# Redefining "Normal" Cholesterol: A New Strategy to Unseat Heart Disease as the Nation's #1 Killer

This special article, written by a leading cardiologist at the Cedars-Sinai Heart Institute in Los Angeles, makes a bold argument: current guidelines for managing LDL cholesterol (the "bad" cholesterol) start treatment too late and aim for targets that may be too high to truly prevent heart attacks. Drawing on evidence from wild animals, traditional human societies, genetic studies, and major clinical trials, the author proposes that the true "normal" LDL range may be roughly 35 to 70 mg/dL—far below today's typical targets. The article carefully weighs the pros and cons of this paradigm shift, including concerns about cost, medication side effects, and the promise of genetic testing, and concludes that adopting these changes could potentially displace coronary artery disease as the nation's number one killer.

# Redefining "Normal" Cholesterol: A New Strategy to Unseat Heart Disease as the Nation's #1 Killer

## Table of Contents

- Key Points
- Why This Research Matters
- The Search for a "Normal" LDL Cholesterol Level
- What Animals and Traditional Societies Tell Us
- Putting the Theory to the Test: Clinical Trial Evidence
- Atherosclerosis Begins in Youth
- Rethinking Who Should Be Treated
- Rethinking the Treatment Target
- The Role of Genetics in Statin Response
- Arguments For and Against the Proposed Changes
- What This Means for Patients
- Study Limitations
- Recommendations for Patients
- Frequently Asked Questions
- Source Information

## Key Points

- Current LDL targets of roughly 130 mg/dL may be too high; proposed true normal range is 35–70 mg/dL.
- Atherosclerosis begins in youth; early plaque has been found in teenagers, supporting earlier treatment.
- In JUPITER, lowering LDL from 108 to 55 mg/dL reduced cardiac events by 44% in an asymptomatic group.
- Genetic variants in PCSK9 and KIF-6 can markedly alter LDL levels and statin benefit, enabling personalized therapy.
- Long-term safety of very low LDL beyond 5-year trials remains unknown; lifestyle modification remains essential.

## Why This Research Matters

Heart disease remains the leading cause of death in the Western world, yet the way doctors manage cholesterol may be fundamentally flawed. This article, published in the Journal of the American College of Cardiology in 2010, was written in anticipation of the new Adult Treatment Panel (ATP) guidelines released in 2011—a set of recommendations that would shape heart disease prevention for the next decade.

The author, Dr. James S. Forrester, argues that the existing ATP III guidelines contain three major problems: how doctors decide who needs treatment, the way treatment targets vary by patient risk level, and the actual cholesterol levels chosen as goals. He proposes a wholesale rethinking based on two fundamental principles: **return LDL cholesterol to its natural "normal" range** and **begin treatment much earlier in the disease process**.

What makes this article so consequential is that these guidelines are not just academic recommendations—they are endorsed by the U.S. Food and Drug Administration and implemented by millions of health care practitioners worldwide. Any change would affect millions of patients.

## The Search for a "Normal" LDL Cholesterol Level

How do you define a "normal" cholesterol level? The traditional approach was straightforward: measure LDL cholesterol in a large population of apparently healthy people, plot the results on a bell-shaped curve, and pick the middle of the range as normal. Using this method, the calculated median LDL cholesterol level in a clinically asymptomatic population was approximately **130 mg/dL**. This number became embedded in the ATP III guidelines both as the level for starting therapy in patients with known heart disease and as the treatment target for those without known disease.

But there are serious problems with this logic. First, being "asymptomatic" (having no symptoms) is not the same as being healthy. Population studies show that **35% of patients who have a myocardial infarction (heart attack) had no symptoms at all before the event**. A "normal" population cannot be defined simply by the absence of symptoms if more than one-third of people who go on to have heart attacks are in that group.

Second, the 130 mg/dL target itself appears to be too weak to protect patients. In statin trials, only **25% to 35% of cardiac events are prevented when LDL cholesterol is reduced to the 100 to 130 mg/dL range**, regardless of whether patients have symptoms. The author concludes that the 130 mg/dL cut point "has little support in the recent published literature."

