Home Ingredients AmealPeptide® (Casein Lactotripeptides VPP and IPP)
Cardiovascular

AmealPeptide® (Casein Lactotripeptides VPP and IPP)

Evidence Level
Limited
1 Clinical Trial
3 Documented Benefits
2/5 Evidence Score

AmealPeptide® is a casein-derived ingredient supplying the lactotripeptides VPP (valyl-prolyl-proline) and IPP (isoleucyl-prolyl-proline), made by Calpis (now part of Asahi Group) by digesting milk casein with an enzyme from the mould Aspergillus oryzae. In company-run Japanese trials it lowered systolic blood pressure by several mmHg, but across 14 European trials the extra drop over placebo was about 1 mmHg, and the European Food Safety Authority concluded that a blood pressure benefit had not been established. The peptides block the ACE enzyme in the test tube, but a human study found they did not do so in the body.

Studied Dose 3.4 mg/day of VPP plus IPP in tablets for 8 weeks (Calpis trial, 70 adults); 1.8, 2.5 or 3.6 mg/day for 6 weeks in a Calpis dose-finding trial, where only 3.6 mg differed from placebo.
Active Compound Casein hydrolysate containing the lactotripeptides valyl-prolyl-proline (VPP) and isoleucyl-prolyl-proline (IPP), produced by digesting milk casein with an Aspergillus oryzae protease.

Benefits

Blood pressure: small and inconsistent effect

In a 2013 meta-analysis of 14 European trials (1,306 people), VPP and IPP lowered systolic blood pressure by 1.28 mmHg and diastolic by 0.59 mmHg more than placebo, a change too small to notice. Japanese trials, most run by Calpis, report larger drops of about 5 to 6 mmHg. The largest European trials found no effect. Unilever, which licensed AmealPeptide from Calpis in 2005, tested enzyme-made peptides in yoghurt drinks in 275 Dutch adults (10.2 mg/day) and in two crossover trials of 69 and 93 people, and none lowered blood pressure. A Wageningen University trial in 135 Dutch adults (14 mg/day) was also null. In 2011 and 2012 the European Food Safety Authority concluded that a benefit for normal blood pressure had not been established, and the EU refused the claim in 2013. Japan, by contrast, lets Calpis's Ameal S drink carry a Food for Specified Health Use label for blood pressure. This is not a treatment for high blood pressure.

Supported by Trial 1

Arterial stiffness: small, mostly company-run trials

In one 8-week Calpis trial in 70 Japanese adults aged 50 to 69 with untreated stage 1 hypertension, 3.4 mg/day of the peptides reduced brachial-ankle pulse wave velocity, a marker of arterial stiffness, by 74 cm/s compared with 8 cm/s on placebo. A 6-week Italian trial in 52 people taking 3 mg/day reported lower pulse wave velocity in the peptide group compared with starting values, but no change in 24-hour blood pressure. Pulse wave velocity is a marker, not a heart outcome, and no large independent trial has confirmed these results.

Supported by Trial 1

ACE blocking: seen in the lab, not in people

VPP and IPP block the ACE enzyme in test-tube and animal studies. In a study of 12 healthy men given fermented milk supplying 11.1 mg/day of IPP plus VPP for 7 days, the peptides were poorly absorbed and did not inhibit ACE, while a single dose of the drug captopril cut ACE activity by 82%. A Dutch trial of 135 adults also found no change in plasma ACE activity. How, or whether, these peptides affect blood pressure in people is not known.

Supported by Trial 1

Mechanism of action

1

ACE inhibition (lab and animal only)

VPP and IPP inhibit angiotensin-converting enzyme (ACE) in laboratory tests and in animals, which would reduce formation of the vessel-constricting hormone angiotensin II. In humans, a 7-day study found the peptides were poorly absorbed and did not inhibit ACE in the blood or the blood vessel lining, so this proposed mechanism is not established in people.

2

Vascular measures (small company trials)

Calpis trials in Japanese adults with mild hypertension reported a larger forearm blood flow response after 1 week (24 men, crossover design) and lower arterial stiffness after 8 weeks (70 adults). Because a human study found the peptides did not block ACE, any vascular effect would need another explanation, and none has been shown in people.

Clinical trials

1
Meta-Analysis (Not a Single Trial): Lactotripeptides and Blood Pressure in Europeans
PubMed

Meta-analysis of randomized controlled trials of the lactotripeptides IPP and VPP on systolic blood pressure in European subjects. (Cicero et al. 2013, American Journal of Hypertension). Two of the four authors were paid by Calpis to perform it. The included trials tested a mix of products (fermented milks and spreads, and peptide powder added to yoghurt drinks or fruit juice), and most do not name the peptide supplier, so only part of this evidence concerns AmealPeptide itself.

