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Effect of peptides derived from food proteins on blood pressure: a meta-analysis of randomized controlled trials

Effect of peptides derived from food proteins on blood pressure: a meta-analysis of randomized... Background: In clinical trials, peptides derived from food proteins have shown an effect on blood pressure. This biological mechanism is mainly due to inhibition of angiotensin-I-converting enzyme (ACE), thereby regulating blood pressure through the renin-angiotensin system. A meta-analysis of these trials is needed to better quantify their effect, sources of variation, and possible publication bias. Objective: To perform a meta-analysis of placebo-controlled clinical trials on peptides derived from food proteins and their effect on blood pressure. Design: 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. Results: Pooled effect of peptides was 5.13 mmHg (95% CI: 7.12, 3.14) for systolic blood pressure, and 2.42 mmHg (95% CI: 3.82, 1.03) for diastolic blood pressure. There were indications of publi- cation bias for diastolic blood pressure data. Conclusions: Peptides derived from food proteins may lead to significantly reduced blood pressure and could therefore be a supplement or alternative to pharmaceutical treatment for mild hypertension. Their effect seems more pronounced, or at least comparable, to that of other food components studied by randomized controlled trials. A high proportion of the reported trials was carried out using the well-known ACE inhibiting tripeptides  Valine-Proline-Proline (VPP) and Isoleucine-Proline-Proline (IPP). Keywords: angiotensin-I-converting enzyme (ACE); clinical trials; hypertension Received: March 19, 2007; Revised: September 28 2007; Accepted: October 20, 2007 igh blood pressure, which is estimated to affect extensive randomized, blinded and placebo-controlled one-third of the Western population, is an clinical trials are needed to scientifically support claimed important risk factor for coronary heart disease, effects. Therefore, it is important to systematically stroke and renal disease (1). Lifestyle modifications, summarize the findings from such clinical trials on including weight loss, quitting smoking, reducing sodium antihypertensive bioactive peptides derived from foods. and alcohol intake, increasing physical activity and Meta-analysis has been defined as ‘the statistical analysis of a large collection of analysis results from changing diet, are recommended for both treatment and individual studies for the purpose of integrating the prevention (2). Besides the recommendation of general lifestyle changes, efforts have been made to produce finding’ (5). It goes beyond an expert literature review functional foods that contain components  nutraceuti- where the results from various studies are discussed and cals  which have a blood pressure reducing effect, and compared, since it synthesizes the results of the individual could be a supplement or alternative to the pharmaceu- studies into a new, pooled, result using statistical tical treatment of hypertension. Bioactive peptides with methodology (6). This enhances the precision of the angiotensin-I-converting enzyme (ACE) inhibitory and estimates of treatment effects, thereby leading to im- antihypertensive effects have been the focus of special provement in clinical strategies (7). Even though the attention. They have been isolated from several food number of expert literature reviews on antihypertensive sources, biochemically characterized, and currently, some peptides from food sources is extensive, to my knowledge commercial food products with clinically proven effects a meta-analysis of placebo-controlled clinical trials has are used (3). Specifically, milk and dairy products have not been performed. A meta-analysis would contribute to been shown to have good effects (4). Results from an improved understanding of the effectiveness of pep- Food & Nutrition Research 2008. # 2008 Are Hugo Pripp. This is an Open Access article distributed under the terms of the Creative Commons Attribution- 1 Noncommercial 3.0 Unpor ted License (http://creativecommons.org/licenses/by-nc/3.0/), permiting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. DOI: 10.3402/fnr.v52i0.1641 Are Hugo Pripp tides in hypertension and whether these could be a Box 1: Search string in PubMed with generated translations feasible supplement to pharmaceutical treatment. The to find clinical trials on effect of peptides derived from food possible presence of publication bias in these trials was proteins on blood pressure also investigated. Search string in PubMed Methods (blood pressure OR hypertension) AND Selection of studies (clinical trial[ptyp] OR randomized controlled trial[ptyp] As part of finding a defined search string in PubMed for OR clinical trial, phase I[ptyp] OR clinical trial, phase II[ptyp] relevant clinical trails, literature reviews and selected OR clinical trial, phase III[ptyp] OR controlled clinical trial[ptyp] clinical trials on bioactive peptides derived from food OR placebo) proteins were studied. Several searches of databases and AND the Internet were also carried out, providing an overview (beverages OR food OR milk proteins OR vegetables of the subject. It was also discovered that some reports OR meat OR fishes) have only been published in Japanese. To avoid problems AND and limitations with the translation of these reports, it (peptides OR ferment* OR sour OR hydrol*) was decided to perform this meta-analysis solely on trials published in English. The strategy was to develop a Expression Translations in PubMed defined search string that would find all relevant clinical Blood pressure ‘‘blood pressure’’[MeSH Terms] OR trials registered in PubMed. The literature reference list (‘‘blood pressure determination’’[TIAB] of the selected trials would then be carefully examined to NOT Medline[SB]) OR ‘‘blood pressure identify any supplementary trials not registered in determination’’[MeSH Terms] OR blood PubMed. The defined search string in PubMed with pressure[Text Word] generated translations of expressions is shown in Box 1. Hypertension ‘‘hypertension’’[MeSH Terms] By 1 July 2007 it gave 227 hits of which 13 trials were OR hypertension[Text Word] found relevant for further examination by meta-analysis. Placebo (‘‘placebos’’[TIAB] NOT Medline[SB]) By examining the literature reference list in those trials, OR ‘‘placebos’’[MeSH Terms] two additional trials were included for meta-analysis OR placebo[Text Word] (Fig. 1). Aihara et al. (8) and Mizuno et al. (9) performed Beverages ‘‘beverages’’[MeSH Terms] separate studies on patients with high-normal blood OR beverages[Text Word] pressure and mild hypertension. Therefore, it was decided Food ‘‘food’’[MeSH Terms] OR food[Text Word] to extract those separate data as independent trials. Milk Proteins ‘‘milk proteins’’[MeSH Terms] OR milk proteins[Text Word] Data abstraction Vegetables ‘‘vegetables’’[MeSH Terms] Number, age and sex-ratio of participants, duration of OR Vegetables[Text Word] intervention, baseline systolic (SBP) and diastolic blood Meat ‘‘meat’’[MeSH Terms] OR meat[Text Word] pressure (DBP), change at end of intervention and daily Fishes ‘‘fishes’’[MeSH