Can very low Low-Density Lipoprotein Cholesterol (LDL-C) levels, such as 15, caused by Repatha (Evolocumab) 120mg subcutaneously every 2 weeks, have deleterious effects or be related to pericardial effusion?

Very Low LDL-C Levels from Repatha: Safety and Pericardial Effusion Connection

Very low LDL-C levels (15 mg/dL) achieved with Repatha (evolocumab) are generally considered safe based on current evidence, and there is no established connection between very low LDL-C and pericardial effusion. 1

Safety of Very Low LDL-C Levels

Cardiovascular Benefits

• Very low LDL-C levels are associated with significant cardiovascular benefits, including reduction in myocardial infarction, cardiovascular death, ischemic stroke, and coronary revascularization 1
• Cardiovascular benefit continues to increase monotonically with lowering LDL-C levels, with no observed benefit plateau even at levels as low as 10 mg/dL 1

Potential Concerns with Very Low LDL-C

• Several studies have investigated potential adverse effects of very low LDL-C levels:
  • Neurocognitive function: No significant evidence of neurocognitive impairment has been found in patients with very low LDL-C levels 1
  • Hemorrhagic stroke: Some studies suggest a possible association with hemorrhagic stroke, but long-term follow-up is still required 1
  • Diabetes: Possible association with new-onset diabetes mellitus, though long-term follow-up is needed 1
  • Cataracts: Unclear association that requires further long-term follow-up 1
  • Cancer: No data supports any association between very low LDL-C and cancer risk 1
  • Hepatobiliary toxicity: While one sub-study (JUPITER) showed increased hepatobiliary diseases in patients with LDL-C <30 mg/dL, four other studies found no significant correlation 1

Mortality Considerations

• Some observational studies have suggested higher mortality in patients with very low LDL-C levels (<70 mg/dL) compared to those with LDL-C 100-129.9 mg/dL 2
• However, these observational studies suffer from confounding factors and cannot establish causality 1
• Patients with genetic conditions causing lifelong very low LDL-C (particularly PCSK9 loss-of-function mutations) appear healthy without evidence of increased mortality 1

Pericardial Effusion and Very Low LDL-C

• There is no established connection between very low LDL-C levels and pericardial effusion in the current medical literature 1
• None of the major studies on evolocumab (Repatha) have reported pericardial effusion as an adverse effect 3, 4, 5
• The most common adverse events reported with evolocumab are nasopharyngitis, influenza, upper respiratory tract infection, and headache 4

Clinical Approach for Patients with Very Low LDL-C

Monitoring Recommendations

• Regular monitoring of lipid levels is recommended for patients on PCSK9 inhibitors like evolocumab 1
• Be vigilant for potential side effects, though current evidence suggests they are rare 1
• For patients with LDL-C <15 mg/dL, consider:
  • Monitoring for potential diabetes development 1
  • Regular ophthalmologic examinations to detect any cataract formation 1
  • Neurological assessment if symptoms develop, though neurocognitive impairment is not expected 1

Treatment Considerations

• For patients achieving very low LDL-C levels with good tolerance, continuing therapy is reasonable given the cardiovascular benefits 1
• 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 events, suggesting that very low levels are considered beneficial 1
• If there are concerns about extremely low LDL-C levels, dose adjustment could be considered, though there is limited evidence supporting the need for this 1

Conclusion on Pericardial Effusion

If a patient on Repatha with very low LDL-C develops pericardial effusion, it is more likely due to other etiologies rather than the low LDL-C level itself. A thorough investigation for other causes of pericardial effusion (infection, autoimmune disease, malignancy, etc.) should be pursued 1.