PCSK9 Inhibitors | Ten Points to Remember

Shimada YJ, Cannon CP.
PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibitors: Past, Present, and the Future. Eur Heart J 2015;May 13:[Epub ahead of print].

The following are 10 points to remember about proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors:

  1. Reduction in low-density lipoprotein cholesterol (LDL-C) with statins has successfully decreased the risk of cardiovascular events, and cardiovascular morbidity and mortality. Despite the efficacy of statins for lowering LDL-C, patients with more severe forms of hypercholesterolemia (including familial hypercholesterolemia [FH]), and those intolerant to statins would benefit from alternatives and combination therapies, particularly if very low levels of LDL-C are more efficacious and safe.
  2. Having been tested in several clinical trials, the PCSK9 inhibitors are a new class of drugs that appear promising as a novel agent for LDL-C reduction. They reduce LDL-C, apolipoprotein B (apoB), non–high-density lipoprotein (non-HDL), and Lp(a), but have minimal effect on triglycerides or HDL-C.
  3. After discovery in 2003, the PCSK9 gene became the third gene after LDL receptor (LDL-R) gene and apoB gene to be associated with the autosomal dominant form of FH. The gain-of-function mutation in the PCSK9 gene results in reduced LDL-R activity and is associated with a high risk for atherosclerotic cardiovascular disease.
  4. In contrast to the gain-of-function mutations, mutations that cause loss of function of PCSK9 have a decrease in LDL-C. Nonsense mutation in each PCSK9 gene results in LDL-C as low as 14-16 mg/dl. Heterozygous loss-of-function mutations in the PCSK9 gene are associated with reduced rates of cardiovascular events (hazard ratio for coronary heart disease in 15-year follow-up of Caucasians was 0.5; 95% confidence interval [CI], 0.32-79; and for African Americans was 0.11; 95% CI, 0.02-0.81), as well as decrease in peripheral artery disease and carotid intima-media thickness.
  5. PCSK9 can directly bind to the LDL-R within the hepatocyte, which results in lysosomal degradation of the complex and less LDL-Rs are recycled. Alternatively, it can enter the circulation and block LDL-R function, resulting in less uptake of LDL-C. PCSK9 inhibitors reduce the degradation of LDL-R, which increases LDL-R number and thereby increases LDL-C clearance. As the PCSK9 inhibitor becomes metabolized over time, there is an increase in plasma-free PCSK9 and recovery of LDL-C concentration. The effects of PCSK9 inhibitors are not affected by age, body mass index, LDL-C, statin use, or statin dosing.
  6. PCSK9-directed targets include monoclonal antibodies, which prevent LDL particles from binding to LDL-R, small interfering RNA (siRNA), which lead to a reduction in plasma levels of PCSK9, and antisense oligonucleotides (ASOs), which lowers plasma levels by blocking messenger RNA for PCSK9. Two of the human monoclonal antibody drugs have had extensive phase 3 studies that have been published. The siRNA and ASO drugs are in phase 1 or preclinical.
  7. When administered every 2 weeks subcutaneously, each of the agents has a dose response that is statin independent, with a reduction of 50-70% with marked fluctuation when given every 4 weeks. Injection site reactions are rare, and the great majority of patients remain on the drug during trials; 2-6% of subjects in phase 3 trials had serious adverse events, which led to discontinuation in 2-10%. Liver function tests >3x ULL were seen in <2%, and high levels of creatine kinase were very rare.
  8. PCSK9 inhibitors have been shown to be very effective in both heterozygous FH and homozygous FH and in patients who cannot achieve a low LDL-C despite maximal dosing of statins. The clinical impact is not known, but could be substantial considering the reduction in cardiovascular events by decreasing the mean LDL-C from 70 mg/dl to 54 mg/dl with ezetamibe in the IMPROVE-IT trial.
  9. A significant percentage of persons with atherosclerotic cardiovascular disease or at risk are statin intolerant, a cohort for whom the PCSK9 inhibitors have been shown to be very effective and tolerated.
  10. The PCSK9 inhibitors are being evaluated by large outcome trials with endpoints of total and cardiovascular mortality, and cardiovascular event rates in persons on highest tolerated doses of statins, as well as using serial coronary arteriography with intravascular ultrasound to assess effect of coronary disease progression and regression. The cost and cost-effectiveness of these novel new agents have yet to be determined.

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