HMG-CoA Reductase Inhibitor

Aka: HMG-CoA Reductase Inhibitor, 3-Hydroxy-3-Methyl-Glutaryl Coenzyme A Reductase, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Statin

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II. Indications

  1. See Hyperlipidemia Management for formal criteria
  2. Coronary Artery Disease
  3. Diabetes Mellitus
    1. Age over 40 years old, comorbidities or long diabetes duration (20 years for DM 1, 10 years for DM 2)
  4. Chronic Kidney Disease
  5. Cerebrovascular Accident
  6. Peripheral Vascular Disease
  7. Hyperlipidemia
    1. Most Statins are approved down to age 10 years (age 8 years for Pravastatin)
    2. If used in children and teens, LDL Cholesterol above 190 is an indication for Statins (esp. with premature CAD FHx)

III. Contraindications

  1. Drug Interactions (see below): Myopathy or hepatitis
  2. Pregnancy (Teratogen)
    1. Spontaneous Abortion and Stillbirth risk
    2. Birth defects in animal studies, but observational studies do not show increased risk
    3. Ensure reliable Contraception while taking Statins
    4. Stop Statin at least 1-2 months before planned pregnancy
    5. Do NOT use in Lactation (small amounts pass into Breast Milk)
    6. In 2021, FDA allows for Statin use in high risk Cardiovascular Risks in pregnancy
      1. https://www.fda.gov/safety/medical-product-safety-information/statins-drug-safety-communication-fda-requests-removal-strongest-warning-against-using-cholesterol
      2. May consider use in prior MI, CVA or Homozygous familial Hypercholesterolemia
  3. Acute Liver Failure or decompensated Cirrhosis
    1. As of 2012 Statins are considered safe in other chronic stable liver disease
      1. Chalasani (2004) Gastroenterology 126(5): 1287-92 [PubMed]
      2. Vuppalanchi (2005) Am J Med Sci 329(2):62-5 [PubMed]
    2. Beneficial in non-Alcoholic Steatohepatitis (NASH)
      1. Lowers Cardiovascular Risk
      2. Transaminases frequently improve on Statins
      3. Rallidis (2004) Atherosclerosis 174(1): 193-6 [PubMed]

IV. Mechanism

  1. Statins inhibit hepatic HMG-CoA reductase
    1. Cholesterol synthesis (facilitated by HMG-CaA Reductase) is therefore slowed
  2. Lipid-related effects
    1. LDL decreased (20-40%)
    2. HDL Increased (5-15%)
    3. Triglycerides decreased
      1. Atorvastatin (40%)
      2. Simvastatin (30%)
      3. Other Statins (10-20%)
  3. Statin Benefit increases with 10 year ASCVD Risk
    1. ASCVD Risk 7.5%: NNT 40 to prevent one ASCVD event with moderate-dose Statin (NNT 26 if high-dose Statin)
    2. ASCVD Risk 10%: NNT 33 to prevent one ASCVD event with moderate-dose Statin (NNT 20 if high-dose Statin)
    3. ASCVD Risk 15%: NNT 20 to prevent one ASCVD event with moderate-dose Statin (NNT 13 if high-dose Statin)
    4. ASCVD Risk 20%: NNT 15 to prevent one ASCVD event with moderate-dose Statin (NNT 10 if high-dose Statin)
    5. ASCVD Risk 25%: NNT 12 to prevent one ASCVD event with moderate-dose Statin (NNT 8 if high-dose Statin)
    6. Grundy (2016) Pharmaceutical Journal
      1. http://www.pharmaceutical-journal.com/research/review-article/primary-prevention-of-cardiovascular-disease-with-statins-assessing-the-evidence-base-behind-clinical-guidance/20200568.article
  4. Other effects (related to decreased coronary events)
    1. Antiproliferation effect on Smooth Muscle Cells
    2. Antioxidant and anti-inflammatory effects
  5. Outcomes: Primary Prevention
    1. NNT taken four years to prevent one coronary event: 81
    2. NNT taken four years to prevent one cerebrovascular event: 81
  6. Outcomes: Secondaary Prevention
    1. NNT taken five years to prevent one death: 50
    2. NNT taken two years to prevent one fatal MI: 77

