PCSK9, or Proprotein Convertase Subtilisin/Kexin type 9, is a molecule that has gained a significant role in cardiovascular health and cholesterol management in recent years. First discovered in 2003, this protein plays a crucial role in cholesterol metabolism in the body. Its discovery has paved the way for a new class of drugs that are making waves in treating high cholesterol levels and, consequently, in preventing cardiovascular diseases.
PCSK9 is predominantly synthesised in the liver, the central organ for cholesterol metabolism. While the liver is the main source, PCSK9 is also produced, to a lesser extent, in the intestines and kidneys. After being produced, PCSK9 is secreted into the bloodstream, where it can travel to various tissues and exert its effects, primarily on the liver cells.
The Discovery of PCSK9
PCSK9 was initially discovered in 2001 by a team of researchers at the University of Texas. The gene encoding PCSK9 was identified while searching for new members of the subtilisin family of proprotein convertases. These are enzymes that activate other proteins by cutting them at specific places. The PCSK9 gene was found on chromosome 1, and its product was found to be highly expressed in the liver, kidney, and small intestine.
Link to Cholesterol Regulation
In 2003, a groundbreaking discovery was made when scientists linked the PCSK9 gene to familial hypercholesterolemia (FH). Before this, other genes were already known to cause FH, but PCSK9 emerged as a new player when some families with FH didn’t seem to fit the known patterns. Here’s what the research uncovered:
- Gain-of-Function: In their research on familial hypercholesterolemia (FH), scientists encountered specific families that didn’t possess the previously known genetic mutations associated with FH, namely those in the LDLR and APOB genes. Further investigation revealed that these families had mutations in the PCSK9 gene. These mutations made PCSK9 more effective at its role, and such mutations were termed “gain-of-function” mutations.
- Loss-of-Function: By 2005, researchers discovered another facet of PCSK9. They identified mutations termed “loss-of-function,” which rendered PCSK9 less active. People with these mutations exhibited lower LDL-cholesterol levels and had a notably reduced risk of heart disease. These individuals appeared to lead normal, healthy lives, with no observable adverse effects resulting from these mutations.
These pivotal discoveries laid the foundation for intensive research into PCSK9 as a promising therapeutic target for hypercholesterolemia.
PCSK9 Mode of Action
PCSK9 is a protein that plays a pivotal role in cholesterol homeostasis. It acts primarily by binding to the LDL receptors (LDLRs) on the surface of liver cells. Normally, LDLRs capture LDL particles from the bloodstream and bring them into the liver cell, where they are broken down by lysosomes in a process called Endocytosis (Fig-1). The LDL receptor is then recycled back to the surface, where it can capture and internalise more LDL particles. Each LDL receptor can be recycled approximately 150 times.
PCSK9 disrupts this process by attaching to the LDL receptor during endocytosis. When attached to PCSK9, the LDL receptor cannot separate from LDL particles during lysosome degradation, preventing the LDL receptor from being recycled (Fig-2). This means fewer receptors are available to clear LDL cholesterol from the blood. As a result, blood levels of LDL cholesterol increase.
Fig-1: LDL receptors mechanism of action
LDL receptors clear LDL from the bloodstream and then return (recycle) to the cell surface. Each LDL receptor can be recycled approximately 150 times.
Fig-2: PCSK9 mechanism of action
PCSK9 binds LDL receptors, preventing their separation from the LDL particle upon entering the endosome, which results in LDLR degradation rather than a return to the cell surface.
PCSK9 Inhibitors: A New Era in Cholesterol Management
While the title ‘PCSK9 inhibitors’ might initially bring to mind the familiar monoclonal antibodies, such as evolocumab and alirocumab, there’s another player in the arena of cholesterol management: Inclisiran. Unlike the monoclonal antibodies that directly bind to and inhibit the PCSK9 protein circulating in our bloodstream, Inclisiran uses a unique mechanism. It’s an RNA interference therapeutic that targets and degrades PCSK9 mRNA within liver cells, effectively curbing the production of the PCSK9 protein at its source. While the end result is similar—reduced levels of PCSK9 protein—Inclisiran represents a fundamentally different approach to achieving this goal. I’ll delve deeper into the Inclisiran groundbreaking mechanism of action in an upcoming post.
PCSK9 Inhibitors: Monoclonal Antibodies
The discovery of PCSK9’s function laid the foundation for a new class of drugs known as PCSK9 inhibitors. These drugs are antibodies designed to bind to PCSK9 and block its activity (Fig-3). By inhibiting PCSK9, they increase the number of LDL receptors on liver cells, thereby enhancing the clearance of LDL cholesterol from the bloodstream. Clinical trials have demonstrated that PCSK9 inhibitors can significantly lower LDL cholesterol levels by up to 55-60%, regardless of other background lipid-lowering therapies such as statins. Additional to LDL-C lowering effects, they also reduce apolipoprotein B (ApoB) by 50%, triglycerides by 15% and lipoprotein (a) [Lp(a)] by 25%. PCSK9-inhibitors are especially useful for patients who are not adequately responsive to traditional statin therapy or who are statin intolerant. Examples of these drugs include evolocumab and alirocumab.
