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American Journal of Clinical Nutrition, doi:10.3945/ajcn.2008.26003
Vol. 88, No. 6, 1697-1702, December 2008
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© 2008 American Society for Clinical Nutrition

Dietary supplements

Enzymatically hydrolyzed lactotripeptides do not lower blood pressure in mildly hypertensive subjects1,2,3

Kim van der Zander, Michiel L Bots, Annette AA Bak, Mettina MG Koning and Peter W de Leeuw

1 From Unilever Food & Health Research Institute, Vlaardingen, Netherlands (KvdZ and MMGK); the Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, Netherlands (MLB and AAAB); and the Cardiovascular Research Institute Maastricht and Academic Hospital Maastricht, Maastricht, Netherlands (PWdL)

2 Supported by Unilever Food & Health Research Institute, Vlaardingen, Netherlands. The test products were provided by the Unilever Food & Health Research Institute.

3 Reprints not available. Address correspondence to PW de Leeuw, Department of Medicine, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, Netherlands. E-mail: p.deleeuw{at}intmed.unimaas.nl.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Several placebo-controlled clinical studies suggest that products containing isoleucyl-prolyl-proline and valyl-prolyl-proline are able to lower blood pressure without adverse effects. The most efficient way of producing high concentrations of these lactotripeptides (LTPs) is enzymatic hydrolysis of dairy protein (casein) with the use of a mixture of several enzymes derived from the nongenetically modified organism Aspergillus oryzae, including proteases and peptidases. To date, no large studies of the blood pressure–lowering properties of enzymatically produced LTP (ELTP) powder in European populations have been published.

Objective: This study was performed to evaluate the hypothesis that consumption of ELTP in a yogurt beverage for 8 wk significantly lowers blood pressure.

Design: In this multicenter, double-blind, parallel, placebo-controlled trial, office blood pressure was evaluated in 275 Dutch hypertensive subjects. Blood pressures 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. Twenty-four–h urine samples were collected at baseline and at the end of the intervention for urinalysis of sodium, potassium, creatinine, and microalbumin excretion.

Results: The results showed that 10.2 mg ELTP/d does not lead to a reduction in systolic blood pressure (P = 0.66) or diastolic blood pressure (P = 0.72) compared with placebo.

Conclusion: This study showed no effect of an ELTP-enriched yogurt beverage on blood pressure in hypertensive subjects in a fairly large study.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Several placebo-controlled clinical studies suggest that products containing isoleucyl-prolyl-proline (IPP) and valyl-prolyl-proline (VPP) are able to lower blood pressure without adverse effects (1-15). Although most of these studies have reported a statistically significant decrease in blood pressure in hypertensive subjects by these lactotripeptides (LTPs), the magnitude of this effect varies considerably. For instance, in Japanese studies, systolic blood pressure (SBP) and diastolic blood pressure (DBP) decreased over the 8-wk intervention by {approx}10 and 4 mm Hg, respectively, at a dose between 2 and 4 mg LTP/d (1-10). On the other hand, in Finnish studies, a mean decrease in SBP and DBP of 4 and 2 mm Hg, respectively, was observed at higher doses of 5–6 mg LTP/d (13, 14). Furthermore, an even higher dose of 52.5 mg LTP had only modest effects on 24-h ambulatory SBP and DBP (–4 and –2 mm Hg, respectively; P < 0.001 and P = 0.048, respectively) and did not lower office blood pressure (OBP) at all (15). Because LTP reduced SBP in the European studies to a lesser degree than the anticipated 4–5 mm Hg based on Asian studies, these studies may have been underpowered to show an effect of LTP over and above that of placebo.