V. Efficacy

  1. Findings
    1. Reduces Myocardial Infarction risk (30%)
      1. Reduces need for Angioplasty (47 vs 20)
      2. Associated with regression on angiogram
      3. Prevents one cardiovascular event in 5 years for 20 with CV disease and 50 at high risk for CV disease
    2. Reduces coronary death rate (42%)
    3. Reduces Cerebrovascular Accident risk (30%)
    4. Conflicting evidence on reducing Dementia risk
      1. Recent prospective articles do not suggest benefit
      2. Rea (2005) Arch Neurol 62:1047-51 [PubMed]
    5. Reduces C-Reactive Protein
      1. Inflammatory factors related to ACS pathogenesis
      2. May explain benefit to normolipidemic patients
    6. In age over 75 years without significant CAD risk, starting Statin may increase mortality without a decrease in CV risk
      1. Han (2017) JAMA Intern Med +PMID:28531241 [PubMed]
  2. References
    1. (1994) Lancet 344(8934):1383-9 [PubMed]
    2. (1997) FDC Reports 59(46):T&G6
    3. (2004) Lancet 363:757-67 [PubMed]
    4. Jick (2000) Lancet 356:1627-31 [PubMed]
    5. Jukema (1995) Circulation 91:2528-40 [PubMed]
    6. Ridker (2001) N Engl J Med 344:1959-65 [PubMed]
    7. Sacks (1996) N Engl J Med 335:1001-9 [PubMed]

VI. Precautions

  1. Do not stop Statins abruptly (worse CAD outcomes)
  2. Elderly (even over age 80) benefit from continued Statin use for CAD prevention

VII. Adverse Effects

  1. See Statin-Induced Myopathy
  2. Compliance and Tolerance
    1. Discontinuation rate with Statins: 15%
    2. Discontinuation rate with other medications: 35%
  3. Mild Gastrointestinal upset
  4. Rash
  5. Insomnia (seen more with lipophilic agents)
    1. May be reduced with Pravastatin or Fluvastatin
  6. Lupus-Like Syndrome
  7. Peripheral Neuropathy
  8. Concurrent use with Coumadin increases bleeding risk
  9. Cataract development
    1. Controversial - some early reports demonstrate Statin users might present 2-3 years earlier than their peers with Cataracts
    2. Fong (2012) Am J Ophthalmol 153(2):222-8 [PubMed]
  10. Cognitive Impairment
    1. Uncommon, and reversible on stopping Statin
    2. Subjective patient reports but not found in initial studies
    3. Statins may also protect cognitive function by affecting atherosclerosis
    4. Consider a water soluble Statin (e.g. Pravastatin) that does not cross blood-brain barrier
    5. Wagstaff (2003) Pharmacotherapy 23(7):871-80 [PubMed]
  11. Diabetes Mellitus
    1. Statins (especially at high dose) are associated with an increase in Hemoglobin A1C
      1. Affects 1-3 patients in 1000 who might be raised from Metabolic Syndrome to meeting criteria for Diabetes Mellitus
      2. Dormuth (2014) BMJ 348:g3244 [PubMed]
      3. Sattar (2010) Lancet 375(9716): 735-42 [PubMed]
  12. Liver Function Abnormalities (1-2% Incidence)
    1. AST and ALT may be increased 2-3x normal
      1. These effects are typically transient
      2. Serious liver injury is rare and idiosyncratic
      3. Liver failure occurs in 1 patient in one million on Statins
        1. Same Incidence in those not on a Statin
    2. FDA No longer recommends routine monitoring of Liver Function Tests as of 2012
      1. Obtain baseline Liver Function Test and then as clinically indicated
    3. Statins are safe in chronic stable liver disease
      1. Statins may actually improve Liver Function Tests (and lower CV risk) in NASH

VIII. Safety

  1. Pregnancy Category X
  2. Contraindicated in Lactation

IX. Pharmacokinetics

  1. First-pass metabolism in all Statins except Pravastatin
  2. Protein binding
    1. Most Statins are 90% Protein bound
    2. Pravastatin is 50% Protein bound
  3. Cytochrome P450 Metabolism
    1. CYP3A4 isoenzyme metabolizes most Statins (except Rosuvastatin and Pravastatin)
    2. CYP2C9 isoenzyme metabolizes Fluvastatin
    3. Pravastatin is not metabolized by P450 system
      1. Safer to use in combination with other drugs
  4. Renal elimination occurs most with Pravastatin

