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Am J Clin Nutr 89: 617-623, 2009. First published December 23, 2008; doi:10.3945/ajcn.2008.26918
 American Journal of Clinical Nutrition, doi:10.3945/ajcn.2008.26918
Vol. 89, No. 2, 617-623, February 2009
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© 2009 American Society for Clinical Nutrition

ORIGINAL RESEARCH COMMUNICATION

Lactotripeptides do not lower ambulatory blood pressure in untreated whites: results from 2 controlled multicenter crossover studies

Linda AJ van Mierlo1,2,3, Mettina MG Koning1,2,3, Kim van der Zander1,2,3 and Richard Draijer1,2,3

1 From the Unilever Food & Health Research Institute, Vlaardingen, Netherlands.

2 Supported by Unilever Food & Health Research Institute, Vlaardingen, Netherlands.

3 Reprints not available. Address correspondence to LAJ van Mierlo, Unilever Food & Health Research Institute, Vlaardingen, Netherlands. E-mail: linda-van.mierlo{at}unilever.com.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Dietary factors directly influence blood pressure (BP). The lactotripeptides (LTPs) IPP (isoleucine-proline-proline) and VPP (valine-proline-proline), formed by hydrolyzing dairy proteins, and potassium, a mineral mainly found in fruit, vegetables, and dairy products, are extensively studied for their BP-lowering effect. The efficacy of LTPs seems modest in whites compared with that in Asians.

Objective: The objective was to study the effects of enzymatically produced LTPs alone or in combination with potassium on ambulatory BP in whites.

Design: Two multicenter, placebo-controlled, randomized, crossover studies were conducted; each consisted of two 4-wk intervention periods separated by a 4-wk washout period. In study 1, 69 subjects received 200 g/d of a dairy drink with 5.8 mg IPP and 4.4 mg VPP or placebo. In study 2, 93 subjects received 100 g/d of a dairy drink with 2.7 mg IPP, 1.9 mg VPP, and 350 mg added K or placebo. The subjects were randomly assigned according to their daytime ambulatory BP.

Results: Mean 24-h systolic and diastolic BP (baseline values—study 1: 137.1/81.6 mm Hg; study 2: 139.2/80.9 mm Hg) remained similar with no significant differences between treatments in either study (P > 0.10). Office BP decreased over the course of both studies (systolic BP > 5 mm Hg), but differences between interventions were not significant (P > 0.10). In both studies, nighttime BP dipped during all treatments (≥15%) but was statistically more significant with placebo (P < 0.05). Sodium excretion increased significantly after consumption of LTPs and potassium compared with after placebo intervention (P = 0.01), but not after consumption of LTPs alone.

Conclusion: The data do not support a BP-lowering effect of LTPs in whites.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Elevated blood pressure (BP) is an important public health challenge because of its high prevalence worldwide (1), poor treatment and control rate (2), and consistent relation with the risk of cardiovascular disease (3). Health authorities recommend adoption of a healthy diet and lifestyle for persons with a high normal BP and for patients who require drug treatment (3, 4). Dietary and lifestyle factors can directly influence BP, particularly a diet rich in fruit and vegetables and in low-fat dairy products, as was shown in the Dietary Approaches to Stop Hypertension (DASH) Study (5). Furthermore a considerable number of human studies have addressed the BP-lowering effect of individual nutrients. Peptides, particularly the milk-derived lactotripeptides (LTPs) IPP (isoleucine-proline-proline) and VPP (valine-proline-proline), and potassium, a mineral mainly found in fruit, vegetables, and dairy products, have been extensively studied for their BP-lowering effect.

Several meta-analyses of >30 intervention studies have shown significant BP-lowering effects of potassium supplementation at relatively high doses (6–9). Most studies that examined the effect of IPP and VPP have also reported significant decreases in BP, although the reported magnitude of the effect varies considerably between data derived from Asian (10–19) and white (20–26) populations.