Terms] OR fishes[Text Word] amount of active component or placebo product were Peptides ‘‘peptides’’[MeSH Terms] obtained from each trail (Tables 1 [1022] and 2). In a OR peptides[Text Word] trial by Mizuno et al. (9), participants were given different amounts of active product. Only data from the group of participants given the highest amount were i1 or 2 which is at start or end of trial, respectively, and abstracted for use in the meta-analysis. j1, 2,..., m is the participants with placebo control. For within subject comparison, the mean effect of Statistical analysis intervention is defined as The effect of intervention or placebo was not estimated n n identically in the trials. This effect was estimated either X X 1 1 I I  (X  X)(1) with a within or between subject comparison of the j 2j 1j n n j1 j1 participants’ blood pressure at the start and end of trial (Table 3). Statistically, let X be the blood pressure for the ij and for placebo intervention group, where i1 or 2 which is at start or end of trial, respectively, and j1, 2,..., n is the m m X X 1 1 participants with active intervention. Further, let Y be P P  (Y  Y ): (2) ij j 2j 1j m m j1 j1 the blood pressure for the placebo control group, where 2 Effect of peptides on hyper tension ¯ ¯ I P (5) Search string in PubMed (Box 1) gave by 1 July with standard error of trial effect given by 2007: n = 227 publications sffiffiffiffiffiffiffiffiffiffiffiffi sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi 2 2 1 1 (n  1)SD  (m  1)SD I P : (6) Studies not addressing effect n m (n  m 2) on blood pressure of food Both fixed and random effects models were examined to protein derived peptides in calculate the mean pooled effect size with confidence humans (n = 211) intervals. The homogeneity among studies was tested Excluded because blood using Cochran’s Q-test (23). In this paper, results pressure monitored after short presented are based on a random effects model. To time (less than one week) calculate a pooled effect size, each study was assigned a intervention with bioactive weight. The random effects weighted model by DerSi- peptides (n = 2) monian and Laird (24) based on the inverse variance was used. Publication bias was visually examined after con- Excluded because of non- struction of a funnel plot, where standard error is plotted English language of paper against net changes in blood pressure. In addition, Egger (n=1) regression and its corresponding test for publication bias were performed (25). The effect and quality of individual trials were examined by making cumulative and exclusion Placebo-controlled clinical trials on effect by sensitivity forest plots (7). Meta-regression with trial peptides derived from food proteins on blood effects as dependent variable and combined amounts of pressure (n = 13) tripeptides Valine-Proline-Proline (VPP) and Isoleucine- Proline-Proline (IPP) in trials as independent variable weighted by the inverse variance from the random effect Other clinical trials found in model was performed. reference list (n=12) of which Statistical calculations for meta-analysis and genera- nine trials excluded because of tion of plots were performed using the MIX software, publication in non-English version 1.54 (26), and weighted least square regression for meta-regression was preformed using SPSS 15.0.1 for language (i.e. Japanese) and Windows (Chicago, IL, USA). one trial because lack of placebo control Results Clinical trials included in meta-analysis (n=15) Study characteristics Characteristics of the included trials for meta-analysis are Fig. 1. Selection of randomized placebo-controlled trials for given in Tables 1 and 2. A total of 826 participants meta-analysis. completed the trials. In the study by Kawase et al. (12) DBP was not measured. All trials have been published in For between subject comparison, the mean effect of international peer-reviewed journals. Mean duration of intervention is defined as intervention was 7.4 weeks with a minimum intervention of 4 weeks. More than half of the trials used intervention n n X X 1 1 with the bioactive peptides IPP and VPP. In most of the I I  X (3) j 2j n n trials, participants were aged more than 50 years on j1 j1 average, with a higher proportion of males than females. and for placebo Quantitative data synthesis m m X X 1 1 Cochran’s Q-test for homogeneity among studies gave P P  Y : (4) j 2j m m Q30.52 for SBP data with a p-value of 0.02, and Q j1½ j1 29.10 for DBP data with a p-value of 0.08. This indicated Estimates of the mean effect of intervention and heterogenicity among the studies, and a random effects placebo with standard deviations (SD and SD ) were model was used for meta-analysis. Exclusion sensitivity I P obtained from the studies. For meta-analysis, the trial plots showed that excluding single studies did not affect effect for both within subject and between subject pooled results from meta-analysis by more than approxi- comparisons could then be estimated by mately 0.5 mmHg (results not shown). The weighted 3 Are Hugo Pripp Table 1. Baseline characteristics of clinical trials included for meta-analysis with mean and standard deviation values Active intervention Placebo control Source n SBP (mmHg) DBP (mmHg) Age Male (%) n SBP (mmHg) DBP (mmHg) Age Male (%) Hata et al. (10) 17 159 (46) 89 (39) 77 (31) 23 13 151 (34) 87 (33) 73 (38) 31 Kawasaki et al. (11) 17 146 (10) 91 (7) 46 (13) 94 12 146 (8) 92 (6) 49 (10) 92 Kawase et al. (12) 10 124 (10) NA NA 100 10 124 (10) NA NA 100 Fujita et al. (13) 30 150 (9) 94 (10) 62 (8) 60 31 149 (7) 93 (9) 61 (10) 58 Seppo et al. (14) 10 148 (13) 94 (6) 49 (6) 30 7 148 (13) 93 (3) 46 (13) 29 Seppo et al. (15) 22 155 (13) 97 (6) 51 (7) 46 17 152 (13) 96 (6) 48 (7) 53 Mizushima et al. (16) 23 148 (10) 95 (10) 44 (10) 100 23 145 (13) 92 (10) 48 (9) 100 Toumilehto et al. (17) 30 153 (10) 98 (7) 51 (10) NA 29 157 (11) 98 (7) 54 (9) NA Aihara et al.* (8) 20 137 (6) 85 (11) 53 (11) 65 20 137 (5) 85 (5) 50 (12) 65 Aihara et al.** (8) 20 147 (9) 92 (9) 52 (12) 80 20 149 (7) 93 (12) 52 (10) 80 Jauhiainen et al. (18) 53 149 (7) 94 (6) 51 (12) 66.0 55 150 (9) 93 (6) 55 (11) 62 Mizuno et al.* (9) 12 134 (3) 82 (5) NA NA 12 133 (3) 82 (2) NA NA Mizuno et al.