ID 661 - Laktotripeptydy

PL: Laktotripeptydy
EN: Lactotripeptides
Pdf: isoleucine-proline-proline

Oświadczenie (2)

1. Charakterystyka żywności / składnika

The food constituent that is the subject of the health claims is “special hydrolysed milk proteins”, “lactotripeptides”, “milk products fermented with L. Helveticus lactic acid bacteria”, “the peptides isoleucine-proline-proline (IPP) and valine-proline-proline (VPP)”.
The information provided on “special hydrolysed milk proteins”, “lactotripeptides” and “milk products fermented with L. Helveticus lactic acid bacteria” is insufficient to allow a full characterisation of these foods or food constituents.
The Panel assumes that the food constituent for which the claims are made is the tripeptides isoleucine-proline-proline (IPP) and valine-proline-proline (VPP), which can be obtained through the fermentation of milk by certain lactic acid bacteria, by enzymatic hydrolysis of casein or by chemical synthesis. All clinical studies presented have been conducted with either directly fermented milk, with powdered fermented milk, or with powdered enzymatically hydrolysed tripeptides. IPP and VPP can be measured in foods by established methods. Bioavailability of intact IPP has been demonstrated in animals and humans (Jauhiainen et al., 2007a; Foltz et al., 2007).
The Panel considers that the food constituent, tripeptides IPP and VPP, which is the subject of the health claims, is sufficiently characterised.

2.1. Utrzymanie prawidłowego ciśnienia tętniczego (ID 615, 661, 1831, 1832, 2891)

The claimed effects are “blood pressure”, “cardiovascular system” and “ACE inhibitor”. The Panel assumes that the target population is the general population.
In the context of the proposed wordings, the Panel notes that the claimed effect relates to the maintenance of a normal blood pressure.
Blood pressure (BP) is the pressure (force per unit area) exerted by circulating blood on the walls of blood vessels. Elevated BP, by convention above 140mmHg (systolic) and/or 90mmHg (diastolic), may compromise the normal function of the arteries.
The Panel considers that maintenance of normal blood pressure is beneficial to human health.

