Redefining "Normal" Cholesterol: Could Lower LDL Targets End Heart Disease as the Nation's #1 Killer?

Table of Contents

• Key Points
• Background: Why This Research Matters
• What Does "Normal" LDL Cholesterol Really Mean?
• The Evidence from Nature and Traditional Societies
• Heart Disease Begins in Youth
• Key Clinical Trials: Testing the Putative Normal Range
• Genetic Insights: PCSK-9 and KIF-6
• Proposed Changes to the Treatment Guidelines
• Arguments For and Against the New Approach
• Clinical Implications for Patients
• Limitations: What This Study Couldn't Prove
• Recommendations for Patients and Doctors
• Frequently Asked Questions
• Source Information

Key Points

• Proposed normal LDL range is 35-70 mg/dl, based on mammals, newborns, and hunter-gatherers.
• Atherosclerosis begins in youth; risk factors in childhood increase plaque area in adulthood.
• JUPITER trial: lowering LDL to 55 mg/dl cut cardiac events by 44% in asymptomatic people.
• PCSK-9 gene variants lower LDL and reduce heart risk; KIF-6 may guide statin intensity.
• Long-term safety of very low LDL is unknown; lifestyle changes remain essential.

Background: Why This Research Matters

In 2011, a group of lipid experts was scheduled to finalize a new set of recommendations that would shape the preventive management of coronary heart disease for the next decade. These guidelines — known as the Adult Treatment Panel (ATP) guidelines — are among the most important in all of medicine for two critical reasons. First, they address the leading cause of illness and death in the Western world. Second, they are endorsed by the U.S. Food and Drug Administration (FDA) and implemented by millions of health care practitioners worldwide.

Ironically, any proposed change to these guidelines cannot be free of controversy. Unlike many guidelines in cardiology, the LDL cholesterol guidelines cannot be based on rigorous medical science alone. Instead, they must find a practical middle ground between scientific proof and logical inference.

This paper proposes a logical rationale for three major changes to the existing management guidelines for low-density lipoprotein cholesterol (LDL-C), the "bad" cholesterol. If combined with effective implementation, these changes could lead to the displacement of atherosclerotic disease (hardening and narrowing of the arteries) as the nation's number one killer.

What Does "Normal" LDL Cholesterol Really Mean?

The earliest approach to defining a normal level of LDL-C was traditional: determine its distribution in a clinically asymptomatic (symptom-free) population. At that time, the calculated median LDL-C level was approximately 130 mg/dl. In the existing ATP III guidelines, this value appears as both the level for initiating therapy in patients with disease and as a therapeutic target for those without known disease.

However, this approach has a critical flaw. 35% of patients who have a myocardial infarction (heart attack) are asymptomatic before the event, meaning they had no warning signs. A "normal" population cannot be defined simply by the absence of symptoms.

Further evidence against the 130 mg/dl threshold comes from statin trials: only 25% to 35% of cardiac events are prevented when LDL-C is reduced to 100 to 130 mg/dl, regardless of whether patients had symptoms or not. This suggests that clinical presentation cannot be used to establish a truly "normal" LDL-C level, and the 130 mg/dl cut point has little support in recent published literature.

The Evidence from Nature and Traditional Societies

An alternative approach was suggested in 2005 by O'Keefe and colleagues. Beginning with the observation that the total cholesterol level in nonatherosclerotic (plaque-free) wild mammalian species is 80 to 110 mg/dl, they calculated the LDL-C level to be approximately 35 to 70 mg/dl across species including baboons, monkeys, horses, bears, rhinoceroses, elephants, and wild pigs.

Humans are born with LDL-C levels in this same range, but the level gradually increases with age. Yet at least two adult human populations do not exhibit this progressive increase:

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

In newborn humans and in these two adult groups, atherosclerotic coronary disease is rare. The consistency of these diverse human data sources, taken together with the mammalian species data, supports the speculation that the putative normal range of LDL-C in adult humans may be approximately 35 to 70 mg/dl.

It's worth noting that humans are the only animal species with LDL-C levels roughly twice the putative normal range — a reasonable question is whether the normal LDL-C for all mammals is in fact the 35 to 70 mg/dl range.

Heart Disease Begins in Youth

As LDL-C levels rise above the putative normal range, atherosclerosis begins to appear surprisingly early in life. At ages 12 to 17 years, LDL-C reaches an average of 87 mg/dl, with approximately 5% to 7% of this age group already at or above 130 mg/dl.