Two recent meta-analyses provided evidence of a significant effect of peptides on BP (27, 28). The meta-analysis by Pripp (28) included intervention studies on both IPP and VPP and other peptides derived from food proteins, and found a significant pooled effect on systolic BP (SBP) of –5.1 mm Hg and on diastolic BP (DBP) of –2.4 mm Hg. A second meta-analysis by Xu et al (27), which only included IPP and VPP intervention studies, also found a significant effect on SBP of –4.8 mm Hg and on DBP of –2.2 mm Hg. Recently, several new IPP and VPP intervention studies were published, most of which found no significant BP-lowering effect (20, 22, 25, 26). These studies were not included in the meta-analyses; thus, it is likely that findings from these meta-analyses overestimated the true underlying effect.

LTPs can be produced by 2 processes: fermentation and enzymatic hydrolysis. In fermented milk, IPP, VPP, and many other dairy peptides are produced from milk casein by the complex proteolytic activity of lactic acid bacteria. Enzymatic LTPs are formed by enzymatic hydrolysis of dairy protein (milk casein) by a single protease. Enzymatic LTPs have a less complex peptide breakdown pattern than does fermented LTP.

To further investigate the BP-lowering effect of IPP and VPP, we studied the effect of enzymatic LTPs on BP in a white population and performed 2 multicenter, randomized, double-blind, placebo-controlled, crossover studies with two 4-wk intervention periods separated by a 4-wk washout period. In total, 162 Scottish subjects not receiving antihypertensive treatment were included. We used ambulatory BP as the primary outcome measure to improve the precision of the BP values and to be able to detect any possible transient effects. In study 1, the effect of 5.8 mg IPP and 4.4 mg VPP was tested. In study 2, the effect of 2.7 mg IPP, 1.9 mg VPP, and 350 mg added K—similar to the level in one serving of fruit, vegetables, or a dairy product—was tested.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
The studies were performed subsequently at 9 general practitioner sites located in Scotland. The Contract Research Organization (CRO; Quintiles Ltd, Bracknell, United Kingdom) was responsible for the management of both studies. The subjects were screened between November 2005 and April 2006. Subjects with untreated elevated BP were recruited in collaboration with general practitioners and qualified for inclusion in the studies if they were white and between 35 and 70 y of age. To minimize the risk of misclassification of a person's BP, office BP (inclusion criteria: SBP > 135 mm Hg) and mean daytime (0900–2100) ambulatory BP (inclusion criteria: SBP 130–160 mm Hg, DBP < 100 mm Hg) were measured at prescreening and at screening. In both studies, subjects were excluded if they had a body mass index (in kg/m2) < 18 or > 32, used protein supplements during the study or <4 wk before the study, had a recorded history of cardiovascular disease or other medical conditions, or had lifestyle habits that could influence the primary outcome of the studies.

All participants received both written and oral information and gave their written consent. Written approval for the studies was obtained from the Multicentre Research Ethics Committee (study 1: Central Manchester Local Research Ethics Committee, South Manchester, United Kingdom; study 2: West Glasgow Research Ethics Committee, Glasgow, United Kingdom). The studies were executed in accordance with Good Clinical Practice policy, according to the principles of the Declaration of Helsinki, revision 2000.

Design
The 2 studies had a double-blind, multicenter, placebo-controlled, randomized full-crossover design and involved 2 treatments and two 4-wk intervention periods separated by a 4-wk washout period. Thus, each subject participated for 12 wk in the study. The studies were designed to compare the BP-lowering effect of a dairy product with LTPs and a dairy product with LTPs and enriched in potassium with that of a placebo product in subjects with elevated BP. The recruited subjects were randomly assigned according to their daytime (0900–2100) ambulatory BP values, which were obtained at baseline. The subjects then consumed the active or placebo product for 4 wk. The treatments were crossed over after the washout and continued in the study for another 4 wk (Figure 1).


Figure 1
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  		FIGURE 1. Flow chart and design of the 2 double-blind, randomized, placebo-controlled, crossover studies in 162 Scottish subjects with untreated elevated blood pressure. LTP, lactotripeptides; BP, blood pressure.

