13th July 2022, Dr Chee L Khoo
In the last issue of GPVoice, we looked at the up-to-date guidelines in the management of dyslipidaemia in primary and secondary prevention. We looked at how complex those guidelines are. We also touched on the fact not all the evidence behind the guidelines is Level A evidence. The PCSK9 inhibitors, in particular, are a relatively new class of lipid lowering agents and the data is still coming in. A recent study evaluated the efficacy and safety of the different PCSK9 inhibitors as adjuvant therapies in statin-treated hypercholesterolemic patients. The results of the systematic review and network meta-analysis were recently published and is worthy a look this week.
What are PCSK9 inhibitors?
Proprotein convertase subtilisin kexin 9 (PCSK9) is an enzyme in the liver that block LDL-C receptors in the liver. These receptors are meant to remove LDL-C from circulation. PCSK9 inhibitors are monoclonal antibodies which bind and inactivate PCSK9 and thereby, reduce the competitive binding to the LDL-C receptors on the surface of the hepatocyte. This directly reduces LDL-C levels. There are currently two PCSK9i on the market, alirocumab (Praluent®) and evolocumab (Repatha®). Both are injectables and both are approved under the PBS with very tight criteria.
A 3rd agent, inclisiran, works by blocking the activation of PCSK9, thereby stopping the binding to the LDL-C receptor on the surface of the hepatocyte. Inclisiran is not available in Australia yet. The company withdrew its application for approval by the PBAB before they were being considered.
See Figure 1.
What can PCSK9 inhibitors do?
In addition to reducing LDL-C as described above, the PCSK8 inhibitors also reduceApoB and lipoprotein A both of which are related to the LDL-C. Now, Apolipoprotein B is the primary apolipoprotein of chylomicrons, VLDL, lipoprotein A, intermediate density lipoprotein (IDL), and LDL-C particles. Lipoprotein(a) is a low-density lipoprotein variant containing a protein called apolipoprotein(a). Genetic and epidemiological studies have identified lipoprotein(a) as a risk factor for atherosclerosis and related diseases, such as coronary heart disease and stroke.
What are the CV outcomes of PCSK9 inhibitors?
The ODYSSEY trials showed that alirocumab as an add-on statin therapy achieved significantly greater reduction in the LDL-C level than placebo ranging from 32 to 70 % (1). Evolocumab as an add-on therapy attained around 46 to 72 percent greater reduction in the LDL-C level than placebo (2). ORION trials demonstrated that compared with placebo, inclisiran as an add-on statin therapy effectively reduced around 50% LDL-C level with no severe adverse reaction reported (3).
Y-T Huang and L-T Ho conducted a systematic review and network meta-analysis to compare the efficacy of different PCSK9 inhibitors with different dosage as an add-on statin therapy in reducing the levels of LDL-C and lipoproteins e.g., ApoB and Lp(a), which are also important causal agents of atherosclerosis, and reducing cardiac events and the safety in adults with hyperlipidaemia (4).
A total of 2,404 articles were identified through database searching, and 1,888 articles remained after removing duplicates by screening the titles and abstracts. 22 articles with 42,786 patients were included in this systemic review and network meta-analysis. They found that statin add-on PCSK9 inhibitors, including evolocumab, alirocumab, and inclisiran vs. placebo or ezetimibe, significantly reduced the levels of LDL-C, ApoB, and Lp(a).
Among the PCSK9 inhibitors, evolocumab 140 mg Q2W was found to be more superior in atherogenic lipid reduction, including LDL-C, ApoB, and Lp(a), than the others except for alirocumab 300 mg QM. However, evolocumab 420 mg QM had similar LDL-C level reduction effects compared with those of alirocumab 300 mg QM [59.70% (48.01%, 71.38%)].
PCSK9 inhibitors have similar side effects other than higher injection-site reaction caused by inclisiran.
