Experts Say Drastically Lowering LDL-Cholesterol to 20-40 mg/dL is Key

Atherosclerotic presents a strange paradox - it is likely the chronic disease most amenable to prevention and treatment, yet it remains the top cause of death and disability globally.

Thomas Dayspring, world-renowned expert mentioned in Attia's "Outlive", on X/Twitter:

This paper is mandatory for those who want to better understand & then eliminate atherosclerosis. All including LDL deniers must realize that humans were never meant to harbor the LDLc (apoB) levels that are now commonplace. NORMAL LDL-C is 20-40 mg/dL Thomas Dayspring (@Drlipid)

However, Dr. Dayspring followed up with:

You heard it here first. That 20-40 mg/dL is a physiologic LDL-C, but not everyone needs to achieve such a level.

The statement by Dr. Dayspring suggests that an LDL cholesterol (LDL-C) level between 20-40 mg/dL is considered physiological, meaning it's a natural level found in the body. However, he also implies that not everyone needs to reach this specific range. This could be due to individual differences in risk factors and health profiles, indicating a need for personalized treatment approaches.

Nonethless, Some eye-opening facts from the cited paper:

• Atherosclerosis begins in early childhood, with fatty streaks evident in the arteries by the teenage years in most people. The disease then slowly progresses over decades. "Atherosclerosis begins in earliest childhood, sometimes even during gestation, presenting as yellow streaks in arterial walls," the authors note.
• Cholesterol is a key driver. The level of LDL or "bad" cholesterol in the blood directly relates to cardiovascular risk. The lower the LDL, the lower the risk, even down to very low levels. "The relationship between low-density lipoprotein cholesterol (LDL-C) and risk for ASCVD is one of the most highly established and investigated issues in the entirety of modern medicine," the review states.
• Current guidelines don't recommend treatment until middle-age for most people. But the authors argue this misses a crucial window to prevent the silent buildup of plaque. "Assuming that just reducing acute events will also prevent long-term consequences of atherosclerosis is unwarranted by current evidence and has not been adequately studied," they write.
• Genetic studies show that keeping LDL very low from birth dramatically reduces lifetime cardiovascular risk by up to 88%. Even moderate lifelong reductions have a big impact. "Mendelian randomization also very convincingly shows that the lower the LDL-C, the less atherosclerosis and the fewer the resulting ASCVD-related events," the authors point out.
• Many factors beyond just cholesterol contribute to risk, like high blood pressure, diabetes, smoking, inflammation, and genetics. Evaluating and controlling all of these gives the best results. "There are many factors that damage the endothelium, contribute to atherosclerosis in other ways and activate the immune system, such as insulin resistance, hypertension, smoking, immunological disease and inflammation elsewhere in the body," the review highlights.

Physicians Often Hesitant to Change

Even when faced with strong scientific evidence, many doctors are hesitant to change the way they treat patients and adopt new approaches. This clinical inertia stems partly from the time constraints of modern medical practice and partly from physicians' cautious nature, preferring to wait for overwhelming proof that a new treatment is definitively better before altering their methods.

Optimal LDL Cholesterol is Much Lower Than Average Levels

The LDL cholesterol levels common in modern society are far higher than what humans are optimally adapted for. A study of newborn babies found an average LDL of only 20 mg/dL, showing that even rapidly developing infants require very little LDL. Populations of humans and animals that maintain very low cholesterol from a young age develop minimal atherosclerosis, indicating that the ideal LDL range to avoid plaque buildup is 20-40 mg/dL. While difficult to achieve with current lifestyles, this provides a benchmark for what is truly normal and healthy.

Statistical analysis shows that LDL levels of around 38 mg/dL are associated with no excess cardiovascular risk, aligning with the LDL levels seen in hunter-gatherer societies. In contrast, the average LDL of someone having a heart attack in the Framingham study was a much higher 150 mg/dL. Even people with LDL under 100 mg/dL, which is considered a healthy level by current standards, still showed a steady increase in risk of dying from heart disease over 26 years of followup in the Cooper Center study. This highlights the importance of lowering atherogenic lipoproteins as much as possible, as early in life as possible.

The "Medicine 3.0" Approach:

The authors lay out preventive recommendations for a new approach:

1. The earlier you can keep LDL low, the better. Ideally, LDL should never exceed 85 mg/dL throughout life. Combined with a healthy lifestyle, this will likely prevent significant plaque from ever developing. "If LDL-C can be kept very low from birth, atherosclerosis will not occur," they state.
2. If LDL starts creeping above 100 mg/dL, and definitely if there are signs of early plaque or other major risk factors, drug treatment should be considered to get LDL under 40 mg/dL. This can stop plaque progression. "Based on the preponderance of evidence, it seems best to set LDL-C goals below 40 mg/dl (1 mmol/dl), or even lower for even higher risk," the authors advise.
3. For those with advanced disease, like previous heart attacks, the data supports aiming for LDL under 20 mg/dL to maximize plaque regression. Newer medications like PCSK9 inhibitors (ie, Repatha) make this increasingly achievable. "Very advanced disease or very high risk would benefit from lowering LDL-C < 20 mg/dl," the review recommends.
4. Screening should start early, with checks of key genes and lipids by age 1-8. After that, regular followup and adjustment of treatment is key, as the duration of cholesterol exposure matters as much as the level. "Screening from birth would have even better results," the authors argue.
5. A nuanced approach is needed for each patient based on their unique combination of measurable risk factors - not just lipids but blood pressure, blood sugar, inflammation, family history, and direct imaging of arteries for plaque when warranted. "Each patient should be evaluated thoroughly and individually for all factors that contribute to risk," the review emphasizes.
6. Special attention is needed for high-risk groups like those with familial hypercholesterolemia (FH), a common genetic disorder that leads to extremely high LDL from birth. For them, medications may be needed starting in childhood to prevent early heart attacks. "If it indicates Familial Hypercholesterolemia not previously detected, treat immediately in cooperation with the pediatrician and follow closely," the authors advise.

What Can You Do to Prevent Heart Disease?

Some action steps:

1. Know your numbers. Get a full lipid panel that includes LDL cholesterol, non-HDL cholesterol, triglycerides, and apoB. Track these over time.
2. Assess your risk factors. Do you have a family history of early heart disease? Conditions like high blood pressure or diabetes? Had your coronary calcium measured? Discuss your personal risk level with your doctor.
3. Optimize your lifestyle. The foundation of heart health is a diet high in vegetables, nuts, whole grains and healthy proteins; regular exercise; avoiding smoking; and maintaining a healthy weight. Make sustainable changes over time.
4. Consider medication if needed. For those with high risk, lifestyle alone may not be enough. Statins are safe, effective, and have decades of evidence behind them. PCSK9 inhibitors and other newer options can help get LDL even lower.
5. Start early and be proactive. Advocate for having your children screened, especially if heart disease runs in your family. And if you're in your 20s, 30s or 40s, the time to act is now, not once complications develop. Regular monitoring and treatment adjustment over time is key.

As the authors conclude, "We have the means; do we have the will?" With the knowledge and tools now available, they believe atherosclerotic cardiovascular disease could become a rare condition. But it will require a fierce urgency and a willingness to treat much earlier and more aggressively than current norms.

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