HMG-CoA Reductase Inhibitors (Statins)
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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). In addition, HMG-CoA reductase inhibitors raise HDL concentrations and lower triglyceride concentrations. The reduction in triglyceride concentrations may be through hepatic synthesis inhibition and lipoprotein lipase activity enhancement in adipocytes.  In addition to specific lipoprotein effects, HMG-CoA reductase inhibitors have been shown to halt the progression and facilitate the regression of atherosclerotic lesions.
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.
Several factors are important when considering selection of a statin:
The 2018 AHA/ACC Cholesterol Clinical Practice Guidelines recommend statin therapy in the following patient populations :
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.
Comparison of HMG-CoA Reductase Inhibitors - Effects of Dose on Lipoprotein Concentrations
% LDL change
% HDL change
% Triglyceride change
Fluvastatin (IR and ER)
HMG-CoA Reductase Inhibitor Comparative Efficacy Trials
Jupiter Study Group. N Engl J Med2008;359; 2195-207.
Randomized Controlled Trial in healthy adults with elevated CRP
Rosuvastatin 20 mg/day
(n = 8901) vs.
(n = 8901) for a median of 1.9 years (maximum 5 years)
Results vs. placebo
Combination of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes: HR 0.56 (95% CI, 0.46 to 0.69)
Framingham 10-year risk < 5%:
HR 0.64 (95% CI, 0.23 to 1.81)
Framingham 10-year risk 5-10%:
HR 0.55 (95% CI, 0.36 to 0.84)
Framingham 10-year risk 11-20%: HR 0.51 (95% CI, 0.39 to 0.68)
Framingham 10-year risk > 20%: HR 0.70 (95% CI, 0.43 to 1.14)
Physician-reported diabetes mellitus: 3% of rosuvastatin vs 2.4% of placebo, p=0.01
Rosuvastatin significantly reduced CVD events in adults with LDL < 130 mg/dl but CRP >= 2 mg/L
Further evaluation demonstrated that the reduced risk is among patients with at least a five percent 10-year risk of an event
Mills JE, Rachlis B, Wu P, et al. J Am Coll Cardiol 2008;52:1769-81.
Meta-analysis of 20 primary prevention randomized controlled trials
(n = 15,907)
(n = 38,367)
(n = 3463)
(n = 7,524)
Results vs. control (placebo, standard treatment, or no treatment)
All-cause mortality: RR 0.93 (95% CI, 0.87-0.99)
CVD death: RR 0.89 (95% CI, 0.81-0.98)
Major CV events: RR 0.85 (95% CI, 0.77-0.95)
Myocardial infarction: RR 0.77 (95% CI, 0.63-0.95)
No statistically significant differences between statin-statin comparison for all-cause mortality and CVD mortality.
For primary prevention, atorvastatin, pravastatin, fluvastatin, and lovastatin reduce all-cause mortality and CVD mortality similarly.
Head-to-head studies are needed to determine if individual drugs have greater efficacy.
Zhou Z, Rahme E, Abrahamowicz, et al. CMAJ 2005; 172(9):1187-94. 
Retrospective cohort of medical database comparing statins in patients >=65 year with an AMI within past 90 days
(n = 6420)
(n = 4480)
(n = 5518)
(n = 1736) fluvastatin
(n = 483)
median daily dose of pravastatin, simvastatin, lovastatin and fluvastatin: 20 mg
median daily dose of atorvastatin: 10 mg
As compared to atorvastatin, adjusted HR for recurrent AMI or death from any cause:
pravastatin 1.00 (0.90–1.11)
simvastatin 1.01 (0.91–1.12)
lovastatin 1.09 (0.95–1.24)
fluvastatin 1.01 (0.80–1.27)
For secondary prevention, statins used at low doses reduced the risk of recurrent AMI or death to a similar extent in elderly patients
Abbreviations: AMI – acute myocardial infarction; CI = confidence interval; CRP = c-reactive protein; CV = cardiovascular; CVD = cardiovascular disease; HR = hazard ratio; RR= relative risk
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. NOTE: Pitavastatin was not available at the time this analysis.
Of the possible adverse effects of HMG-CoA reductase inhibitors, myopathy is the most serious. The incidence of myopathy is dose dependent; therefore, any situation that may cause increased serum concentrations (e.g., use of more then 1 statin, concomitant use with certain drugs) should be avoided. Statin-induced myopathy may present as diffuse myalgias, unexplained muscle tenderness or weakness, and/or marked elevation of CPK. Fortunately, rhabdomyolysis appears to be a rare event. Among 36,062 patients who received a statin, 10 (9 simvastatin recipients and 1 lovastatin recipient) developed rhabdomyolysis as compared with 5 of 35,046 placebo recipients.
Rarely, statins have been associated with elevated hepatic transaminases of at least 3-times the upper limit of normal. In most cases, elevated hepatic enzymes are transient and resolve or improve on continued therapy or after a brief therapy interruption. Evaluation of liver function tests is advised; statins are contraindicated for use by patients with active liver disease including unexplained persistent transaminase elevations.
In a meta-analysis of 13 trials (91,140 patients) and a mean statin exposure of 4 years, a 9% increase in the likelihood of the development of diabetes (OR 1.09. 95% CI 1.02 to 1.17) or 1 additional case of diabetes for every 255 patients taking statin therapy was found. When comparing statins, there was no difference in the risk of diabetes mellitus. The risk is highest in trials that included high-risk patients (i.e., age 70—82 years with or at high risk of cardiovascular disease, myocardial infarction within the last 6 months, or heart failure).
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.
Atorvastatin, lovastatin, and simvastatin are all 3A4 substrates. Coadministration of drugs that are strong CYP 3A4 inhibitors with any of these statins can markedly increase the statin serum concentration and increase the risk of myopathy, rhabdomyolysis, and acute renal failure.
Increased drug concentrations of statins may increase the risk of myopathy. Use of more than 1 statin is generally inadvisable. Also, cautious use with other drugs that also increase myopathy risk (e.g., gemfibrozil, niacin, fenofibrate) is advised. Although clinical situations sometimes require the combined use of statins and fibric acid derivatives, caution is advised. Additionally, concomitant use of simvastatin and gemfibrozil is contraindicated because of the increased risk of rhabomyolysis with this drug combination.
Statins are contraindicated for use by females who are pregnant or may become pregnant because of the potential effects on cholesterol pathways. Cholesterol and other products of the cholesterol biosynthesis pathway are essential components for fetal and infant development, including synthesis of steroids and cell membranes. Treatment with a statin should immediately discontinued as soon as pregnancy is recognized. Statins are also contraindicated for use in women who are breast-feeding their infants. If pharmacotherapy is necessary in the nursing mother, a nonabsorbable resin such as cholestyramine, colesevelam, or colestipol should be considered. These agents do not enter the bloodstream and will not be excreted during lactation.
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Livalo (pitavastatin) package insert. Montgomery, AL: Kowa Pharmaceuticals America, Inc; 2022 Nov.
Pravachol (pravastatin sodium) package insert. Princeton, New Jersey: Bristol-Myers Squibb Company; 2022 May.
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Mills EJ, Rachlis B, Wu P, et al. Primary prevention of cardiovascular mortality and events with statin treatments: a network meta-analysis involving more than 65,000 patients. J Am Coll Cardiol 2008;52(22):1769-81.
Zhou Z, Rahme E, Abrahamowicz M, et al. Effectiveness of statins for secondary prevention in elderly patients after acute myocardial infarction: an evaluation of class effect. CMAJ 2005;172(9):1187-94.
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