PCSK9 inhibitors are administered by subcutaneous injection. They have a half-life of approximately 17 days, allowing for 2–4 weekly dosing. Evolocumab is typically dosed at 140 mg every 2 weeks but can also be given 420 mg monthly.
Fig-3: PCSK9 inhibitors (Monoclonal Antibodies) mechanism of action
PCSK9 inhibitors are antibodies designed to bind to PCSK9 and block its activity, thereby allowing LDL receptors to be recycled and resurfaced after endocytosis. This will lead to more clearance of LDL particles and reduced LDL cholesterol. PCSK9 inhibitors are administered by subcutaneous injection. They have a half-life of approximately 17 days, allowing for 2–4 weekly dosing. Evolocumab is typically dosed at 140 mg every 2 weeks but can also be given 420 mg monthly.
PCSK9 Inhibitors Cardiovascular Outcome Trials
Two approved PCSK9i drugs underwent dedicated trials to assess their safety and efficacy: the FOURIER trial for evolocumab and the ODYSSEY OUTCOMES trial for alirocumab. These drugs work similarly to lower LDL-C, but the study designs and populations differed.
The FOURIER trial tested evolocumab on 27,564 patients with cardiovascular diseases like prior heart attacks (81%), strokes (19%), or significant peripheral artery disease (13%). These patients were mostly on statins, with an average age of 63 and 25% being women. The criteria included LDL-C levels of at least 70 mg/dL. During the trial, evolocumab reduced LDL-C by 59%. In just over two years, it resulted in a 15% reduction in cardiovascular death, heart attack, stroke, unstable angina, or coronary stenting, and a 20% reduction in cardiovascular death, heart attack, or stroke, with an absolute risk reduction of 2% at three years.
The ODYSSEY OUTCOMES trial examined alirocumab on 18,924 patients who had recently experienced heart-related issues. The majority were on high-intensity statins, had an average age of 58, and 25% were women. Their criteria also included LDL-C levels of at least 70 mg/dL. Alirocumab reduced LDL-C by 48%, less than evolocumab due to specific protocols. Over roughly three years, it led to a 15% drop in primary heart-related outcomes —death from coronary disease, stroke, non-fatal heart attack and unstable angina — and a 14% relative risk reduction in death from any cause.
Relative Risk Reduction of Cardiovascular End Points With PCSK9 Inhibitors
|Adverse limb events
PCSK9 inhibitors safety
A key aspect of both cardiovascular trials was the thorough evaluation of the drug’s safety. This is particularly crucial for PCSK9i because many patients can’t tolerate the primary cholesterol-lowering medication (statins). While there was a slight rise in reactions at the injection site in both the FOURIER and ODYSSEY OUTCOMES trials, other side effects didn’t show any notable increase, including muscle pain, rise in liver enzymes, diabetes, cataracts, or cognitive functions. A study within FOURIER named EBBINGHAUS measured cognitive abilities and revealed no difference in cognition between those on evolocumab and those on a placebo
When to use PCSK9 inhibitors
The current guidelines advise the use of PCSK9 inhibitors for patients with a history of atherosclerotic cardiovascular disease (ASCVD) – including prior heart attacks, CABG, cardiac stenting, or very high coronary calcium scores, as well as significant CAD detected through cardiac imaging – or Familial Hypercholesterolemia (FH). These patients should be at a high risk of future cardiovascular events and must have maximised their statin therapy. Other non-statin medications, like Ezetimibe and Bempedoic Acid, should be considered if their LDL cholesterol remains off-target. If, after all these interventions, the LDL-c level remains above 1.8 mmol/L (70 mg/dl), PCSK9 inhibitors are recommended (Fig-4).
References and further reading
- Goldstein J.L, Brown M.S. The LDL receptor. Arterioscler Thromb Vasc Biol . 2009
- Sabatine M.S, Giugliano R.P, Keech A.C, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med . 2017
- Schwartz G.G, Steg P.G, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med . 2018
- Roth E.M, Davidson M.H. PCSK9 inhibitors: mechanism of action, efficacy, and safety. Rev Cardiovasc Med . 2018
- Kasichayanula S, Grover A, Emery M.G, et al. Clinical pharmacokinetics and pharmacodynamics of evolocumab, a PCSK9 inhibitor. Clin Pharmacokinet . 2018
- Giugliano R.P, Mach F, Zavitz K, et al. Cognitive function in a randomized trial of evolocumab. N Engl J Med . 2017
- Sabatine M.S. PCSK9 inhibitors: what we know, what we should have understood, and what is to come. Eur Heart J . 2022