Lipoprotein apheresis | Emerging therapies

Lipoprotein apheresis

  • Lipoprotein Apheresis (LA) is an extracorporeal treatment that removes ApoB-containing lipoproteins from the circulation and is usually performed at a transfusion medicine or haemodialysis centre.
  • For patients who require LA, the earlier they are started the better the prognosis. In HoFH patients ideally by age 5 and not later than 8 years.
  • Expected LDL cholesterol reductions:
    • acute – LDL cholesterol level reduction of 55 – 70% can be achieved by a single treatment
    • long-term treatment – weekly or fortnightly can achieve close to normal LDL cholesterol values.
  • Statin and other drug therapies (e.g. Ezetimibe, Niacin) should be continued during LA.
  • Concomitant therapy with an ACE inhibitor is contraindicated owing to the risk of hypotension.
  • The removal of LDL in this high risk category improves:
    • CHD outcomes – e.g. angina pectoris
    • progression of atherosclerosis and aortic fibrosis
    • endothelial function and markers of inflammation.
  • Indications:
    • HoFH patients
    • compound HeFH patients
    • severe HeFH patients with progressive CHD who are refractory or intolerant to maximal cholesterol lowering medication
    • during pregnancy where patients have severely elevated LDL cholesterol levels as in HoFH patients with established CHD.

Emerging therapies

  • Optimal reduction in plasma levels of LDL cholesterol is not achievable in many FH patients.
  • Substantial reduction in patient LDL cholesterol has been achieved through the development of highly innovative treatments used in conjunction with standard therapy.
  • These therapies include: 

    • PCSK9 inhibitors
      • Monoclonal antibodies prevent the binding of PCSK9 to the LDL receptor, thereby preventing degradation of the receptor and increasing the availability of receptors on the cell surface to clear LDL from the circulating blood.
      • PCSK9 inhibitors have been shown to reduce LDL cholesterol levels by up 70%, can be given with statin therapy and are administered by subcutaneous injection monthly.
      • Short term studies show no serious side effects and those displayed are injection site related.

    • Mipomersen
      • Second generation antisense oligonucleotide that targets the messenger ribonucleic acid (mRNA) of apoB and VLDL.
      • Mipomersen action reduces the action of apoB on VLDL thus reducing the amount of VLDL secreted.
      • Mipomersen is cleared via the renal system and is not metabolised by P450 cytochrome enzyme.
      • Mipomersen is administered by subcutaneous injection weekly and can be given with standard cholesterol lowering therapy. A mean reduction in LDL cholesterol of 25%, apoB of 27% and Lp(a) 31% has been demonstrated during trials. Side effects are predominately related to injection site (76%).

    • Lomitapide
      • Lomitapide acts by inhibiting the microsomal triglyceride transfer protein responsible for assembly and secretion of VLDL.
      • A reduction of LDL cholesterol of 50.9% has been demonstrated in clinical trials.  Dosage is daily by tablet (5mg – max 60mg) with the most frequent adverse event (93%) being gastrointestinal in nature. Elevated alanine aminotransaminase has been reported to a lesser degree.

    • Cholesteryl ester transfer protein (CETP) inhibitors
      • CEPT inhibitors were primarily developed to raise HDL cholesterol; however strong CEPT inhibitors such as anacetrapid and evacetrapib also significantly decrease LDL cholesterol.
      • LDL cholesterol reduction results from a decrease transfer of cholesteryl ester onto apoB containing particles.
      • Patients with FH will probably experience LDL cholesterol reduction similar to those without FH of 30-40%.
      • Rates of adverse effects were found to be similar to those seen with placebo. 

       

    • These therapies require long-term monitoring to demonstrate efficacy, safety and tolerability.