Lipid profile

LDL Cholesterol Levels and All-Cause Mortality: Understanding the U-Shaped Relationship and Impact on Lifespan

Recent epidemiological research has revealed a complex relationship between low-density lipoprotein cholesterol (LDL-C) levels and mortality risk. Contrary to the conventional "lower is better" paradigm, evidence increasingly suggests a U-shaped association, where both very low and very high LDL-C levels are associated with increased mortality risk. This comprehensive analysis examines mortality risks across specific LDL-C ranges and their impact on lifespan.

The U-Shaped Relationship Between LDL-C and Mortality

Multiple large-scale studies have demonstrated a U-shaped relationship between LDL-C levels and all-cause mortality. This pattern suggests that both extremes of the LDL-C spectrum are associated with adverse outcomes, with an optimal range somewhere in the middle.

A nationally representative cohort study with a median follow-up of 23.2 years found that compared to those with LDL-C 100-129.9 mg/dL, individuals with LDL-C <70 mg/dL had a 45% higher risk of all-cause mortality (HR 1.45, 95% CI 1.10-1.93)¹. Similarly, those with LDL-C ≥190 mg/dL had elevated cardiovascular mortality (HR 1.49, 95% CI 1.09-2.02)¹.

A large retrospective cohort study of primary prevention patients showed a clear U-shaped relationship with crude 10-year mortality rates of 19.8%, 14.7%, 11.7%, 10.7%, 10.1%, and 14.0% across LDL-C categories of 30-79, 80-99, 100-129, 130-159, 160-189, and ≥190 mg/dL, respectively²³. This demonstrates increased mortality at both low and very high LDL-C levels.

Mortality Risk by Specific LDL-C Ranges

<70 mg/dL (<1.80 mmol/L): Significantly Elevated Risk

Very low LDL-C levels are consistently associated with increased mortality across multiple studies:

A nationally representative cohort study showed that individuals with LDL-C <70 mg/dL had a 45% higher risk of all-cause mortality (HR 1.45), 60% higher risk of cardiovascular mortality (HR 1.60), and a striking 304% higher risk of stroke mortality (HR 4.04) compared to those with LDL-C 100-129.9 mg/dL¹.

Another study found that compared to individuals with LDL-C levels ≥144 mg/dL, those with LDL-C levels below 70 mg/dL had a 154% higher risk of all-cause mortality (HR 2.54, 95% CI 1.58-4.07)⁴.

Among primary prevention patients, LDL-C 30-79 mg/dL was associated with 23% higher mortality risk (HR 1.23, 95% CI 1.17-1.30) compared to the reference group of 80-99 mg/dL²³.

70-99.9 mg/dL (1.80-2.6 mmol/L): Moderate Risk

Evidence for this range shows mixed results:

Compared to LDL-C 100-129.9 mg/dL, no significant difference in all-cause mortality was observed for LDL-C 70-99.9 mg/dL (HR 1.03, 95% CI 0.86-1.22)¹.

A study focusing on primary prevention patients used 80-99 mg/dL as the reference group, suggesting higher mortality in this range compared to 100-189 mg/dL²³.

100-129.9 mg/dL (2.7-3.3 mmol/L): Optimal for Many

This range is frequently used as the reference group in studies due to its association with low mortality risk:

In primary prevention patients aged 50-89 years not on statin therapy, LDL-C 100-129 mg/dL was associated with 13% lower mortality risk (HR 0.87, 95% CI 0.83-0.91) compared to the reference group of 80-99 mg/dL²³.

A study of ischemic stroke patients found that LDL-C of approximately 103 mg/dL was associated with the lowest mortality risk¹.

130-159.9 mg/dL (3.4-4.0 mmol/L): Low All-Cause Mortality

This range is associated with relatively low all-cause mortality in several studies:

No significant difference in all-cause mortality was observed compared to 100-129.9 mg/dL (HR 0.92, 95% CI 0.83-1.02)¹.

In primary prevention patients, LDL-C 130-159 mg/dL was associated with 12% lower all-cause mortality risk (HR 0.88, 95% CI 0.84-0.93) compared to 80-99 mg/dL²³.

A study of older adults found that the third quartile of LDL-C (3.4-3.8 mmol/L) was associated with the lowest risk of all-cause mortality⁵.

160-189.9 mg/dL (4.1-4.9 mmol/L): Mixed Results

This range shows favorable all-cause mortality but potential cardiovascular risk:

Slightly lower all-cause mortality compared to 100-129.9 mg/dL (HR 0.88, 95% CI 0.76-1.01)¹.