For clinical studies, 3 different test products containing IPP and VPP are available: directly fermented milk (1-4, 6, 8, 9, 12-15), powdered fermented milk (FLTP powder) (5, 11), and powdered enzymatically hydrolyzed LTP (ELTP) (7, 10). The most efficient way of producing high concentrations of LTP is the enzymatic hydrolysis of dairy protein (casein) with a mixture of several enzymes derived from the nongenetically modified organism Aspergillus oryzae, including proteases and peptidases (16, 17). After denaturization of the enzymes by sterilization, the resulting dried casein hydrolysate powder (ELTP powder) contains {approx}0.7% LTPs. Japanese researchers have confirmed the blood pressure–lowering potential of ELTP in animal and human studies (7, 10, 17). We observed a dose-dependent blood pressure–lowering effect of ELTP on office DBP (P = 0.030) but not on SBP (PW de Leeuw, K van der Zander, AA Kroon, RJMW Rennenberg, and MMG Koning, unpublished observations, 2008) in a study of 41–42 subjects per treatment group. Furthermore, in a recent study, Engberink et al (18) could not support a blood pressure–lowering effect of ELTP (containing 10.4 mg LTP) compared with placebo in a study of 32 subjects per treatment group. It may be that these studies, which are summarized in Table 1Go, did not have enough power to show a small but significant effect of any dose of these peptides compared with placebo. To date, no other large studies of the blood pressure–lowering properties of ELTP in European populations have been published. Therefore, the present study was performed to evaluate the hypothesis that consumption of ELTP in a yogurt beverage for 8 wk significantly lowers blood pressure in European hypertensive subjects.


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  		TABLE 1. Previous intervention studies on the effects of lactotripeptides (LTPs) on blood pressure1

 

   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
The study was performed at 3 sites located in the Netherlands from September 2005 until March 2006. Participants were recruited from Maastricht, Utrecht, and Amersfoort and their surroundings by preselection from databases, through advertisements in newspapers, and by door-to-door flyers. Subjects who expressed their interest in the study completed a telephone screening. Of these subjects, apparently eligible candidates received the information brochure and answered the personal and selection questionnaire. Finally, suitable subjects visited the research centers for screening. Subjects qualified for the study when they were between 35 and 70 y of age, were able to stop antihypertensive medication use ≥3 wk before screening, and fulfilled the blood pressure criteria. To minimize the risk of misclassification of a person's blood pressure, blood pressure was measured in duplicate on 2 separate screening visits (the second after an overnight fast). Inclusion criteria were an average (based on the 2 visits) systolic blood pressure between 140 and 179 mm Hg and an average diastolic blood pressure <100 mm Hg. Exclusion criteria were the use of blood pressure–lowering medication or nonsteroidal anti-inflammatory drug use, abnormal results of biochemical analyses of blood and urine, smoking, unstable weight, alcohol abuse, milk allergy, and pregnancy.

The Medical Ethics Committee of the Maastricht University and Academic Hospital approved the study protocol. The Medical Ethics Committee of University Medical Center Utrecht gave local approval (Utrecht and Amersfoort). All participants received both written and oral information and gave their written consent. The study was performed according to the International Conference on Harmonisation–Good Clinical Practice guidelines.

Study design
This study was designed as a multicenter, randomized, double-blind, parallel, placebo-controlled trial. When subjects qualified for inclusion in the trial, they were randomly assigned to receive either the test or the control product (Figure 1Go). The ELTP formulation was incorporated in a yogurt drink, and their effect was assessed compared with a control yogurt drink. Over a period of 8 wk, subjects consumed 2 bottles of test product (100 g) with their breakfast. The effect of treatment was measured between 2.5 and 3 h after intake by measuring OBP at baseline (visit days 1, 2, and 3), after 4 wk of intervention (visits day 4 and 5), and at week 8 of intervention (visit days 6, 7, and 8). Before the OBP measurements were made, subjects were weighed. Urine was collected for 24-h at the beginning and end of the study for urinalysis (see below). To calculate the background dairy intake of the subjects, records were kept for 3 d (2 weekdays and one weekend day) before randomization and at the end of the intervention.


Figure 1
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  		FIGURE 1.. Flow chart showing the selection process, randomization, and dropout rate of the study participants. ITT, intention-to-treat; LTP, Lactotripeptides; BP, blood pressure.

 
Diet instructions
For the duration of the study, subjects were asked to maintain their habitual sodium and dairy intakes and physical activity patterns. They had to refrain from the consumption of nondairy fermented foods, alcohol-containing beverages, or strenuous exercise for ≥12 h before the test day, which started after an overnight fast. Because of the effect of caffeine on blood pressure, only one caffeinated beverage was allowed per test day at breakfast. On the first test day, volunteers recorded what and how much they ate for breakfast and the time of consumption. On the basis of these records, subjects had exactly the same food and drinks on subsequent test days.

