Can low-density lipoprotein (LDL) be too low?

From the Guidelines

Low-density lipoprotein (LDL) can be too low, and levels below 30 mg/dL may be associated with an increased risk of hemorrhagic stroke, as evidenced by the most recent study published in the European Heart Journal in 2021 1.

Key Findings

• The study found that participants achieving very low LDL-C have not shown any correlation between marked LDL-C reduction and neurocognitive impairment 1.
• However, several studies have reported a possible correlation between lower LDL-C and haemorrhagic stroke incidence or associated mortality, including the SPARCL study which showed that patients with prior stroke treated with atorvastatin 80 mg had a higher incidence of intracranial haemorrhage compared to placebo 1.
• A CTT meta-analysis showed evidence of a small increased rate of haemorrhagic stroke among patients treated with statins, but the excess risk was small and much less frequent than the reduction in ischaemic strokes and was not associated with an increase in mortality 1.
• Other meta-analyses, however, did not find any association between haemorrhagic stroke and statin use or lower LDL-C, and an analysis of ODYSSEY OUTCOMES results showed that alirocumab significantly decreased the risk of any stroke and the risk of ischaemic stroke without increasing the risk of haemorrhagic stroke 1.

Clinical Implications

• The findings suggest that while low LDL levels are generally beneficial for cardiovascular health, extremely low levels (below 30 mg/dL) may be associated with an increased risk of hemorrhagic stroke.
• Healthcare providers should be aware of this potential risk and monitor patients with very low LDL levels for signs of hemorrhagic stroke.
• The use of high-dose statins and PCSK9 inhibitors should be carefully considered in patients at risk of hemorrhagic stroke, and alternative treatments may be necessary in some cases.
• Further research is needed to fully understand the relationship between low LDL levels and hemorrhagic stroke risk, but the current evidence suggests that levels below 30 mg/dL should be approached with caution 1.

From the Research

LDL Cholesterol Levels

• The optimal range of LDL cholesterol is still a topic of debate, with some studies suggesting that lower levels are associated with a lower risk of cardiovascular disease 2, 3.
• Several studies have shown that very low LDL cholesterol levels, even as low as 20-30 mg/dL, can be achieved with aggressive lipid-lowering therapies without significant adverse effects 3, 4, 5.
• The idea that "lower is better" for LDL cholesterol is supported by clinical trials, human genetics, and biology, with some studies suggesting that normal LDL cholesterol levels might be too high for optimal health 2, 6.

Safety of Low LDL Cholesterol Levels

• Research on cholesterol homeostasis has identified complex mechanisms that guarantee cell functions even when circulating cholesterol levels are very low, suggesting that very low LDL cholesterol levels may not be harmful 6.
• Studies have not found an increased risk of cancer or neurodegenerative disease associated with low LDL cholesterol levels, and some have even suggested a potential benefit in these settings 6, 5.
• However, a potential increased risk of hemorrhagic stroke has been reported, highlighting the importance of tight monitoring and control of blood pressure in patients with very low LDL cholesterol levels 6.
• A dose-dependent increased risk of newly diagnosed diabetes has been reported with statin treatment, but this adverse effect has not been found with more recently approved lipid-lowering drugs 6.

Clinical Implications

• The American College of Cardiology and American Heart Association recommend an LDL cholesterol target of 70 mg/dL for patients at high or very high risk, but some studies suggest that even lower levels may be beneficial 3, 4.
• Clinicians should consider the individual patient's risk factors and tailor their LDL cholesterol target level accordingly, with the goal of achieving the lowest possible level without significant adverse effects 4.
• Further research is needed to determine the optimal LDL cholesterol level and to fully understand the potential risks and benefits of very low LDL cholesterol levels 2, 5.