1,306 European adults (Finland, the Netherlands, Scotland, Denmark, Italy) in 14 randomized trials, mostly with high-normal blood pressure or mild hypertension, taking 1.8 to 10.4 mg/day for 4 to 21 weeks.

Systolic blood pressure fell 1.28 mmHg more than on placebo (95% CI 0.48 to 2.09) and diastolic 0.59 mmHg more. The authors called this a moderate reduction, but most individual trials, including the three largest, showed no significant effect on their own. A separate Calpis-funded meta-analysis of 18 Japanese trials estimated a 5.63 mmHg systolic drop.

Side effects and drug interactions

Common Potential side effects

Few side effects were reported in trials. A 4-week Calpis study in 48 people taking five times the usual amount found no clinically important adverse events and no excessive drop in blood pressure.
Mild digestive upset is occasionally reported.
Avoid if you have a milk-protein allergy.

Important Drug interactions

Blood pressure medication: an added lowering effect is possible in principle; tell your doctor, and do not use this in place of prescribed treatment.
ACE inhibitors (such as lisinopril): a human study found the peptides did not inhibit ACE, so an interaction is theoretical; tell your doctor.
Tell your doctor if you take cardiovascular medication.

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Frequently asked questions about AmealPeptide® (Casein Lactotripeptides VPP and IPP)

What is AmealPeptide?

AmealPeptide® is a casein-derived ingredient supplying the lactotripeptides VPP (valyl-prolyl-proline) and IPP (isoleucyl-prolyl-proline), made by Calpis (now part of Asahi Group) by digesting milk casein with an enzyme from the mould Aspergillus oryzae.

What is AmealPeptide used for?

AmealPeptide is researched primarily for Cardiovascular. In a 2013 meta-analysis of 14 European trials (1,306 people), VPP and IPP lowered systolic blood pressure by 1.28 mmHg and diastolic by 0.59 mmHg more than placebo, a change too small to notice.

What is the recommended dosage of AmealPeptide?

The clinically studied dose is 3.4 mg/day of VPP plus IPP in tablets for 8 weeks (Calpis trial, 70 adults); 1.8, 2.5 or 3.6 mg/day for 6 weeks in a Calpis dose-finding trial, where only 3.6 mg differed from placebo. Always follow the product label and check with a healthcare provider for personal advice.

Is AmealPeptide safe, and does it have side effects?

Side effects and cautions reported for AmealPeptide include: Few side effects were reported in trials. A 4-week Calpis study in 48 people taking five times the usual amount found no clinically important adverse events and no excessive drop in blood pressure. Mild digestive upset is occasionally reported. It may also interact with some medications. AmealPeptide is not right for everyone, so check with a healthcare provider first if you are pregnant or breastfeeding, have a medical condition, or take prescription medication.

Does AmealPeptide interact with any medications?

Possible interactions include: Blood pressure medication: an added lowering effect is possible in principle; tell your doctor, and do not use this in place of prescribed treatment. If you take prescription medication, check with a pharmacist or doctor before using it.

How strong is the scientific evidence for AmealPeptide?

NutraSmarts rates the evidence for AmealPeptide as Limited (2 out of 5). It is backed by 1 study summary and 9 cited references summarized on this page. A higher rating reflects more, larger, and better-designed human studies.

References(9 citations)

Evidence ratings on NutraSmarts are based on the totality of human clinical research, with emphasis on randomized controlled trials, meta-analyses, and systematic reviews. The references below directly support claims made throughout this page.

