PCSK9?

PCSK9..New emerging Research based Cholestrol Lowering & improving quality of life….!Here is a comprehensive overview of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9), including its biological function, clinical importance, PCSK9 inhibitors, and key clinical trials:

🔬 What is PCSK9?

PCSK9 is a protein encoded by the PCSK9 gene, primarily produced in the liver. It plays a major role in cholesterol metabolism by binding to LDL receptors (LDLR) on the surface of hepatocytes and promoting their degradation. This reduces the liver’s ability to remove LDL cholesterol (LDL-C) from the blood.

🧠 Mechanism of Action

LDL cholesterol binds to LDL receptors on liver cells.
Normally, LDL is taken up and the receptor is recycled.
PCSK9 binds to LDLR, leading to lysosomal degradation of the receptor.
Fewer LDL receptors → less LDL clearance → higher blood LDL-C.

💊 PCSK9 Inhibitors

PCSK9 inhibitors are monoclonal antibodies or small interfering RNAs that inhibit PCSK9 activity, thereby increasing LDLR recycling and reducing LDL-C levels significantly.

🔹 Types of PCSK9 Inhibitors

Drug Name Type Mechanism FDA Approval

Alirocumab (Praluent) mAb Binds PCSK9 2015
Evolocumab (Repatha) mAb Binds PCSK9 2015
Inclisiran (Leqvio) siRNA Inhibits PCSK9 synthesis in liver 2021

📊 Major Clinical Trials

FOURIER Trial

Drug: Evolocumab

Design: Phase III, 27,564 patients with ASCVD

Results:

LDL-C ↓ by 59%

15% ↓ in major CV events (MI, stroke, CV death)

Conclusion: Evolocumab is effective in reducing LDL-C and improving CV outcomes.

Published: NEJM 2017

ODYSSEY OUTCOMES Trial

Drug: Alirocumab

Design: 18,924 patients post-ACS

Results:

LDL-C ↓ from 92 to 53 mg/dL

15% ↓ in composite CV endpoints

All-cause mortality ↓

Conclusion: Benefit in high-risk post-ACS patients

Published: NEJM 2018

ORION Trials (Inclisiran)

ORION-9, ORION-10, ORION-11:

Drug: Inclisiran

Design: Multiple phase III trials (familial hypercholesterolemia, ASCVD)

Results:

LDL-C ↓ by 50–60%

Dosing: Every 6 months (after initial and 3-month doses)

Advantages: Biannual dosing improves compliance

Published: NEJM 2020

✅ Indications

Familial hypercholesterolemia (HeFH and HoFH)

Atherosclerotic cardiovascular disease (ASCVD) patients not at LDL-C goals despite maximally tolerated statins

Statin-intolerant patients (off-label or as adjunct)

⚠️ Side Effects and Considerations

Common Side Effects Rare/Serious

Injection site reactions Hypersensitivity
Myalgias (less than statins) Neurocognitive effects (rare)
Elevated LFTs (rare) Cost may limit access

💡 Latest Developments & Pipeline

Oral PCSK9 inhibitors: Early phase development (e.g., MK-0616 from Merck).
Gene editing (CRISPR): Promising results in silencing PCSK9 gene (preclinical to phase I).

📈 PCSK9 in Clinical Practice

Used as add-on therapy to statins + ezetimibe when LDL-C goals aren’t achieved.

Shown to reduce CV events, especially in high-risk populations.

Inclisiran offers the advantage of longer dosing intervals (twice a year).

📚 Key References