Very Low VLDL and LDL Cholesterol: Safety and Implications
Direct Answer
Yes, multiple high-quality studies have examined very low lipid levels, and the evidence shows that very low LDL cholesterol (<30 mg/dL) achieved through LDL receptor upregulation (statins, PCSK9 inhibitors, ezetimibe) is safe and provides continued cardiovascular benefit without a lower threshold, though the question specifically about VLDL is less well-studied. 1
Key Evidence on Very Low Lipid Levels
Cardiovascular Benefits Continue at Very Low Levels
Cardiovascular benefit increases monotonically with lowering LDL-C levels with no observed benefit plateau, even down to levels as low as 10 mg/dL. 1
The FOURIER trial demonstrated strong relationships between achieved LDL cholesterol down to concentrations of 8 mg/dL and progressive reduction in major cardiovascular outcomes (cardiovascular death, myocardial infarction, stroke, coronary revascularization, unstable angina). 1
A post hoc spline analysis from ODYSSEY OUTCOMES showed that all-cause mortality declines with lower achieved LDL-C levels down to 30 mg/dL (adjusted P = 0.017 for linear trend). 1
The log-linear relationship between LDL-C and cardiovascular disease risk persists at low levels, meaning each mg/dL reduction provides proportional benefit regardless of baseline level. 1
Safety Profile of Very Low LDL Levels
The mechanism by which low cholesterol is achieved matters critically for safety. 1
Increased LDL-C clearance through LDL receptor upregulation (via statins, PCSK9 inhibitors, ezetimibe) appears to have fewer side effects compared to decreased lipoprotein secretion or production. 1
Individuals with PCSK9 loss-of-function mutations living with lifelong low LDL-C appear healthy without evidence of neurocognitive impairment, higher incidence of diabetes, cataracts, or stroke, and experience significantly fewer coronary events. 1
Potential Concerns That Have Been Investigated
The evidence on adverse effects is mixed and requires careful interpretation:
Diabetes: 1
- Possible association with new-onset diabetes mellitus
- Long-term follow-up is required for definitive conclusions
Hemorrhagic Stroke: 1
- Possible association with intraparenchymal hemorrhagic stroke
- Long-term follow-up is required
Cataracts: 1
- One pooled analysis of alirocumab trials showed higher cataract rates (2.6% vs 0.8%) in patients with LDL-C ≤25 mg/dL versus >25 mg/dL 1
- However, unclear if there is a true association; long-term follow-up required 1
No Evidence of Association With: 1
- Cancer
- Hepatobiliary toxicity
- Neurocognitive impairment
- Hypogonadism
- Hematuria
Mortality Considerations
A critical caveat exists regarding observational data on very low cholesterol and mortality: 1, 2
Some observational studies in elderly populations not on lipid-lowering agents showed that lower LDL-C paralleled with higher mortality. 1
Patients with LDL-C <77 mg/dL hospitalized for acute myocardial infarction had higher in-hospital mortality. 1
A U.S. population study found that individuals with LDL-C <70 mg/dL had increased hazard ratios for all-cause mortality (HR 1.45), CVD mortality (HR 1.60), and stroke mortality (HR 4.04) compared to those with LDL-C 100-129.9 mg/dL. 2
However, these observational findings likely reflect confounding by indication (i.e., sicker patients have lower cholesterol due to their illness, not that low cholesterol causes poor outcomes). 1
VLDL-Specific Evidence
The question specifically asks about VLDL, which has been studied far less than LDL: 3
VLDL-cholesterol was not associated with risk of major adverse cardiovascular events (MACE) or all-cause mortality in patients with manifest cardiovascular disease. 3
However, the highest quartile of VLDL-C showed increased risk for major adverse limb events (MALE) with HR 1.49 (95% CI 1.16-1.93) compared to the lowest quartile. 3
Large VLDL particles are significantly correlated with atherosclerosis, insulin resistance, and diabetes incidence. 4
Clinical Implications
For patients achieving very low LDL-C (<30 mg/dL) through standard lipid-lowering therapy (statins, ezetimibe, PCSK9 inhibitors), current evidence supports safety and continued cardiovascular benefit. 1
There is a paucity of data on the benefits and safety of attaining and maintaining LDL-C <15 mg/dL over the long term. 1
Clinicians should not be uncomfortable encountering patients with very low LDL-C achieved through LDL receptor upregulation, as evidence to date supports lack of significant correlation between very low LDL-C and major side effects when achieved through this mechanism. 1