2.20 Statins

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.

Comparative information – statins

LDL Lowering Effects

• Atorvastatin, Rosuvastatin and Simvastatin are more potent than Fluvastatin or Pravastatin.
• Administration but the strongest cholesterol (LDL-C) lowering effect are to be found with atorvastatin and rosuvastatin.
• Shorter acting statins (fluvastatin, pravastatin and simvastatin) should be taken in the evening (Maximises levels when liver is most active in producing cholesterol), however – this is not too important if taking dose in the evening effects compliance.
• Nighttime dose is not necessary with longer acting stations (atorvastatin or rosuvastatin).  Mainly beneficial for very short acting statins such as simvastatin and fluvastatin.

Dosage

Side effects are typically dose-related – start with lower dose and increase if necessary based on lipid levels and overall CV risk

Start at higher dose if patient has high risk of CV disease,  Dose increases are usually made at intervals of at least 4-6 weeks

 

More than 80% of the lipid lowering effect is seen with 50% of the maximum dose (e.g. atorvastatin 40mg – See NPS and AMH diagram).

Adding another agent at this point is more effective than increasing the statin dose at lowering LDL levels (although effect on long term clinical outcome is unknown).