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Effect of Low Cholesterol on Steroid Hormones and Vitamin E Levels: Just a Theory or Real Concern?

Low-density lipoprotein cholesterol (LDL-C) is one of the most important causal risk factors for atherosclerotic disease. Primary and secondary prevention studies have shown that lowering LDL-C significantly reduces the risk of cardiovascular morbidity and mortality. Intensive statin therapy compared with moderate statin therapy incrementally reduces LDL-C, progression of coronary atherosclerosis, and rates of cardiovascular events.1,2 Because cholesterol is needed for adrenal and gonadal steroid hormone biosynthesis, vitamin transport, and cell membrane function, there is a theoretical concern that very low levels of LDL-C achieved with intensive lipid-lowering therapy may lead to adverse effects because of reduced delivery of free intracellular cholesterol. Some reassurance is provided by people with genetic variants that lead to lifelong reduction in LDL-C levels; such individuals appear healthy and have a low incidence of cardiac events.3

Article, see p 731 

In this issue of Circulation Research , Blom et al4 explored the safety of very low levels of LDL-C induced by evolocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9). The authors thoroughly investigated its effects on steroid hormone and vitamin E levels. In a phase 3, double-blind, randomized, placebo-controlled trial of 901 patients with LDL-C ≥75 mg/dL and risk factors for cardiovascular disease, participants were randomized to monthly subcutaneous evolocumab or placebo for 52 weeks.5 Steroid hormone and vitamin E levels were measured at baseline and 52 weeks. Cortisol and adrenocorticotropic hormone concentrations were assayed to monitor adrenal steroidogenesis. Estradiol in women and testosterone in men were measured to determine the effect on gonadal steroid synthesis. The investigators measured plasma vitamin E concentrations in all patients, and they measured serum, lipoprotein, and red cell membrane vitamin E concentrations in a subset of 100 study participants.

The investigators found an ≈60% reduction in LDL-C in patients …