Atorvastatin


Atorvastatin, sold under the brand name Lipitor among others, is a statin medication used to prevent cardiovascular disease in those at high risk and to treat abnormal lipid levels. For the prevention of cardiovascular disease, statins are a first-line treatment in reducing cholesterol. It is taken by mouth.
Common side effects may include diarrhea, heartburn, nausea, muscle pain and, less frequently, joint pain. Muscle symptoms often occur during the first year and are commonly influenced by pre-existing health issues and the nocebo effect. Most patients can continue therapy with dose adjustment or statin switching. Rare but serious side effects may include rhabdomyolysis, liver problems and diabetes. Use during pregnancy may harm the fetus. Like all statins, atorvastatin works by inhibiting HMG-CoA reductase, an enzyme found in the liver that plays a role in producing cholesterol.
Atorvastatin was patented in 1986, and approved for medical use in the United States in 1996. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication. In 2023, it was the most commonly prescribed medication in the United States, with more than 115million prescriptions filled for over 29 million people. In Australia, it was one of the top ten most prescribed medications between 2017 and 2023.

Medical uses

The primary uses of atorvastatin are for the treatment of dyslipidemia and for the prevention of cardiovascular disease.

Dyslipidemia

A 2014 meta-analysis showed high-dose statin therapy was significantly superior compared to moderate or low-intensity statin therapy in reducing plaque volume in people with acute coronary syndrome. The SATURN trial, which compared the effects of high-dose atorvastatin and rosuvastatin, also confirmed these findings.

Kidney disease

Atorvastatin may have modest renal protective effects at higher daily oral doses, as shown by a slowed progression or maintenance of the estimated glomerular filtration rate and a reduction in urinary protein excretion.
Prior to contrast medium administration, pre-treatment with atorvastatin therapy can reduce the risk of contrast-induced acute kidney injury in people with pre-existing chronic kidney disease who undergo interventional procedures such as cardiac catheterisation, coronary angiography or percutaneous coronary intervention. A meta-analysis of 21 RCTs confirmed that high dose atorvastatin therapy is more effective than regular dose or low dose statin therapy at preventing CI-AKI. Atorvastatin therapy can also help to prevent in-hospital dialysis post CM administration, however there is no evidence that it reduces all-cause mortality associated with CI-AKI. Overall, the evidence concludes that statin therapy, irrespective of the dose, is still more effective than no treatment or placebo at reducing the risk of CI-AKI.

Administration

Statins have been evaluated in clinical trials in combination with fibrates to manage dyslipidemia in people who also have type 2 diabetes, and a high cardiovascular disease risk; however, there is limited clinical benefit noted for most cardiovascular outcomes.
Statins with shorter half-lives are more effective when taken in the evening, so their peak effect occurs when the body's natural cholesterol production is at its highest. A recent meta-analysis suggested that statins with longer half-lives, including atorvastatin, may also be more effective at lowering LDL cholesterol if taken in the evening. However, the only study included in the meta-analysis of atorvastatin in people with heart disease did not specifically investigate if morning or evening dosing was more effective for reducing LDL cholesterol. The trial did confirm that, irrespective of dosing time, atorvastatin is very effective at reducing total cholesterol, LDL cholesterol, and triglycerides, and increasing HDL cholesterol levels. Hence, atorvastatin should be taken at the same time each day, at a time that is most convenient for the patient, so it does not compromise compliance.

Specific populations

  • Geriatric: Plasma concentrations of atorvastatin in healthy elderly subjects are higher than those in young adults. Clinical data suggests a comparable reduction in cardiovascular events among geriatric population and adults under 65 years of age. However, limited information is available on the benefits of use in patients over 75 years old who have not already had a cardiovascular event such as a heart attack.
  • Pediatric: Pharmacokinetic data is not available for this population.
  • Gender: Plasma concentrations are generally higher in women than in men, but there is no clinically significant difference in the extent of LDL reduction between men and women.
  • Kidney impairment: Kidney disease has no statistically significant influence on plasma concentrations of atorvastatin and dose adjustment considerations should only be made in context of the patient's overall health.
  • Hemodialysis: Previous studies have demonstrated a lack of clear and significant clinical benefit of statins in reducing composite cardiovascular and all-cause mortality in adults on hemodialysis, despite a reduction in total/ LDL cholesterol levels. The SHARP study suggested that the combination of a statin and ezetimibe is effective in reducing the risk of major atherosclerotic events in all CKD populations, including those on dialysis, but could not establish mortality benefit.
  • * Although limited studies have identified that statins may reduce all-cause mortality and composite cardiac events in hemodialysis patients with a higher baseline LDL-C level, findings are inconsistent and potentially misleading. Evidence suggests that LDL-C levels are not a reliable predictor of mortality in the hemodialysis population given the complex interplay of patient factors in ESRD. Therefore, LDL-C levels cannot be considered a true predictor of composite risk. Additionally, the impact and relevance of hemodialysis on statin levels and efficacy were not addressed in these trials.
  • Liver impairment: Increased drug levels can be seen in people with advanced cirrhosis. Despite these concerns, a 2017 systematic review and analysis of available evidence has shown that statins, such as atorvastatin, are relatively safe to use in stable, asymptomatic cirrhosis and may even reduce the risk of liver disease progression and death.