** (9) 21 149 (5) 88.6 (5) NA NA 20 150 (5) 89 (5) NA NA Sano et al. (19) 72 138 (7) 85 (5) 51 (10) 40.3 72 138 (6) 85 (5) 50 (10) 38.9 Cade ´ e et al. (20) 24 138 (12) 87 (10) 56 (11) 25 24 137 (15) 85 (10) 56 (12) 16.7 Lee et al. (21) 27 144 (9) 91 (6) 55 (10) 52 26 141 (12) 90 (6) 48 (12) 62 Pins et al. (22) 15 137 (11) 84 (7) 46 (13) 47 15 135 (9) 82 (6) 47 (14) 47 *Data from participants with high-normal blood pressure. **Data from participants with mild hypertension. pooled effect size for trials with bioactive peptides derived There were some signs of heterogeneity and publication from food proteins was 5.13 mmHg (95% CI: 7.12, bias among the trials, but exclusion sensitivity analysis 3.14) for SBP (Fig. 2), and 2.42 mmHg (95% CI: did not indicate that one specific trail had a major impact 3.82, 1.03) for DBP (Fig. 3). Meta-regression relating on the pooled effect estimate. A high proportion of the combined amounts per day of IPP and VPP (mg) with reported trials were carried out using the ACE-inhibiting effect on blood pressure was performed, but no statisti- tripeptides VPP and IPP. cally significant effect at the 5% level was found. On studying the research literature on bioactive peptides Difference between studies with Western or Asian popu- derived from food proteins, it is striking that the number of lation was also examined. Asian studies had a somewhat research papers and literature reviews is extensive com- larger reduction in blood pressure, but there was no pared to the number of controlled clinical trials. Nutra- statistically significant difference at the 5% level. No ceuticals or functional foods are not subject to the same statistically significant effect was found for the propor- strict legislation and documentation requirement using tion of males in the studies. randomized controlled clinical trials, as is the case for pharmaceuticals. Much work is based on in vitro assays or Publication bias to a certain extent animal (rat) experiments. Extensive Funnel plots of SBP and DBP (Fig. 4) indicated signs of searches in other databases, such as the Cochrane Library publication bias for DBP. This was partly confirmed by or the Internet, did not yield additional English-language the Egger regression test for publication bias, which gave placebo-controlled clinical trials published in peer- p-values of 0.31 and 0.08 for SBP and DBP results, reviewed journals. However, there are some other respectively. There was no indication of repeated pub- trials written in Japanese. Based on official English lications of the same trials. translations of abstracts, many of the trials used IPP and VPP peptides as active components and their effect on blood pressure was comparable to those reported in this Discussion meta-analysis. Results from the meta-analysis of the clinical trails Cochrane’s Q-test indicated heterogenicity among the showed that peptides derived from food proteins studies. The trials were performed by different groups with can significantly reduce SBP and DBP, with pooled mean effects of 5.13 mmHg (95% CI: 7.12, 3.14) different active components. The number of trials was also and 2.42 mmHg (95% CI: 3.82, 1.03), respectively. too limited to perform meta-regression to test for many 4 Effect of peptides on hyper tension Table 2. Daily intervention of bioactive components from different food sources and duration of clinical trials included for meta-analysis Duration Source Daily intervention Active component Food source Placebo (weeks) Hata et al. (10) 100 ml fermented milk 1.5 mg VPP and 1.1 mg IPP Milk 100 ml artificially 8 peptide acidified milk Kawasaki et al. 100 ml beverage with 3 mg VY peptide Fish 100 ml beverage without 4 (11) hydrolyzed sardine muscle hydrolyzed sardine muscle Kawase et al. (12) 400 ml fermented milk Whey protein Milk 400 ml artificially 8 with whey protein concentrate concentrate acidified milk Fujita et al. (13) 10 tablets with active 1.5 g Katsuobushi oligopeptide Bonito (fish) 10 tablets with inactive 5 Katsuobushi oligopeptide Katsuobushi powder Seppo et al. (14) 150 ml fermented milk 1.5 mg VPP and 1.1 mg IPP Milk 150 ml ordinary 8 with strain that increase peptide fermented milk production of bioactive peptides Seppo et al. (15) 150 ml fermented milk with 2.5 mg VPP and 2.25 mg IPP Milk 150 ml ordinary 8 process to increase production peptide fermented milk of bioactive peptides Mizushima et al. 160 g fermented milk 1.92 mg VPP and 1.15 mg IPP Milk 160 g artificially acidified 4 (16) peptide milk Toumilehto et al. 150 ml fermented milk with 2.5 mg VPP and 2.5 mg IPP Milk 150 ml ordinary 10 (17) Lb. helveticus peptide fermented milk Aihara et al. (8) 12 g dried product from 8.3 mg VPP and 4.7 mg IPP Milk 12 g dried product made 4 fermented milk peptide without fermentation Jauhiainen et al. 300 ml milk fermented with Lb. 30 mg VPP and 22.5 mg IPP Milk 300 ml ordinary 10 (18) helveticus peptide fermented milk Mizuno et al. (9) Two tablets of hydrolyzed 3.6 mg of VPPIPP peptide Milk Tablets without casein hydrolyzed casein Sano et al. (19) 200 ml fruit juice with 1.47 mg VPP and 1.6 mg IPP Milk 200 ml fruit juice 12 hydrolyzed casein peptide without hydrolyzed casein Cade ´ e et al. (20) Tablets containing C12 3.8 g C12 peptide Milk Placebo tablets 4 Peptide (DMV International, The Netherlands) Lee et al. (21) 125 ml skimmed milk based Whey powder Milk 125 ml skimmed milk 12 beverage with whey powder based beverage Pins et al. (22) Hydrolyzed whey powder Hydrolyzed whey powder Milk Unhydrolyzed whey 6 mixed with water powder mixed with water *Data from participants with high-normal blood pressure. **Data from participants with mild hypertension. sources of heterogenicity, and the effect of daily intake of publication bias, especially for DBP results. One might VPP and IPP was not significant. Meta-regression can be speculate that some studies with low accuracy, e.g. with carried out to relate the results of trials to the average few included participants and with little or negative participant’s characteristics, such as blood pressure or age, effects, have not been published in international peer- but an interpretation of such results is difficult and should reviewed journals. Typically, this could have been minor be carried out with care. This is because the relationship research or student projects. Therefore, the random effects with participant averages across trials may not be the same model was used because of the possible presence of as the relationship for participants within trials (27). heterogenicity and its appropriateness to test whether a Therefore, it was not performed in this meta-regression. treatment will have an effect ‘on average’ (28). Egger regression, funnel plots (Fig. 4) and cumulative Results from this meta-analysis gave a significant Forrest plots (results not shown) did indicate signs of reduction on both SDP and DBP at pB0.01. However, 5 Are Hugo Pripp Table 3. Calculating the effect of trials based on within or between subject comparison of intervention and placebo control treatment Intervention Placebo control Effect of trial SBP DBP SBP DBP SBP DBP Study n Mean SD Mean SD n Mean SD Mean SD Effect SE Effect SE Within subject comparison of blood pressure Hata et al. (10) 17 14.1 12.8 6.9 10.3 13 4.4 13.0 2.2 6.9 9.7 4.7 4.7 3.3 Seppo et al. (14) 10 14.9 9.4 8.8 6.8 7 4.1 11.4 2.0 5.2 10.8 5.0 6.9 3.1 Seppo et al. (15) 19 15.4 8.3 9.3 4.8 17 9.4 13.2 5.5 7.4 6.0 3.6 3.8 2.1 Mizushima et al. (16) 23 5.2 11.3 2.0 8.0 23 3.7 10.6 0.3 8.3 1.5 3.2 1.7 2.4 Toumilehto et al. (17) 30 15.8 13.2 10.3 6.5 29 13.5 11.9 9.8 7.5 2.3 3.3 0.5 1.8 Aihara et al.* (8) 20 5.0 8.9 6.0 6.7 20 2.0 8.9 1.0 8.9 3.0 2.8 5.0 2.5 Aihara et al.** (8) 20 10.0 15.7 7.5 15.7 20 0.5 11.2 0.5 8.9 10.5 4.3 7.0 4.0 Jauhianinen et al. (18) 53 5.1 9.4 1.1 5.6 55 3.1 11.5 2.1 6.1 2.0 2.0 1.0 1.1 Cade ´ e et al. (20) 24 10.7 7.8 6.9 5.9 24 3.6 11.8 2.7 7.8 7.1 2.9 4.2 2.0 Between subject comparison of blood pressure Kawasaki et al. (11) 17 137.1 12.0 85.3 8.6 12 142.5 11.5 91.0 8.7 5.4 4.4 5.7 3.2 Kawase et al. (12) 10 118.0 9.5  10 125.0 14.2  7.0 5.4 Fujita et al. (13) 30 137.5 11.5 86.5 8.2 31 148.5 9.9 92.0 8.4 11.0 2.7 5.5 2.1 Mizuno et al.* (9) 12 131.1 5.8 79.8 6.0 12 133.1 5.5 79.2 4.3 2.0 2.3 0.6 2.1 Mizuno et al.