HMG-CoA Reductase Inhibitors (Statins)

• HMG-CoA reductase inhibitors (Statins) lower total cholesterol, low density lipoprotein (LDL), and triglyceride concentrations and increase high density lipoprotein (HDL) concentrations with varying potencies.
• Primary use is for primary and secondary prevention of coronary heart disease.
• Serious class-related adverse effects are hepatotoxicity and myopathy. Myopathy risk can be reduced by avoiding high statin concentrations, which can be a result of the dose, impaired elimination, and/or drug interactions.

HMG-CoA reductase inhibitors competitively inhibit the enzyme hydroxymethylglutaryl-CoA (HMG-CoA) reductase. HMG-CoA reductase is the rate-limiting hepatic enzyme responsible for converting HMG-CoA to mevalonate, which is a precursor of sterols including cholesterol. HMG-CoA reductase inhibitors decrease LDL concentrations by reducing hepatic cholesterol production and increasing LDL clearance from the blood. The sustained inhibition of cholesterol synthesis in the liver also decreases concentrations of very low density lipoproteins (VLDL).[36344] In addition, HMG-CoA reductase inhibitors raise HDL concentrations and lower triglyceride concentrations.[45507] The reduction in triglyceride concentrations may be through hepatic synthesis inhibition and lipoprotein lipase activity enhancement in adipocytes. [45539] In addition to specific lipoprotein effects, HMG-CoA reductase inhibitors have been shown to halt the progression and facilitate the regression of atherosclerotic lesions.[33273][45542][33274][45543]

In addition to the beneficial lipoprotein effects, statins appear to have anti-ischemic and anti-anginal properties possibly by plaque stabilization. Statins deplete the lipid content of plaques and inhibit LDL oxidation, inflammation, and apoptosis within the plaque. Also, increased collagen content and anti-inflammatory mediator expression occurs. Statins may also preserve myocardial perfusion and may also provide ischemia-reperfusion injury protection.[45548][45549][45550][45551][45552][45555][45556][45553][45554][45559][45560]

Several factors are important when considering selection of a statin:

• LDL reduction needed
• Concomitant drugs - some statins are contraindicated for use with other drugs and/or the statin dose is affected; simvastatin and lovastatin interact with many drugs that affect their dose.
• Renal function

The 2018 AHA/ACC Cholesterol Clinical Practice Guidelines recommend statin therapy in the following patient populations [63783]:

• Patients with clinical atherosclerotic cardiovascular disease (ASCVD) should begin high-intensity statin or maximally tolerated statin therapy to reduce LDL-C levels by 50% or greater. If patients are unable to tolerate high-intensity therapy, moderate-intensity statin therapy should be utilized to reduce LDL-C levels by 30% to 49%.
• Patients at very high risk of ASCVD, such as those with a history of multiple major ASCVD events or 1 major ASCVD event with multiple high-risk conditions, should receive maximally-tolerated statin therapy to achieve an LDL-C level less than 70 mg/dL.
• In patients unable to achieve an LDL-C less than 70 mg/dL on maximally-tolerated statin therapy, it may be reasonable to add ezetimibe therapy.
• In patients on maximally tolerated statin therapy and ezetimibe therapy with an LDL-C of 70 mg/dL or greater, a PCSK9 inhibitor may be added.
• Patients with severe primary hypercholesterolemia (LDL-C = 190 mg/dL or greater) should begin high-intensity statin therapy without calculation of the 10-year ASCVD risk.
• In patients unable to achieve an LDL-C less than 100 mg/dL on statin therapy, it may be reasonable to add ezetimibe therapy.
• In patients on statin and ezetimibe therapy with an LDL-C of 100 mg/dL or greater and multiple risk factors for ASCVD events, a PCSK9 inhibitor may be added.
• Patients 40 to 75 years of age with diabetes mellitus and LDL-C 70 mg/dL or greater should begin moderate-intensity statin therapy without calculating 10-year ASCVD risk.
• In diabetic patients at higher risk (i.e., 50 to 75 years of age or with multiple risk factors), it is reasonable to initiate high-intensity statin therapy to reduce LDL-C level by 50% or greater.
• Nondiabetic patients 40 to 75 years of age with an LDL-C 70 mg/dL or greater and 10-year ASCVD risk of 7.5% or greater should begin moderate-intensity statin therapy if a patient-caregiver risk discussion of treatment options favor statin therapy. If initiated on statin therapy, reduce LDL-C 30% or greater. If 10-year ASCVD risk is 20% or greater, reduce LDL-C by 50% or greater.
• Nondiabetic patients 40 to 75 years of age with 10-year ASCVD risk of 7.5% to 19.9% with risk-enhancing factors (i.e. family history of premature ASCVD, persistently elevated LDL-C 160 mg/dL or greater, metabolic syndrome, CKD, history of preeclampsia or premature menopause (age less than 40 years), chronic inflammatory disorders, persistent elevations of triglycerides of 175 mg/dL or greater, apolipoprotein B 130 mg/dL or greater, C-reactive protein 2 mg/L or greater, ABI less than 0.9 or lipoprotein 50 mg/dL or greater) should be initiated on statin therapy.
• For nondiabetic patients with an ASCVD of 5% to 7.5% and risk-enhancing factors, it may be justifiable to initiate moderate-intensity statin therapy.
• Patients 75 years or older with an LDL-C of 70 to 189 mg/dL may be initiated on moderate-intensity statin therapy; however, it also may be reasonable to discontinue statin therapy in older adults with physical or cognitive decline, multimorbidity, frailty, or reduced life expectancy.
• Children and adolescents 10 years of age or older with an LDL-C persistently 190 mg/dL or greater or 160 mg/dL or greater with familial hypercholesterolemia that have failed 3 to 6 months of lifestyle therapy may be started on statin therapy.

Assess adherence and lipid levels 4 to 12 weeks after statin therapy initiation. Lipid panels should be repeated every 3 to 12 months as needed.[63783]

Comparison of HMG-CoA Reductase Inhibitors - Effects of Dose on Lipoprotein Concentrations

HMG-CoA Reductase Inhibitor Comparative Efficacy Trials

Abbreviations: AMI – acute myocardial infarction; CI = confidence interval; CRP = c-reactive protein; CV = cardiovascular; CVD = cardiovascular disease; HR = hazard ratio; RR= relative risk

General

Statins appear to be fairly well tolerated at least among clinical trial populations. In a meta-analysis of 36,062 patients who received atorvastatin, rosuvastatin, fluvastatin, pravastatin, simvastatin, or lovastatin, 1017 patients had an adverse event. In contrast, 811 of 35,046 placebo recipients had an adverse event. The data suggest that the relative likelihood of an adverse event is atorvastatin > pravastatin = simvastatin = lovastatin > fluvastatin.[45526] NOTE: Pitavastatin was not available at the time this analysis.

General

Some statins are contraindicated for use or require dose modifications if used with another drug. Most of these interactions that require a dose modification are to prevent supratherapeutic statin concentrations and thus toxicity.