## What Animals and Traditional Societies Tell Us

Five years before this article, O'Keefe and colleagues took a completely different approach to defining normal LDL cholesterol. Instead of studying sick humans, they looked at the animal kingdom and human history.

Their starting point was the total cholesterol level of **80 to 110 mg/dL found in nonatherosclerotic wild mammalian species**—including baboons, monkeys, horses, bears, rhinoceroses, elephants, and wild pigs. From this, they calculated the LDL cholesterol level to be approximately **35 to 70 mg/dL**.

Humans are born with LDL cholesterol levels in this exact range, but levels gradually rise with age. However, at least two adult human populations do not show this progressive rise:

-
**Hunter-gatherer societies**—diverse in geographic location and ethnic origin, but living the way humans did 10,000 years ago—maintain LDL levels in the 35 to 70 mg/dL range.
-
**Rural Chinese populations** in modern societies often have blood levels that fall within this same range.

In neonates, hunter-gatherers, and these rural populations, **atherosclerotic coronary disease is rare**. The consistency of these diverse data sources—mammalian species, human newborns, and isolated human societies—supports the speculation that the putative (presumed) normal range of LDL cholesterol in adult humans is approximately 35 to 70 mg/dL.

This observation raises a provocative question: since humans are the only free-living animal species with cholesterol levels roughly double this range, perhaps we are the outliers—and our "normal" cholesterol is actually a disease state. The accompanying figure comparing LDL levels across species shows that the mean LDL level in U.S. adults is approximately twice the range found in wild animals.

## Putting the Theory to the Test: Clinical Trial Evidence

The next logical step was to test what happens when cholesterol is lowered into this proposed normal range. Two recent randomized clinical trials (studies where patients are randomly assigned to receive treatment or a placebo) provided the evidence.

The **ASTEROID trial** (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound) reduced LDL cholesterol from 130 mg/dL to **61 mg/dL** using intensive statin therapy. The breakdown of the reductions was notable: 12% of patients achieved LDL below 40 mg/dL, and 41% achieved levels between 40 and 60 mg/dL. The result: **regression of carotid atherosclerosis**—meaning existing plaque in the arteries actually shrank.

The **JUPITER trial** (Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin) was even more striking. It took an asymptomatic intermediate-risk population with a mean LDL of 108 mg/dL and reduced it to **55 mg/dL**. This produced a **44% reduction in adverse cardiac events**. In patients whose on-treatment LDL was at or below 70 mg/dL, the event rate was just **1.4%**. Importantly, neither trial identified increased statin-induced toxicity (side effects) at these lower LDL levels.

These findings are corroborated by mathematical extrapolation of data from earlier trials:

- In secondary prevention angiographic trials (studies of patients who already had heart disease), **lesion progression reaches zero at an LDL level of 67 mg/dL**, and coronary events reach zero at approximately 30 mg/dL.
- In primary prevention trials (studies of patients without known heart disease), **major adverse cardiac events reach zero at an on-treatment LDL level of 57 mg/dL**.

Thus, clinical trials join the evidence from mammals, human newborns, and isolated societies: the putative normal LDL range of 35 to 70 mg/dL is biologically and clinically meaningful.

## Atherosclerosis Begins in Youth

One of the most critical insights in this article is that heart disease is not an old person's problem. Decades before the first heart attack, the disease process is already underway.

As LDL levels rise above the putative normal range, atherosclerosis begins to appear surprisingly early:

- By ages **12 to 17 years**, LDL cholesterol reaches an average of 87 mg/dL, and **5% to 7% of this age group already has LDL at or above 130 mg/dL**.
- Intracoronary ultrasound imaging of donor hearts at the time of transplantation—at an average of 2,014 sites within 1,477 segments of 574 coronary arteries in 262 recipients—revealed that **plaques of at least 0.5 mm were present in 17% of 13- to 19-year-olds** and increased to **60% in 30- to 39-year-olds**.
- In the full transplant donor population, **52% had atherosclerotic lesions**, ranging from 17% in individuals younger than 20 years to 85% in those older than 50 years. In those with lesions, intima thickness averaged 1.1 mm, and the average area stenosis was 33%.