** (9) 21 135.0 10.9 83.9 8.8 20 147.2 10.8 87.3 7.3 12.2 3.4 3.4 2.5 Sano et al. (19) 72 132.3 7.3 81.2 4.8 72 136.4 8.0 83.7 5.6 4.1 1.3 2.5 0.9 Lee et al. (21) 27 143.7 13.5 90.4 6.5 26 137.0 14.4 87.7 6.6 6.7 3.8 2.7 1.8 Pins et al. (22) 15 126.0 6.2 77.0 5.4 15 133.0 7.4 80.0 5.8 7.0 2.5 3.0 2.1 *Data from participants with high-normal blood pressure. **Data from participants with mild hypertension. Hata et al., 1996 (10) Hata et al., 1996 (10) Kawasaki et al. 2000 (11) Kawasaki et al. 2000 (11) Kawase et al., 2000 (12) Fujita et al., 2001 (13) Fujita et al., 2001 (13) Seppo et al., 2002 (14) Seppo et al., 2002 (14) Seppo et al., 2003 (15) Seppo et al., 2003 (15) Mizushima et al., 2004 (16) Mizushima et al., 2004 (16) Toumilehto et al., 2004 (17) Toumilehto et al., 2004 (17) Aihara et al., 2005* (8) Aihara et al., 2005* (8) Aihara et al., 2005** (8) Aihara et al., 2005** (8) Jauhiainen et al., 2005 (18) Jauhiainen et al., 2005 (18) Mizuno et al., 2005* (9) Mizuno et al., 2005* (9) Mizuno et al., 2005** (9) Mizuno et al., 2005** (9) Sano et al., 2005 (19) Sano et al., 2005 (19) Cadée et al., 2007 (20) Cadée et al., 2007 (20) Lee et al., 2007 (21) Lee et al., 2007 (21) Pins et al., 2007 (22) Pins et al., 2007 (22) -2.42 (-3.82; -1.03) -5.3 (-7.12; -3.14) -30 -20 -10 0 10 20 -30 -20 -10 0 10 20 Mean difference in mmHg (95% CI) Mean difference in mmHg (95% CI) Fig. 2. Standard forest plot from meta-analysis on systolic Fig. 3. Standard forest plot from meta-analysis on diastolic blood pressure. Cochran’s Q-test for homogeneity was Q blood pressure. Cochran’s Q-test for homogeneity was Q 30.52, p-value0.02. 29.10, p-value0.08. 6 Effect of peptides on hyper tension Systolic blood pressure Another interesting result from this stratified meta- analysis was that the Cochrane Q-test was significant for trials without VPP and IPP (p0.02 for both SBP and DBP), but not for trials with IPP and VPP (p0.16 and 0.08 for SBP and DBP, respectively). Bioinformatic modelling has, for instance, indicated that the pre- hydrolysis of proteins in foods may influence bioavail- ability and the ACE-inhibitory effect after digestion (29). The effect of peptides may also be related to the association found between protein intake and reduced blood pressure from meta-analysis of epidemiological data on dietary protein intake (30). Research on bioactive peptides is extensive within the dairy field, and most of -20 -15 -10 -5 0 5 10 the clinical trials used milk-based products (Table 2). Mean difference in mmHg However, lack of controlled clinical trials examining the effect of different proteins makes it difficult to say if the Diastolic blood pressure original protein source for bioactive peptides is important for their effect on blood pressure. This area needs further studies. Antihypertensive peptides have limitations as pharma- ceuticals since they are susceptible to degradation by proteolytic enzymes in the stomach and intestines during digestion and because of their limited bioavailability (31). However, compared to other blood pressure reducing components derived from food sources, bioactive pep- 5 tides seem to be competitive. For instance, meta-analysis of fibre supplementation gave a non-significant reduction of SBP by 1.2 mmHg and a significant 1.5 mmHg -20 -15 -10 -5 0 5 10 reduction of DBP (32, 33). Recent meta-analyses of Mean difference in mmHg potassium and magnesium supplementation found no significant effect on blood pressure (34, 35), but is Fig. 4. Funnel plots of mean effects on systolic and diastolic somewhat contradicted by other previous meta-analyses blood pressure to detect signs of publication bias. (3638). Calcium supplementation has shown to signifi- cantly effect SBP by 1.86 mmHg (95% CI: 2.91, their blood pressure reducing effect seems limited in the 0.81) and DBP by 0.99 mmHg (95% CI: 1.61, range of 27 mmHg. 0.37) in a meta-analysis by van Mierlo et al. (39), but Many of the clinical trials were also carried out using this significant effect has been contradicted by Dickinson the well-known ACE inhibiting tripeptides, IPP and VPP. et al. (40), who claimed it was due to poor quality, Additional clinical trials on non-specific food protein heterogeneity and biases among trials. For individuals hydrolysates could provide a better understanding if the with elevated blood pressure, a Cochrane review on effect on blood pressure is limited to some specific peptide structures or is a general property of many salt reduction found a significant reduction in SBP of peptides derived from food proteins. Lee et al. (21) was 5.06 mmHg (95% CI 5.81, 4.31) and DBP of the only study in which active treatment did not, on 2.70 mmHg (95% CI 3.16, 2.24). Blood pressure average, reduce blood pressure. They used a hydrolysate, reduction in individuals with normal blood pressure was and the content of specific bioavailable ACE-inhibiting somewhat less (41). In meta-analysis, fish oil supplemen- peptides, such as Valine-Tyrosine (VY), IPP or VPP, was tation showed an effect on SBP of 2.1 mmHg (95% CI: not identified. That could indicate that the presence of 3.2, 1.0) and DBP of 1.6 mmHg (95% CI: 2.2, some specific bioactive peptides is important for clinical 1.0) (42). Meta-analysis of clinical trials with garlic effect, but further investigations are needed to draw such preparations showed a significant reduction in blood conclusions. Stratified meta-analysis of trials with or pressure, but the investigators concluded that there was without tripeptides IPP and VPP gave 4.59 mmHg insufficient evidence to recommend it as a routine clinical (95% CI: 6.61, 2.57) or 5.42 mmHg (95% CI: therapy for the treatment of hypertensive subjects (43). 10.10, 0.76) for SBP and 2.20 mmHg (95% CI: Even though this meta-analysis only showed a limited 3.73, 0.67) or 2.87 mmHg (95% CI: 6.17, 0.44) effect of peptides derived from food proteins on blood for DBP, respectively. pressure, it could be an alternative or supplement to Standard error Standard error Are Hugo Pripp hypertension  a pilot study on humans. Milchwissenschaft pharmacological treatment in combination with other 2002; 57: 1247. lifestyle changes. In more severe hypertension, when a 15. 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How should meta-regression on subjects with high-normal blood pressure or mild hyperten- analysis be undertaken and interpreted? Statist Med 2002; 21: sion. J Am Coll Nutr 2005; 24: 25765. 155973. 9. Mizuno S, Matsuura K, Gotou T, Nishimura S, Kajimoto O, 28. Petitti DB. Meta-analysis, decision analysis, and cost-effective- Yabune M, et al. Antihypertensive effect of casein hydrolysate in ness analysis. New York, NY: Oxford University Press; 2000. a placebo-controlled study in subjects with high-normal blood 29. Pripp AH. Initial proteolysis of milk proteins and its effect on pressure and mild hypertension. Br J Nutr 2005; 94: 8491. formation of ACE-inhibitory peptides during gastrointestinal 10. Hata Y, Yamamoto M, Ohni M, Nakajima K, Nakamura Y, proteolysis: a bioinformatic, in silico, approach. Eur Food Res Takano T. A placebo-controlled study of the effect of sour milk Technol 2005; 221: 7126. on blood pressure in hypertensive subjects. Am J Clin Nutr 30. 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Semin Nephrol 1999; 19: 4949. committee on prevention, detection, evaluation and treatment 38. Mizushima S, Cappuccio FP, Nichols R, Elliott P. Dietary of high blood pressure. Hypertension 2003; 42: 120652. magnesium intake and blood pressure: a qualitative overview of the observational studies. J Hum Hypertens 1998; 12: 44753. 39. van Mierlo LA, Arends LR, Streppel MT, Zeegers MP, Kok FJ, Are Hugo Pripp Grobbee DE, et al. Blood pressure response to calcium Research Services Depar tment, Biostatistics Group, Rikshospitalet, supplementation: a meta-analysis of randomized controlled Sognsvannsveien 20, 0027 Oslo, Norway. trials. J Hum Hypertens 2006; 20: 57180. E-mail: are.hugo.pripp@rikshospitalet.no 40. Dickinson HO, Nicolson DJ, Cook JV, Campbell F, Beyer FR, Ford GA. et al. Calcium supplementation for the http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Food & Nutrition Research Pubmed Central