The monotonically progressive (steadily worsening) nature of coronary atherosclerosis with decades of age has been documented by intracoronary ultrasound imaging of donor hearts at the time of heart transplantation. In a study of 262 heart transplant recipients, examining 2,014 sites within 1,477 segments in 574 coronary arteries:

• 52% of the population had atherosclerotic lesions (defined as intimal thickness of at least 0.5 mm)
• Lesions were found in 17% of individuals younger than 20 years
• This increased to 60% in 30 to 39 year olds
• And reached 85% in those older than 50 years
• In those with lesions, intimal thickness averaged 1.1 mm and area stenosis (narrowing) was 33%

The presence of these ultrasound-identified plaques predicts long-term illness and death at follow-up.

Of critical importance to the new guidelines: those at risk of developing atherosclerosis can be identified in youth. In the Bogalusa Heart Study, autopsy of young adults who had a previous risk factor analysis showed that those with 3 or more childhood risk factors had a 9-fold increase in atherosclerotic plaque area compared with those with no risk factors.

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

Finally, LDL-C lowering during early atheroma development induces regression (shrinking of plaques). In children with familial hypercholesterolemia (a genetic condition causing very high cholesterol), pravastatin 20 to 40 mg/day for 2 years induced a 24% reduction in LDL-C, accompanied by a significant reduction in carotid intima-media thickness (a measurement of artery wall thickness) compared with both baseline and placebo controls — with no difference in growth, muscle, liver enzymes, or endocrine function.

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

Key Clinical Trials: Testing the Putative Normal Range

Two recent randomized clinical trials allowed researchers to take the next logical step: examining the effect of actually lowering LDL-C into the putative normal range of 35 to 70 mg/dl.

ASTEROID trial (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound):

• Reduction of LDL-C from 130 mg/dl to 61 mg/dl
• 12% of patients achieved LDL-C below 40 mg/dl, and 41% achieved levels between 40 and 60 mg/dl
• Result: regression of carotid atherosclerosis (plaque shrinkage)

JUPITER trial (Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin):

• Reduction of LDL-C from 108 mg/dl to 55 mg/dl in an asymptomatic intermediate-risk population
• Result: a 44% reduction in adverse cardiac events
• In patients achieving on-treatment LDL-C below 70 mg/dl, the event rate was only 1.4%
• Notably, neither trial identified increased statin-induced toxicity at lower on-treatment LDL-C levels

These new data are supported by linear extrapolation of on-treatment LDL-C levels in both secondary angiographic and primary prevention trials:

• In secondary prevention trials (patients with known disease): lesion progression reaches zero at an LDL-C of 67 mg/dl, and coronary events reach zero at approximately 30 mg/dl
• In primary prevention trials (patients without known disease): major adverse cardiac events reach zero at an on-treatment LDL-C level of 57 mg/dl

Thus, to the lipid profiles in mammals, neonatal humans, and isolated human societies, we may add clinical trials that point to the same conclusion: the putative normal LDL-C level may be approximately 35 to 70 mg/dl.

Genetic Insights: PCSK-9 and KIF-6

An experiment of nature provides powerful evidence about the benefits of a lifetime of lower LDL-C. In the ARIC (Atherosclerosis Risk in Communities) study of a free-living population of 12,787 subjects, approximately 3% had sequence variants in the gene colloquially called PCSK-9 (pro-protein convertase subtilisin/kexin type 9 serine protease).

These genetic variants lower LDL-C by a mean of approximately 19% compared with the general population. The findings were striking:

• 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 PCSK-9 was associated with a 15% reduction in LDL cholesterol and a 47% reduction in risk.
• Overall, individuals with the PCSK mutation had a 62% lower rate of cardiac events over the first 15 years of observation.

These data suggest that a lifetime of lower LDL-C levels is powerfully protective — and raise the inference that if therapeutic lowering of LDL-C had a similar long-term impact in higher-risk asymptomatic younger individuals, well-constructed guidelines could result in a major reduction in cardiac events.

