How Low is Safe for LDL-C?
There is no established lower safety threshold for LDL-C, and levels as low as 0.5 mmol/L (approximately 20 mg/dL) appear safe based on current evidence, with cardiovascular benefits continuing to accrue even at these very low levels. 1, 2
Evidence from Genetic Conditions Supporting Safety
Multiple genetic conditions provide compelling evidence that lifelong very low LDL-C is safe:
Individuals with PCSK9 loss-of-function mutations maintain LDL-C levels below 1.0 mmol/L (40 mg/dL) throughout life without adverse health effects and demonstrate significantly reduced cardiovascular risk. 1, 3
Familial hypobetalipoproteinemia patients with homozygous mutations achieve LDL-C as low as 0.7 mmol/L (27 mg/dL) without diabetes or cardiovascular disease. 1
Abetalipoproteinemia patients with essentially absent serum LDL-C show no specific adverse consequences attributable to their extremely low cholesterol levels. 1
Clinical Trial Evidence for Very Low LDL-C
The cardiovascular benefit relationship with LDL-C lowering shows no plateau effect:
The FOURIER trial demonstrated continued cardiovascular benefit down to LDL-C levels of 0.26 mmol/L (10 mg/dL) without reaching a benefit plateau. 1
Meta-analysis of patients starting with median LDL-C of 1.6-1.8 mmol/L (63-70 mg/dL) and achieving levels as low as 0.5 mmol/L (21 mg/dL) showed consistent 21% relative risk reduction per 1.0 mmol/L (38.7 mg/dL) LDL-C lowering, with no offsetting adverse effects. 4
The ODYSSEY OUTCOMES trial showed all-cause mortality declining linearly down to LDL-C of 0.78 mmol/L (30 mg/dL), though data below this level remain limited. 1
Recommended Target Levels by Risk Category
For very high-risk patients (established coronary disease, recent acute coronary syndrome, recurrent events):
- Primary target: <1.4 mmol/L (<55 mg/dL) with ≥50% reduction from baseline 2, 5
- For recurrent events within 2 years: consider <1.0 mmol/L (<40 mg/dL) 2, 3
For high-risk patients:
Safety Profile at Very Low Levels
Extensive clinical trial data demonstrate safety:
No increased risk of serious adverse events, myalgias, liver enzyme elevation, new-onset diabetes, hemorrhagic stroke, or cancer has been observed with LDL-C levels below 1.3 mmol/L (50 mg/dL). 4, 6
No convincing evidence of neurocognitive impairment exists in patients achieving very low LDL-C levels. 3, 6
Historical epidemiological concerns about very low cholesterol and increased mortality have not been confirmed in randomized controlled trials and are attributed to confounding factors. 1, 3
Important Caveats
Measurement accuracy becomes problematic at very low levels:
- The Friedewald equation significantly underestimates LDL-C below 1.8 mmol/L (70 mg/dL) and should not be used for calculated LDL-C below 0.8 mmol/L (30 mg/dL). 2, 7
- Direct measurement or the Martin/Hopkins method provides more accurate results at low LDL-C levels. 2, 7
Limited long-term data exists for LDL-C <0.4 mmol/L (<15 mg/dL):
- While short-term safety appears favorable, consider monitoring for potential diabetes development in patients maintaining LDL-C <0.4 mmol/L (<15 mg/dL). 3
Practical Lower Limit
Based on current evidence, LDL-C levels as low as 0.5 mmol/L (20 mg/dL) can be justified in the highest cardiovascular risk patients where plaque stabilization and regression are necessary. 8, 4 This represents the lowest level with substantial clinical trial data supporting both efficacy and safety, though genetic evidence suggests even lower levels are likely safe.