    Contraindications

  • Active liver disease: cholestasis, hepatic encephalopathy, hepatitis, and jaundice
  • Pregnancy: Atorvastatin is classified as a pregnancy category X medication by the U.S. Food and Drug Administration, indicating that it is contraindicated during pregnancy due to evidence of potential harm to the fetus and a lack of demonstrated benefit in this population. While limited human data suggest that atorvastatin is unlikely to cause major congenital anomalies, some studies have reported an association with adverse pregnancy outcomes such as low birth weight and preterm labor. Statins, including atorvastatin, act by inhibiting HMG-CoA reductase, a key enzyme in the biosynthesis of cholesterol. Cholesterol is essential for fetal development, particularly during early embryogenesis, as it plays a critical role in cell membrane formation and steroid hormone production. Due to these concerns, atorvastatin should be discontinued prior to conception or as soon as pregnancy is confirmed.
  • Breastfeeding: Small amounts of other statin medications have been found to pass into breast milk, although atorvastatin has not been studied specifically. Due to risk of disrupting a breastfeeding infant's metabolism of lipids, atorvastatin is not regarded as compatible with breastfeeding.
  • Markedly elevated CPK levels or if a myopathy is suspected or diagnosed after dosing of atorvastatin has begun. Very rarely, atorvastatin may cause rhabdomyolysis, and it may be very serious leading to acute kidney injury due to myoglobinuria. When rhabdomyolysis is suspected or diagnosed, atorvastatin therapy is discontinued immediately. The likelihood of developing a myopathy is increased by the co-administration of cyclosporine, fibric acid derivatives, erythromycin, niacin, and azole antifungals.

    Side effects

Major

  • Type 2 diabetes is observed in a small number of people, and is an uncommon class effect of all statins. It appears it may be more likely in people who were already at a higher risk of developing diabetes before starting a statin due to multiple risk factors, for example raised fasting glucose levels. However, the benefits of statin therapy in preventing fatal and non-fatal stroke, fatal coronary heart disease, and non-fatal myocardial infarction are significant. For most people the benefits of statin therapy far outweigh the risk of developing diabetes. A 2010 meta-analysis demonstrated that every 255 people treated with a statin for four years produced a reduction of 5.4 major coronary events and induced only one new case of diabetes.
  • In some case and clinical studies mild muscle pain or weakness have been reported, compared to a placebo. However, this increase was not related to statin therapy in 90% of cases in a large meta-analysis of randomized controlled trials. In patients taking higher statin doses, a similarly low increase in muscle pain and weakness was present with no clear evidence of a dose-response relationship. Duration of treatment with atorvastatin is unlikely to increase the risk of muscle-related side effects as most occur within the first year of treatment, after which the risk is not increased further. The known cardiovascular benefits of atorvastatin over time outweigh the low risk of muscle-related side effects.
  • Statin-induced rhabdomyolysis is rare, occurring in less than 0.1% of people who take statins. Statin induced rhabdomyolysis, as with other statin associated muscle symptoms, occurs most commonly in the first year of treatment but can occur at any time during treatment. Risk factors for statin induced rhabdomyolysis include older age, renal impairment, high dose statins and use of medications that reduce the breakdown of statins or fibrates.
  • Persistent liver enzyme abnormalities have been documented. Elevations threefold greater than normal were recorded in 0.5% of people treated with atorvastatin 10 mg-80 mg rather than placebo. Usage instructions in package inserts for this statin define the requirement that hepatic function be assessed with laboratory tests before beginning atorvastatin treatment and repeated periodically as clinically indicated—usually a clinicians' judgement. Package inserts for this statin recommend actions should liver abnormalities be detected. Ultimately, this is the judgment of the prescribing physician.