Simvastatin

Simvastatin, sold under the brand name Zocor among others, is a statin, a type of lipid-lowering medication.[2] It is used along with exercise, diet, and weight loss to decrease elevated lipid levels.[2] It is also used to decrease the risk of heart problems in those at high risk.[2] It is taken by mouth.[2]

Common side effects include constipation, headaches, and nausea.[2] Serious side effects may include muscle breakdown, liver problems, and increased blood sugar levels.[2] A lower dose may be needed in people with kidney problems.[2] There is evidence of harm to the developing baby when taken during pregnancy[2][3] and it should not be used by those who are breastfeeding.[2] It is in the statin class of medications and works by decreasing the manufacture of cholesterol by the liver.[2]

Simvastatin is made from the fungus Aspergillus terreus. It was patented by Merck in 1980, and came into medical use in 1992.[4][5] Simvastatin is available as a generic medication,[2] and is on the World Health Organization's List of Essential Medicines.[6] In 2023, it was the 22nd most commonly prescribed medication in the United States, with more than 24million prescriptions.[7][8]

Medical uses

The primary uses of simvastatin are to treat dyslipidemia and to prevent atherosclerosis-related complications such as stroke and heart attacks in those who are at high risk.[2] It is recommended to be used as an addition to a low-cholesterol diet.[2]

In heart protection studies, simvastatin showed the ability to lower LDL cholesterol by about 1·5 mmol/L, which resulted in substantial reductions in mortality rates. Simvastatin also reduced the numbers of other events like heart attacks, strokes, and revascularizations and MI significantly.[9]

The Heart Protection Study evaluated the effects of simvastatin in people with risk factors including existing cardiovascular disease, diabetes, or stroke, but having relatively low LDL cholesterol. In this trial, which lasted 5.4 years, overall mortality was reduced by 13% and cardiovascular mortality was reduced by 18%. People receiving simvastatin experienced 38% fewer nonfatal heart attacks and 25% fewer strokes.[10]

Statins in general have been proposed as beneficial in reducing the progression of Age-related Macular Degeneration (AMD).

Contraindications

Simvastatin is contraindicated with pregnancy, breastfeeding, and liver disease. Pregnancy must be avoided while on simvastatin due to potentially severe birth defects. Patients cannot breastfeed while on simvastatin due to potentially disrupting the infant's lipid metabolism.[14] High doses of simvastatin are also contraindicated with the widely used antihypertensive amlodipine. A lower dose is also recommended in people taking the calcium channel blockers, verapamil and diltiazem, as well as those taking amiodarone.[15][16]

Adverse effects

Common side effects (>1% incidence) may include indigestion and eczema. There is evidence to suggest that rare side effects such as joint pain, memory loss, and muscle cramps are more likely to occur in patients who take higher doses of simvastatin.[10] Cholestatic hepatitis, hepatic cirrhosis, rhabdomyolysis (destruction of muscles and blockade of renal system), and myositis have been reported in patients receiving the drug chronically.[17] Serious allergic reactions to simvastatin are rare.[18]

A type of DNA variant known as a single nucleotide polymorphism (SNP) may help predict individuals prone to developing myopathy when taking simvastatin; a study ultimately including 32,000 patients concluded the carriers of one or two risk alleles of a particular SNP, rs4149056,[19] were at a five-fold or 16-fold increased risk, respectively.[20]

Interactions

Simvastatin has important interactions with grapefruit juice and other drugs, including some that are commonly used for the treatment of cardiovascular disease. These interactions are clinically important because increasing simvastatin serum levels above those normally provided by the maximum recommended dose increases the risk of muscle damage, including the otherwise rare and potentially fatal side effect of rhabdomyolysis.

Consuming large amounts of grapefruit juice increases serum levels of simvastatin by up to three-fold, increasing the risk of side effects.[27][28][29][30] The FDA recommends that people taking statins should avoid consuming large quantities of grapefruit juice (more than 1 quart/946 ml) per day to reduce risk of myopathy.[31]

Simvastatin also interacts with other drugs, including some used to treat cardiovascular problems.

Pharmacology

History

The development of simvastatin was closely linked with lovastatin. Biochemist Jesse Huff and his colleagues at Merck began researching the biosynthesis of cholesterol in the early 1950s.[36] In 1956, mevalonic acid was isolated from a yeast extract by Karl Folkers, Carl Hoffman, and others at Merck, while Huff and his associates confirmed that mevalonic acid was an intermediate in cholesterol biosynthesis. In 1959, the HMG-CoA reductase enzyme (a major contributor of internal cholesterol production) was discovered by researchers at the Max Planck Institute. This discovery encouraged scientists worldwide to find an effective inhibitor of this enzyme.[37]

By 1976, Akira Endo had isolated the first inhibitor, mevastatin, from the fungus Penicillium citrinium while working at Daiichi Sankyo in Japan.[38] In 1979, Hoffman and colleagues isolated lovastatin from a strain of the fungus Aspergillus terreus. While developing and researching lovastatin, Merck scientists synthetically derived a more potent HMG-CoA reductase inhibitor from a fermentation product of A. terreus, which was designated MK-733 (later to be named simvastatin).

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