Description

Fenofibrate is a medication that belongs to the class of drugs known as fibrates (or fibric acid derivatives). It is a lipid-regulating agent that is used to treat various types of dyslipidemia (abnormal levels of lipids in the blood). Fenofibrate works primarily by activating a key nuclear receptor that regulates lipid metabolism.

Indications

Fenofibrate is used to manage several lipid disorders, with its main indications being:

• Severe Hypertriglyceridemia: It is used to reduce very high levels of triglycerides in the blood, which can be a risk factor for pancreatitis.

• Primary Hypercholesterolemia and Mixed Dyslipidemia: It is used to lower high levels of LDL (“bad”) cholesterol and total cholesterol, and to raise low levels of HDL (“good”) cholesterol. It is often used in combination with other lipid-lowering therapies or as an alternative when statins are not tolerated.
• Atherosclerosis: By improving the lipid profile, fenofibrate helps to reduce the progression of atherosclerosis (the buildup of plaque in arteries), which in turn lowers the risk of cardiovascular events.

Mechanism of Action

Fenofibrate’s mechanism of action is primarily mediated through its activation of a nuclear transcription factor called Peroxisome Proliferator-Activated Receptor Alpha (PPARα).

1. PPARα Activation: Fenofibrate binds to and activates PPARα, which is a key regulator of gene expression involved in lipid and lipoprotein metabolism.

2. Increased Lipolysis: Activation of PPARα leads to an increase in the synthesis and activity of lipoprotein lipase (LPL). LPL is an enzyme that breaks down triglycerides in lipoproteins (like VLDL and chylomicrons) into free fatty acids. This increased breakdown of triglycerides is the primary reason fenofibrate so effectively lowers triglyceride levels.
3. Decreased VLDL Production: Fenofibrate also reduces the hepatic synthesis of the apolipoprotein C-III (apo C-III), an inhibitor of LPL. By reducing apo C-III, it further enhances LPL activity. It also reduces the liver’s production of very-low-density lipoprotein (VLDL), which is the primary carrier of triglycerides in the blood.

4. Increased HDL Cholesterol: By increasing the synthesis of apolipoprotein A-I and apolipoprotein A-II, fenofibrate leads to an increase in HDL (“good”) cholesterol levels. HDL helps remove cholesterol from the arteries and transport it back to the liver for disposal.

5. Reduced LDL Cholesterol: While its main effect is on triglycerides, fenofibrate can also cause a modest reduction in LDL cholesterol. This is achieved by promoting the conversion of dense LDL particles into a more benign form and by increasing the catabolism (breakdown) of LDL.
6. In summary, fenofibrate works by revving up the body’s natural processes for breaking down triglycerides and increasing the good cholesterol, while also reducing the production of the bad lipoproteins that contribute to heart disease.