 
Test products
The test products were ready-to-drink yogurt drinks. The active products and placebo products used in the studies were similar in appearance, color, taste, and smell and were provided in nontransparent white cups that differed only in terms of the coding on the bottles. All products were provided by Unilever (Vlaardingen, Netherlands). The products were made from pasteurized semiskim milk that was acidified with a standard yogurt strain to produce a yogurt drink. The active substance was LTPs obtained by enzymatic hydrolysis of sodium caseinate. After hydrolysis, the powder was produced by spray-drying. This powder was added to the yogurt. The extra protein content achieved by adding hydrolyzed casein in the active product was corrected for in the placebo product by adding whey-protein-isolate. Pectin for stability and sugar, fruit puree, and flavoring for taste were added. The dairy products contained naturally present potassium (150 mg/100 g). The active product used in study 2 was enriched with food-grade potassium gluconate, which provided 350 mg K. The nutritional composition of the products is shown in Table 1. In study 1, the subjects randomly received a daily dose of 200 g of dairy drink with 5.8 mg IPP and 4.4 mg VPP or placebo. In study 2, the subjects randomly received a daily dose of 100 g of dairy drink with 2.7 mg IPP and 1.9 mg VPP enriched with potassium (350 mg) or placebo. To assess compliance, the subjects were asked to return used and unused cups of the test products. The research staff and subjects remained blinded to the type of treatment during the study.


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  		TABLE 1. Nutrient composition of the test products per 100 g of dairy drink1

 
Diet
For the duration of the studies, the subjects were asked to maintain their normal diet and lifestyle, except that the subjects were instructed to not consume protein supplements. On the measurement days, the subjects were asked to refrain from strenuous exercise and to refrain from consuming specific fermented foods (eg, meat, fish and soy products, and foods containing licorice). The subjects were asked to consume fermented milk products and alcoholic beverages as accustomed to, but not to vary more than one volume unit between the visit days. Furthermore, the subjects were asked to fast and consume only water from 2200 onward on the evening before a visit day and were instructed to eat breakfast and consume the test products daily in the morning with breakfast and standardized between 2.5 and 3 h before the office BP measurement. On a visit day, no food or drink (except for water) was allowed after breakfast until after the office BP was measured. The subjects were asked to eat, on all subsequent visit days, exactly the same breakfast that they had consumed on the day of visit 1. Because of a possible BP effect of caffeine, each subject was asked to consume no more than one caffeinated beverage as part of his or her breakfast.

Blood pressure measurements
At baseline and after both intervention periods, the subject's 24-h ambulatory BP was measured (study 1: monitor A/A type Spacelabs 90217; Spacelabs Medical, Issaquah, WA; study 2: monitor A/A type TM-2430; A&D Company Ltd, Tokyo, Japan). The monitor was programmed to take readings on the nondominant arm every 20 min during the day and every hour during the night for a length of ≥25 h. The values obtained from the first hour were discarded. The subjects were instructed on how to operate the monitor and were asked to refrain from any strenuous activity. The subjects were asked to sit down if possible or stand still and relax their arms during the readings. Other than refraining from strenuous activity and avoiding the consumption of particular standardized food products, the subjects were instructed to maintain their usual lifestyle habits. The ambulatory BP measurement was automatically repeated if the measurement was not successful (eg, if the monitor malfunctioned or if the subject moved his or her arm during the assessment). It was preferable that all 24-h ambulatory BP measurements per subject were made on the same day of the week during the study. Daytime (0900–2100), nighttime (0000–0600), and the first 2 h after consumption of the product ambulatory BP were derived from the 24-h ambulatory BP measurements.

At baseline, after both intervention periods and after the washout period, office BP was measured on the subject's dominant arm on each visit. The subjects were asked to rest for 15 min; an automatic arm cuff (monitor A/A type Omron HEM 907; Omron Healthcare Europe BV, Hoofddorp, Netherlands) was fitted to obtain 6 successive measurements of office BP. When possible, the same monitor was used for each subject during the study. If an error occurred during any of the first 6 measurements of office BP, additional measurements were made. The mean of the last 4 successful measurements was calculated and used in the studies. For all subjects, measurements were made at a fixed time point during the day, preferably 2.5–3 h after consumption of the product. Measurements were performed between 0900 and 1300 on weekdays to reduce variability.