Effect of peptides derived from food proteins on blood pressure: a meta-analysis of randomized controlled trials

Food & Nutrition Research , Volume 52 – Jan 18, 2008

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Pubmed Central
Copyright
© 2008 Are Hugo Pripp
ISSN
1654-6628
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1654-661X
DOI
10.3402/fnr.v52i0.1641
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Abstract

Background: In clinical trials, peptides derived from food proteins have shown an effect on blood pressure. This biological mechanism is mainly due to inhibition of angiotensin-I-converting enzyme (ACE), thereby regulating blood pressure through the renin-angiotensin system. A meta-analysis of these trials is needed to better quantify their effect, sources of variation, and possible publication bias. Objective: To perform a meta-analysis of placebo-controlled clinical trials on peptides derived from food proteins and their effect on blood pressure. Design: 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. Results: Pooled effect of peptides was 5.13 mmHg (95% CI: 7.12, 3.14) for systolic blood pressure, and 2.42 mmHg (95% CI: 3.82, 1.03) for diastolic blood pressure. There were indications of publi- cation bias for diastolic blood pressure data. Conclusions: Peptides derived from food proteins may lead to significantly reduced blood pressure and could therefore be a supplement or alternative to pharmaceutical treatment for mild hypertension. Their effect seems more pronounced, or at least comparable, to that of other food components studied by randomized controlled trials. A high proportion of the reported trials was carried out using the well-known ACE inhibiting tripeptides  Valine-Proline-Proline (VPP) and Isoleucine-Proline-Proline (IPP). Keywords: angiotensin-I-converting enzyme (ACE); clinical trials; hypertension Received: March 19, 2007; Revised: September 28 2007; Accepted: October 20, 2007 igh blood pressure, which is estimated to affect extensive randomized, blinded and placebo-controlled one-third of the Western population, is an clinical trials are needed to scientifically support claimed important risk factor for coronary heart disease, effects. Therefore, it is important to systematically stroke and renal disease (1). Lifestyle modifications, summarize the findings from such clinical trials on including weight loss, quitting smoking, reducing sodium antihypertensive bioactive peptides derived from foods. and alcohol intake, increasing physical activity and Meta-analysis has been defined as ‘the statistical analysis of a large collection of analysis results from changing diet, are recommended for both treatment and individual studies for the purpose of integrating the prevention (2). Besides the recommendation of general lifestyle changes, efforts have been made to produce finding’ (5). It goes beyond an expert literature review functional foods that contain components  nutraceuti- where the results from various studies are discussed and cals  which have a blood pressure reducing effect, and compared, since it synthesizes the results of the individual could be a supplement or alternative to the pharmaceu- studies into a new, pooled, result using statistical tical treatment of hypertension. Bioactive peptides with methodology (6). This enhances the precision of the angiotensin-I-converting enzyme (ACE) inhibitory and estimates of treatment effects, thereby leading to im- antihypertensive effects have been the focus of special provement in clinical strategies (7). Even though the attention. They have been isolated from several food number of expert literature reviews on antihypertensive sources, biochemically characterized, and currently, some peptides from food sources is extensive, to my knowledge commercial food products with clinically proven effects a meta-analysis of placebo-controlled clinical trials has are used (3). Specifically, milk and dairy products have not been performed. A meta-analysis would contribute to been shown to have good effects (4). Results from an improved understanding of the effectiveness of pep- Food & Nutrition Research 2008. # 2008 Are Hugo Pripp. This is an Open Access article distributed under the terms of the Creative Commons Attribution- 1 Noncommercial 3.0 Unpor ted License (http://creativecommons.org/licenses/by-nc/3.0/), permiting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. DOI: 10.3402/fnr.v52i0.1641 Are Hugo Pripp tides in hypertension and whether these could be a Box 1: Search string in PubMed with generated translations feasible supplement to pharmaceutical treatment. The to find clinical trials on effect of peptides derived from food possible presence of publication bias in these trials was proteins on blood pressure also investigated. Search string in PubMed Methods (blood pressure OR hypertension) AND Selection of studies (clinical trial[ptyp] OR randomized controlled trial[ptyp] As part of finding a defined search string in PubMed for OR clinical trial, phase I[ptyp] OR clinical trial, phase II[ptyp] relevant clinical trails, literature reviews and selected OR clinical trial, phase III[ptyp] OR controlled clinical trial[ptyp] clinical trials on bioactive peptides derived from food OR placebo) proteins were studied. Several searches of databases and AND the Internet were also carried out, providing an overview (beverages OR food OR milk proteins OR vegetables of the subject. It was also discovered that some reports OR meat OR fishes) have only been published in Japanese. To avoid problems AND and limitations with the translation of these reports, it (peptides OR ferment* OR sour OR hydrol*) was decided to perform this meta-analysis solely on trials published in English. The strategy was to develop a Expression Translations in PubMed defined search string that would find all relevant clinical Blood pressure ‘‘blood pressure’’[MeSH Terms] OR trials registered in PubMed. The literature reference list (‘‘blood pressure determination’’[TIAB] of the selected trials would then be carefully examined to NOT Medline[SB]) OR ‘‘blood pressure identify any supplementary trials not registered in determination’’[MeSH Terms] OR blood PubMed. The defined search string in PubMed with pressure[Text Word] generated translations of expressions is shown in Box 1. Hypertension ‘‘hypertension’’[MeSH Terms] By 1 July 