Simvastatin


Continuing Education Activity

Simvastatin is an oral HMG-CoA reductase inhibitor indicated as an adjunct to diet. It is a semi-synthetic derivative of lovastatin, the first FDA-approved statin. Simvastatin helps lower cholesterol production and reduce dyslipidemia-associated complications. High concentrations of LDL cholesterol can lead to artery damage, potentially leading to cardiac complications and stroke. However, there are several more effective statins with more favorable adverse effect profiles. This activity outlines the indications, mechanism of action, methods of administration, significant adverse effects, contraindications, and monitoring, of simvastatin, so providers can direct patient therapy in treating hyperlipidemia as part of the interprofessional team.

Objectives:

  • Identify the mechanism of action of simvastatin.
  • Review the indications for using simvastatin in lipid control.
  • Explain the adverse event profile of simvastatin and how it compares with other statin medications.
  • Summarize interprofessional team strategies for improving care coordination and communication to examine simvastatin use and improve patient outcomes.

Indications

Simvastatin is an oral HMG-CoA reductase inhibitor indicated as an adjunct to diet. It is a semi-synthetic derivative of lovastatin, the first FDA-approved statin. Simvastatin helps lower cholesterol production and reduce dyslipidemia-associated complications. High concentrations of LDL cholesterol can lead to artery damage, potentially leading to cardiac complications and stroke.

FDA-Approved Indications

  • Homozygous/heterozygous familial hypercholesterolemia
  • Heterozygous NonFamilial hypercholesterolemia
  • Hypertriglyceridemia
  • Dysbetalipoproteinemia 
  • Reduction of adverse cardiovascular events 

Simvastatin is also used off-label for prophylactic and therapeutic indications.

Non-FDA-Approved Indications

  • Prophylaxis of adverse cardiovascular outcomes post-acute-coronary-syndrome hospitalization 
  • Prophylaxis of atrial fibrillation among patients with stable coronary artery disease

Simvastatin is used as monotherapy and is available in combination products to treat dyslipidemia. Combination products include:

  • Simvastatin/ezetimibe[1]
  • Simvastatin/niacin extended-release (ER)

Mechanism of Action

Clinicians prescribe statin therapy to lower cholesterol concentrations; simvastatin targets cholesterol production. The biosynthesis of this molecule consists of a multi-step pathway. The rate-limiting step in this pathway involves the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase enzyme. Using acetyl-CoA as a substrate, mevalonic acid is formed, and subsequent reactions lead to the formation of cholesterol. Simvastatin acts on the rate-limiting step and serves as an HMG-CoA reductase inhibitor, consequently leading to decreased cholesterol concentrations.

Statins also possess additional properties in addition to their ability to lower cholesterol concentrations. These include inhibition of platelet aggregation, reduction in inflammation at the site of atherosclerotic plaque, and improved endothelial function. These properties are commonly taken advantage of when prescribing statin therapy for individuals with normal cholesterol levels. Studies have shown that early statin therapy initiation has reduced the incidence of cardiovascular events, leading to reduced mortality.[2]

Administration

Simvastatin is approved for oral administration and is available in 5-mg, 10-mg, 20-mg, 40-mg, and 80-mg tablets. A suspension dosage form is also available for those with difficulty swallowing.

Recommended Dosages*

Homozygous Familial Hypercholesterolemia

  • 40 mg once every evening

Heterozygous Familial Hypercholesterolemia

  • Initial 10 to 20 mg once every evening; max dose 40 mg once every evening
  • Pediatric patients age 10 to 17: Initial 10 mg once every evening; max dose 40 mg once every evening

Hypertriglyceridemia

  • Initial 10 to 20 mg once every evening; max dose 40 mg once every evening

Reduction in Cardiovascular Events

  • Initial 10 to 20 mg once every evening; max dose 40 mg once every evening
  • In patients with coronary heart disease (CHD), the initial dose is 40 mg once every evening

A dose restriction exists for simvastatin 80 mg due to a higher risk of myopathy and possible rhabdomyolysis, especially within the first 12 months of use. Therefore, the 80-mg strength is restricted for only those patients who have been on the 80-mg regimen for 12 or more months with no reported myopathy. Simvastatin 80 mg is not recommended for patients with LDL targets that are not at goal, even with simvastatin 40 mg. Recommendations are to use a high-intensity statin instead. For stable patients on the simvastatin 80-mg dose, a change of therapy is necessary if initiating an interacting medication.

*Doses are adjusted to target goal LDL levels.

Dose Adjustments

Dose adjustments are necessary with simvastatin when taken concomitantly with certain pharmacotherapy. Adjustments in simvastatin strength reduce potential statin-associated toxicities, including fatigue and myopathy.

Potent CYP3A4 inhibitors (clarithromycin, HIV protease inhibitors, cyclosporine)

  • Simvastatin is contraindicated:
    • Verapamil, diltiazem, dronedarone
      • Max dose is simvastatin 10 mg
    • Amiodarone, amlodipine, ranolazine
      • Max dose is simvastatin 20 mg

Adverse Effects

Common adverse effects include a headache, myalgia, abdominal pain, constipation, and upper respiratory infections. Rarer, yet more severe, causations include cardiovascular effects such as atrial fibrillation, hepatic abnormalities, including cholestatic hepatitis, greater than a 3-fold elevation in transaminases, jaundice, and potential liver failure. Adverse musculoskeletal effects include greater than a three-fold increase in creatine phosphokinase (CPK) levels, rhabdomyolysis, and compartment syndrome in the lower legs.[3][4]

Drug concentrations, and consequently, incidence and severity of adverse effects, are significantly increased when coadministered with CYP3A4 inhibitors. Concomitant medications administered with simvastatin should have an assessment performed for potential drug interactions to minimize the risk of adverse effects.