Borderline higher cardiovascular mortality (HR 1.30, 95% CI 0.98-1.72)¹.

In primary prevention patients, this range was associated with 9% lower mortality risk (HR 0.91, 95% CI 0.84-0.98) compared to 80-99 mg/dL²³.

≥190 mg/dL (≥4.9 mmol/L): Elevated Cardiovascular Risk

High LDL-C levels are consistently associated with increased cardiovascular mortality:

No significant difference in all-cause mortality compared to 100-129.9 mg/dL (HR 1.08, 95% CI 0.88-1.32)¹.

Significantly increased cardiovascular mortality (HR 1.49, 95% CI 1.09-2.02) and coronary heart disease mortality (HR 1.63, 95% CI 1.12-2.39)¹.

In primary prevention patients, LDL-C ≥190 mg/dL showed 19% higher mortality risk (HR 1.19, 95% CI 1.06-1.34) compared to 80-99 mg/dL²³.

Impact on Lifespan

Genetic evidence suggests that elevated LDL-C levels may reduce lifespan. A Mendelian randomization study found that a 1-standard deviation increase in genetically proxied LDL-C was associated with 1.2 years lower lifespan (95% CI −1.55, −0.87)⁶. This study also found that genetic variants associated with LDL-C modification through PCSK9 were associated with a reduction in lifespan of 0.99 years (95% CI −1.43, 0.55)⁶.

However, the relationship between LDL-C and lifespan appears to be complex and potentially heterogeneous across different populations. Of particular note, one study found that high LDL-C is inversely associated with mortality in most people over 60 years, challenging the universal application of aggressive cholesterol-lowering strategies in elderly populations⁷.

Optimal LDL-C Ranges for Different Populations

The optimal LDL-C range associated with the lowest mortality risk varies by population:

Primary Prevention Populations

Among adults without established cardiovascular disease aged 50-89 years not on statin therapy, the lowest mortality risk appeared within the broad range of 100-189 mg/dL²³. This finding is noteworthy as it suggests an optimal range considerably higher than current guideline recommendations for many individuals.

Older Adults

In a study of older adults, the nadir in LDL-C level with the lowest mortality risk was around 3.3-3.4 mmol/L (approximately 128-132 mg/dL)⁵. Another study found the lowest mortality risk at around 3.6 mmol/L (140 mg/dL).

Elderly Populations (Over 60 Years)

High LDL-C is inversely associated with mortality in most people over 60 years, suggesting that aggressive LDL-C lowering may not benefit this population⁷.

Factors Affecting the LDL-C and Mortality Relationship

Reverse Causation

The association between very low LDL-C and increased mortality may be partially explained by underlying health conditions that both lower cholesterol and increase mortality risk. Studies have attempted to address this by excluding patients who died shortly after baseline measurements or those with extremely low LDL-C levels at baseline²³.

Age and Sex Differences

Some studies have found that the U-shaped relationship between LDL-C and mortality may vary by sex and age, with reduced all-cause mortality risks with higher LDL-C only significant in males but not females in some cohorts⁵.

Clinical Implications

These findings have important implications for clinical practice and guideline recommendations:

LDL-C targets should potentially be personalized based on individual risk profiles rather than applying a "lower is better" approach universally.
For primary prevention in adults without established cardiovascular disease, the optimal LDL-C range appears to be 100-189 mg/dL, which is higher than current guideline recommendations for many individuals²³.
For elderly patients (over 60 years), aggressive LDL-C lowering may not provide mortality benefits and could potentially be harmful⁷.
The risks associated with very low LDL-C (<70 mg/dL) should be considered when prescribing intensive lipid-lowering therapy.

Conclusion

The relationship between LDL-C levels and mortality risk follows a U-shaped curve, with both very low (<70 mg/dL) and very high (≥190 mg/dL) levels associated with increased mortality risks.

The optimal LDL-C range varies by population but generally falls within 100-160 mg/dL (2.6-4.1 mmol/L) for primary prevention adults. This challenges the "lower is always better" paradigm for LDL-C management and suggests that extremely aggressive LDL-C lowering may not benefit all patients equally.

Genetic evidence supports that higher LDL-C levels may reduce lifespan, but the effect may be heterogeneous across different populations and age groups. A personalized approach to LDL-C management, considering age, sex, and primary versus secondary prevention status, may be more appropriate than a one-size-fits-all approach aiming for ever-lower LDL-C levels.