The LDL-C level has long been the primary target for cardiovascular risk prevention; thus, further LDL-C lowering may be beneficial for the further reduction of cardiovascular risk. Besides LDL-C lowering, substantial ApoB and Lp(a) lowering caused by PCSK9 inhibitors in statin-treated hypercholesteremia patients may contribute to additional reduction of residual cardiovascular risk (Sacks, 2006; Ridker et al., 2008; Lieb et al., 2018). The discrepancy of the degree of LDL-C and ApoB reduction may be due to the different physiologic roles in lipid metabolism. LDL-C represents the cholesterol mass of LDL particles, while ApoB reflects the total number of LDL, VLDL, and other atherogenic lipoprotein particles due to each of these lipoproteins being with one ApoB molecule. PCSK9 inhibitors keep LDL receptors from degradation to increase LDL-C uptake into cells for metabolism. However, not only LDL particles but also other atherogenic lipoproteins include ApoB, thus resulting in the dissociation between LDL-C and ApoB reduction trend (Sacks, 2006).
Schmidt et al. conducted a Cochrane systematic review and meta-analysis to evaluate the effect of PCSK9 inhibitors in reducing LDL-C and CVD risk, concluding that PCSK9 inhibitors reduced LDL-C and decreased CVD risk but may have increased the risk of any adverse events and led to little or no difference in mortality (5).
How safe is ultra-low LDL-C?
No significant risk difference of AEs was found between PCSK9 inhibitors and placebo, except the higher injection-site reaction noted in inclisiran use.
What are the authority criteria for prescribing PCSK9 inhibitors under the PBS?
The restrictive criteria has become relaxed. In patients who have reached maximal tolerated statins +/- ezetimibe and their LDL-C is still > 2.6 mmol/L, they need to have the following to qualify:
- ASCVD in ≥ 2 vascular territories
- Multi-vessel CAD >50% stenosis
- ≥ 2 major CV events in 5 years
- T2D + Microalb or >60y or ATSIC
- TIMI risk score for secondary prevention >4
It’s as simple as that. If you have a patient who should have their LDL-C lowered, write a note for your specialist colleague to initiate the PCSK9 inhibitor. They may not be as up to date with the PBS as you are.
You will have a chance to participate in discussions with A/Prof Christian Mussap and Dr Jay Ramanathan on “Why and how to implement combination lipid lowering therapy” on Wednesday 20th July at the Holiday Inn, Warwick Farm. For details and registration, click here.
References:
- Schwartz GG, Steg PG, Szarek M et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018; 379: 2097-2107
- Giugliano, R. P., Desai, N. R., Kohli, P., Rogers,W. J., Somaratne, R., Huang, F., et al. Efficacy, Safety, and Tolerability of a Monoclonal Antibody to Proprotein Convertase Subtilisin/kexin Type 9 in Combination with a Statin in Patients with Hypercholesterolaemia (LAPLACE-TIMI 57): a Randomised, Placebo-Controlled, Dose-Ranging, Phase 2 Study. Lancet 380 (9858), 2007–2017. doi:10.1016/s0140-6736(12)61770-x
- Ray, K. K., Landmesser, U., Leiter, L. A., Kallend, D., Dufour, R., Karakas,M., et al. (2017). Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol. N. Engl. J. Med. 376 (15), 1430–1440. doi:10.1056/NEJMoa1615758
- Huang Y-T, Ho L-T, Hsu H-Y, Tu Y-K and Chien K-L (2022) Efficacy and Safety of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors as Adjuvant Treatments for Patients with Hypercholesterolemia Treated with Statin: A Systematic Review and Network Meta-analysis. Front. Pharmacol. 13:832614. doi: 10.3389/fphar.2022.832614
- Schmidt, A. F., Pearce, L. S., Wilkins, J. T., Overington, J. P., Hingorani, A. D., and Casas, J. P. (2017). PCSK9 Monoclonal Antibodies for the Primary and Secondary Prevention of Cardiovascular Disease. Cochrane Database Syst. Rev. 4 (4), Cd011748. doi:10.1002/14651858.CD011748.pub2