2007 it gave 227 hits of which 13 trials were OR hypertension[Text Word] found relevant for further examination by meta-analysis. Placebo (‘‘placebos’’[TIAB] NOT Medline[SB]) By examining the literature reference list in those trials, OR ‘‘placebos’’[MeSH Terms] two additional trials were included for meta-analysis OR placebo[Text Word] (Fig. 1). Aihara et al. (8) and Mizuno et al. (9) performed Beverages ‘‘beverages’’[MeSH Terms] separate studies on patients with high-normal blood OR beverages[Text Word] pressure and mild hypertension. Therefore, it was decided Food ‘‘food’’[MeSH Terms] OR food[Text Word] to extract those separate data as independent trials. Milk Proteins ‘‘milk proteins’’[MeSH Terms] OR milk proteins[Text Word] Data abstraction Vegetables ‘‘vegetables’’[MeSH Terms] Number, age and sex-ratio of participants, duration of OR Vegetables[Text Word] intervention, baseline systolic (SBP) and diastolic blood Meat ‘‘meat’’[MeSH Terms] OR meat[Text Word] pressure (DBP), change at end of intervention and daily Fishes ‘‘fishes’’[MeSH Terms] OR fishes[Text Word] amount of active component or placebo product were Peptides ‘‘peptides’’[MeSH Terms] obtained from each trail (Tables 1 [1022] and 2). In a OR peptides[Text Word] trial by Mizuno et al. (9), participants were given different amounts of active product. Only data from the group of participants given the highest amount were i1 or 2 which is at start or end of trial, respectively, and abstracted for use in the meta-analysis. j1, 2,..., m is the participants with placebo control. For within subject comparison, the mean effect of Statistical analysis intervention is defined as The effect of intervention or placebo was not estimated n n identically in the trials. This effect was estimated either X X 1 1 I I  (X  X)(1) with a within or between subject comparison of the j 2j 1j n n j1 j1 participants’ blood pressure at the start and end of trial (Table 3). Statistically, let X be the blood pressure for the ij and for placebo intervention group, where i1 or 2 which is at start or end of trial, respectively, and j1, 2,..., n is the m m X X 1 1 participants with active intervention. Further, let Y be P P  (Y  Y ): (2) ij j 2j 1j m m j1 j1 the blood pressure for the placebo control group, where 2 Effect of peptides on hyper tension ¯ ¯ I P (5) Search string in PubMed (Box 1) gave by 1 July with standard error of trial effect given by 2007: n = 227 publications sffiffiffiffiffiffiffiffiffiffiffiffi sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi 2 2 1 1 (n  1)SD  (m  1)SD I P : (6) Studies not addressing effect n m (n  m 2) on blood pressure of food Both fixed and random effects models were examined to protein derived peptides in calculate the mean pooled effect size with confidence humans (n = 211) intervals. The homogeneity among studies was tested Excluded because blood using Cochran’s Q-test (23). In this paper, results pressure monitored after short presented are based on a random effects model. To time (less than one week) calculate a pooled effect size, each study was assigned a intervention with bioactive weight. The random effects weighted model by DerSi- peptides (n = 2) monian and Laird (24) based on the inverse variance was used. Publication bias was visually examined after con- Excluded because of non- struction of a funnel plot, where standard error is plotted English language of paper against net changes in blood pressure. In addition, Egger (n=1) regression and its corresponding test for publication bias were performed (25). The effect and quality of individual trials were examined by making cumulative and exclusion Placebo-controlled clinical trials on effect by sensitivity forest plots (7). Meta-regression with trial peptides derived from food proteins on blood effects as dependent variable and combined amounts of pressure (n = 13) tripeptides Valine-Proline-Proline (VPP) and Isoleucine- Proline-Proline (IPP) in trials as independent variable weighted by the inverse variance from the random effect Other clinical trials found in model was performed. reference list (n=12) of which Statistical calculations for meta-analysis and genera- nine trials excluded because of tion of plots were performed using the MIX software, publication in non-English version 1.54 (26), and weighted least square regression for meta-regression was preformed using SPSS 15.0.1 for language (i.e. Japanese) and Windows (Chicago, IL, USA). one trial because lack of placebo control Results Clinical trials included in meta-analysis (n=15) Study characteristics Characteristics of the included trials for meta-analysis are Fig. 1. Selection of randomized placebo-controlled trials for given in Tables 1 and 2. A total of 826 participants meta-analysis. completed the trials. In the study by Kawase et al. (12) DBP was not measured. All trials have been published in For between subject comparison, the mean effect of international peer-reviewed journals. Mean duration of intervention is defined as intervention was 7.4 weeks with a minimum intervention of 4 weeks. More than half of the trials used intervention n n X X 1 1 with the bioactive peptides IPP and VPP. In most of the I I  X (3) j 2j n n trials, participants were aged more than 50 years on j1 j1 average, with a higher proportion of males than females. and for placebo Quantitative data synthesis m m X X 1 1 Cochran’s Q-test for homogeneity among studies gave P P  Y : (4) j 2j m m Q30.52 for SBP data with a p-value of 0.02, and Q j1½ j1 29.10 for DBP data with a p-value of 0.08. This indicated Estimates of the mean effect of intervention and heterogenicity among the studies, and a random effects placebo with standard deviations (SD and SD ) were model was used for meta-analysis. Exclusion sensitivity I P obtained from the studies. For meta-analysis, the trial plots showed that excluding single studies did not affect effect for both within subject and between subject pooled results from meta-analysis by more than approxi- comparisons could then be estimated by mately 0.5 mmHg (results not shown). The weighted 3 Are Hugo Pripp Table 1. Baseline characteristics of clinical trials included for meta-analysis with mean and standard deviation values Active intervention Placebo control Source n SBP (mmHg) DBP (mmHg) Age Male (%) n SBP (mmHg) DBP (mmHg) Age Male (%) Hata et al. (10) 17 159 (46) 89 (39) 77 (31) 23 13 151 (34) 87 (33) 73 (38) 31 Kawasaki et al. (11) 17 146 (10) 91 (7) 46 (13) 94 12 146 (8) 92 (6) 49 (10) 92 Kawase et al. (12) 10 124 (10) NA NA 100 10 124 (10) NA NA 100 Fujita et al. (13) 30 150 (9) 94 (10) 62 (8) 60 31 149 (7) 93 (9) 61 (10) 58 Seppo et al. (14) 10 148 (13) 94 (6) 49 (6) 30 7 148 (13) 93 (3) 46 (13) 29 Seppo et al. (15) 22 155 (13) 97 (6) 51 (7) 46 17 152 (13) 96 (6) 48 (7) 53 Mizushima et al. (16) 23 148 (10) 95 (10) 44 (10) 100 23 145 (13) 92 (10) 48 (9) 100 Toumilehto et al. (17) 30 153 (10) 98 (7) 51 (10) NA 29 157 (11) 98 (7) 54 (9) NA Aihara et al.* (8) 20 137 (6) 85 (11) 53 (11) 65 20 137 (5) 85 (5) 50 (12) 65 Aihara et al.** (8) 20 147 (9) 92 (9) 52 (12) 80 20 149 (7) 93 (12) 52 (10) 80 Jauhiainen et al. (18) 53 149 (7) 94 (6) 51 (12) 66.0 55 150 (9) 93 (6) 55 (11) 62 Mizuno et al.* (9) 12 134 (3) 82 (5) NA NA 12 133 (3) 82 (2) NA NA Mizuno et al.