Additional measurements
Body weight was measured at baseline, after both intervention periods and after the washout period. The subjects were weighed after voiding and while not wearing shoes. Well-being was measured on a 5-point scale (1 = excellent and 5 = very poor) at baseline, after both the intervention periods and after the washout period. Safety indicators (measures of liver function, kidney function, and hematology) were analyzed in blood collected at baseline and after the last intervention period into a 4-mL EDTA-containing tube, an 8-mL clotting tube, and a 2-mL NaF-containing tube. The subjects were asked to collect 24-h urine samples at baseline, after both intervention periods, and after the washout period. The urine was weighed, and the volume was measured. Urinary sodium, potassium, creatinine and, albumin concentrations were measured on a Roche Modular instrument (Hoffman La-Roche, Basel, Switzerland). The Roche ISE indirect method was used to measure sodium and potassium, the Roche Jaffe Kinetic Colormetric assay for creatinine, and the Roche BCG method for albumin.

All adverse events (AEs) experienced during the study were reported on a clinical report form. The intensity of the AE was graded on a 3-point scale (mild, moderate, or severe) and was reported in detail on the clinical report form. The relation of the adverse event to the treatment was also assessed by the investigator.

Statistical analysis
Raw data were collected by electronic data capture entry, and the resulting spreadsheets were archived at the Contract Research Organization; 100% of the inclusion and exclusion criteria and main outcome variables were verified, and 10% of all other data were verified. The treatment codes were broken after the blind data analysis.

Two statistical analyses were performed based on the intention-to-treat (ITT) population and on the per protocol population. The ITT population (primary population) consisted of all subjects who had been randomly assigned for treatment and had received at least one dose of the study product. Decisions about which subjects were to be excluded from the per protocol population were made during 2 data review meetings before deblinding of the data.

The values reported in text and tables are least-squares means ± SEMs based on the ITT population, except for baseline data, which are reported as means ± SD. Mixed linear models (analysis of covariance) were used to compare the differences between treatments. This procedure corrected for the imbalance between groups and missing values and was used to test the period effect and the carryover effect. The following variables were included in the models: treatment, period, and interaction. The following covariates were included as continuous variables and random effects and were left in the model if the variables were shown to have a significant effect: baseline BP value, age, sex, and weight change during the study. The absolute values for 24-h ambulatory BP and office SBP and DBP were statistically evaluated for differences between the active period and the placebo period within each subject.

Results of the power calculation showed that, for each crossover study, 48 subjects should have been sufficient to detect a change in SBP of 3 mm Hg with a power of 0.9 and one-sided {alpha} = 0.05. The analyses were performed by using SAS software (version 9.1.3; SAS Institute, Cary, NC).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Subjects and compliance
A total of 263 subjects underwent screening for ambulatory BP, and 162 subjects were enrolled in the 2 studies: 69 subjects were randomly assigned to treatment in study 1 and 93 to treatment in study 2. Study 1 was completed by 64 subjects (1 person was excluded because of an abnormal laboratory results, 4 persons withdrew consent, and 2 persons were excluded because they could not comply with the visit schedule). Study 2 was completed by 91 subjects (1 person was excluded because of lymphedema, and 1 person was excluded because they did not tolerate the intervention product). The number of subjects screened and randomized overall and per study is shown in Figure 1. Treatment compliance was excellent. In both studies, >95% of the drinks were consumed as indicated by the number of (empty) bottles returned. Scores for well-being were high at baseline and remained high throughout the studies (mean: <2). Both Scottish study populations consisted of slightly overweight and older men and women with untreated elevated BP (Table 2).


