Summary:
How LDL cholesterol (LDL-C) is removed from the body:
LDL-C is removed from the blood by the liver. It binds to special receptors on the surface of liver cells (called LDL receptors). Once inside the cell, LDL-C is broken down, and the receptor goes back to the surface to catch more LDL-C. The more receptors there are, the more LDL-C is removed from the blood — lowering cholesterol levels.
A protein called PCSK9 can bind to these receptors and cause them to be destroyed. This means fewer receptors are available, and more LDL-C stays in the blood — raising cholesterol levels.
How the medications work:
The antibodies Alirocumab and Evolocumab block PCSK9. This helps preserve more LDL receptors on the liver cells, so more LDL-C is removed from the blood. These drugs can lower LDL-C levels by up to 85%.
They also lower other blood fats like triglycerides, raise “good” HDL cholesterol, and reduce Lipoprotein(a), although the exact reasons for these effects are still unclear.
Study results:
Conclusion:
PCSK9 inhibitors like Alirocumab and Evolocumab are highly effective at lowering LDL cholesterol and reducing the risk of heart-related diseases.
LDL cholesterol (LDL-C) is removed from the blood by the liver. For this purpose, LDL-C binds to a receptor on the surface of the liver (LDL receptor or LDL-R). LDL-C is then taken into the cell via the receptor. Vesicles containing LDL-C and the LDL receptor fuse with endosomes. Within the endosomes, the pH level drops, and LDL-C separates from the receptor. LDL-C is then broken down in lysosomes. The LDL receptor returns to the cell surface to take up new LDL-C.
If many LDL receptors are available on the cell surface, a lot of LDL-C is broken down, and blood levels of LDL-C decrease. If only a few LDL receptors are present on the cell surface, LDL-C levels increase. The number of LDL receptors on the cell surface is regulated by a protein called proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 is produced in the liver cells, released into the plasma, and can bind to LDL receptors. The PCSK9/LDL receptor complex is transported to the lysosomes and degraded. As a result, fewer LDL receptors are transported to the liver cell surface. This means that fewer receptors are available to remove LDL-C from the blood.
The antibodies Alirocumab and Evolocumab neutralize PCSK9. This increases the number of LDL receptors on the surface of liver cells, allowing more LDL-C to be removed and degraded. These antibodies can reduce LDL-C levels by 60 to 85% in monotherapy or combination therapy. When combined with a statin-based therapy, PCSK9 inhibitors reduce LDL-C 46 to 73% more than placebo and 30% more than ezetimibe. PCSK9 inhibitors also lower triglycerides, raise HDL-C, and reduce Lp(a) by about 30%. The exact mechanism behind these changes in the lipid profile is unknown.
In the FOURIER study with Evolocumab, cardiovascular risk was significantly reduced. In the FOURIER-Outcomes Study (Fourier Open-Label Extension), the observation period was extended to over eight years. The median LDL-C was 30 mg/dL, and 63.2% of patients achieved LDL-C levels below 40 mg/dL. The Number Needed to Treat (NNT) over five years was 66. There was no increase in side effects compared to placebo over the entire observation period. The most common side effects were itching at the injection site and flu-like symptoms.
Similarly, in the ODYSSEY-Outcomes study, Alirocumab achieved comparable results. In pretreated patients, LDL-C levels were reduced from 90 mg/dL to 40 mg/dL. The primary composite endpoint consisted of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or hospitalization due to unstable angina pectoris. Alirocumab significantly reduced the risk of experiencing a cardiovascular event by 15%. All-cause mortality was also reduced by 15%. There was a nominally statistically significant reduction in cardiovascular events with an NNT of 49.
https://www.nejm.org/doi/full/10.1056/NEJMoa1801174
Furtado, Remo & Giugliano, Robert. (2020). What Lessons Have We Learned and What Remains to be Clarified for PCSK9 Inhibitors? A Review of FOURIER and ODYSSEY Outcomes Trials. Cardiology and therapy. 9. 10.1007/s40119-020-00163-w.
Mechanism of Action of PCSK9 Inhibitors
The specific antibodies (PCSK9 inhibitors) Alirocumab and Evolocumab are human IgG subtypes and bind specifically to PCSK9. This means that free PCSK9 is bound into an antibody complex, preventing it from attaching to the LDL receptor. This results in a functional PCSK9 deficiency, promoting recycling of the LDL receptors. As a result, more LDL receptors are available on the surface of liver cells to remove LDL-C from the blood, leading to a reduction in LDL-C levels.
Despite statin therapy, 20% of patients still show progression of coronary plaques.
For Alirocumab and Evolocumab, it has been shown that adding them to high-dose statin therapy further reduces plaque size and stabilizes plaques. For the first time, medications are available that can lower LDL-C levels to values without increased CVD risk, even in patients with familial hypercholesterolemia.
PCSK9 Inhibitor | Dosage (starting dose / subcutaneous injection) |
Alirocumab |
– 75 mg prefilled pen, once every 2 weeks – 150 mg prefilled pen, once every 2 weeks – 300 mg prefilled pen, once monthly |
Evolocumab | – 140 mg prefilled pen, once every 2 weeks |