** (9) 21 149 (5) 88.6 (5) NA NA 20 150 (5) 89 (5) NA NA Sano et al. (19) 72 138 (7) 85 (5) 51 (10) 40.3 72 138 (6) 85 (5) 50 (10) 38.9 Cade ´ e et al. (20) 24 138 (12) 87 (10) 56 (11) 25 24 137 (15) 85 (10) 56 (12) 16.7 Lee et al. (21) 27 144 (9) 91 (6) 55 (10) 52 26 141 (12) 90 (6) 48 (12) 62 Pins et al. (22) 15 137 (11) 84 (7) 46 (13) 47 15 135 (9) 82 (6) 47 (14) 47 *Data from participants with high-normal blood pressure. **Data from participants with mild hypertension. pooled effect size for trials with bioactive peptides derived There were some signs of heterogeneity and publication from food proteins was 5.13 mmHg (95% CI: 7.12, bias among the trials, but exclusion sensitivity analysis 3.14) for SBP (Fig. 2), and 2.42 mmHg (95% CI: did not indicate that one specific trail had a major impact 3.82, 1.03) for DBP (Fig. 3). Meta-regression relating on the pooled effect estimate. A high proportion of the combined amounts per day of IPP and VPP (mg) with reported trials were carried out using the ACE-inhibiting effect on blood pressure was performed, but no statisti- tripeptides VPP and IPP. cally significant effect at the 5% level was found. On studying the research literature on bioactive peptides Difference between studies with Western or Asian popu- derived from food proteins, it is striking that the number of lation was also examined. Asian studies had a somewhat research papers and literature reviews is extensive com- larger reduction in blood pressure, but there was no pared to the number of controlled clinical trials. Nutra- statistically significant difference at the 5% level. No ceuticals or functional foods are not subject to the same statistically significant effect was found for the propor- strict legislation and documentation requirement using tion of males in the studies. randomized controlled clinical trials, as is the case for pharmaceuticals. Much work is based on in vitro assays or Publication bias to a certain extent animal (rat) experiments. Extensive Funnel plots of SBP and DBP (Fig. 4) indicated signs of searches in other databases, such as the Cochrane Library publication bias for DBP. This was partly confirmed by or the Internet, did not yield additional English-language the Egger regression test for publication bias, which gave placebo-controlled clinical trials published in peer- p-values of 0.31 and 0.08 for SBP and DBP results, reviewed journals. However, there are some other respectively. There was no indication of repeated pub- trials written in Japanese. Based on official English lications of the same trials. translations of abstracts, many of the trials used IPP and VPP peptides as active components and their effect on blood pressure was comparable to those reported in this Discussion meta-analysis. Results from the meta-analysis of the clinical trails Cochrane’s Q-test indicated heterogenicity among the showed that peptides derived from food proteins studies. The trials were performed by different groups with can significantly reduce SBP and DBP, with pooled mean effects of 5.13 mmHg (95% CI: 7.12, 3.14) different active components. The number of trials was also and 2.42 mmHg (95% CI: 3.82, 1.03), respectively. too limited to perform meta-regression to test for many 4 Effect of peptides on hyper tension Table 2. Daily intervention of bioactive components from different food sources and duration of clinical trials included for meta-analysis Duration Source Daily intervention Active component Food source Placebo (weeks) Hata et al. (10) 100 ml fermented milk 1.5 mg VPP and 1.1 mg IPP Milk 100 ml artificially 8 peptide acidified milk Kawasaki et al. 100 ml beverage with 3 mg VY peptide Fish 100 ml beverage without 4 (11) hydrolyzed sardine muscle hydrolyzed sardine muscle Kawase et al. (12) 400 ml fermented milk Whey protein Milk 400 ml artificially 8 with whey protein concentrate concentrate acidified milk Fujita et al. (13) 10 tablets with active 1.5 g Katsuobushi oligopeptide Bonito (fish) 10 tablets with inactive 5 Katsuobushi oligopeptide Katsuobushi powder Seppo et al. (14) 150 ml fermented milk 1.5 mg VPP and 1.1 mg IPP Milk 150 ml ordinary 8 with strain that increase peptide fermented milk production of bioactive peptides Seppo et al. (15) 150 ml fermented milk with 2.5 mg VPP and 2.25 mg IPP Milk 150 ml ordinary 8 process to increase production peptide fermented milk of bioactive peptides Mizushima et al. 160 g fermented milk 1.92 mg VPP and 1.15 mg IPP Milk 160 g artificially acidified 4 (16) peptide milk Toumilehto et al. 150 ml fermented milk with 2.5 mg VPP and 2.5 mg IPP Milk 150 ml ordinary 10 (17) Lb. helveticus peptide fermented milk Aihara et al. (8) 12 g dried product from 8.3 mg VPP and 4.7 mg IPP Milk 12 g dried product made 4 fermented milk peptide without fermentation Jauhiainen et al. 300 ml milk fermented with Lb. 30 mg VPP and 22.5 mg IPP Milk 300 ml ordinary 10 (18) helveticus peptide fermented milk Mizuno et al. (9) Two tablets of hydrolyzed 3.6 mg of VPPIPP peptide Milk Tablets without casein hydrolyzed casein Sano et al. (19) 200 ml fruit juice with 1.47 mg VPP and 1.6 mg IPP Milk 200 ml fruit juice 12 hydrolyzed casein peptide without hydrolyzed casein Cade ´ e et al. (20) Tablets containing C12 3.8 g C12 peptide Milk Placebo tablets 4 Peptide (DMV International, The Netherlands) Lee et al. (21) 125 ml skimmed milk based Whey powder Milk 125 ml skimmed milk 12 beverage with whey powder based beverage Pins et al. (22) Hydrolyzed whey powder Hydrolyzed whey powder Milk Unhydrolyzed whey 6 mixed with water powder mixed with water *Data from participants with high-normal blood pressure. **Data from participants with mild hypertension. sources of heterogenicity, and the effect of daily intake of publication bias, especially for DBP results. One might VPP and IPP was not significant. Meta-regression can be speculate that some studies with low accuracy, e.g. with carried out to relate the results of trials to the average few included participants and with little or negative participant’s characteristics, such as blood pressure or age, effects, have not been published in international peer- but an interpretation of such results is difficult and should reviewed journals. Typically, this could have been minor be carried out with care. This is because the relationship research or student projects. Therefore, the random effects with participant averages across trials may not be the same model was used because of the possible presence of as the relationship for participants within trials (27). heterogenicity and its appropriateness to test whether a Therefore, it was not performed in this meta-regression. treatment will have an effect ‘on average’ (28). Egger regression, funnel plots (Fig. 4) and cumulative Results from this meta-analysis gave a significant Forrest plots (results not shown) did indicate signs of reduction on both SDP and DBP at pB0.01. However, 5 Are Hugo Pripp Table 3. Calculating the effect of trials based on within or between subject comparison of intervention and placebo control treatment Intervention Placebo control Effect of trial SBP DBP SBP DBP SBP DBP Study n Mean SD Mean SD n Mean SD Mean SD Effect SE Effect SE Within subject comparison of blood pressure Hata et al. (10) 17 14.1 12.8 6.9 10.3 13 4.4 13.0 2.2 6.9 9.7 4.7 4.7 3.3 Seppo et al. (14) 10 14.9 9.4 8.8 6.8 7 4.1 11.4 2.0 5.2 10.8 5.0 6.9 3.1 Seppo et al. (15) 19 15.4 8.3 9.3 4.8 17 9.4 13.2 5.5 7.4 6.0 3.6 3.8 2.1 Mizushima et al. (16) 23 5.2 11.3 2.0 8.0 23 3.7 10.6 0.3 8.3 1.5 3.2 1.7 2.4 Toumilehto et al. (17) 30 15.8 13.2 10.3 6.5 29 13.5 11.9 9.8 7.5 2.3 3.3 0.5 1.8 Aihara et al.