Statins
Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase is the rate-limiting enzyme for endogenous cholesterol synthesis. Its inhibition reduces cholesterol availability and increases low-density lipoprotein (LDL) receptor synthesis and LDL uptake by hepatocytes. HMG-CoA reductase inhibitors (statins) reduce concentrations of total cholesterol and low-density lipoprotein cholesterol (LDL-C), and to a lesser extent triglycerides. They produce a small increase in high-density lipoprotein cholesterol (HDL-C).
The statins currently available in Australia are atorvastatin, fluvastatin, pravastatin, rosuvastatin and simvastatin. They are principally removed by hepatic excretion. They have a prolonged duration of action and are given once daily.
Adverse effects: Statins are well tolerated in the short to medium term. Dose adjustment may be required in some circumstances (eg concomitant cyclosporin, erythromycin or protease inhibitors).
Statin therapy can unmask underlying muscle disorders and can lead to significant increase in creatine kinase, which may persist for months or even years. The most common problems are myalgia associated with elevated plasma creatine kinase levels and (rarely) rhabdomyolysis. They can also cause abnormalities of liver function. Usually, creatine kinase elevation related to statin or statin-fibrate combination therapy begins to decrease within a few days, and is back to normal within three to four weeks. Mild elevation of the transaminases can occur in the presence of fatty liver, and statin and/or fibrate therapy over time can lead to a decrease in transaminases. Fatty liver is not a contraindication to lipid-lowering therapy.
Interactions: The statins have different metabolic pathways and the potential for interactions therefore depends on the individual statin being used. Patients on concomitant warfarin and fluvastatin, rosuvastatin or simvastatin therapy can have an increased international normalised ratio (INR) and increased risk of bleeding. Atorvastatin and pravastatin do not appear to interact with warfarin. Co-administration of statins with gemfibrozil, fenofibrate, cyclosporin or nicotinic acid can increase the risk of myopathy, rhabdomyolysis and renal failure. Drugs that inhibit cytochrome P450 (CYP) 3A4 isoenzymes (eg erythromycin, azole antifungals, amiodarone) can inhibit the metabolism of atorvastatin and simvastatin and increase the risk of adverse effects. Fluvastatin is mainly metabolised by CYP2C9, and drugs that inhibit this isoenzyme (eg fluconazole) also can increase the risk of adverse effects. The clearance of pravastatin and rosuvastatin is not dependent on cytochrome P450 enzyme metabolism, and interactions involving drugs metabolised by these enzymes are uncommon.
Factors modifying the dose of lipid-lowering drugs (Table 3.1)
| Factor | Dose adjustment |
| ALT (alanine aminotransferase) | |
| transiently >1.5 x ULN | withhold any increase and monitor ALT |
| persistently >1.5 x ULN | interrupt therapy[NB1] and monitor ALT |
| CK (creatine kinase) | |
| >1.5 x ULN with muscle symptoms | interrupt therapy[NB1] and monitor CK and muscle symptoms |
| transiently elevated (1.5 to 5 x ULN) with no muscle symptoms | withhold any increase and monitor CK and muscle symptoms |
| >5 x ULN with or without muscle symptoms | interrupt therapy[NB1] and monitor CK and muscle symptoms |
| concurrent use of statins and fibrates | halve both doses and give separately—fibrate in the morning and statin at night; monitor CK and muscle symptoms |
| concurrent use with drugs that compete for cytochrome P450 pathway (eg CYP3A4) | monitor CK and muscle symptoms, and reduce dose if necessary |
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