A Study of Nattokinase Supplementation Shows No Effect on Progression of Atherosclerosis

You might recall a Chinese study from a few years back claiming a sizable effect on atherosclerotic plaque for supplementation with nattokinase. The result was a 36% reversal in plaque size, which is several times larger than can be reliably achieved with approaches such as statins and their successors, drugs that lower blood cholesterol. The dose was 6000FU/day for 6 months. My attention was recently drawn to the publication of results for a US study using dose of 2000FU/day for several years. In that study, there was no effect on the progression of atherosclerosis, and certainly no marked reversal.

Medicine in general has a serious replication issue, in that all too many claimed results evaporate when a more rigorous study is undertaken. One only has to look at the NIA Interventions Testing Program to see many claims of longer mouse life spans refuted by more careful work. Problems with replication and study quality are particularly the case for clinical work conducted outside the US and Western Europe. One can find a great many researchers in wealthier nations who are immediately and reflexively skeptical of studies in their field that were conducted in other parts of the world.

That aside, is this a question of different doses and patients with a different severity of disease? Perhaps, but when one sees data with this sort of inconsistency, it casts doubt on whether there is or can be an effect size large enough to be interesting. Nattokinase does appear to have an effect on mammalian biochemistry and cell behavior that could influence atherosclerosis, but that is never the point. Mechanisms are what they are, the question is always whether or not the effect size of manipulating the mechanism in this way, with this treatment, is large enough to pursue.

Nattokinase atherothrombotic prevention study: A randomized controlled trial

Described to be antithrombotic and antihypertensive, nattokinase is consumed for putative cardiovascular benefit. However, no large-scale, long-term cardiovascular study has been conducted with nattokinase supplementation. To determine the effect of nattokinase on subclinical atherosclerosis progression and atherothrombotic biomarkers. In this double-blinded trial, 265 individuals of median age 65.3 years, without clinical evidence of cardiovascular disease (CVD) were randomized to oral nattokinase 2,000 fibrinolytic units (FU) daily or matching placebo. The primary outcome was rate of change in subclinical atherosclerosis measured by serial carotid ultrasound every 6 months as carotid artery intima-media thickness (CIMT) and carotid arterial stiffness (CAS). Additional outcomes determined at least every 6 months were clinical parameters including blood pressure and laboratory measures including metabolic factors, blood rheology parameters, blood coagulation and fibrinolysis factors, inflammatory markers and monocyte/macrophage cellular activation markers.

After median 3 years of randomized treatment, annualized rate of change in CIMT and CAS did not significantly differ between nattokinase supplementation and placebo. Additionally, there was no significant effect of nattokinase supplementation on blood pressure or any laboratory determination. The results of this trial show that nattokinase supplementation has a null effect on subclinical atherosclerosis progression in healthy individuals at low risk for CVD.

Nattokinase Atherothrombotic Prevention Study (NAPS)

The potential for nattokinase to "thin" blood and to reduce blood clotting by positive antithrombotic and fibrinolytic effects presents a unique opportunity to safely study such effects on cardiovascular disease and cognition. Using nattokinase under primary prevention conditions, the investigators propose to conduct a randomized, double-blinded, placebo-controlled trial to determine whether decreasing atherothrombotic risk can reduce the progression of atherosclerosis and cognitive decline. The investigators propose to randomize 240 healthy non-demented women and men to nattokinase supplementation or to placebo for three years. The primary trial endpoints will be measurement of carotid arterial wall thickness and arterial stiffness, early changes of atherosclerosis that can be measured safely by non-invasive imaging techniques.

At the conclusion of this trial, the investigators expect to have sufficient evidence as to whether reducing the propensity for thrombus formation and/or increasing fibrinolytic activity can prevent the progression of atherosclerosis and cognitive decline. These results will provide novel and important data that will be informative concerning primary prevention through the atherothrombotic pathway. Providing evidence for a reduction in atherosclerosis progression and cognitive decline with nattokinase is likely to shift the current clinical paradigm for the prevention of these chronic age-related processes. In addition, such evidence will serve to create a new field of discovery and opportunity for prevention of cardiovascular disease and dementia.


A Chinese study that can't be reproduced, shocking!!!

Posted by: JohnD at September 8th, 2021 7:02 PM

Some substances work in very wide range of doses, just weaker, others need certain minimum threshold otherwise they have no effect. And they may need additional substances (that are present in normal diet of study subjects) to exert this influence. Trying several doses - 2000FU - 6000FU - 12000FU daily would be more convincing. Trying the dose that may be 1/3 of just around minimum working dose doesn't expand knowledge (we still do not know if it works and what is the working minimal dose if it has such effect) just wastes resources.

Posted by: SilverSeeker at September 9th, 2021 5:49 AM

My expectations from the NAPS study were high until I finally read it. I do agree with @SilverSeeker - trialing such a small (and only) dose of nattokinase was a waste of time and resources. Would be good to see if larger doses affect blood coagulation parameters.

Posted by: Natto at November 19th, 2021 7:00 AM

I agree with other commentators. A multidose study is needed. Also, the NAPS study included those with subclinical disease who are at low risk. I would be much more interested in a study that looked at those with clinical disease who are at high risk. I do not believe that this study discredited nattokinase. I believe the study was poorly designed and possibly somewhat designed to discredit nattokinase on purpose. Why use low doses in low risk people???

Posted by: Karen Ludlow at July 21st, 2022 7:29 PM
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