Pharmacogenetics (using genetics to guide drug choice) may also help target treatment. In the PROVE IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) trial, a common polymorphism called KIF-6 (the kinesin-like protein 6 Trg 719 Arg polymorphism) was shown to influence both intracellular transport and endothelial function:

• In carriers of KIF-6, intensive statin therapy (atorvastatin 80 mg) was associated with a 6.8-fold greater reduction in cardiac events than in non-carriers, despite achieving the same level of on-treatment LDL-C and C-reactive protein (CRP).
• The number needed to treat (the number of patients who must be treated to prevent one event) with atorvastatin versus pravastatin was 10 in KIF-6 carriers — but 125 in non-carriers.
• Non-carriers of the KIF-6 variant — approximately 40% of the U.S. population — experienced virtually no difference in adverse outcomes despite the major differences in on-treatment LDL-C levels between the two treatment groups.

This finding suggests that the dose and/or use of statins could be tempered by better selection of therapeutic candidates if pharmacogenetic testing can identify those most likely to benefit.

Proposed Changes to the Treatment Guidelines

Based on the evidence, the author proposed reconsidering all three principal features of the ATP III guidelines for LDL-C management. Below is a comparison of the existing and proposed approaches:

• Initiation of treatment: Based on events (absolute 10-year risk) → Proposed: based on pathogenesis (relative risk within the individual's age group)
• Use of statins: Those who meet risk criteria → Proposed: further stratified by genetic capability of response
• Choice of statin: No recommendation → Proposed: use a generic drug first in asymptomatic individuals
• Target of treatment: Stratified by risk → Proposed: putative normal LDL-C range (35–70 mg/dl) in all treated individuals, in the absence of toxicity

Rethinking Initiation Criteria

The ATP III initiation levels now seem far too high. Examples include 190 mg/dl for Framingham low-risk individuals and 130 to 160 mg/dl for asymptomatic individuals with risk factors. In the asymptomatic JUPITER population, with a mean LDL-C level of 108 mg/dl, approximately one-half of the patients had a calculated 10-year Framingham risk level below 10% — yet there was still a 44% reduction in events when LDL-C was reduced to the middle of the putative normal range.

An even more serious problem involves calculating risk based on the 10-year probability of a cardiac event. This risk calculation is very heavily weighted by age — the calculated mean 10-year risk for 25-year-old men increases 7-fold over 30 years. Younger individuals with a high risk factor burden clearly have a high probability of atherosclerotic disease, but they have a low calculated 10-year risk. As a result, they do not become candidates for treatment until the disease is very well established.

The magnitude of this limitation is substantial: approximately one-half of those in whom coronary artery disease develops first present with either sudden death or acute infarction.

Reorienting the initiation criteria toward the pathogenesis of atherosclerosis (the disease process itself) rather than its first clinical manifestation is feasible. Three methods are currently available:

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

As an example: a young individual with risk in the upper 10% of that 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. To dislodge atherosclerotic disease from its number one position, it seems essential that new guidelines incorporate the concept that a long-term disease requires a long-term solution — meaning management should begin earlier in the course of the disease.

Rethinking the LDL-C Target

A logical LDL-C target for individuals selected for therapy is the putative normal range of 35 to 70 mg/dl, with the proviso that it can be achieved at acceptable cost, without toxicity, and that neither patient nor health care provider uses drug therapy as a substitute for lifestyle modification.

Pathologic, epidemiologic, and clinical trial data suggest that a single putative normal LDL-C target might reasonably replace existing arbitrary multiple targets stratified by risk. The 70 mg/dl target for individuals with coronary artery disease and diabetes is already widely accepted as highly beneficial. Simply offering this benefit to all individuals selected for treatment seems reasonable — both because asymptomatic individuals may have life-threatening disease and because the pathogenesis of the disease is identical.

Controlling the Potential Major Expansion in Statin Use

An inevitable outcome of changing the LDL-C initiation and target would be a significant increase in the use of statin drugs. The emergence of pharmacogenetic testing (using a person's genetic profile to predict drug response) offers a possible solution to overuse. One reason potent lipid-lowering therapy fails to markedly reduce cardiac events is the "too little/too late" hypothesis. A second, seldom-considered reason is that the drugs may simply be ineffective in as-yet-unrecognized subsets of patients — and pharmacogenetics suggests this is highly likely.