The presence of these ultrasound-identified plaques is not merely cosmetic—it predicts long-term morbidity and mortality at follow-up.

Perhaps most concerning, **those at risk of developing atherosclerosis can be identified in youth**, and the consequences are severe. The Bogalusa Heart Study performed autopsies on young adults who had undergone risk factor analysis in childhood. Those with **3 or more childhood risk factors had a 9-fold increase in atherosclerotic plaque area** compared with those with none.

Lipid abnormalities in childhood also predict early clinical disease. In adults whose cardiovascular disease onset occurred between ages 39 and 45, their childhood mean triglyceride level was **127 mg/dL** and body mass index (BMI) was **24 kg/m²**, contrasted with those without clinical disease who had a triglyceride level of **72 mg/dL** and BMI of **20 kg/m²**.

The good news is that early intervention works. In children with familial hypercholesterolemia (a genetic condition causing very high cholesterol), taking pravastatin 20 to 40 mg/day for 2 years induced a **24% reduction in LDL cholesterol**, accompanied by a significant reduction in carotid intima-media thickness compared with both baseline and placebo controls, with **no difference in growth, muscle, or liver enzymes, or endocrine function**.

The conclusion is sobering: atherosclerotic disease begins in youth, the risk of developing clinical disease can be identified decades before its presentation, and the disease can be arrested or reversed during this period.

## Rethinking Who Should Be Treated

Under the current ATP III guidelines, treatment initiation is based on the calculated **10-year risk of a cardiac event**—but this approach has fundamental flaws that the author argues are "very heavily weighted by age."

The existing initiation levels now seem far too high: for example, **190 mg/dL for Framingham low-risk individuals** and **130 to 160 mg/dL for asymptomatic individuals with risk factors**. The JUPITER trial powerfully illustrates the problem: in an asymptomatic population with a mean LDL of 108 mg/dL, approximately one-half had a calculated 10-year Framingham risk below 10%, yet they still experienced a 44% event reduction when LDL was lowered to the middle of the putative normal range.

The 10-year risk calculation is heavily age-weighted—so much so that the calculated mean 10-year risk for a 25-year-old man **increases 7-fold over 30 years**. Younger individuals with a high risk factor burden clearly have a high probability of atherosclerotic disease, but their low calculated 10-year risk means they do not become candidates for treatment until the disease is very well established. This matters enormously: **approximately one-half of those in whom coronary artery disease develops first present with either sudden death or acute infarction**—their first symptom is their last.

The author suggests that reorienting initiation criteria toward the pathogenesis of atherosclerosis (the disease process itself) rather than its first clinical manifestation is eminently feasible. Three methods are currently available:

1. Express an individual's risk **relative to the average risk for that person's age group**.
1. Express the individual's calculated risk **relative to optimal values** for that age group.
1. Calculate the **Framingham risk over 30 years** rather than the current 10-year period.

Each method can support simple, objective initiation criteria. For example, a young individual with risk in the **upper 10% of their age group**, or a calculated **2- to 3-fold greater risk than optimum**, or a **40% 30-year risk** might be identified as a candidate for pharmacologic therapy. The essential concept: a long-term disease requires a long-term solution—management must begin earlier in the course of the disease to dislodge atherosclerosis from its number one position.

## Rethinking the Treatment Target

If the goal is to treat people earlier, the logical target is the putative normal range itself—35 to 70 mg/dL—provided it can be achieved at acceptable cost, without toxicity, and without replacing lifestyle modification. The author is careful to note that a naturally or lifestyle-induced low LDL is not necessarily the same as medication-induced low LDL.

Genetic evidence provides powerful insight into what a lifetime of lower LDL might accomplish. In the **ARIC study** (Atherosclerosis Risk in Communities), a free-living population study of 12,787 subjects, approximately 3% carry sequence variants in the gene colloquially called **PCSK-9** (pro-protein convertase subtilisin/kexin type 9 serine protease). These variants lower LDL cholesterol by a mean of approximately 19% compared with the general population—and the consequences are dramatic:

- Among **3,363 black subjects**, the mutations were associated with a **28% reduction in mean LDL cholesterol** and an **88% reduction in the risk of coronary heart disease**.
- Among **9,524 white subjects**, a sequence variation in PCSK9 was associated with a **15% reduction in LDL cholesterol** and a **47% reduction in risk**.
- Overall, individuals with the PCSK mutation had a mean **62% lower rate of cardiac events over the first 15 years of observation**.