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  		TABLE 2. Baseline characteristics of the participants in study 1 and study 21

 
Blood pressure results
In study 1, no significant differences in 24-h SBP/DBP were found between treatments (LTPs compared with placebo) after 4 wk of intervention. Also, daytime SBP/DBP, nighttime DBP, and SBP/DBP 2 h after intake did not change significantly, except for nighttime SBP, for which the decrease was less pronounced after the LTP treatment than after placebo (Table 3). In study 2 also, 24-h SBP/DBP, daytime SBP/DBP, nighttime DBP, and SBP/DBP 2 h after intake did not change significantly between treatments (LTPs plus potassium compared with placebo) after 4 wk of intervention. Again, nighttime SBP decreased significantly less after the LTPs plus potassium treatment than after placebo (Table 4). In both studies, nighttime BP decreased by ≥15% after each treatment. In contrast with 24-h ambulatory BP, office BP decreased during both studies (SBP > 5 mm Hg), regardless of the intervention. In both studies, heart rate did not change significantly during the intervention, and no significant differences were found between treatments (LTPs compared with placebo) after 4 wk of intervention. Also, no carryover effects were found for the primary outcome models with covariates, except for a significant carryover effect in study 1 for nighttime ambulatory DBP (P = 0.001). Similar results were obtained in both studies in the per protocol analysis and when the covariates were not included (data not shown). Post hoc analysis of daytime BP during the first 4, 8, and 12 h after consumption of the enzymatic LTP-containing drink showed no immediate and/or transient BP-lowering effects (data not shown).


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  		TABLE 3. Study 1: Ambulatory blood pressure (BP), office BP, and heart rate after 4 wk of intervention with the placebo drink or the lactotripeptide (LTP) dairy drink1

 

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  		TABLE 4. Study 2: Ambulatory blood pressure (BP), office BP, and heart rate after 4 wk of intervention with the placebo drink or the lactotripeptide (LTP) + potassium dairy drink1

 
Other outcomes
Weight did not change significantly between the different treatment groups in the 2 studies. Also, no significant changes in urinary albumin, creatinine, and potassium were found between the treatment periods in both studies; urinary sodium was significantly higher after the LTP plus potassium treatment than after placebo in study 2 (Table 5).


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  		TABLE 5. Studies 1 and 2: urinary excretion of sodium and potassium (mmol/24 h) and the ratio of sodium to potassium at the end of the intervention periods

 
In study 1, 44 subjects experienced a total of 81 AEs, which were determined not to be related to treatment. Most of the AEs were mild, and all subjects recovered. The 3 most frequent AEs were acute nasopharyngitis (n = 14), joint pain (n = 4), and dizziness and giddiness (n = 4). Two serious AEs (SAEs) were experienced, both of which lasted for 1 d and were determined not to be related to treatment; the subjects recovered from both SAEs. In study 2, 55 subjects experienced 101 AEs, which were determined not to be related to treatment. Most AEs were mild and all subjects recovered. The 4 most frequent AEs were hay fever (n = 8), head cold (n = 8), headaches (n = 7), and lower back pain (n = 5). One SAE was experienced, which was mild; the subject recovered, and the SAE was determined not to be related to the study treatment.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The results of the present 2 multicenter crossover studies showed no antihypertensive effect of daily consumption of a dairy drink with enzymatic LTPs (5.8 mg IPP and 4.4 mg VPP) or enzymatic LTPs (2.7 mg IPP and 1.9 mg VPP) plus potassium (350 mg added) in a population of 162 Scottish subjects. The lack of effect on 24-h ambulatory and office BP confirm that whites may not benefit from LTP treatment to the extent previously reported for Asians. Possible explanations for the discrepant findings include differences in diet, genetics, or physical background between Asians and whites, such as intakes of sodium and fermented products, LTP dose per kilogram body weight, and baseline BP values.

We found a significantly greater reduction in nighttime ambulatory SBP in the placebo group than in the active group in both studies (P < 0.05), but no effect was found in the studies of nighttime ambulatory DBP. Nighttime BP values might have been less reliable than daytime and 24-h BP values because fewer measurements of nighttime BP were made every hour (from 0000 to 0600); daytime BP was measured every 20 min during the day (from 0900 to 2100). Whether the decrease in nighttime BP has any physiologic relevance with respect to end-organ damage is unclear: during LTP treatment in both studies, BP still decreased by ≥15%, which is considered to be a healthy pattern (29). This finding requires additional research focusing on LTPs and nighttime BP.

