Fibrates, PPARα and severe hypertriglyceridaemia
Fibrates activate PPARα, a protein that switches genes on, which raises lipoprotein lipase, the enzyme that breaks down triglycerides, and so lowers triglycerides.
Remember
Fibrates activate PPARα to cut triglycerides, so they are used for severe hypertriglyceridaemia (very high triglycerides, above 10 mmol/L) to reduce the risk of pancreatitis.
A fibrate, such as fenofibrate, bezafibrate or ciprofibrate, works by activating PPARα. This is a nuclear transcription factor, meaning a protein inside the cell nucleus that switches genes on or off.
When PPARα is activated, it increases lipoprotein lipase, an enzyme that breaks down triglycerides in lipoproteins, and increases the uptake of fatty acids in the liver. This enhances the clearance of triglyceride-rich lipoproteins, and triglycerides fall by about 30 to 50%. HDL often rises, but how LDL responds depends on the lipid pattern, and in some patients with high triglycerides LDL can even rise.
As a simple memory aid, fibrates are for triglycerides, while statins, which block cholesterol synthesis, are for LDL.
Fibrates are mainly used for severe hypertriglyceridaemia (very high triglycerides), especially above 10 mmol/L. At that level there is a risk of acute pancreatitis (sudden inflammation of the pancreas), so reducing the triglycerides is the priority. They are also used when the lipid pattern is mixed, with low HDL and raised triglycerides. Fibrates are usually started by a specialist.
Combining a fibrate with a statin increases the risk of rhabdomyolysis, the breakdown of skeletal muscle that releases its contents into the blood and can damage the kidneys. The risk is greatest with gemfibrozil, which is contraindicated with statins because of fatal cases.
Key facts
- Target
- PPARα, a nuclear transcription factor (a protein that switches genes on).
- Action
- more lipoprotein lipase and more fatty acid uptake in the liver.
- Main effect
- triglycerides fall by about 30 to 50%, HDL often rises, and the LDL response depends on the lipid pattern.
- Main use
- severe hypertriglyceridaemia, especially above 10 mmol/L, because of the risk of acute pancreatitis.
- Statin interaction
- taking a fibrate with a statin increases the risk of rhabdomyolysis, and gemfibrozil with statins is contraindicated because of fatal cases.
- Contraindication
- gallbladder disease.
Exam traps
- Inhibiting HMG-CoA reductase reduces cholesterol synthesis and is the action of statins, not fibrates. Statins mainly lower LDL cholesterol and lower triglycerides only modestly, by about 15%.
- Blocking the NPC1L1 transporter reduces absorption of cholesterol from the gut, but that is how ezetimibe works. Fibrates do not act on this transporter.
- PPARγ activation is the mechanism of the thiazolidinediones, such as pioglitazone, which are used in type 2 diabetes, while fibrates act on PPARα.
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