Understanding PCSK9 and anti-PCSK9 therapies

•PCSK9 increases LDL-receptor degradation. Inhibitors increase hepatic uptake of LDL-C.•Monoclonal antibodies to PCSK9 lower LDL-C -35% to -67% on top of statin therapy.•LDL-C is lowered similarly in familial and nonfamilial hypercholesterolemic patients.•PCSK9 monoclonal antibodies substantially lower nonHDL-C, apo B, and Lp(a) levels.•Phase II dose-ranging studies in patient on a stable background of statin therapy for 12 weeks demonstrate similar LDL-C-lowering efficacy, with alirocumab at 50, 100, and 150 mg administered subcutaneously (SC) every 2 weeks (Q2W) lowering LDL-C -35%, -59%, and -67%, respectively, compared with LDL-C reductions of -42%, -60%, and -66%, respectively, with 70, 105, and 140 mg SC Q2W of evolocumab.•In patients receiving atorvastatin 10 mg daily, a phase II study found that escalation of the dose to 80 mg daily, or adding alirocumab 150 mg Q2W, or both, resulted in an LDL-C reduction of -17%, -66%, and -73%, respectively. This shows that the LDL-C reduction achieved with the PCSK9 antibody-statin combination is mostly additive and mostly because of the lowering achieved with the antibody.•Patients with homozygous familial hypercholesterolemia experienced an LDL-C reduction of -47% if they had two receptor-dysfunction mutations, -25% if they one receptor-defective and one receptor-negative mutation, and an increase in LDL-C with two receptor-negative mutations demonstrating that the particular mutation determines the efficacy of the PCSK9 monoclonal antibody in these patients. In contrast, patients with heterozygous familial hypercholesterolemia achieved LDL-C lowering of >50%, similar to that achieved in non-familial hypercholesterolemia patients, when given a PCSK9 monoclonal antibody suggesting that the antibody is effective mostly by upregulating the nonmutated LDL receptor.•Studies with PCSK9 monoclonal antibody have been found to reduce LDL-C >50% compared with 12% to 20% with ezetimibe in patients who are unable to tolerate 2 or more statins. Adverse event (AE) occurred less frequently and led to fewer therapy discontinuations with the antibody therapy.•In spite of the hypothesis that PCSK9 monoclonal antibody monotherapy may be less efficacious in lowering LDL-C but have a longer duration of effect, it has not been demonstrated in phase III trials.•PCSK9 monoclonal antibodies also substantially (40%-50%) lower non-HDL-C and apolipoprotein B levels and modestly reduce triglyceride and Lp(a) levels.•The most common adverse effect seen with PCSK9 monoclonal antibody therapy is low LDL-C, although many would argue that this effect is a positive effect. A search for symptoms of low LDL-C (such as those associated with abetalipoproteinemia) including symptoms of fat malabsorption syndromes, hepatic steatosis, progressive neurologic degenerative disease, retinitis pigmentosa, and acanthocytosis has not been encountered in any of the PCSK8 monoclonal antibodies under development.•Discontinuation of PCSK9 monoclonal antibody therapy occurs slightly more frequently than placebo (1%), but no particular AE has been identified. As well, there has been no worsening of statin adverse effects when a PCSK8 monoclonal antibody is administered with it including no elevations in liver function transaminases, no muscle-related AEs, and no progression to diabetes or adverse changes in blood glucose or hemoglobin A1c. Injection-site reactions generally occur in 2% to 5% of patients and are marginally more prevalent in patients receiving SC injections of PCSK9 monoclonal antibodies than in those receiving placebo. These effects are episodic, self-limiting, and mild. The development of binding and neutralizing antibodies has been monitored and not found to be a problem.

Inhibitors of proprotein convertase subtilisin kexin type 9 (PCSK9) represent a new therapeutic category of drugs for the treatment of dyslipidemia and atherosclerotic cardiovascular disease. To appreciate the efficacy of these agents and interpret research results, it is important to understand the dynamic relationship between PCSK9, low-density lipoprotein-receptors, intrahepatic cholesterol synthesis, and blood cholesterol levels. Drugs which negate the action of PCSK9 can produce substantial reductions in atherogenic lipoprotein cholesterol-carrying particles and thereby hold the potential for further reducing events associated with atherosclerotic cardiovascular disease. This article will describe and discuss PCSK9 interactive mechanisms and apply them to the interpretation of clinical trial results, which involve PCSK9 monoclonal antibodies.