3.1. Utrzymanie prawidłowego ciśnienia tętniczego (ID 615, 661, 1831, 1832, 2891)

A total of 70 different references were provided to substantiate this claimed effect. Human intervention studies either conducted in hypertensive subjects on pharmacological treatment for hypertension, reporting clinical outcomes other than BP, or not reporting the daily dose of IPP and VPP used in the intervention were not considered as pertinent to substantiate the claimed effect.
Most of the human intervention studies provided investigated the effects of known doses of IPP and VPP on BP in normotensive, pre-hypertensive or untreated hypertensive subjects were reviewed in a meta-analysis of randomised controlled trials (RCTs) published in 2008 (Xu et al., 2008). This meta- analysis included all RCTs published between 1996 and 2005. The total number of subjects in these studies was 623 (316 in the intervention groups and 307 in the control groups). The authors identified nine publications in which VPP (ranging from 1.5 to 3.3mg/d) and IPP (ranging from 1.1. to 2.5 mg/day) were administered for 4 weeks or longer (Aihara et al., 2005; Jauhiainen et al., 2005; Mizuno et al., 2005; Sano et al., 2005; Mizushima et al., 2004; Tuomilehto et al., 2004; Seppo et al., 2002; Seppo et al., 2003; Hata et al., 1996). The Panel notes that, in the original publication by Jauhiainen et al. (2005), the reported daily doses of IPP and VPP were 22.5mg and 30mg, respectively.
In the studies by Aihara et al. (2005) and Mizuno et al. (2005), subjects with pre-hypertension and subjects with hypertension were randomised and analysed separately and these two populations were included as separate studies in the meta-analysis. Also, the two phases of the cross-over intervention by Tuomilehto et al. (2004) were included as independent studies. The Panel notes that, in phase II of this cross-over study, subjects were the same as in phase I and therefore cannot be analysed independently. Also, baseline BP values at the beginning of phase II were not comparable between intervention and control groups, so that the randomisation in phase I did not hold for the second part of the study.
Out of the 12 interventions considered in the meta-analysis, 6 were conducted in Japan and 5 in Finland. The overall pooled estimate of the effects of IPP and VPP consumption on systolic BP (SBP) was a significant change of -4.8 mmHg (95% confidence interval -6.0 to -3.7) and for diastolic BP (DBP) a significant change of -2.2 mmHg (95% confidence interval -3.1 to -1.3). No linear relationship was observed between the amount of tripeptides consumed and the decrease in BP.
Six additional RCTs have been published (not included in the meta-analysis above) on the effects of IPP and VPP on BP in humans (Hirota et al., 2007; van der Zander et al., 2008a and 2008b; Engberink et al., 2008; de Leeuw et al., 2009; van Mierlo et al., 2009).
In the placebo-controlled, double-blind crossover study by Hirota et al. (2007) conducted on 25 male adults with mild hypertension, the consumption of 3.42 mg of VPP and of 3.87 mg of IPP daily for 1 week did not lead to any significant changes in BP compared to placebo. The Panel acknowledges the
short duration of the study, which was originally designed to test the effects of VPP and IPP intake on endothelial function (primary outcome).
In a double-blind, randomised crossover design, 42 participants consumed for 4 weeks a fermented IPP (15.9mg/d) and VPP (18.7mg/d)-containing product or a placebo product, with a 4-week washout period in between (van der Zander et al., 2008a). Sample size was calculated with SBP as primary outcome. When all subjects were considered together, no differences between the active and the placebo interventions were observed either at the beginning or at the end of the study. In a post hoc subgroup analysis, treatment with IPP and VPP-containing milk showed significant decreases in both SBP and DBP in participants with SBP>130mmHg at the start of the study, but no differences were observed in those with SBP≤130mmHg. The Panel notes that no interaction analysis between SBP values at baseline and SBP changes during the intervention was performed to justify such post hoc analysis, and that the number of subjects with SBP>130mmHg (and with SBP≤130mmHg) has not been reported. No changes were observed in plasma concentrations of angiontensin I, angiotensin II, ACE activity or active plasma renin concentrations.
In a double-blind, parallel, placebo-controlled trial, 135 Dutch subjects with elevated SBP randomly received a daily dose of 200 mL dairy drink with 14 mg IPP+VPP (obtained by either concentrating fermented milk, by enzymatic hydrolysis, or by chemical synthesis) or placebo for 8 weeks (Engberink et al., 2008). The primary outcome was 8-week change in office SBP. Secondary outcomes were changes in DBP, home BP, 24-hour ambulatory BP, plasma ACE-activity, and plasma angiotensin II. Consumption of IPP and VPP did not affect SBP or DBP compared with placebo, regardless of the method by which IPP and VPP were obtained. Consumption of IPP and VPP also did not have a significant effect on secondary outcome measures.
In a multicentre, double-blind, parallel, placebo-controlled trial, 275 hypertensive subjects were randomised to consume either a yogurt beverage providing 5.8 mg IPP and 4.4 mg VPP daily (10.2mg/d in total) or a control yogurt for 8 weeks (van der Zander et al., 2008b). BP and body weight were measured on several days at baseline and at weeks 4 and 8 of the intervention between 2.5 and 3 h after intake of the test product. No significant changes in SBP or DBP were observed with the consumption of the test food as compared to placebo.
An additional publication reports the results of two multicentre, placebo-controlled, randomised, crossover studies, each consisting of two 4-week intervention periods separated by a 4-week washout period (van Mierlo et al., 2009). In study 1, 69 subjects received 200 g/d of a dairy drink with 5.8 mg IPP and 4.4 mg VPP (10.2mg/d in total) or placebo. In study 2, 93 subjects received either 100 g/d of a dairy drink containing 2.7 mg IPP, 1.9 mg VPP, and 350 mg added potassium or placebo. Subjects had high normal or grade I hypertension and were randomly assigned to the order of the intervention according to their daytime ambulatory BP. No significant differences between treatments in either study were observed for mean 24-h SBP or DBP. Office BP decreased over the course of both studies, but differences between intervention groups and placebo were not significant. In both studies, night- time BP dipped during all treatments but was statistically more significant with placebo.
Finally, in a randomised, double-blind, parallel-group, dose-response intervention, 166 subjects with diagnosis of hypertension received either a milk product containing IPP and VPP (1.13 mg and 1.17 mg in the low-dose product, 2.30 mg and 2.26 mg in the medium dose product, and 4.56 mg and 4.47 mg in the high dose product, corresponding to total daily doses of tripeptides of 2.3 mg, 4.6 mg and 9 mg, respectively) or placebo for 8 weeks. Results indicated that test products containing IPP and VPP lowered DPB (but not SBP) dose-dependently. When the results over 8 weeks were corrected for the placebo response, neither SBP not DBP changed significantly in either intervention group. The percentages of subjects who showed a fall in SBP >3 mmHg or who attained an SBP below 140 mmHg were 54% (placebo), 64% (low), 76% (medium) and 71% (high dose) respectively, with a significant p-per-trend across groups. This effect could only be demonstrated for office BP and
not for home or ambulatory BP. Results also suggested that the magnitude of the fall in BP was a function of baseline BP (de Leeuw et al., 2009).
The Panel notes that, although some small studies have observed a significant decrease in SBP with the administration of lactotripeptides at doses around 5mg/d in untreated pre-hypertensive or moderately hypertensive subjects, these results have not been supported by large intervention trials providing daily doses of lactotripeptides in the range of 2.7 mg to 14 mg in either normotensive or untreated hypertensive subjects.
The Panel concludes that the evidence provided is insufficient to establish a cause and effect relationship between the consumption of the tripeptides VPP and IPP and the maintenance of normal blood pressure.

Warunki i możliwe ograniczenia stosowania oświadczenia

Minimum 3 mg/day