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.
Simvastatin is also used off-label for prophylactic and therapeutic indications.
Simvastatin is used as monotherapy and is available in combination products to treat dyslipidemia. Combination products include:
Statin therapy is prescribed to lower cholesterol concentrations; simvastatin targets cholesterol production. Biosynthesis of this molecule is comprised 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 concentrations of cholesterol.
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 incidence of cardiovascular events, including mortality.
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.
Homozygous Familial Hypercholesterolemia
Heterozygous Familial Hypercholesterolemia
Reduction in Cardiovascular Events
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 the use of simvastatin 40 mg. Recommendations are to use a high-intensity statin instead. For patients who are stable on the simvastatin 80-mg dose, a change of therapy is warranted if initiating an interacting medication.
*Doses are adjusted to target goal LDL levels.
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.
Strong CYP3A4 Inhibitors (Clarithromycin, HIV Protease Inhibitors, Cyclosporine)
Verapamil, Diltiazem, Dronedarone
Amiodarone, Amlodipine, Ranolazine
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.
Drug concentrations, and consequently incidence and severity of adverse effects, are greatly increased when coadministered with CYP3A4 inhibitors. Concomitant medications administered with simvastatin should be assessed for potential drug interactions to minimize the risk of adverse effects.
Patients contraindicated to simvastatin pharmacotherapy include those who have active liver disease, including those who have elevated hepatic enzymes, pregnancy and women who may become pregnant or are breastfeeding. Concomitant use with certain medications (see above) is also a contraindication with simvastatin and drug profiles should be carefully reviewed 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 leading to limited options for dyslipidemia treatment during pregnancy. Alternative treatment options must be explored to treat elevated concentrations during pregnancy to minimize associated complications such as hypertriglyceridemia associated acute pancreatitis. Pregnancy has been delayed or avoided in reported cases to avoid the possible complications from untreated dyslipidemia.
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 those with pre-existing elevated transaminases are excluded from simvastatin therapy. Simvastatin can transiently increase transaminase concentrations within the first few months of therapy. These subsequently return to baseline. Liver function and enzymes should be monitored while on simvastatin pharmacotherapy.
Continuous laboratory monitoring is not warranted for patients on simvastatin therapy. To gauge effectiveness, a lipid profile is evaluated 4 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 evaluated at baseline and periodically after that, especially in high-risk patients such as those with renal insufficiency. Patients with complex medication profiles (polypharmacy) should be closely monitored for musculoskeletal and hepatic complaints due to potential simvastatin toxicities.
In cases of severe musculoskeletal symptoms, discontinuation of simvastatin is warranted. In milder cases, temporary discontinuation followed by a re-challenge at a lower dose is currently accepted in practice. If re-challenging simvastatin at a lower dose leads to similar adverse effects, discontinuation followed by an alternative statin is recommended. Discontinuation is also warranted if severe hepatotoxicity or hyperbilirubinemia or jaundice is observed.
Simvastatin has been used for many years in the treatment of dyslipidemia and high-risk patients such as people with diabetes. Common clinical pearls can help limit potential adverse effects and enhance patient outcomes.