Test and control products
Unilever manufactured both the test and the control product from pasteurized yogurt. The substance added to the test product was a casein hydrolysate powder, enzymatically hydrolyzed by an Aspergillus oryzae protease (Arla Foods, Copenhagen, Denmark). The test product (200 g ELTP-enriched yogurt beverage) contained 28.9 mg IPP/L and 22.0 mg VPP/L. The addition of ELTP in the test product led to an extra protein and lactic acid content that was corrected for with skim milk powder and a lactic acid solution in the control product. Furthermore, pectin was added for stability and sugar and flavor for taste. Consequently, the nutritional composition of both test products was 13% carbohydrate, 1.5% fat, 3.6% protein, 90 mg Ca/100 g, and 141 mg K/100 g. Both used (empty) and unused bottles had to be returned to the research center by the volunteers to assess adherence with the product.

Blood pressure measurements
OBP was taken on 2 (week 4) or 3 (baseline and week 8) consecutive days, while the subjects were in a sitting position, on the left arm after 15 min of rest with an oscillometric automatic device (Omron HEM 907; Omron Healthcare, Inc, Bannockburn, IL). Each measurement was derived from ≥3 successive readings separated by 30 s. If the difference in SBP between the last 2 measurements was >7 mm Hg, an additional measurement was performed. The mean of the last 2 readings was used for analysis. The first blood pressure measurements of each test day was not used in the statistical analysis of the data, but served the purpose of getting the volunteers accustomed (and thus relaxed) to the measurements.

Twenty-four–h urinalysis
From the 24-h urine sample, 10 mL was used for the measurement of Na+, K+, microalbumin, and creatinine excretion. Medical Laboratories Stein & Colleagues analyzed all samples in one run after storage of the urine at –20 °C.

Statistical considerations
On the basis of previous experiments, we expected a within-subject variance in SBP over time of 71 (SD2). Therefore, to demonstrate a decrease in SBP of 3 mm Hg with a power of 90%, 135 subjects were needed in each arm of the study. To allow for dropout, 13 more subjects were recruited. Statistical analysis was performed by using SAS Software (version 9.1; SAS Institute, Cary, NC). Descriptive analyses included distribution statistics (number of available observations, mean, SD) for continuous data.

For OBP, the means of all measurements during the consecutive days of each week (4 or 8) were averaged, and change from baseline (week 0) was considered the response variable for the analysis. Data from visits 1, 2, and 3 were averaged for baseline values; those from visit 4 and 5 for the response at 4 wk; and those from visits 6, 7, and 8 for the response at 8 wk of intervention.

The effects of treatment on both primary (blood pressure) and secondary outcomes (urinalysis, weight, and background diet) were evaluated for each week (4 or 8) by means of an analysis of covariance, including treatment, subject, and baseline blood pressure in the model. The difference in efficacy between placebo and active ingredient was estimated on the basis of adjusted means. No adjustments were made for multiplicity due to testing multiple (secondary) variables. The secondary analyses were expected to support the primary results. Tests on blood pressure variables were 1-sided, whereas they were 2-sided for the other variables with a significance level of 5%. Finally, we tested a restricted set of prespecified potential confounders on the magnitude of the treatment effect. These included starting cohort, weight change, site, and change in urinary the Na+/K+ excretion ratio (only at week 8).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
We enrolled 283 subjects into this study according to the flow chart in Figure 1Go. From the intention-to-treat population (ie, all individuals who had been randomly assigned and received at least one dose of the study treatment), 111 subjects had been taking antihypertensive medication in the past 3 mo before the study, but not during the intervention. Four volunteers dropped out during the study intervention; 2 withdrew consent because of personal circumstances (allocated to ELTP) and 2 because their blood pressure increased to levels above the exclusion criteria (allocated to control). The characteristics of the study population at the start of the study are presented in Table 2Go. The groups were well balanced. Also, estimated adherence to treatment was excellent and comparable between the treatment groups (98% in both groups).


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  		TABLE 2. Baseline characteristics of study subjects1

 
Office blood pressure
Eight weeks of intervention showed a minor decrease in blood pressure that was not statistically significantly different between the ELTP and control treatments (Table 3Go). The results of the per-protocol population (n = 258), which included only those who adhered to the protocol, displayed similar results (data not shown). In exploratory post hoc confounder analysis, the magnitude of blood pressure lowering was not affected by age, sex, cohort, research site, previous use of antihypertensive medication, BMI, and urinary excretion of sodium and potassium. A posterior power analysis using the actual measured within-subject variance of 24, showed that the present study had a power of >90% to detect a significant difference of 3 mm Hg between the treatment arms at week 8.