These data suggest that a single putative normal LDL target might reasonably replace the existing multiple arbitrary targets stratified by risk. The **70 mg/dL target for individuals with coronary artery disease and diabetes is already widely accepted as highly beneficial**. The author argues it is simply reasonable to offer this same benefit to all individuals selected for treatment—because asymptomatic individuals may have life-threatening disease, and the pathogenesis of the disease is identical regardless of symptoms.

## The Role of Genetics in Statin Response

An inevitable consequence of lowering the initiation threshold and treatment target would be a significant expansion in the use of statin drugs. One possible solution to overuse lies in **pharmacogenetics**—using genetic testing to predict which patients are most likely to benefit from therapy.

Why is this needed? There are two reasons statin therapy may fail to prevent cardiac events: the "too little, too late" hypothesis, and the fact that drugs may simply be ineffective in as-yet-unrecognized patient subsets. Pharmacogenetics suggests this second reason is highly likely.

The **KIF-6 polymorphism** provides a compelling example. The kinesin-like protein 6 Trg 719 Arg polymorphism is thought to influence both intracellular transport and endothelial function. In the **PROVE IT trial** (Pravastatin or Atorvastatin Evaluation and Infection Therapy), which compared atorvastatin 80 mg with pravastatin 40 mg:

- In **carriers of the KIF-6 variant**, intensive statin therapy was associated with a **6.8-fold greater reduction in cardiac events** than in non-carriers, despite the same level of on-treatment LDL cholesterol and C-reactive protein (CRP).
- In **non-carriers** (approximately 40% of the U.S. population), there was **virtually no difference in adverse outcomes** despite the major differences in on-treatment LDL levels between the high-dose and standard-dose groups.
- The **number needed to treat** (NNT; the number of patients who must receive intensive treatment to prevent one event) was **10 in KIF-6 carriers but 125 in non-carriers**.

In other words, genetic testing could allow doctors to target intensive therapy to those most likely to benefit, dramatically improving the cost-effectiveness and risk-benefit ratio of treatment. A figure comparing carriers with non-carriers in the PROVE IT trial shows a clear divergence in event rates over 30 months for carriers, while non-carriers show nearly identical event rates regardless of which statin they received.

The author emphasizes that while this proposal has a reasonable basis in published literature, it still requires further validation and currently represents a concept, not a specific recommendation.

## Arguments For and Against the Proposed Changes

The author is balanced in presenting the case against making these significant guideline changes.

**Arguments against changing the guidelines include:**

- The stepwise approach to LDL initiation levels and targets is a well-established structure that doctors are familiar with.
- Guidelines typically are based on randomized clinical trials, whereas the putative normal range of LDL is based on inference from multiple indirect data sources.
- Higher drug doses imply an inevitable risk of increased drug toxicity.
- The risk of long-term aggressive therapy beyond the 5-year clinical trials is unknown, and long-delayed adverse effects are exceptionally difficult to detect.
- Even with potent agents, a low LDL target will not be achievable in many individuals.
- Younger people may be reluctant to take a daily medication, creating practical hurdles to implementation.
- Lowering initiation levels and targets increases the number of people on therapy—which necessarily means the number of individuals not benefiting from therapy will also increase.
- The impact on health care costs is unpredictable.

**The author's response to these concerns is equally direct:** because the principal issues surrounding guideline change are likely to be uncertainty about cost and toxicity, the text of new guidelines should strongly emphasize a prudent, conservative approach to implementation—presenting the target as a desirable option rather than a mandate, and including both cautionary data and caveats about the tradeoffs among the potency, cost, and toxicity of statins.

The author acknowledges that these two issues—cost and toxicity—will probably outweigh achievement of the target in **at least one-fourth of treated patients**. In guideline jargon, the level of evidence supporting this approach is clearly **Level C** (supported only by inference from existing data), but the author points out that the current guidelines are also Level C.

