Does achieving very low low‑density lipoprotein (LDL) cholesterol increase cardiovascular risk or cause adverse effects?

Very Low LDL Cholesterol Does NOT Increase Cardiovascular Risk

Achieving very low LDL cholesterol levels (<30 mg/dL) is safe and provides continuous cardiovascular benefit without a lower threshold, with no convincing evidence of significant adverse effects. 1, 2

Cardiovascular Benefits Continue to Increase at Very Low Levels

• Cardiovascular benefit increases monotonically with lowering LDL-C levels, with no observed benefit plateau even at levels as low as 10 mg/dL. 1, 2

• In the FOURIER-OLE analysis with up to 8.6 years of follow-up, patients achieving LDL-C <20 mg/dL had the lowest risk of cardiovascular death, myocardial infarction, stroke, coronary revascularization, and unstable angina compared to higher LDL-C groups, with no significant safety concerns. 3

• The ODYSSEY OUTCOMES trial demonstrated that all-cause mortality declines with lower achieved LDL-C levels down to 30 mg/dL (adjusted P=0.017 for linear trend), with alirocumab reducing all-cause death by 22% (HR 0.78; 95% CI 0.65-0.94; P=0.01). 1

• For every 38.7 mg/dL reduction in LDL-C, there is approximately a 22% relative risk reduction in major cardiovascular events, with this relationship being continuous and log-linear without a lower threshold. 4

Genetic Evidence Supports Long-Term Safety

• Individuals with PCSK9 loss-of-function mutations who have lifelong LDL-C levels as low as 20-30 mg/dL are healthy, without evidence of neurocognitive impairment, increased diabetes, cataracts, or stroke, and experience significantly fewer coronary events. 1, 2

• Patients with familial hypobetalipoproteinemia type 2 (FHBL2) with LDL-C as low as 27 mg/dL show no diabetes or cardiovascular disease, providing strong evidence that the human body tolerates very low LDL-C levels well. 1, 2

• Hundreds of healthy patients with genetic conditions causing lifelong very low LDL-C have been described without significant adverse effects, demonstrating long-term safety over decades. 1, 5

Safety Profile: No Significant Adverse Effects

No statistically significant associations exist between lower achieved LDL-C levels and increased risk of serious adverse events, new or recurrent cancer, cataracts, hemorrhagic stroke, new-onset diabetes, neurocognitive adverse events, muscle-related events, or non-cardiovascular death. 3

Specific Safety Considerations:

• Neurocognitive function: No significant evidence of neurocognitive impairment has been found in patients with very low LDL-C levels, including those with genetic conditions and those treated with PCSK9 inhibitors. 1, 2

• Hepatobiliary concerns: While one sub-study of JUPITER (median follow-up only 1.9 years) showed higher incidence of hepatobiliary diseases with LDL-C <30 mg/dL, four other sub-studies found no significant correlation, and patients with LDL-C <25 mg/dL treated with alirocumab do not have increased risk for hepatic steatosis. 1

• Hemorrhagic stroke: Some studies suggest a possible association between very low LDL-C and hemorrhagic stroke, but this requires long-term follow-up and has not been consistently demonstrated. 1, 2

• Hormones and vitamins: Patients with LDL-C <25 mg/dL had no significant difference in levels of gonadal hormones or fat-soluble vitamins A, D, and K, with elevated vitamin E levels when adjusted for LDL-C values. 1

Common Pitfall: Confusing Observational Data with Causation

Critical caveat: Some observational studies have shown associations between very low LDL-C and increased mortality in elderly populations not on lipid-lowering agents, but these suffer from confounding and reverse causation (illness causing low cholesterol rather than low cholesterol causing illness). 1, 6

• The key distinction is between naturally occurring very low LDL-C in sick populations versus therapeutically achieved very low LDL-C in patients on lipid-lowering therapy. 1

• In randomized controlled trials where LDL-C is lowered pharmacologically, no increased mortality is observed—in fact, mortality decreases. 1, 3

Clinical Recommendation Algorithm

For patients achieving very low LDL-C (<30 mg/dL) on lipid-lowering therapy:

1. Continue current therapy if well-tolerated, as cardiovascular benefit continues to increase at these levels. 2, 5

2. Monitor for potential diabetes development in patients with LDL-C <15 mg/dL, though evidence for this association is limited. 2

3. Regular lipid monitoring is recommended for patients on PCSK9 inhibitors. 2

4. Do not reduce therapy intensity based solely on achieving very low LDL-C levels, as there is no established lower safety threshold. 1, 3

Guideline-Supported Targets

• The 2019 ESC/EAS Cholesterol Guidelines recommend LDL-C targets <55 mg/dL for very high-risk patients and <40 mg/dL for those with recurrent vascular events, indicating that very low levels are considered beneficial and safe. 2, 5

• Current evidence supports LDL-C levels as low as 20 mg/dL as safe based on studies up to 8.6 years duration. 4, 3