Contraindications

Patients with contraindications to simvastatin pharmacotherapy include those with active liver disease, including those who have elevated hepatic enzymes, pregnancy, and women who may become pregnant or who are breastfeeding. Concomitant use with certain medications (see above) is also a contraindication with simvastatin, and drug profiles should undergo a careful review prior to initiation.

Pregnancy is a known secondary cause for dyslipidemia leading to a potential increase in triglyceride and LDL-C concentrations. Statin therapy is contraindicated during pregnancy resulting in limited options for dyslipidemia treatment during pregnancy. Alternative treatment options are necessary to treat elevated concentrations during pregnancy to minimize associated complications such as hypertriglyceridemia associated with acute pancreatitis. Pregnancy has been delayed or avoided in reported cases to avoid the possible complications from untreated dyslipidemia.[5]

Although rare, a serious complication of statin therapy is liver toxicity with elevated levels of transaminases. Due to a potential increase in liver enzymes, patients with active liver disease and pre-existing elevated transaminases are excluded from simvastatin therapy. Simvastatin can transiently increase transaminase concentrations within the first few months of treatment. These subsequently return to baseline. The clinician should monitor liver function and enzymes while their patients are on simvastatin pharmacotherapy.[6]

Monitoring

Continuous laboratory monitoring is not necessary for patients on simvastatin therapy. To gauge therapeutic effectiveness, a lipid profile is evaluated four weeks after initiation and periodically after that leading to potential dose adjustments. Liver function tests are also performed at baseline and subsequently, as clinically necessitated, to evaluate liver toxicities. Common symptoms include abdominal pain, yellowing of the skin, loss of appetite, and fatigue. Creatine kinase levels are also assessed at baseline and periodically after that, especially in high-risk patients such as those with renal insufficiency. Patients with complex medication profiles (polypharmacy) require close monitoring for musculoskeletal and hepatic complaints due to potential simvastatin toxicities.[7]

Toxicity

Severe cases of musculoskeletal symptoms warrant discontinuation of simvastatin. In milder cases, temporary discontinuation followed by a re-challenge at a lower dose is the currently accepted practice. If re-challenging simvastatin at a lower dose leads to similar adverse effects, discontinuation followed by an alternative statin is the recommended next step.[8] Discontinuation is also warranted if severe hepatotoxicity or hyperbilirubinemia or if jaundice occurs.

Enhancing Healthcare Team Outcomes

Simvastatin has been in use for many years to treat dyslipidemia and high-risk patients such as people with diabetes. Common clinical pearls can help limit potential adverse effects and enhance patient outcomes.

  • Due to an increased risk of myopathy, the 80-mg dose is restricted to patients who have been stable on 80 mg for at least 12 months. If additional LDL-lowering is required, switch to a high-intensity statin.
  • Use a lower starting dose and monitor for patients who are of Chinese descent.[9]
  • Use further caution in patients who are chronic alcohol consumers and/or have a history of liver disease.
  • Avoid the consumption of grapefruit juice.

Simvastatin therapy can address dyslipidemia in those patients with such a profile. However, newer statin agents with fewer interactions and adverse effects have replaced it as the first-line agent for statin therapy. For those patients who receive dyslipidemia therapy with simvastatin, the interprofessional healthcare team, consisting of clinicians, specialists, nurses, and pharmacists, should work together to monitor for therapeutic results and adverse effects, and the pharmacist can suggest equivalent dosing with other statins less prone to adverse events. This can drive better patient outcomes with fewer side effects. [Level 5]


Article Details

Article Author

Om Talreja

Article Author

Connor Kerndt

Article Editor:

Manouchkathe Cassagnol

Updated:

6/5/2021 12:37:30 PM

PubMed Link:

Simvastatin

References

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Gryn SE,Hegele RA, Ezetimibe plus simvastatin for the treatment of hypercholesterolemia. Expert opinion on pharmacotherapy. 2015 Jun     [PubMed PMID: 25920750]

[2]

De Denus S,Spinler SA, Early statin therapy for acute coronary syndromes. The Annals of pharmacotherapy. 2002 Nov     [PubMed PMID: 12398573]

[3]

Chochola M,Lubanda JC,Skalicka L,Varejka P,Horejs J,Prskavec T,Balík M,Semrád M,Linhart A, [Bilateral leg compartment syndrome due to severe myonecrosis caused by inappropriate use of simvastatin]. Journal des maladies vasculaires. 2008 Dec     [PubMed PMID: 18819764]

[4]

Parkin L,Paul C,Herbison GP, Simvastatin dose and risk of rhabdomyolysis: nested case-control study based on national health and drug dispensing data. International journal of cardiology. 2014 Jun 1     [PubMed PMID: 24726164]

[5]

Russi G, Severe dyslipidemia in pregnancy: The role of therapeutic apheresis. Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis. 2015 Dec     [PubMed PMID: 26626968]

[6]

Calderon RM,Cubeddu LX,Goldberg RB,Schiff ER, Statins in the treatment of dyslipidemia in the presence of elevated liver aminotransferase levels: a therapeutic dilemma. Mayo Clinic proceedings. 2010 Apr     [PubMed PMID: 20360293]

[7]

Page SR,Yee KC, Rhabdomyolysis in association with simvastatin and dosage increment in clarithromycin. Internal medicine journal. 2014 Jul     [PubMed PMID: 25041770]

[8]

Taylor BA,Panza G,Thompson PD, Increased creatine kinase with statin treatment may identify statin-associated muscle symptoms. International journal of cardiology. 2016 Apr 15     [PubMed PMID: 26874453]

[9]

Liao JK, Safety and efficacy of statins in Asians. The American journal of cardiology. 2007 Feb 1     [PubMed PMID: 17261409]