As clinicians, we know that lowering low-density lipoprotein cholesterol (LDL-C) with statins alone or in combination with nonstatin therapies such as a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (eg, alirocumab, evolocumab) provides cardiovascular (CV) benefit. Patients on combination lipid-lowering therapy commonly present with LDL-C levels < 25 mg/dL (< 0.6465 mmol/L), and in clinical trials, extremely low LDL-C (< 10 mg/dL [< 0.2586 mmol/L]) has been observed. These findings have led many clinicians to question whether very low LDL-C affects formation of cell membranes, vitamin synthesis, and production of adrenal hormones.
To address the safety of very low LDL-C (defined in this article as < 25 mg/dL [< 0.6465 mmol/L]), we will review the challenges of obtaining an accurate LDL-C estimate; cholesterol metabolism; effects of low LDL-C concentrations in cord blood; genetic mutations associated with low LDL-C; study data on the effects of statins and PCSK9 inhibitors on adrenal steroids, gonadal steroids, and vitamin levels; and adverse event reporting in participants with low LDL-C in randomized controlled trials.
Obtaining an Accurate LDL-C Estimate
The challenges of accurately estimating LDL-C add to the complexity of assessing the safety of very low LDL-C levels. In some patients, the commonly used Friedewald equationunderestimates the actual LDL-C level.