Recognizing that guidelines classify data sources, however, no one needs to be misled about the strength of supporting information. At the practical level, **potent generic statins allow this strategy to be implemented at low individual patient cost**. The author poses a thought-provoking question: "whether a low-cost generic statin used in a well-defined at-risk population might provide both more benefit and less risk than aspirin" (a medication universally accepted for heart disease prevention).

## What This Means for Patients

If these proposed changes were adopted, the implications for patients would be substantial:

-
**More people would qualify for treatment**, including younger adults who currently have "acceptable" 10-year risk scores but already have significant risk factor burdens.
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**Treatment goals would be lower**—a single target around 70 mg/dL (or potentially lower) would replace the current variable targets, which range from 70 to 190 mg/dL depending on individual patient circumstances.
-
**Treatment would start earlier**, potentially in childhood or young adulthood for those at high risk, based on the evidence that the disease process begins in youth.
-
**Genetic testing may play a larger role** in determining who receives intensive therapy, potentially identifying those most likely to benefit while sparing others unnecessary medication.
-
**Lifestyle modification remains essential**—the author is explicit that drug therapy should not be used as a substitute for healthy living.

The JUPITER data are particularly relevant to patients: even individuals with "normal" LDL levels around 108 mg/dL—who would not traditionally qualify for statin therapy—experienced a 44% reduction in cardiac events when their cholesterol was lowered to 55 mg/dL. For a patient, this suggests the question of who needs cholesterol-lowering treatment is more complex than a simple blood test reading.

## Study Limitations

This article has significant limitations that the author openly acknowledges:

-
**Level of evidence is C**: the entire argument relies on inference from existing data, not on a single prospective randomized trial designed to test the hypothesis that treating to 35 to 70 mg/dL from youth improves outcomes more than current practice.
-
**The duration of the disease vastly exceeds the duration of randomized trials**. Atherosclerosis begins in youth and progresses over decades, while clinical trials typically last 2 to 5 years. From first principles, a short trial cannot be assumed to predict either efficacy or toxicity over 40 to 60 years of therapy with scientific rigor.
-
**Run-in periods distort toxicity data**: the acute toxicity results of trials are made grossly misleading by the 1-month run-in period before randomization, during which patients who experience early side effects are excluded from the trial.
-
**Short-term absence of toxicity cannot be taken to predict long-term absence of toxicity**.
-
**The alleged efficacy of LDL lowering is derived predominantly from 5-year clinical trials**, whereas the magnitude of benefit from an earlier and sustained lifetime of lower LDL is poorly defined in therapeutic (as opposed to genetic) settings.

The author notes that unlike many guidelines in cardiology, the LDL cholesterol guidelines now and for the foreseeable future **must be based on logical inference rather than scientific rigor**—which is precisely why the article presents both the rationale and the caveats.

## Recommendations for Patients

While this article is written for medical experts, several important messages emerge for patients and their families:

1.
**Know your numbers early**. Since atherosclerosis begins in youth, checking cholesterol in childhood and young adulthood has far more value than waiting until middle age. If you have children with risk factors (such as a family history of early heart disease), talk to their pediatrician about lipid screening.
1.
**Don't be falsely comforted by a "normal" LDL level**. The current definition of normal—around 130 mg/dL—may be too high to prevent the progression of atherosclerosis. A "normal" result does not necessarily mean "healthy."
1.
**Lifestyle matters at every age**. The author emphasizes that drug therapy is not a substitute for lifestyle modification. Diet, exercise, weight management, and not smoking are foundational—regardless of whether you take a statin.
1.
**Understand your overall risk, not just your 10-year risk**. The 10-year risk calculation is heavily age-weighted and can falsely reassure younger adults with significant risk factors. Ask your doctor about your lifetime or 30-year risk, and discuss your risk relative to others in your age group.
1.
**Early treatment can reverse early disease**. The pravastatin study in children with familial hypercholesterolemia shows that early LDL lowering can reduce carotid intima-media thickness without affecting growth or development. If you have a genetic form of high cholesterol, aggressive treatment from a young age may be more beneficial than waiting.
1.
**Watch for advances in genetic testing**. The KIF-6 and PCSK-9 findings suggest that genetic testing may eventually help doctors personalize statin therapy—identifying who will benefit most and who may not need intensive treatment. Ask your doctor if these tests are appropriate for you or your family.
1.
**Expect the conversation to change**. As guidelines evolve, you may find your doctor recommending statin therapy at lower LDL levels than previously thought necessary. This is not overtreatment—it reflects a growing understanding that early, sustained control of cholesterol is key to preventing heart disease.