  1. Cicero AF, Aubin F, Azais-Braesco V, et al. Do the lactotripeptides isoleucine-proline-proline and valine-proline-proline reduce systolic blood pressure in European subjects? A meta-analysis of randomized controlled trials. Am J Hypertens. 2013;26(3):442-9..PubMedUsed to support: Meta-analysis of 14 randomized trials in 1,306 European adults: IPP and VPP lowered systolic blood pressure by 1.28 mmHg and diastolic by 0.59 mmHg more than placebo, which the authors called a moderate reduction, while most individual trials, including the three largest, showed no significant effect on their own. Two authors were paid by Calpis, and the trials tested a mix of fermented-milk and peptide-powder products, not only AmealPeptide.
  2. Wuerzner G, Peyrard S, Blanchard A, Lalanne F, Azizi M. The lactotripeptides isoleucine-proline-proline and valine-proline-proline do not inhibit the N-terminal or C-terminal angiotensin converting enzyme active sites in humans. J Hypertens. 2009;27(7):1404-9..PubMedUsed to support: In 12 healthy men given fermented milk with 4.5 mg IPP and 6.6 mg VPP daily for 7 days, the peptides were poorly absorbed and did not inhibit plasma or endothelial ACE, whereas one 50 mg dose of captopril cut plasma ACE activity by 82%.
  3. Geleijnse JM, Engberink MF. Lactopeptides and human blood pressure. Curr Opin Lipidol. 2010;21(1):58-63..PubMedUsed to support: Review: six placebo-controlled trials in 780 UK and Dutch adults (2 to 10 mg/day IPP plus VPP, 4 to 8 weeks) showed little evidence of a blood pressure effect and no ACE inhibition in the body; earlier Finnish and Japanese trials reported drops of about 5 mmHg, and an effect in those populations could not be excluded.
  4. Nakamura T, Mizutani J, Ohki K, Yamada K, Yamamoto N, Takeshi M, Takazawa K. Casein hydrolysate containing Val-Pro-Pro and Ile-Pro-Pro improves central blood pressure and arterial stiffness in hypertensive subjects: a randomized, double-blind, placebo-controlled trial. Atherosclerosis. 2011;219(1):298-303..PubMedUsed to support: Calpis-run randomized trial in 70 Japanese adults aged 50 to 69 with untreated stage 1 hypertension: 3.4 mg/day VPP plus IPP in tablets for 8 weeks lowered central systolic pressure (-11.0 vs -4.5 mmHg), brachial systolic pressure (-10.5 vs -3.9 mmHg) and brachial-ankle pulse wave velocity (-73.9 vs -8.4 cm/s) compared with placebo. Not independently replicated.
  5. Mizuno S, Matsuura K, Gotou T, Nishimura S, Kajimoto O, Yabune M, Kajimoto Y, Yamamoto N. Antihypertensive effect of casein hydrolysate in a placebo-controlled study in subjects with high-normal blood pressure and mild hypertension. Br J Nutr. 2005;94(1):84-91..PubMedUsed to support: Calpis-run single-blind trial in 131 Japanese adults with high-normal blood pressure or mild hypertension: tablets of Aspergillus oryzae casein hydrolysate supplying 0, 1.8, 2.5 or 3.6 mg/day VPP plus IPP for 6 weeks lowered systolic pressure by -1.7, -6.3, -6.7 and -10.1 mmHg; only the 3.6 mg arm differed significantly from placebo, and diastolic pressure did not change.
  6. van der Zander K, Bots ML, Bak AA, Koning MM, de Leeuw PW. Enzymatically hydrolyzed lactotripeptides do not lower blood pressure in mildly hypertensive subjects. Am J Clin Nutr. 2008;88(6):1697-702..PubMedUsed to support: Unilever-run double-blind trial in 275 Dutch adults with hypertension: 10.2 mg/day of enzymatically produced lactotripeptides in a yoghurt drink for 8 weeks did not lower systolic (P=0.66) or diastolic (P=0.72) blood pressure compared with placebo.
  7. Engberink MF, Schouten EG, Kok FJ, van Mierlo LA, Brouwer IA, Geleijnse JM. Lactotripeptides show no effect on human blood pressure: results from a double-blind randomized controlled trial. Hypertension. 2008;51(2):399-405..PubMedUsed to support: Randomized trial in 135 Dutch adults with elevated systolic pressure: 14 mg/day of IPP plus VPP (from fermented milk, enzymatic hydrolysis or chemical synthesis) for 8 weeks did not change office, home or 24-hour blood pressure, plasma ACE activity or angiotensin II compared with placebo.
  8. Chanson-Rolle A, Aubin F, Braesco V, Hamasaki T, Kitakaze M. Influence of the Lactotripeptides Isoleucine-Proline-Proline and Valine-Proline-Proline on Systolic Blood Pressure in Japanese Subjects: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. PLoS One. 2015;10(11):e0142235..PubMedUsed to support: Meta-analysis of 18 trials in 1,194 Japanese adults: IPP and VPP lowered systolic blood pressure by 5.63 mmHg versus placebo (8.35 mmHg in people with hypertension, 3.42 mmHg without), with significant heterogeneity. Three authors were paid by Calpis to perform the review.
  9. Fekete ÁA, Givens DI, Lovegrove JA. Casein-derived lactotripeptides reduce systolic and diastolic blood pressure in a meta-analysis of randomised clinical trials. Nutrients. 2015;7(1):659-81..PubMedUsed to support: Independent meta-analysis of 30 trials: pooled drops of 2.95 mmHg systolic and 1.51 mmHg diastolic, significantly larger in Japanese than European studies; 24-hour ambulatory blood pressure did not change significantly, and publication bias and small-study effects shrank the systolic effect and made the diastolic effect non-significant.