So Far, PCSK9 Inhibitors Work for All Heterozygous FH Patients.

T wo proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies have obtained approval by the United States Food and Drug Administration: evolocumab (Amgen) and ali-rocumab (Sanofi/Regeneron). Per their package inserts, both are "indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (FH) or clinical atherosclerotic cardiovascular disease, who require additional lowering of low-density lipoprotein-cholesterol (LDL-C)." Evolocumab has an additional indication for homozygous FH patients. Several issues cloud the use of PCSK9 inhibitors in FH (also referred to as autosomal dominant hypercholesterol-emia) patients and may be causing confusion for both clini-cians and payers. First, what does "maximally tolerated statin" refer to? It may be interpreted as no statin in patients with complete statin intolerance or it may imply high-intensity statin therapy (atorvastatin 40 or 80 mg daily and rosuvastatin 20 or 40 mg daily). Second, which patients require additional lowering of LDL-C? Recent guidelines de-emphasize LDL-C goals, although many clinicians likely continue to treat to LDL-C target levels. Third, how should FH be diagnosed? No standard FH diagnostic criteria—or even International Classification of Diseases-9 or-10 codes—exist in the United States. FH can be clinically diagnosed with elevated LDL-C levels (usually >190 mg/dL) plus a suspicious family history. Or more complex scoring systems, like the Dutch Lipid Clinic Network Scoring criteria, stratify patients into unlikely, possible, probable, or definite FH. Fourth, should specialists (eg, car-diologists, endocrinologists, or lipid specialists) be required to diagnose FH or prescribe PCSK9 monoclonal antibodies? Fifth, is there a role for genetics in predicting how heterozy-gous FH patients respond to PCSK9 monoclonal antibodies? In homozygous FH patients with biallelic null mutations, evolocumab fails to reduce LDL-C. 1 Does something similar occur in heterozygous FH patients with PCSK9 mutations? PCSK9 mutations affect PCSK9's affinity for the LDL receptor (LDLR). Could they also result in variable affinities for a PCSK9 monoclonal antibody? Although studies of alirocumab and evolocumab have already been done in heterozygous FH patients, they did not require genetic screening for inclusion. In the current issue of Circulation: Cardiovascular Genetics, Hopkins et al 4 describe the results of an interventional study of alirocumab (150 mg every 2 weeks) administered to 13 FH patients harboring PCSK9 gain-of-function mutations. The study represents the first such investigation in humans with gain-of-function PCSK9 mutations. Alirocumab achieved 50% to 70% LDL-C reductions— with 12 of 13 patients getting to an LDL-C <70 mg/dL— …