Statins are drugs used to lower blood cholesterol levels. They are among the most widely used medicines in cardiovascular pharmacology. Statins continue to be prescribed at an ever-growing rate in patients over the age of 40 years.
Statins are HMG-CoA reductase inhibitors, drugs that have been around since 1987. Lovastatin was the first approved statin; a naturally occurring statin found in small quantities in foods such as oyster mushrooms and red yeast rice.
Many different statins have since been developed, such as:
An earlier statin – cerivastatin – was withdrawn from the market (2001) due to the risk of fatal rhabdomyolysis.
Statins are used for the primary and secondary prevention of cardiovascular disease, as well as primary hyperlipidemia.
- Primary prevention – statins are used to reduce the risk from serious cardiovascular events, such as heart attack and stroke, in patients over the age of 40 who present with real and significant long-term risk.
- Secondary prevention – statins help reduce the risk of additional cardiovascular events in patients with pre-existing cardiovascular disease.
- Hyperlipidemia – statins are used to reduce harmful levels of cholesterol in the bloodstream.
Elevated levels of cholesterol are linked to cardiovascular disease. Statins work to lower harmful LDL cholesterol and reduce the long-term risk of heart attack and stroke.
Mechanism of Action
Statins are HMG-CoA reductase inhibitors.
HMG-CoA reductase is an enzyme; the rate-limiting enzyme in the mevalonate pathway of cholesterol production.. By competitively inhibiting the rate-limiting enzyme, statins reduce LDL levels in the blood.
Statins reduce hepatic cholesterol production. Most circulating cholesterol does not come from the liver but rather from internal physiological processes. When statins reduce hepatic cholesterol production, blood cholesterol levels fall.
As cholesterol levels start to fall:
- Hepatic cells upregulate the production of LDL receptors to extract cholesterol from the blood circulation.
- As low-density and very-low-density lipoproteins (“bad cholesterol”) pass by these receptors, they are extracted and ultimately converted to bile acids and other byproducts.
That said, statins do more than reduce LDL cholesterol.
Studies show that statins also improve endothelial integrity and the regulation of inflammatory processes that otherwise leads to atheroma formation. Statins also maintain plaque stability and reduce the risk of blood clot formation.
Via these mechanisms, HMG-CoA reductase inhibitors prove effective in the treatment of both primary and secondary prevention of cardiovascular disease and hyperlipidemia.
Common side effects of statins include:
- Gastrointestinal disturbances
More serious effects include:
- Muscle pain – approximately 1-in-10 patients taking a statin experience muscle pain and myopathies. Rarely, patients experience rhabdomyolysis – a condition in which muscle breaks down, the toxic byproducts of which enter the bloodstream and present as toxic agents to the kidney, increasing the risk of kidney failure.
- Diabetes – statins increase the risk of type 2 diabetes in at-risk patients.
- Elevated liver enzymes – such as increasing alanine transaminase (ALT) levels.
- Increased risk of cataracts
Aspects of clinical pharmacology of statins to consider include:
- Statins should be used with caution in patients with hepatic impairment.
- That because statins are excreted via the kidneys, doses should be reduced in patients with renal dysfunction.
- Other antihyperlipidemic drugs – such as gemfibrozil, a fibrate – increase the risk of rhabdomyolysis when taken with statins.
- Statins are contraindicated in pregnancy. Cholesterol synthesis is essential for healthy fetal formation.
- Statins with a short half-life – such as simvastatin, lovastatin, and fluvastatin – are advised to be taken in the evening because endogenous cholesterol production is highest at night. Furthermore, dietary intake of cholesterol is also at its lowest in the evening/at night.
- Grapefruit juice elevates plasma concentration of certain statins such as atorvastatin, simvastatin, and lovastatin because they are metabolized by CYP3A4. Grapefruit juice contains furanocoumarins that inhibit the intestinal CYP 3A4 enzyme (but not the liver CYP 3A4 enzyme). In contrast, statins such as fluvastatin and rosuvastatin are metabolized by CYP2C9 and therefore have no significant interaction with grapefruit juice.
- The risk of statin toxicity increases if taken with CYP inhibitors. Examples include macrolide antibacterials, HIV protease inhibitors, antiarrhythmic drugs – such as diltiazem and amiodarone, and antifungals – such as voriconazole. In cases where a macrolide antibacterial (such as clarithromycin) is deemed clinically necessary, the statin can be withheld for a short period.
That concludes our review of statins pharmacology. Check back to our pharmacy blog soon for more exclusive content to help you master the science of drugs and medicines!