added with potassium. +Data from participants with normal BP. ++Data from participants with high-normal BP. LD, low dose; MD, medium dose; HD, high dose.

As far as the effects of the differences in the amount of IPP and VPP (mg) introduced daily on the extent of BP decrease, the meta-regression analysis did not show any statistically significant dose-dependent effect (5% level). Similarly no significant effect was observed for age, baseline BP and study duration.

Discussion

Our meta-analysis of placebo-controlled studies on the effect of VPP and IPP lactotripeptides shows that they could have a small but significant impact on office SBP and DBP control in untreated subject with a wide range of baseline BP level. The results are in agreement with those of a previous meta-analysis published by Pripp8 testing the hypothesis that bioactive peptides (not only the VPP and IPP) could influence office BP values. In particular, the results of such a cumulative review concluded that bioactive peptides can significantly reduce BP with pooled effects of −5.1 mm Hg (95% CI: −7.1, −3.1) for SBP and −2.4 mm Hg (95% CI: −3.8, −1.0) for DBP values.8 The present data also agree with the results of a second and more specific meta-analysis focused on studies involving the use of milk lactotripeptides and showing an average pooled effect of −4.8 mm Hg (95% CI: −6.0, −3.7) for office SBP and −2.2 mm Hg (95% CI: −3.1, −1.3) for office DBP.35 In the present meta-analysis a significant heterogeneity was found between studies carried out on Asian subjects and those involving the European population. Such a difference in the racial response to lactotripeptides was not described in the meta-analysis published by Pripp,8 that differ from our review as it did not include the results of some large recent trials involving the European population and reporting only a small and non significant effect of lactrotripeptides on BP. The same explanation might account for the discrepancies between our meta-analysis and the data published by Xu et al.35 and supporting a correlation between the BP decrease in response to lactotripeptides and baseline BP values. It is interesting that the actual size of the effect of bioactive peptides on BP might be influenced by the methodology employed for BP measurement, as well as by a differential effect on central BP, relatively to brachial measurement. Some trials have shown that the BP-lowering effect of lactotripeptide could be more evident when considering 24-h ambulatory BP values,21, 29 whereas van Mierlo et al.26 were unable to confirm such observation. Unfortunately, the number and the size of trials that have used this more accurate approach to BP measurement are too small to carry out a separate meta-analysis of data and more information on this topic are warranted for the future. As far as the possibility that the small impact of lactotripeptides on brachial BP may be associated with a significant reduction in central BP, only one recent and non-controlled trial has investigated the effects of such substance on central SBP and augmentation index,36 showing a favourable effect of lactotripeptides on both parameters.

On the other side, the different effect of lactotripeptides in Asians and Caucasians could lead to some other speculations. In particular some recent large trials showed that Japanese subjects have great preventive results from dosages of drugs directly36 or indirectly37 interacting with the renin–angiotensin system that are much lower than those usually active in Caucasians. Thus, the small, even not statistically significant action of lactotripeptides on plasma renin activity could lead to a larger anti-hypertensive activity in Asians. Another possibility to be explored is a different pharmacokinetics of lactotripeptides in Asians, also in the context of a different dietary and nutrigenomic pattern. Finally, and more easily, we were unable to study the relationship between patient body mass index and clinical effect of lactotripeptides, because of lack of data reporting in most of trials: this could give further interesting information on this argument.

As expected the meta-analysis has some important limitations. The main limitation of this meta-analysis is the lack of any qualitative selection of the trials included in the final review of data. Indeed, according with the pre-specified procedure we only excluded from the meta-analysis the non-controlled trials, those not including the complete set of data to be entered in the final database, as well as the preliminary reports of studies published in their final version with a larger sample size (then included in the meta-analysis). However, we are aware that a part of the Japanese study have a weaker methodology than the most recent European ones (for example, insufficient blinding). Another limitation of the study is that the patients enrolled in the different trials were classified as normotensive, border-line and hypertensives on the basis of different guidelines, whereas a comparable categorization of the population was impossible because of the lack of access to individual data. Finally, as most of the studies do not account for the dietary information, it is difficult to estimate any possible effect of the association between lactotripeptide and specific dietary patterns on BP control.

However, this meta-analysis add some relevant data when compared with the two available previous ones.8, 35 As above stated, in fact, both previous meta-analyses did not include data from the most recent and sometimes larger studies carried out on Caucasians. Moreover, the Pripp's meta-analysis was not focused on lactrotripeptides, but on overall bioactive peptides.

Cumulatively, the results of the available studies seem to support a small but significant effect of bioactive peptides (lactotripeptides) on both systolic and DBPBP and this can have important epidemiological and preventive implications in terms of BP control in the general population. Recently, the results of a huge a meta-analysis carried out on 147 randomized clinical trials and involving 464.000 subjects has suggested that a BP reduction of the same size of that observed in the present meta-analysis in response to bioactive peptides would result in a significant reduction of the risk of major cardiovascular events.37 In particular a decrease of 5 mm Hg in SBP or 2.5 mm Hg in DBP might reduce the risk of coronary artery disease by about 12%, whereas the risk of stroke would be reduced by 20%, regardless of the drug used to achieve the effective BP decrease.38 If applied to a large sample of the population as a nutritional approach the use of bioactive peptides (in particular lactotripeptides) could be associated with an overall shift of the individual BP values toward a more physiological distribution and this would result in a remarkable preventive effect in terms of cardiovascular diseases.39, 40

In conclusion, VPP and IPP lactotripeptides assumed as functional foods may lead to significantly reduced SBP, particularly in Asian subjects. The relevance of this findings in other ethnicities or associated with different dietary pattern has to be further investigated.

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Correspondence to A F G Cicero.

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Cicero, A., Gerocarni, B., Laghi, L. et al. Blood pressure lowering effect of lactotripeptides assumed as functional foods: a meta-analysis of current available clinical trials. J Hum Hypertens 25, 425–436 (2011). https://doi.org/10.1038/jhh.2010.85

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Keywords

  • lactotripeptides
  • blood pressure
  • meta-analysis
  • placebo-controlled trials

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