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  		TABLE 3. Diet markers and blood pressure during follow-up1

 
Body weight, background diet, and adverse events
Body weight did not change significantly during the 8-wk study period (0.5 ± 0.1 kg in the ELTP group compared with 0.6 ± 0.1 kg in the control group; P = 0.48). The background diet, as measured by 24-h urinary excretion of sodium and potassium and derived from the diary, also showed no significant changes during the study (Table 3Go).

Adverse events were registered from all of the subjects (n = 283) who participated in the study and have been coded according to ICD-9. A total of 169 subjects reported adverse events (AEs). Three serious AEs (hip operation, death after heart failure between screening and the start of the study, and a case of severe hypertension) were reported but were considered to be unrelated to the study. Only 2 AEs (severe hypertension and headache) led to discontinuation of (placebo) treatment. Frequency, intensity, and duration of AEs between treatment groups were not significantly different. The most common complaints were brief periods of upper respiratory tract infections and headache (ICD-9 codes 460.00, acute nasopharyngitis, and 784.00 headache): 49 reports during ELTP-milk treatment and 59 reports during placebo treatment. Gastrointestinal AEs (ICD-9 code 787-related, diarrhea, vomiting, pyrosis, etc) were not very common (12 reports in each group). None of the AEs were considered to be related to any of the test products.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The results of the current study in 275 mild hypertensive subjects showed that 10.2 mg ELTP/d did not lead to a reduction in OBP compared with placebo. This lack of effect does not seem to result from inadequate intake as estimated adherence with the product in this study was excellent. Nevertheless, we recognize that our method of assessing adherence was rather crude, and that actual adherence may have been lower. Our findings are in contrast with those obtained in several populations, mainly Japanese and Finnish (1, 2, 4-7, 10-13, 15). What could explain the discrepancy in results between our study and the others?

We studied people who were generally healthy—except for elevated blood pressure—with sodium, potassium, and dairy intakes representative of the typical Dutch population. The number of subjects would a priori have been sufficient to demonstrate a blood pressure reduction from ELTP in this study. The posterior power analysis showed that the study was very well powered. Because the variability in measurements was reduced as much as possible by measuring OBP on several consecutive days, and was comparable with the variability associated with 24-h ambulatory measurements in other studies, the lack of effect was likely due to large individual variability in blood pressure responses to ELTP treatment. Nevertheless, we found no difference in the number of responders (based on a lowering of SBP of ≥3 mm Hg or the attainment of a SBP <140 mm Hg) between the ELTP and placebo treatments. This further supports the conclusion that ELTP does not affect blood pressure.

From a theoretical point of view, several variables—such as baseline blood pressure, race, and background diet—were able to modify the response to ELTP. It has been suggested that LTP-enriched products would have a greater effect in mild-to-moderate hypertensive patients and do not affect blood pressure in normotensive subjects (7, 10, 11). However, this cannot explain the lack of effect in this study, because blood pressure was clearly elevated in our patients (average blood pressure at baseline: 150/86 mm Hg). The potential influence of race and background diet as a cause of a differential effect in Asian and European populations is more difficult to assess. No studies that investigated different ethnicities have been reported. Therefore, it remains speculative why Japanese researchers showed a significant reduction in blood pressure by ELTP, whereas this could not be confirmed in European subjects (7, 10). It was observed that mainly small studies showed a large blood pressure–lowering effects, whereas large studies showed smaller or no effects, which suggests publication bias.

Until now, investigators used 3 different test products containing IPP and VPP in clinical studies: direct fermented milk (1-4, 6, 8, 9, 12-15), FLTP (5, 11), and ELTP powder (7, 10). Direct fermented milk has been investigated in most of the studies and resulted in an average decrease of {approx}8 mm Hg SBP. Powdered fermented milk and powdered enzymatically hydrolyzed casein have been less well studied, but seemed to generate smaller effects on SBP: decreases of {approx}6 and 3 mm Hg for FLTP and ELTP, respectively. These results have led to the speculation that a specific production route is important to the generation of LTP-induced blood pressure–lowering effects; therefore, ELTP does not affect blood pressure or at least exploits rather modest effects compared with fermented products. However, it is unknown whether the smaller SBP decreases observed were due to the lower number of subjects that have been studied so far or that ELTP is indeed less effective than fermented products. Because fermented milk products at a similar LTP level have different (bioactive) peptide profiles, these products could theoretically generate a larger drop in blood pressure than ELTP. However, further research on fermented products or a head-to-head comparison of different LTP production routes on blood pressure reduction is needed to confirm this hypothesis.

