How Low is Too Low for Cholesterol Levels?
There is no specific threshold for "too low" cholesterol, as 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 Low LDL Cholesterol
LDL cholesterol is a well-established causative factor for cardiovascular disease, with a log-linear relationship between LDL-C levels and cardiovascular risk. Clinical trials consistently demonstrate that lowering LDL-C significantly reduces major adverse cardiovascular events.
- Individuals with genetic conditions resulting in lifelong very low LDL-C (such as PCSK9 loss-of-function mutations) generally demonstrate good health, suggesting that pharmacologically achieved very low LDL-C may be safe 1
- 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
Safety Considerations for Very Low LDL Cholesterol
While extremely low LDL cholesterol levels raise theoretical concerns, evidence suggests they are generally well-tolerated:
- Clinical trials have not demonstrated significant side effects from LDL lowering per se 2
- Even at extremely low LDL-C levels, critical capacities for steroid hormone and bile acid production are preserved 3
- The presence of a cholesterol blood-brain barrier protects cells in the central nervous system 3
Potential Concerns
Some epidemiological studies have suggested associations between very low serum cholesterol levels and:
- Increased total mortality
- Cerebral hemorrhage
- Cancer
- Depression
- Infectious disease
However, these associations have generally not established causality and may be explained as secondary phenomena 2, 3
Monitoring Patients with Very Low LDL-C
For patients achieving LDL-C <30 mg/dL, it's prudent to:
- Continue therapy if well-tolerated, especially in high cardiovascular risk patients
- Monitor for potential adverse effects including:
- Neurocognitive symptoms
- Liver function abnormalities
- Glucose metabolism changes
- Hematuria
- Sleep disturbances 1
Guideline Recommendations
Current guidelines provide the following recommendations for LDL-C targets:
European Society of Cardiology/European Atherosclerosis Society (ESC/EAS):
- LDL-C <55 mg/dL for very high-risk patients
- LDL-C <40 mg/dL for patients experiencing a second vascular event within 2 years 1
American College of Cardiology:
- LDL-C <100 mg/dL for most high-risk patients
- Optional goal of <70 mg/dL for very high-risk patients 1
Conclusion
The concept of LDL cholesterol being "too low" should be reconsidered in light of current evidence. While monitoring for potential side effects is prudent, the cardiovascular benefits of achieving very low LDL-C levels likely outweigh potential risks, particularly in high-risk patients. The physiologic range for LDL cholesterol in humans is likely 50-70 mg/dL, considerably lower than the average adult level of approximately 119 mg/dL 4.