* (8) 20 5.0 8.9 6.0 6.7 20 2.0 8.9 1.0 8.9 3.0 2.8 5.0 2.5 Aihara et al.** (8) 20 10.0 15.7 7.5 15.7 20 0.5 11.2 0.5 8.9 10.5 4.3 7.0 4.0 Jauhianinen et al. (18) 53 5.1 9.4 1.1 5.6 55 3.1 11.5 2.1 6.1 2.0 2.0 1.0 1.1 Cade ´ e et al. (20) 24 10.7 7.8 6.9 5.9 24 3.6 11.8 2.7 7.8 7.1 2.9 4.2 2.0 Between subject comparison of blood pressure Kawasaki et al. (11) 17 137.1 12.0 85.3 8.6 12 142.5 11.5 91.0 8.7 5.4 4.4 5.7 3.2 Kawase et al. (12) 10 118.0 9.5  10 125.0 14.2  7.0 5.4 Fujita et al. (13) 30 137.5 11.5 86.5 8.2 31 148.5 9.9 92.0 8.4 11.0 2.7 5.5 2.1 Mizuno et al.* (9) 12 131.1 5.8 79.8 6.0 12 133.1 5.5 79.2 4.3 2.0 2.3 0.6 2.1 Mizuno et al.** (9) 21 135.0 10.9 83.9 8.8 20 147.2 10.8 87.3 7.3 12.2 3.4 3.4 2.5 Sano et al. (19) 72 132.3 7.3 81.2 4.8 72 136.4 8.0 83.7 5.6 4.1 1.3 2.5 0.9 Lee et al. (21) 27 143.7 13.5 90.4 6.5 26 137.0 14.4 87.7 6.6 6.7 3.8 2.7 1.8 Pins et al. (22) 15 126.0 6.2 77.0 5.4 15 133.0 7.4 80.0 5.8 7.0 2.5 3.0 2.1 *Data from participants with high-normal blood pressure. **Data from participants with mild hypertension. Hata et al., 1996 (10) Hata et al., 1996 (10) Kawasaki et al. 2000 (11) Kawasaki et al. 2000 (11) Kawase et al., 2000 (12) Fujita et al., 2001 (13) Fujita et al., 2001 (13) Seppo et al., 2002 (14) Seppo et al., 2002 (14) Seppo et al., 2003 (15) Seppo et al., 2003 (15) Mizushima et al., 2004 (16) Mizushima et al., 2004 (16) Toumilehto et al., 2004 (17) Toumilehto et al., 2004 (17) Aihara et al., 2005* (8) Aihara et al., 2005* (8) Aihara et al., 2005** (8) Aihara et al., 2005** (8) Jauhiainen et al., 2005 (18) Jauhiainen et al., 2005 (18) Mizuno et al., 2005* (9) Mizuno et al., 2005* (9) Mizuno et al., 2005** (9) Mizuno et al., 2005** (9) Sano et al., 2005 (19) Sano et al., 2005 (19) Cadée et al., 2007 (20) Cadée et al., 2007 (20) Lee et al., 2007 (21) Lee et al., 2007 (21) Pins et al., 2007 (22) Pins et al., 2007 (22) -2.42 (-3.82; -1.03) -5.3 (-7.12; -3.14) -30 -20 -10 0 10 20 -30 -20 -10 0 10 20 Mean difference in mmHg (95% CI) Mean difference in mmHg (95% CI) Fig. 2. Standard forest plot from meta-analysis on systolic Fig. 3. Standard forest plot from meta-analysis on diastolic blood pressure. Cochran’s Q-test for homogeneity was Q blood pressure. Cochran’s Q-test for homogeneity was Q 30.52, p-value0.02. 29.10, p-value0.08. 6 Effect of peptides on hyper tension Systolic blood pressure Another interesting result from this stratified meta- analysis was that the Cochrane Q-test was significant for trials without VPP and IPP (p0.02 for both SBP and DBP), but not for trials with IPP and VPP (p0.16 and 0.08 for SBP and DBP, respectively). Bioinformatic modelling has, for instance, indicated that the pre- hydrolysis of proteins in foods may influence bioavail- ability and the ACE-inhibitory effect after digestion (29). The effect of peptides may also be related to the association found between protein intake and reduced blood pressure from meta-analysis of epidemiological data on dietary protein intake (30). Research on bioactive peptides is extensive within the dairy field, and most of -20 -15 -10 -5 0 5 10 the clinical trials used milk-based products (Table 2). Mean difference in mmHg However, lack of controlled clinical trials examining the effect of different proteins makes it difficult to say if the Diastolic blood pressure original protein source for bioactive peptides is important for their effect on blood pressure. This area needs further studies. Antihypertensive peptides have limitations as pharma- ceuticals since they are susceptible to degradation by proteolytic enzymes in the stomach and intestines during digestion and because of their limited bioavailability (31). However, compared to other blood pressure reducing components derived from food sources, bioactive pep- 5 tides seem to be competitive. For instance, meta-analysis of fibre supplementation gave a non-significant reduction of SBP by 1.2 mmHg and a significant 1.5 mmHg -20 -15 -10 -5 0 5 10 reduction of DBP (32, 33). Recent meta-analyses of Mean difference in mmHg potassium and magnesium supplementation found no significant effect on blood pressure (34, 35), but is Fig. 4. Funnel plots of mean effects on systolic and diastolic somewhat contradicted by other previous meta-analyses blood pressure to detect signs of publication bias. (3638). Calcium supplementation has shown to signifi- cantly effect SBP by 1.86 mmHg (95% CI: 2.91, their blood pressure reducing effect seems limited in the 0.81) and DBP by 0.99 mmHg (95% CI: 1.61, range of 27 mmHg. 0.37) in a meta-analysis by van Mierlo et al. (39), but Many of the clinical trials were also carried out using this significant effect has been contradicted by Dickinson the well-known ACE inhibiting tripeptides, IPP and VPP. et al. (40), who claimed it was due to poor quality, Additional clinical trials on non-specific food protein heterogeneity and biases among trials. For individuals hydrolysates could provide a better understanding if the with elevated blood pressure, a Cochrane review on effect on blood pressure is limited to some specific peptide structures or is a general property of many salt reduction found a significant reduction in SBP of peptides derived from food proteins. Lee et al. (21) was 5.06 mmHg (95% CI 5.81, 4.31) and DBP of the only study in which active treatment did not, on 2.70 mmHg (95% CI 3.16, 2.24). Blood pressure average, reduce blood pressure. They used a hydrolysate, reduction in individuals with normal blood pressure was and the content of specific bioavailable ACE-inhibiting somewhat less (41). In meta-analysis, fish oil supplemen- peptides, such as Valine-Tyrosine (VY), IPP or VPP, was tation showed an effect on SBP of 2.1 mmHg (95% CI: not identified. That could indicate that the presence of 3.2, 1.0) and DBP of 1.6 mmHg (95% CI: 2.2, some specific bioactive peptides is important for clinical 1.0) (42). Meta-analysis of clinical trials with garlic effect, but further investigations are needed to draw such preparations showed a significant reduction in blood conclusions. Stratified meta-analysis of trials with or pressure, but the investigators concluded that there was without tripeptides IPP and VPP gave 4.59 mmHg insufficient evidence to recommend it as a routine clinical (95% CI: 6.61, 2.57) or 5.42 mmHg (95% CI: therapy for the treatment of hypertensive subjects (43). 10.10, 0.76) for SBP and 2.20 mmHg (95% CI: Even though this meta-analysis only showed a limited 3.73, 0.67) or 2.87 mmHg (95% CI: 6.17, 0.44) effect of peptides derived from food proteins on blood for DBP, respectively. pressure, it could be an alternative or supplement to Standard error Standard error Are Hugo Pripp hypertension  a pilot study on humans. Milchwissenschaft pharmacological treatment in combination with other 2002; 57: 1247. lifestyle changes. In more severe hypertension, when a 15. 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