Foltz et al (19) recently confirmed that IPP is able to enter the blood circulation undegraded after oral ingestion of an ELTP-enriched yogurt beverage. Although the acute oral bolus of LTP in that study is 5 times that in the current study, the maximum levels of IPP were observed 41.7 ± 15.7 min after intake of the ELTP-enriched beverage and 54.2 ± 7.9 min after intake of the control product. This raises the question of whether a reduction in blood pressure could be observed between 2.5 and 3 h after intake in this study. In contrast, however, Jauhiainen et al (15) observed a significant fall in 24-h ambulatory blood pressure after consumption of fermented milk for 10 wk. This could suggest that fermented milk is indeed more potent at reducing blood pressure than is ELTP. However, there may be more bioactives present in fermented milk products than in IPP alone, which could contribute to the effect over 24 h. A study that investigated the development of hypertension in spontaneously hypertensive rats indicated that intake of fermented milk indeed attenuated high blood pressure more effectively than did pure synthetically produced LTP or pure LTP combined with minerals (20). In conclusion, this study showed no effect of an ELTP-enriched yogurt beverage on the blood pressure of hypertensive subjects.


   ACKNOWLEDGMENTS
 
We thank Peter Holleman, Linda van Osch, Inge Verkooijen, and Frans Thomassen for their substantive contributions to the study conduct.

The authors' responsibilities were as follows—KvdZ: designed the study, monitored the study conduct, analyzed and interpreted the data, and wrote the manuscript; MLB: provided significant advice and consultation, critically evaluated the manuscript, and collected, analyzed, and interpreted the data; AAAB (Principle Investigator at the Utrecht/Amersfoort site and study physician): designed the study, provided significant advice and consultation, and critically evaluated the manuscript; MMGK: designed the study, monitored the study conduct, interpreted the data, and critically evaluated the manuscript; PWdL (Principle Investigator at the Maastricht site and study physician): designed the study, provided significant advice and consultation, interpreted the data, and critically evaluated the manuscript; and MLB, AAAB, and PWdL: had full access to all of the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis. The sponsor monitored the study, but was not involved in on-site data collection, data analysis, or data interpretation. KvdZ and MMGK are employees of the Unilever Food & Health Research Institute, Vlaardingen, Netherlands. No conflicts of interest were declared by the other authors.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Hata Y, Yamamoto M, Ohni M, Nakajima K, Nakamura Y, Takano T. A placebo-controlled study of the effect of sour milk on blood pressure in hypertensive subjects. Am J Clin Nutr 1996;64:767–71.[Abstract/Free Full Text]
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  7. Mizuno S, Matsuura K, Gotou T, et al. Antihypertensive effect of casein hydrolyzate prepared using an Aspergillus oryzae protease in a placebo-controlled clinical study for subjects with high-normal blood pressure and mild-hypertension. Br J Nutr 2005;94:84–91.[CrossRef][Medline]
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  14. Tuomilehto J, Lindstrom J, Hyyrynen J, et al. Effect of ingesting sour milk fermented using Lactobacillus helveticus bacteria producing tripeptides on blood pressure in subjects with mild hypertension. J Hum Hypertens 2004;18:795–802.[CrossRef][Medline]
  15. Jauhiainen T, Vapaatalo H, Poussa T, Kyronpalo S, Rasmussen M, Korpela R. Lactobacillus helveticus fermented milk lowers blood pressure in hypertensive subjects in 24-h ambulatory blood pressure measurement Am J Hypertens 2005;18:1600-5.[CrossRef][Medline]
  16. Matsuura K, Mizuno S, Nishimura S, Gotou T, Yamamoto N. Quantitative analysis of antihypertensive peptides, Val-Pro-Pro and Ile-Pro-Pro, in casein hydrolyzate with Aspergillus oryzae protease by a LC-MS method. Milchwissenschaft 2004;60:24–7.
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Received for publication February 14, 2008. Accepted for publication August 31, 2008.




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