Familial Hypercholesterolemia: New Horizons for Diagnosis and Effective Management

Abstract

Familial hypercholesterolemia (FH) is a common genetic cause of premature cardiovascular disease (CVD). The reported prevalence rates for both heterozygous FH (HeFH) and homozygous FH (HoFH) vary significantly, and this can be attributed, at least in part, to the variable diagnostic criteria used across different populations. Due to lack of consistent data, new global registries and unified guidelines are being formed, which are expected to advance current knowledge and improve the care of FH patients. This review presents a comprehensive overview of the pathophysiology, epidemiology, manifestations, and pharmacological treatment of FH, whilst summarizing the up-to-date relevant recommendations and guidelines. Ongoing research in FH seems promising and novel therapies are expected to be introduced in clinical practice in order to compliment or even substitute current treatment options, aiming for better lipid-lowering effects, fewer side effects, and improved clinical outcomes.

Homozygous familial hypercholesterolemia with an update on cholesterol management

“…Anichkov first demonstrated the role of high cholesterol in atherosclerosis in 1913 [ 1 ]. Subsequently, the molecular basis of hypercholesterolemia has been determined [ 2 ]. HeFH is the most common inherited cardiovascular disorder (prevalence of 1:250–300), increasing premature ACVD risk ~20-fold [ 2 ].…”

“…LDL-apheresis, although not widely available, is highly effective at LDL removal (by 50–70%) from plasma, reducing cardiovascular events by 80–90% [ 2 ]. However, target interval LDL-C levels may not be achieved despite immediate post-treatment reduction.…”

“…PCSK9 inhibitors are monoclonal antibodies inhibiting degradation of LDLR, thus increasing cholesterol clearance by hepatocytes [ 2 ]. Two Food and Drug Administration-approved PCSK9 inhibitors, alirocumab and evolucumab, are given as injections every 2–4 weeks [ 2 ].…”

“…PCSK9 inhibitors are monoclonal antibodies inhibiting degradation of LDLR, thus increasing cholesterol clearance by hepatocytes [ 2 ]. Two Food and Drug Administration-approved PCSK9 inhibitors, alirocumab and evolucumab, are given as injections every 2–4 weeks [ 2 ]. Evolocumab reduces LDL-C in HoFH patients with or without lipoprotein apheresis (Trial Assessing Long Term USe of PCSK9 Inhibition in Subjects With Genetic LDL Disorders study) accompanied by a reduction in cardiovascular events [ 5 ].…”

“…Phase II and III, single-arm studies in HoFH show dose-dependent LDL-C reductions between 25 and 51% [ 10 ]. An observational study showed a 15% reduction in major adverse cardiovascular events for every 1 mmol/L LDL-C reduction [ 2 ]. The monitoring of transaminases is necessary during lomitapide treatment due to increased hepatic fat [ 2 ].…”