In study 2, the urinary excretion of sodium increased significantly with the LTPs plus potassium intervention compared with the placebo. Potassium excretion did not change significantly in any of the studies. Therefore, the 350-mg difference in potassium between the intervention and placebo groups was probably too small to reliably measure because other factors that can influence potassium excretion can have a larger effect. The increase in sodium excretion in study 2 might have been due to the potassium content of the intervention product, which triggered greater sodium excretion (30, 31). However, per the literature, a dose of 350 mg potassium might be too small to demonstrate a natriuretic effect.

A strength of the present studies was their randomized, double-blind, placebo-controlled design. We chose to measure ambulatory BP during the screening period and to use this value as the primary study outcome. Studies have shown that ambulatory BP more accurately reflects treatment-induced decreases in BP than does office BP, because of a higher reproducibility over time and an absent or negligible "white coat" or placebo effect (4). We observed in both studies a continuous decrease in office BP, regardless of the intervention. In contrast, 24-h ambulatory BP levels remained stable during the intervention periods. This finding supports the importance of using ambulatory BP to detect small changes in BP. Furthermore ambulatory BP has shown to be a better predictor of cardiovascular disease risk (4). Compliance with the test product was excellent, and dropout rates were low. High dropout rates are considered to be one of the major drawbacks of a crossover design. Also, baseline characteristics, including initial BP levels, were similar between the treatment groups, and body weight did not change during the intervention periods in either study. No carryover effects were observed in any of the models with covariates, except for a significant carryover effect in study 1 for nighttime ambulatory DBP (P = 0.001).

A limitation of the present studies was the relatively short intervention period (4 wk). Although previous studies of LTPs observed BP changes after intervention periods as short as 1 or 2 wk, many showed significant effects on BP after 4- or 8-wk intervention periods. Furthermore, the doses of LTPs (2.7 mg IPP and 1.9 mg VPP/d) and potassium (350 mg added/d) in study 2 were chosen based on a hypothesized additive or synergistic effect of the combination of LTPs and potassium. However, on the basis of the results in study 1 (5.8 mg IPP and 4.4 mg VPP/d), it is unlikely that LTPs contributed to an effect on BP in study 2. Therefore, the current design of study 2 may not have been sufficiently powered to detect BP changes due to a solely small increase in potassium intake (Table 4). A higher level of potassium, similar to 3 servings of good food sources of potassium ({approx}1 g/d) and proven to reduce BP in intervention studies (32, 33), would have been a more appropriate amount to test.

In conclusion, we were unable to show a BP-lowering effect in whites after daily consumption of enzymatic LTPs (5.8 mg IPP and 4.4 mg VPP) or enzymatic LTPs (2.7 mg IPP and 1.9 mg VPP) with an additional amount of potassium (350 mg) using ambulatory BP as the primary outcome. The data do not support a BP-lowering effect of LTPs in whites.


   ACKNOWLEDGMENTS
 
We thank Quintiles UK Ltd for the excellent conduction of the studies (led by Sian Perrington) and greatly appreciate the contribution of Veronique Bianco and Henk van der Knaap to the statistical analyses of the studies and of Peter Zock to the critical evaluation of the manuscript.

The authors’ responsibilities were as follows—LAJvM and RD: designed and monitored the studies, analyzed and interpreted the data, and wrote the manuscript; MMGK: designed the studies, interpreted the data, and critically evaluated the manuscript; and KvdZ: designed the studies and interpreted the data. The sponsor monitored the studies but was not involved in on-site data collection. All authors were working at the Unilever Food & Health Research Institute (Vlaardingen, Netherlands) at the time the studies were conducted. Unilever markets food products, some of which address cardiovascular risk factors.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication September 30, 2008. Accepted for publication November 14, 2008.





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