Is nattokinase effective for increasing large, buoyant LDL (Low-Density Lipoprotein)-A particles?

Nattokinase for Large, Buoyant LDL Particles

Do not use nattokinase to increase large, buoyant LDL particles—there is no evidence it affects LDL particle size distribution, and the highest quality randomized controlled trial shows it has no effect on atherosclerosis progression or lipid parameters.

Evidence Against Nattokinase for LDL Particle Modification

Definitive Clinical Trial Data

• The largest and highest quality study—a 3-year, double-blind, randomized controlled trial of 265 individuals—demonstrated that nattokinase supplementation (2,000 fibrinolytic units daily) had no effect on subclinical atherosclerosis progression, blood pressure, or any lipid parameters compared to placebo 1
• This trial specifically measured carotid artery intima-media thickness and arterial stiffness serially over 3 years and found null results, indicating nattokinase does not impact cardiovascular risk markers 1

Limited and Contradictory Evidence

• One small Chinese study (76 patients, 26 weeks) suggested nattokinase reduced carotid plaque size and lowered total cholesterol, LDL-C, and triglycerides while increasing HDL-C 2
• However, this study had significant methodological limitations: small sample size, short duration, and lack of blinding, making it substantially weaker evidence than the 2021 randomized controlled trial 2
• Another small study showed nattokinase decreased coagulation factors (fibrinogen, factor VII, factor VIII) but found blood lipids were unaffected by nattokinase 3

Mechanism of Action Does Not Target LDL Particle Size

• Nattokinase is a serine protease with fibrinolytic and antithrombotic properties, primarily affecting blood clotting factors rather than lipoprotein metabolism 4, 3
• While some preclinical data suggests nattokinase may activate hormone-sensitive lipase and enhance lipoprotein lipase activity, these mechanisms have not translated to clinically meaningful effects on LDL particle distribution in humans 5

Evidence-Based Approach to Increasing Large, Buoyant LDL

Primary Strategy: Carbohydrate Restriction and Metabolic Optimization

• Reduce refined carbohydrate intake as the first-line intervention, since insulin resistance drives the formation of small, dense LDL particles 6
• Improve glycemic control in diabetic patients, as this is the most effective way to shift LDL particle distribution toward larger, more buoyant particles 6
• Achieve 5-10% weight loss through caloric restriction, which directly improves the small, dense LDL phenotype 6
• Engage in at least 150 minutes per week of moderate-intensity aerobic exercise 6

Critical Understanding of LDL Particle Biology

• Smaller LDL particles more easily penetrate the arterial intima due to passive molecular sieving that favors smaller particle size 7
• Small, dense LDL particles are more susceptible to oxidation and are characteristic of phenotype B, which includes hypertriglyceridemia, low HDL-C, abdominal obesity, and insulin resistance 7
• Larger, buoyant LDL particles are less atherogenic because they penetrate arterial walls less readily and are less susceptible to oxidative modification 7

Dietary Modifications That Actually Work

• Limit saturated fatty acids to <7% of total energy intake 6, 8
• Restrict dietary cholesterol to <200 mg/day 6, 8
• Add plant stanols/sterols (2 g/day) 6, 8
• Increase soluble fiber intake (10-25 g/day) 6, 8

Important Caveat About Saturated Fat

• Saturated fat restriction primarily reduces large LDL particles, not small dense LDL particles, in the majority of individuals 6
• This is a critical pitfall—do not rely solely on saturated fat restriction to improve LDL particle size distribution 6
• The focus must be on carbohydrate restriction and metabolic optimization for patients with insulin resistance 6

Pharmacological Options When Needed

• High-dose statins provide the most robust evidence for cardiovascular risk reduction and can reduce LDL particle number 6, 8
• Consider fibrates (gemfibrozil or fenofibrate) for patients with persistently elevated small LDL particles despite statin therapy, particularly when LDL-C is 100-129 mg/dL 6
• PCSK9 inhibitors for very high-risk patients not achieving goals with statins and ezetimibe 6, 8
• Monitor carefully for myopathy when combining statins with fibrates 6

Monitoring Strategy

• Measure LDL particle number in patients with diabetes, elevated triglycerides and low HDL, premature CVD, family history of premature CVD, or recurrent CVD despite optimal therapy 6, 8
• Use non-HDL cholesterol as a surrogate target when LDL particle number measurement is unavailable 6, 8
• Assess lipid profile every 3-6 months until target achieved, then every 6-12 months 6, 8
• Do not assume normal LDL-C means absence of risk—patients with metabolic syndrome or diabetes may have normal LDL-C but elevated small, dense LDL particle numbers 6, 8

Safety Considerations for Nattokinase

• While nattokinase appears generally safe with no significant adverse events reported in clinical trials, it has anticoagulant effects and could theoretically increase bleeding risk 3, 1
• Given the lack of efficacy for lipid modification and the availability of proven therapies, there is no clinical rationale for using nattokinase to modify LDL particle size 1