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Jan.30.2012

HMG-CoA Reductase Inhibitors (Statins)

Summary

  • 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.

Pharmacology/Mechanism of Action

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]

Therapeutic Use

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

Daily dose

% LDL change

% HDL change

% Triglyceride change

Atorvastatin

10 mg

20 mg

40 mg

80 mg

 

-39

-43

-50

-60

 

+6

+9

+6

+5

 

-19

-26

-29

-37

Fluvastatin (IR and ER)

20 mg

40 mg

80 mg

 

-22

-25

-35

 

+3

+4

+6

 

-12

-14

-18

Lovastatin

10 mg

20 mg

40 mg

 

-21

-27

-31

 

+5

+8

+5

 

-10

-7

-8

Lovastatin ER

10 mg

20 mg

40 mg

60 mg

 

-24

-30

-36

-41

 

+9

+12

+13

+12

 

-17

-13

-10

-25

Pitavastatin

1 mg

2 mg

4 mg

 

-32

-36

-43

 

+8

+7

+5

 

-15

-19

-18

Pravastatin

10 mg

20 mg

40 mg

80 mg

 

-22

-32

-34

-37

 

+7

+2

+12

+3

 

-15

-11

-24

-19

Rosuvastatin

5 mg

10 mg

20 mg

40 mg

 

-45

-52

-55

-63

 

+13

+14

+8

+10

 

-35

-10

-23

-28

Simvastatin

5 mg

10 mg

20 mg

40 mg

80 mg

 

-26

-30

-38

-41

-47

 

+10

+12

+8

+9

+8

 

-12

-15

-19

-18

-24

Comparative Efficacy

HMG-CoA Reductase Inhibitor Comparative Efficacy Trials

Citation

Design/Regimen

Results

Conclusion

Jupiter Study Group. N Engl J Med2008;359; 2195-207.[34555]

 

 

 

Randomized Controlled Trial in healthy adults with elevated CRP

 

Rosuvastatin 20 mg/day

(n = 8901) vs.

placebo

(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.[45562]

Meta-analysis of 20 primary prevention randomized controlled trials

 

atorvastatin

(n = 15,907)

pravastatin

(n = 38,367)

fluvastatin

(n = 3463)

lovastatin

(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. [45563]

Retrospective cohort  of medical database comparing statins in patients >=65 year with an AMI within past 90 days

 

atorvastatin

(n = 6420)

pravastatin

(n = 4480)

simvastatin

(n = 5518)

lovastatin

(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

Adverse Reactions/Toxicities

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.

Myopathy/Rhabdomyolysis

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.[45526]

Hepatotoxicity

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.[36344][45526]

Diabetes mellitus

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).

Drug Interactions

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.

Strong CYP 3A4 inhibitors

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.

Other drugs associated with myopathy

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.

Safety Issues

Pregnancy/Breast-feeding

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.

[33273]Crouse JR III, Raichlen JS, Riley WA, et al. Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial. JAMA 2007;297:1344-53.

[33274]Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006;295:1556-65.

[34555]Ridker PM, Danielson D, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-207.

[36344]Livalo (pitavastatin) package insert. Montgomery, AL: Kowa Pharmaceuticals America, Inc; 2020 Sept.

[45507]Pravachol (pravastatin sodium) package insert. Princeton, New Jersey: Bristol-Myers Squibb Company; 2020 Sept.

[45526]Silva MA, Swanson AC, Gandhi PJ, et al. Statin-related adverse events: a meta-analysis. Clin Ther 2006;28:26-35.

[45539]Saiki A, Murano T, Watanabe F, et al. Pitavastatin enhanced lipoprotein lipase expression in 3T3-L1 preadipocytes. J Atheroscler Thromb. 2005;12(3):163–8.

[45542]Bots ML, Palmer MK, Dogan S, et al. Intensive lipid lowering may reduce progression of carotid atherosclerosis within12 months of treatment: the METEOR study. J Intern Med 2009;265(6):698–707.

[45543]Nissen SE, Tuzcu EM, Schoenhagen P, et al. Reversal of atherosclerosis with aggressive lipid lowering (REVERSAL) investigators. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. New England Journal of Medicine 2005;352(1):29-38.

[45548]Pedersen TR, Kjekshus J, Pyorala K, et al. Effect of simvastatin on ischemic signs and symptoms in the Scandinavian simvastatin survival study (4S). Am J Cardiol. 1998;81(3):333–5.

[45549]Aengevaeren WR, Uijen GJ, Jukema JW, et al. Functional evaluation of lipid-lowering therapy by pravastatin in the Regression Growth Evaluation Statin Study (REGRESS). Circulation 1997;96(2):429–35.

[45550]Pitt B, Waters D, Brown WV, et al. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. Atorvastatin versus Revascularization Treatment Investigators. N Engl J Med 1999;341(2):70–6.

[45551]Deanfield JE, Selleir P, Thaulow E, et al. Potent anti-ischaemic effects of statins in chronic stable angina: incremental benefitbeyond lipid lowering? Eur Heart J 2010;31(21):2650-9.

[45552]Crisby M, Nordin-Fredriksson G, Shah PK, et al. Pravastatin treatment increases collagen content and decreases lipid content,inflammation, metalloproteinases, and cell death in human carotidplaques: implications for plaque stabilization. Circulation 2001;103(7):926–33.

[45553]Mostaza JM, Gomez MV, Gallardo F, et al. Cholesterol reduction improves myocardial perfusion abnormalities in patients with coronary artery disease and average cholesterol levels. J Am Coll Cardiol 2000;35(1):76–82.

[45554]Omori H, Nagashima H, Tsurumi Y, et al. Direct in vivo evidence of a vascular statin: a single dose of cerivastatin rapidly increases vascular endothelial responsiveness in healthy normocholesterolaemic subjects. Br J Clin Pharmacol 2002;54(4):395–9.

[45555]Liu PY, Liu YW, Lin LJ, et al. Evidence for statin pleiotropy in humans: differential effects of statins and ezetimibe on rho-associated coiled-coil containing protein kinase activity, endothelial function, and inflammation. Circulation 2009;119(1):131–8.

[45556]Kayikcioglu M, Payzin S, Yavuzgil O, et al. Benefits of statin treatment in cardiac syndrome-X. Eur Heart J 2003;24(22):1999–2005.

[45559]Briguori C, Visconti G, Focaccio A, et al. Novel approaches for preventing or limiting events (Naples) II trial: impact of asingle high loading dose of atorvastatin on periprocedural myocardial infarction. J Am Coll Cardiol 2009;54(23):2157–63.

[45560]Briguori C, Colombo A, Airoldi F, et al. Statin administration before percutaneous coronary intervention: impact on periprocedural myocardial infarction. Eur Heart J 2004;25(20):1822–8.

[45562]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.

[45563]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.

[63783]Grundy SM, Stone NJ, Bailey AL et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. J Am Coll Cardiol. 2018.

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