Ultimately, the author's vision is captured in one observation: humans are the only free-living animal in which atherosclerosis develops naturally, and our average LDL levels are roughly double that of every other mammalian species. The question his article poses to the medical community is straightforward: should we accept this as normal, or redefine what normal really means?

## Frequently Asked Questions

### My LDL is around 130 mg/dL. Is that considered healthy?

The article says this level has little support in recent literature. It comes from averaging asymptomatic people, but being symptom-free is not the same as being healthy—35% of heart attack patients had no prior symptoms. Also, statin trials that lower LDL to 100–130 mg/dL only prevent 25–35% of cardiac events, so 130 may be too high for true protection.

### Will I need to start taking statins earlier in life?

The author proposes a major shift: begin treatment earlier, possibly in childhood or young adulthood for high-risk people. This is because atherosclerosis begins in youth—5–7% of 12–17 year olds already have LDL at or above 130. Early treatment can even reverse early disease, as shown in a children's pravastatin study. This is a proposal, not current standard care.

### Are lower LDL levels safe, especially below 70 mg/dL?

In two major trials—ASTEROID and JUPITER—lowering LDL to around 55–61 mg/dL caused regression of artery plaque and fewer heart events, with no increase in short-term toxicity. However, these trials lasted only a few years. Long-term effects of very low LDL over decades are unknown, and the article acknowledges this uncertainty.

### What did the JUPITER trial show about people with 'normal' cholesterol?

JUPITER included asymptomatic middle-risk people with an average LDL of 108 mg/dL—levels many would consider normal. Taking rosuvastatin reduced their LDL to 55 mg/dL and cut adverse cardiac events by 44%. In those whose LDL fell below 70, the event rate was just 1.4%. This suggests even people without high LDL may benefit from treatment.

### How might genetic testing change who gets intensive statin therapy?

Genetic testing could identify who benefits most. In the PROVE IT trial, people carrying the KIF-6 gene variant had a 6.8-times greater reduction in cardiac events from intensive statin therapy compared to non-carriers. Only 10 carriers needed treatment to prevent one event, versus 125 non-carriers. Thus, testing could make therapy more cost-effective and avoid unnecessary medication.

### What should I do today based on this article's recommendations?

First, have your cholesterol checked early in life, not just in middle age. Second, do not be falsely comforted by an LDL near 130 mg/dL—it may still allow disease progression. Third, lifestyle changes remain essential and are not replaced by drugs. Fourth, ask your doctor about your 30-year or lifetime risk, not just 10-year risk, since the 10-year calculation is heavily weighted by age.

## Source Information

**Original Article:** "Redefining Normal Low-Density Lipoprotein Cholesterol: A Strategy to Unseat Coronary Disease as the Nation's Leading Killer"

**Journal:** Journal of the American College of Cardiology, Vol. 56, No. 8, 2010, pages 630–636 (J Am Coll Cardiol 2010;56:630–6)

**Publication Details:** © 2010 by the American College of Cardiology Foundation. ISSN 0735-1097/$36.00. Published by Elsevier Inc. doi:10.1016/j.jacc.2009.11.090

**Disclosures:** The author received Speakers' Bureau honoraria in the past 2 years from Merck, Pfizer, AstraZeneca, Bristol-Myers Squibb, Berkeley Heart Lab, Sanofi-Aventis, and St. Jude Medical. Manuscript received November 3, 2009; revised manuscript received November 25, 2009; accepted November 30, 2009.

*Note: This patient-friendly article is based on peer-reviewed research published in a reputable medical journal. It is intended for educational purposes only and does not constitute medical advice. Always consult your physician about your individual cholesterol management plan.*


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