HMG-CoA reductase inhibitors or statins include atorvastatin, fluvastatin, pravastatin, rosuvastatin and simvastatin.  They all share a common suffix – ‘statin’, hence they are collectively referred to as ‘statins’.  Statins are reversible competitive inhibitors of the enzyme HMG-CoA reductase.  The enzyme HMG-CoA reductase is a rate limiting step in the conversion of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonate which eventually is used in the synthesis of cholesterol.  The conversion of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonate is carried out in the liver and the statins block this conversion leading to reduced hepatic production.

Cholesterol is necessary for a broad range of physiological functions including the production of hormones, bile, cell membranes, catecholamines and other neurotransmitters.  The supply of cholesterol is sourced via two main mechanisms (see figure below):

1. Production of endogenous cholesterol by the liver and
2. Dietary consumption of cholesterol.

When dietary supply of cholesterol is in excess, statins can be used to reduce the endogenous (liver) production of cholesterol.  Reduced liver production of cholesterol makes total blood cholesterol scarcer.  More cholesterol is scavenged from the circulating blood thereby reducing circulating plasma cholesterol levels.  Because there is less circulating cholesterol, there is a reduction of build-up of cholesterol containing fatty plaques is the arteries.

Common side effects of statins include myalgia, mild and transient GI symptoms, insomnia, nightmares, dizziness and elevated aminotransferase levels.  Statins are associated with myalgia, myopathy and a particularly serious expression of myalgia – rhabdomyolysis.

Rhabdomyolysis is the breakdown of skeletal muscle fibers with the resultant degraded products released into the bloodstream.  Symptoms of rhabdomyolysis included:

• severe unexplainable severe muscle pain – typically in the larger muscles
• muscle weakness
• dark brown or red urine.

This may be accompanied by reduced urine output.  While rare, rhabdomyolysis is a serious condition and should be treated without delay.

Myopathy vs rhabdomyolysis

Stop statin if CK conc is 10x ULN or persistent unexplained muscle pain (even if CK is normal)

Alirocumab (‘ali-roc-u-mab’) and Evolocumab (‘evo-loc-u-mab’)

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a class of drugs that reduce circulating cholesterol levels, particularly low-density lipoprotein cholesterol (LDL-C). PCSK9 is a protein that binds to LDL receptors (LDLR) on the surface of liver cells. Normally, LDL receptors capture LDL-C particles from the bloodstream and internalize them into liver cells, where they are degraded and removed from circulation. However, when PCSK9 binds to LDL receptors, it leads to their degradation, reducing the number of receptors available to clear LDL-C from the blood.

PCSK9 inhibitors, such as monoclonal antibodies, work by binding to PCSK9 and preventing it from attaching to LDL receptors. This inhibition spares the LDL receptors from degradation, allowing them to recycle back to the liver cell surface. With more LDL receptors available, the liver can remove more LDL-C from the bloodstream, thereby significantly lowering the levels of circulating LDL-C. This mechanism is particularly beneficial for patients who have not achieved target LDL-C levels with statins alone or who are intolerant to statins.

The PSCK9 inhibitors are monoclonal antibody-type drugs, therefore adverse effects include injection site reactions, rashes, nasopharyngitis, infections (e.g. ‘flu, URTIs, gastroenteritis), hypersensitivity reactions.

Inclisiran (‘in-clis-eran’)

Inclisiran is a small interfering RNA (siRNA) drug designed to reduce the expression of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene. It targets and binds to the messenger RNA (mRNA) encoding PCSK9, preventing its translation into the PCSK9 protein.

Once inclisiran enters liver cells, it incorporates into the RNA-induced silencing complex (RISC). The RISC-inclisiran complex binds to the PCSK9 mRNA, leading to its cleavage and degradation. This reduces the production of the PCSK9 protein.

With lower PCSK9 levels, the degradation of low-density lipoprotein receptors (LDLRs) on liver cells decreases. Normally, PCSK9 binds to LDL receptors and promotes their degradation, reducing the liver’s ability to remove LDL-C from the blood.

The reduction in PCSK9 levels results in more LDL receptors being available on the surface of liver cells. These receptors bind and remove more LDL-C from the bloodstream, leading to a significant reduction in circulating LDL-C levels.

By this mechanism, inclisiran effectively lowers LDL-C levels, offering a promising therapeutic option for patients with hypercholesterolemia and those at high risk of cardiovascular diseases.

📺 Watch video: PSCK9 inhibitor and inclisiran pharmacology. (2:09 min)

Of the 3 classes of lipid lowering drugs – statins, ezetimibe and PSCK9 inhibitors, the PSCK9 inhibitors are the most potent at reducing circulating LDL-C levels.  They can reduce circulating LDL-C levels by between 30-60%.

Next most potent class of cholesterol lowering thearpy are the statin class which can achieve a LDL-C lowering effect of between 25-55%.  It is noteworthy that atorvastain and rosuvastatin, the two most potent statins have the greatest effect on lowering LDL-C.

Last is ezetimibe which can achieve a 15-25% reduction in circulating LDL-C levels.

If the patient has triglyceridemia, probably the most effective drug treatment are the fibrates.  Fibrates can reduce triglycerides by 40-80% with a LDL reduction benefit of 5-15%.

Cost

It is worth understanding the cost of lipid-lowering therapies to the patient or the PBS.  The following information provides a comparison of the cost to treat eleveated cholesterol for the first 6 months of treatment for hypercholesterolemia.