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 Inadequate Lipid Effects

Even in 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 significantly inferior to simvastatin 20mg, and the authors acknowledged the lipid-lowering effect was not correlated with the observed reduction in atherosclerosis 3
• The 2022 study required an extremely high dose (10,800 FU/day—more than 5 times the typical dose) to show any lipid effects, and even then, the mechanism was unclear 4

What Actually Works: The Evidence-Based Algorithm

Target LDL-C Aggressively

For patients seeking atherosclerosis regression:

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
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

Timeline for Plaque Stabilization

• 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
• Lipid intervention angiographic trials suggest improved clinical outcomes relate to plaque passivation, reversal of endothelial dysfunction, or decrease in prothrombotic factors—all mediated through LDL reduction 6

Critical Pitfalls to Avoid

Do Not Pursue Unproven Alternatives

• Do not pursue "alternative" strategies (omega-3 fatty acids, supplements, HDL-raising alone) expecting plaque regression—omega-3 fatty acids are primarily for triglyceride management, not LDL reduction or plaque regression 1
• Do not delay aggressive LDL lowering in favor of unproven supplements or alternative therapies—this results in inadequate LDL-C reduction and increased cardiovascular risk 1
• 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

Nattokinase's Potential Role (If Any)

If nattokinase has any cardiovascular role, it would be limited to:

• Modest effects on clotting factors (fibrinogen, factor VII, factor VIII) in the 7-19% reduction range 5
• This is fundamentally different from plaque regression and does not address the underlying atherosclerotic process 6
• The clinical significance of these clotting factor reductions without corresponding atherosclerosis effects remains unproven 2

The Bottom Line for Clinical Practice

For patients seeking atherosclerosis reversal, prescribe evidence-based lipid-lowering therapy (statins ± ezetimibe ± PCSK9 inhibitors) targeting LDL-C <55 mg/dL rather than nattokinase. 6, 1 The 2021 randomized controlled trial definitively shows nattokinase does not affect atherosclerosis progression, and all proven plaque regression strategies work exclusively through aggressive LDL cholesterol reduction—a mechanism nattokinase does not reliably achieve. 1, 2