PCSK9 inhibitor

**Mechanism** - PCSK9 (proprotein convertase subtilisin/kexin type 9) is a serine protease made mainly by hepatocytes and secreted into plasma. It binds the LDL receptor (LDLR) on the hepatocyte surface. The LDLR-PCSK9 complex is internalized and sent to the lysosome for degradation instead of recycling to the cell surface. - Less LDLR on the surface means less LDL-C clearance and higher plasma LDL-C. - PCSK9 inhibitors prevent this degradation. More LDLRs recycle to the surface, so hepatic LDL uptake rises and plasma LDL-C falls. - Statins upregulate PCSK9 expression as a side effect of SREBP-2 activation. This blunts their effect and is part of the rationale for combining the two.

**Agents** - *Evolocumab (Repatha)* and *alirocumab (Praluent)* are fully human monoclonal antibodies that bind circulating PCSK9. They are given subcutaneously every 2-4 weeks (alirocumab q2 or q4 weeks; evolocumab q2 weeks or monthly). - *Inclisiran (Leqvio)* is a small interfering RNA (siRNA) that degrades PCSK9 mRNA in hepatocytes, so it blocks PCSK9 synthesis rather than binding the protein. It is dosed subcutaneously at day 0, at 3 months, and then every 6 months. - Newer oral PCSK9 inhibitors (e.g., enlicitide) are in late-stage development. Do not expect them on boards yet.

**Efficacy** - LDL-C falls by about 50-60% on top of statin therapy. - FOURIER (evolocumab) and ODYSSEY OUTCOMES (alirocumab, post-ACS) showed reduced MACE (MI, stroke, coronary revascularization). Neither showed a clear reduction in cardiovascular mortality.

**Indications** - Heterozygous familial hypercholesterolemia (HeFH). - Homozygous familial hypercholesterolemia (HoFH). Evolocumab works only if some residual LDLR function exists, so patients with null (receptor-negative) mutations respond poorly. - Clinical ASCVD with LDL-C still above goal on maximally tolerated statin plus ezetimibe. - Statin intolerance.

**Adverse effects** - Injection-site reactions, nasopharyngitis or upper respiratory symptoms, and myalgias or flu-like symptoms. - Rare hypersensitivity reactions. - Concerns about neurocognitive effects have not been borne out (EBBINGS substudy). - There is no significant hepatotoxicity or myopathy signal, and no dose adjustment is needed in renal impairment.

**Key associations (high-yield)** - *Gain-of-function PCSK9 mutations* cause an autosomal dominant familial hypercholesterolemia phenotype with high LDL-C and premature ASCVD. The other FH causes are LDLR mutations (most common) and ApoB-100 defects (familial defective ApoB-100). - *Loss-of-function PCSK9 mutations* give very low LDL-C (~40% in some populations) and lifelong protection from coronary disease. This is the genetic validation for the drug class. - *Related lipid-lowering classes:* - Statins inhibit HMG-CoA reductase. - Ezetimibe blocks NPC1L1 at the intestinal brush border. - Bempedoic acid inhibits ATP citrate lyase. - Bile acid sequestrants (e.g., cholestyramine). - Lomitapide inhibits MTP and is used in HoFH. It causes hepatic steatosis and GI effects. - Mipomersen is an ApoB-100 antisense oligonucleotide (hepatotoxicity). - Because the monoclonal antibodies are proteins, they are not metabolized by CYP450. They have no significant drug interactions and need no hepatic or renal adjustment.

**Exam pearl:** A patient with familial hypercholesterolemia and persistently high LDL-C despite high-intensity statin plus ezetimibe should be started on a PCSK9 inhibitor. Choose a different agent, such as lomitapide, if the question describes HoFH with absent LDLR function.