Arguments For and Against the New Approach

There are strong arguments for avoiding these significant changes to the current guidelines:

• The stepwise approach to LDL-C initiation levels and targets is a well-established structure.
• Guidelines typically are based on randomized clinical trials, whereas the putative normal range of LDL-C is based on inference.
• The principal concern for most will be uncertainties surrounding toxicity and cost in implementation.
• 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.
• Long-delayed adverse effects are exceptionally difficult to detect by their nature.
• Even with potent agents, a low LDL-C target will not be achievable in many individuals — the target will be unachievable in at least one-fourth of treated patients.
• Younger people may be reluctant to take a daily drug, creating practical hurdles to implementation.
• Because lowering initiation levels and targets increases the number of people on therapy, the number of individuals not benefiting from therapy must also increase.
• The impact on health care cost is unpredictable.

The author notes that acute toxicity results from trials are made grossly misleading by the 1-month run-in period before randomization (a period during which patients who experience side effects are excluded). Short-term absence of toxicity cannot be taken to predict long-term absence of toxicity.

Because of these concerns, the text of new guidelines must place strong emphasis on a prudent, conservative approach to implementation, presenting the target as a desirable option rather than a mandate. Such guidelines should include both cautionary data and caveats concerning the tradeoffs among potency, cost, and toxicity of statins — recognizing that these issues will probably outweigh achievement of the target in at least one-fourth of treated patients.

On the other side, several arguments support making the change:

• Potent generic statins allow the new strategy to be implemented at low individual patient cost.
• A better distribution of individuals selected for statin therapy probably can be achieved through pharmacogenetics to predict the magnitude of response to therapy.
• Long-term preventive therapy for coronary artery disease has a well-established precedent — one may ask whether a low-cost generic statin used in a well-defined at-risk population might provide both more benefit and less risk than aspirin.
• Guideline classification systems make clear the strength of supporting information — no one need be misled about the strength of evidence.

Clinical Implications for Patients

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

• More people would qualify for statin therapy, including younger adults who currently have "low" 10-year risk scores but high lifetime risk.
• Treatment targets would be lower — the goal for most treated patients would be an LDL-C level of 35 to 70 mg/dl, similar to levels found in hunter-gatherer societies and newborn humans.
• Genetic testing might be used to identify who benefits most from intensive statin therapy, potentially sparing non-carriers of genetic variants like KIF-6 from unnecessary aggressive treatment.
• The paper anticipates that at least 25% of treated patients would not achieve the lower target, meaning doctors would need to balance ideal goals with practical realities, cost, and side effects.
• Lifestyle modification remains essential — a naturally or lifestyle-induced low LDL-C is not necessarily the same as medication-induced low LDL-C, and drug therapy should never be a substitute for healthy habits.

For patients, this means having an informed conversation with your doctor about your lifetime risk of heart disease — not just your 10-year risk — and understanding that "normal" cholesterol levels in modern society may not be optimal levels. The paper also emphasizes that coronary artery disease is a lifelong disease that begins in youth, so prevention may need to start decades earlier than current guidelines suggest.

Limitations: What This Study Couldn't Prove

In guideline jargon, the level of evidence of the putative normal LDL-C level is clearly level C, supported only by inference from existing data — as are the current guidelines. A further daunting issue is that if atherosclerotic disease begins in youth, then the duration of disease vastly exceeds the duration of randomized trials of lipid-lowering therapy used to support guideline development.

The author states this limitation directly: a 2-to-5-year trial cannot be assumed to predict either efficacy or toxicity over 40 to 60 years of therapy with scientific rigor. The remarkable implication is that, unlike other guidelines, those for LDL-C now and for the foreseeable future will be based on inference rather than scientific rigor.

Additional limitations include:

• Humans are the only free-living animal in which atherosclerosis develops, so animal research cannot fully define natural history.
• The traditional use of "apparently normal" individuals to establish a normal range cannot be used for LDL-C, because 35% of heart attack victims were asymptomatic before their event.
• The 1-month run-in period before randomization in clinical trials makes acute toxicity results misleading.
• Short-term absence of toxicity in trials cannot be taken to predict long-term safety over decades of therapy.

