Can low density lipoprotein (LDL) cholesterol levels that are too low be harmful?

Is Very Low LDL Cholesterol Harmful?

Very low LDL cholesterol levels (<30 mg/dL) appear to be generally safe for most patients, with cardiovascular benefits likely outweighing potential risks, particularly in high-risk individuals. 1

Understanding LDL Cholesterol and Safety Thresholds

Extensive research has established that LDL cholesterol (LDL-C) is a causative factor for coronary artery disease, with a log-linear correlation between LDL-C levels and cardiovascular risk. Randomized controlled trials consistently demonstrate that lowering LDL-C significantly reduces major adverse cardiovascular events, including cardiovascular death, myocardial infarction, stroke, and coronary revascularization 1.

The safety profile of very low LDL-C can be examined through several lenses:

Evidence from Genetic Conditions

• Individuals with PCSK9 loss-of-function mutations who have lifelong very low LDL-C levels appear healthy without evidence of neurocognitive impairment, increased diabetes, cataracts, or stroke 1
• These individuals experience significantly fewer coronary events compared to control groups 1
• However, patients with certain genetic conditions like familial hypobetalipoproteinemia may develop fatty liver disease leading to hepatic fibrosis, cirrhosis, and potentially hepatocellular carcinoma 2

Potential Concerns with Very Low LDL-C

Several potential concerns have been raised:

1. Diabetes risk: Some studies suggest increased rates of diabetes in patients achieving LDL-C <30 mg/dL on rosuvastatin 2
2. Hemorrhagic stroke: Possible association requiring longer-term follow-up 1
3. Neurocognitive effects: Patients on PCSK9 inhibitors like evolocumab have reported more neurocognitive events compared to controls, though not directly related to achieved LDL-C levels 2
4. Other potential issues: Hematuria, hepatobiliary disorders, and insomnia have been reported in some studies 2

Current Guideline Recommendations

The 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines recommend:

• LDL-C <55 mg/dL for very high-risk patients (Class I recommendation)
• LDL-C <40 mg/dL for patients experiencing a second vascular event within 2 years (Class IIb) 1

The American College of Cardiology suggests:

• LDL-C <100 mg/dL for most high-risk patients
• Optional goal of <70 mg/dL for very high-risk patients 2

Balancing Benefits and Risks

The cardiovascular clinical benefit increases monotonically with lowering LDL-C levels, with no observed benefit plateau even at levels as low as 10 mg/dL 1. However, there is limited data regarding long-term safety of exposure to LDL-C <15 mg/dL in randomized controlled trials.

For patients who achieve very low LDL-C levels (<30 mg/dL), monitoring is recommended for:

• Neurocognitive symptoms
• Liver function abnormalities
• New-onset diabetes
• Hematuria
• Sleep disturbances 2

Special Considerations

A 2022 prospective cohort study found that both very low (<70 mg/dL) and very high (≥190 mg/dL) LDL-C levels were associated with increased risks of cardiovascular mortality in the general population 3. Very low LDL-C was also associated with higher risks of all-cause and stroke mortality. However, this observational study may be subject to confounding factors.

Clinical Decision Algorithm

1. For patients at very high cardiovascular risk (established ASCVD, diabetes with target organ damage, or multiple risk factors):

   • Target LDL-C <55 mg/dL is appropriate
   • Further reduction to <40 mg/dL may be considered for those with recurrent events

2. For patients achieving LDL-C <30 mg/dL:

   • Continue therapy if well-tolerated and at high cardiovascular risk
   • Monitor for potential adverse effects (neurocognitive symptoms, liver function, glucose metabolism, hematuria)
   • Consider the mechanism of LDL-C reduction (increased LDL clearance appears safer than decreased lipoprotein production) 1

3. For patients with very low LDL-C (<30 mg/dL) who develop concerning symptoms:

   • Evaluate for potential medication-related adverse effects
   • Consider adjusting therapy if significant side effects occur, weighing cardiovascular risk reduction benefits against adverse effects

The evidence suggests that for most patients at high cardiovascular risk, the benefits of achieving very low LDL-C levels outweigh potential risks, though continued monitoring for adverse effects remains prudent.