Can nattokinase reverse atherosclerosis?

Can Nattokinase Reverse Atherosclerosis?

No, nattokinase cannot be recommended for reversing atherosclerosis based on the highest quality evidence—a large randomized controlled trial showed no effect on atherosclerosis progression, and all proven strategies for plaque regression work exclusively through aggressive LDL cholesterol lowering, which nattokinase does not achieve at clinically meaningful levels. 1, 2

The Evidence Against Nattokinase for Atherosclerosis Reversal

Highest Quality Trial Shows Null Effect

The most rigorous evidence comes from the Nattokinase Atherothrombotic Prevention Study, a double-blinded randomized controlled trial of 265 individuals followed for a median of 3 years. 2 This study found:

• No significant difference in carotid intima-media thickness (CIMT) progression between nattokinase and placebo 2
• No effect on carotid arterial stiffness 2
• No impact on blood pressure or any laboratory parameters 2
• The study population was healthy individuals at low cardiovascular risk, representing an ideal population to detect early atherosclerosis prevention effects 2

Why This Trial Trumps Other Studies

While smaller studies from 2017 and 2022 suggested benefits, these had critical methodological limitations that make them unreliable compared to the 2021 randomized controlled trial:

• The 2017 Chinese study (76 patients) and 2022 study (1,062 participants) were open-label without placebo controls, introducing substantial bias 3, 4
• The 2022 study's dramatic claims of 66.5-95.4% improvement rates are inconsistent with the null findings from the properly controlled 2021 trial 4, 2
• When properly blinded and placebo-controlled methodology is applied, the apparent benefits disappear 2

The Fundamental Mechanism Problem

All Proven Plaque Regression Requires Aggressive LDL Lowering

The American Heart Association and American College of Cardiology are unequivocal: all confirmed strategies for plaque regression fundamentally work through aggressive LDL cholesterol lowering, with no proven alternative mechanisms that achieve plaque regression independent of reducing LDL-C levels. 1

Key mechanistic principles:

• Atherosclerosis regression continues as LDL cholesterol reaches as low as 15 mg/dL, and this relationship holds regardless of the mechanism used to achieve LDL lowering 1
• Whether using statins, ezetimibe, PCSK9 inhibitors, or CETP inhibitors, the plaque regression effect is mediated through the degree of LDL-C reduction achieved, not through independent pleiotropic mechanisms 1
• Combinations of maximally tolerated statins with ezetimibe can produce profound effects on atherosclerosis stabilization and regression—but this occurs through their dramatic LDL cholesterol reduction 1

Nattokinase's Lipid Effects Are Inadequate

Even in the studies claiming benefit, nattokinase's lipid-lowering effects are modest and inconsistent:

• The 2009 study showed no effect on blood lipids despite reducing clotting factors 5
• The 2017 study showed lipid reductions, but these were significantly less than statin therapy (the comparator group) 3
• The 2022 study claimed lipid improvements but lacked placebo control to determine if changes were clinically meaningful 4
• The properly controlled 2021 trial showed no significant effect on any lipid parameters 2

What Actually Works: The Evidence-Based Algorithm

Target Aggressive LDL Reduction

For patients seeking atherosclerosis regression, the evidence-based approach is:

1. Target LDL-C <55 mg/dL (1.4 mmol/L) with at least 50% reduction from baseline for very high-risk patients 1

2. Start with high-intensity statin therapy (reduces LDL-C by 45-50%) 1

3. Add ezetimibe when maximum tolerated statin dose fails to achieve target (provides additional 20-25% LDL-C reduction) 1, 6

4. Consider PCSK9 inhibitors for patients at very high cardiovascular risk with persistently elevated LDL-C despite maximum tolerated statin plus ezetimibe therapy (reduces LDL-C by approximately 60%) 1

5. Very aggressive LDL cholesterol lowering for 3-4 years may stabilize plaque in most patients, with subsequent maintenance on maximal statin therapy adequate to suppress new plaque formation 1

Supporting Evidence for This Approach

• The IMPROVE-IT trial showed that ezetimibe plus simvastatin significantly reduced major cardiovascular events by ~7% when started within 10 days of an acute coronary syndrome, with intravascular ultrasound demonstrating greater regression of coronary artery plaque volume 6
• Multiple lipid intervention angiographic trials suggest that improved clinical outcome relates to plaque stabilization, reversal of endothelial dysfunction, or decrease in prothrombotic factors—all mediated through LDL reduction 6
• The MIRACL trial and subsequent studies confirmed that early intensive lipid lowering after acute coronary syndromes provides benefit 6

Critical Pitfalls to Avoid

Do Not Pursue Nattokinase Expecting Plaque Regression

Do not delay aggressive LDL lowering in favor of nattokinase or other unproven supplements—this results in inadequate LDL-C reduction and increased cardiovascular risk. 1

• Nattokinase's primary demonstrated effect is on clotting factors (fibrinogen, factor VII, factor VIII), not on atherosclerosis itself 5
• Even if nattokinase has fibrinolytic properties, fibrinolysis does not reverse established atherosclerotic plaque 6, 1
• The atherosclerotic process involves oxidative stress, endothelial dysfunction, inflammatory mediators, smooth muscle cell proliferation, and lipid-laden macrophages—none of which are addressed by fibrinolytic activity alone 6

Do Not Assume Different Mechanisms Provide Additive Benefits

Do not assume that different LDL-lowering mechanisms provide additive plaque regression benefits beyond their LDL-lowering effects—the magnitude of LDL reduction, not the mechanism, determines plaque regression. 1

This principle applies equally to nattokinase: even if it had some lipid-lowering effect (which the best evidence refutes), it would need to achieve the same degree of LDL reduction as proven therapies to have comparable benefit.

The Bottom Line for Clinical Practice

For patients asking about nattokinase for atherosclerosis:

• Explain that the highest quality randomized controlled trial showed no benefit 2
• Emphasize that all proven plaque regression strategies work through aggressive LDL lowering to targets <55 mg/dL 1
• Redirect to evidence-based therapies: high-intensity statins, ezetimibe, and PCSK9 inhibitors as needed 1, 6
• Address modifiable risk factors through therapeutic lifestyle changes including diet low in saturated fats, increased physical activity, and smoking cessation 6
• Do not waste time with nattokinase when proven, guideline-recommended therapies are available 6, 1