Recommendations for Patients and Doctors

While this paper is a review and proposal rather than a clinical trial, it offers practical guidance that patients can discuss with their health care providers:

1. Know your numbers early. Since atherosclerosis begins in youth, consider having your cholesterol checked in young adulthood — and don't wait until symptoms appear.
2. Ask about lifetime risk, not just 10-year risk. A young person with multiple risk factors may have a low 10-year risk but a very high lifetime risk of heart disease.
3. Consider the "putative normal" perspective. The evidence suggests that LDL-C levels of 35 to 70 mg/dl may be truly normal for humans, and levels well above 100 mg/dl carry risk even if they are "average" in modern society.
4. Don't skip lifestyle changes. A naturally low LDL-C achieved through diet, exercise, and healthy habits is not the same as a medication-induced low LDL-C — drug therapy should complement, not replace, lifestyle modification.
5. If you're prescribed a statin, low-cost generic options may be appropriate. The paper suggests using a generic drug first in asymptomatic individuals.
6. Recognize that guideline changes take time. Even if these proposals were fully adopted, they would be implemented gradually, and targets should be viewed as desirable options rather than rigid mandates — especially when balancing cost, potency, and potential toxicity.
7. Stay informed about pharmacogenetic testing. While still requiring further validation, genetic testing may eventually help identify which patients benefit most from intensive statin therapy.

LDL-C management recommendations are being developed in a new era in which longer-term risk stratification, more objective initiation criteria, a reasonable LDL-C target, and pharmacogenetic stratification are all clearly possible. Since the concepts of a putative normal LDL-C and initiation criteria based on pathogenesis both incorporate uncertainties, it may be worthwhile to recognize the fundamental principle: a long-term disease requires a long-term solution.

Frequently Asked Questions

What LDL cholesterol level is considered truly normal for humans?

Based on evidence from wild mammals, newborn humans, hunter-gatherer societies, and some rural populations, the proposed normal LDL range is 35 to 70 mg/dl. This is much lower than the average level of about 130 mg/dl seen in modern asymptomatic populations, which may not represent true health.

Why might heart disease start in youth even if I feel fine?

Research shows atherosclerosis begins early. In one transplant study, 17% of people under 20 had arterial lesions, rising to 60% by ages 30-39. Childhood risk factors, like high triglycerides or BMI, are linked to more plaque in adulthood. This means prevention may need to start decades before symptoms appear.

Can lowering LDL cholesterol to 35-70 mg/dl really prevent heart attacks?

In the JUPITER trial, lowering LDL from 108 to 55 mg/dl reduced cardiac events by 44%. In ASTEROID, reaching about 61 mg/dl led to plaque regression. However, these were relatively short trials, and long-term benefits and risks over many decades are not yet proven.

What are PCSK-9 and KIF-6 gene variants, and do they affect treatment?

PCSK-9 variants naturally lower LDL and reduce heart risk—by 88% in black subjects and 47% in white subjects in one study. KIF-6 variants may predict greater benefit from intensive statins, with a much lower number needed to treat. Genetic testing is promising but not yet routine.

Is it safe to have very low LDL cholesterol from statin therapy?

In the ASTEROID and JUPITER trials, achieving very low LDL levels (below 70 mg/dl) was not linked to increased toxicity during the study period. However, these trials lasted only a few years. Long-term safety over decades of such low levels is unknown, and side effects are still possible.

Should I get my cholesterol checked when I am young?

The article suggests that since atherosclerosis begins in youth, checking LDL early—even in young adulthood—could help identify risk before symptoms occur. However, decisions about testing and treatment should be made with a doctor, considering your full risk profile and not just your age or 10-year risk.

What should I ask my doctor about my heart disease risk?

Ask about your lifetime risk of heart disease, not just your 10-year risk. Discuss whether your LDL target should be lower than current guidelines, and remember that lifestyle changes are essential—medication should complement, not replace, healthy habits. Also ask about generic statins and potential genetic testing.

My doctor says my LDL cholesterol is 'normal' and I don't need a statin. Should I get a second opinion about starting treatment?

A second opinion can help if you have been told your LDL cholesterol is 'normal' or that you do not need treatment yet. Evidence from clinical trials and genetic studies suggests a truly normal LDL may be 35 to 70 mg/dl, lower than the usual 130 mg/dl target. Lowering LDL to this range reduced cardiac events by 44% in one large trial and caused plaque shrinkage in another. However, long-term side effects beyond five years are unknown, and lifestyle changes remain essential. A second opinion can clarify your lifetime risk and whether pharmacogenetic testing, such as looking at the KIF-6 gene, might guide treatment. Diagnostic Detectives Network provides independent expert second opinions.

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

DOI: 10.1016/j.jacc.2009.11.090

Publication Date: August 17, 2010

Disclosures: Dr. Forrester has 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.

This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and does not constitute medical advice. Patients should consult their health care providers about their individual cholesterol management.