Targeting LDL: is lower better and is it safe?

Area of Science:

• Cardiology
• Clinical Medicine
• Pharmacology

Background:

• Low-density lipoprotein cholesterol (LDL-C) is a primary target for cardiovascular disease (CVD) risk reduction.
• Established outcome trials confirm LDL-C reduction benefits, even at levels below 1.8 mmol/L.

Purpose of the Study:

• To evaluate the benefits of achieving even lower LDL-C levels than currently targeted.
• To address the accuracy of LDL-C measurement methods at very low concentrations.
• To examine the potential harms associated with very low LDL-C levels.

Main Methods:

• Review of large randomized outcome trials.
• Analysis of LDL-C measurement methodologies, including the Friedewald calculation.
• Assessment of safety data regarding potential adverse events at low LDL-C levels.

Main Results:

• Cardiovascular disease risk reduction is linked to the absolute reduction in LDL-C.
• The Friedewald calculation can underestimate LDL-C values below 1.8 mmol/L, impacting risk assessment.
• Current evidence does not strongly support a link between very low LDL-C and increased risks of cancer, hemorrhagic stroke, or violent death.

Conclusions:

• Achieving very low LDL-C levels, potentially below 1.3 mmol/L, warrants further investigation for CVD risk reduction.
• Accurate LDL-C measurement is crucial for precise risk assessment and treatment guidance.
• Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are expected to provide key insights into the efficacy and safety of extremely low LDL-C levels.