X. Dosing

  1. Specific LDL and HDL targets have been replaced with high-intensity Statin if 10 year Cardiovascular Risk >20%
  2. High intensity Statin (age <75 years with 10 year Cardiovascular Risk >20%)
    1. Atorvastatin 40-80 mg orally daily
    2. Rosuvastatin 20-40 mg orally daily
  3. Low intensity Statin (age >75 years, or Statin intolerant)
    1. Atorvastatin 10-20 mg orally daily
    2. Rosuvastatin 25-10 mg orally daily
    3. Simvastatin 20-40 mg orally daily
    4. Pravastatin 40-80 mg orally daily
    5. Lovastatin 40 mg orally daily

XI. Medications (from least to most potent)

  1. Fluvastatin (Lescol, generic)
    1. Dose 20 mg lowers LDL 17% (recommended starting dose)
    2. Dose 40 mg lowers LDL 23%
    3. Dose 80 mg lowers LDL 33%
  2. Pravastatin (Pravachol, generic)
    1. Dose 10 mg lowers LDL 19%
    2. Dose 20 mg lowers LDL 24% (recommended starting dose)
    3. Dose 40 mg lowers LDL 34%
    4. Dose 80 mg lowers LDL 40%
  3. Lovastatin (Mevacor, generic)
    1. Starting Dose: 20 mg qd
    2. Dose 20 mg lowers LDL 29% (recommended starting dose)
    3. Dose 40 mg lowers LDL 31%
    4. Dose 80 mg lowers LDL 48%
  4. Pitavastatin (Livalo)
    1. Dose 1 mg lowers LDL 29%
    2. Dose 2 mg lowers LDL 36 to 39%
    3. Dose 4 mg lowers LDL 41 to 45%
  5. Cerivastatin (Baycol, not available in US)
    1. Cerivastatin recalled in United States (August 2001)
    2. Dose 0.2 mg lowers LDL 25% (start if Renal Failure)
    3. Dose 0.3 mg lowers LDL 30% (recommended starting dose)
    4. Dose 0.4 mg lowers LDL 36%
    5. Dose 0.8 mg lowers LDL 44%
  6. Simvastatin (Zocor, generic)
    1. Dose 10 mg lowers LDL 28%
    2. Dose 20 mg lowers LDL 35% (recommended starting dose)
    3. Dose 40 mg lowers LDL 40% (maximum dose recommended in U.S. as of 2011)
    4. Dose 80 mg lowers LDL 48% (dose no longer recommended due to complications)
  7. Atorvastatin (Lipitor, generic)
    1. Dose 10 mg lowers LDL 38% (recommended starting dose)
    2. Dose 20 mg lowers LDL 46%
    3. Dose 40 mg lowers LDL 51%
    4. Dose 80 mg lowers LDL 54%
    5. Triglycerides lowered 40%
  8. Rosuvastatin (Crestor, generic but still >$200/month as of summer 2016)
    1. Dose 5 mg lowers LDL 45%
    2. Dose 10 mg lowers LDL: 52%
    3. Dose 20 mg lowers LDL 55%
    4. Dose 40 mg lowers LDL: 63%
    5. Indications to start at lower dose (5 mg)
      1. Asians
        1. Higher drug levels leads to higher toxicity risk
      2. Renal Insufficiency (max 10 mg if CrCl < 30 ml/min)
      3. Hypothyroidism (uncontrolled)
      4. Age over 65 years
      5. Cyclosporine use (max dose 5 mg daily)
      6. Concurrent Gemfibrozil (max dose 10 mg daily)

XII. Management: Statin choices if special concerns

  1. Preferred agents if risk of Drug Interactions
    1. Pravastatin (no CYP 450 METABOLISM)
    2. Fluvastatin
  2. Preferred agents if Renal Function impaired
    1. Atorvastatin
    2. Fluvastatin
    3. Avoid Pravastatin if Creatinine Clearance <60 ml/min
      1. If used, start dosing at 10 mg and titrate slowly

XIII. Monitoring: Liver transaminase testing (AST,ALT)

  1. Protocols below are no longer routinely indicated as of March 2012
    1. FDA recommends only obtaining baseline Liver Function Test and then as clinically indicated
    2. Statins are contraindicated in Acute Liver Failure or decompensated Cirrhosis
    3. Statins should be discontinued if symptoms of liver injury and elevated Serum Bilirubin
  2. No history of liver disease (old pre-2012 guidelines, listed for historical purposes only)
    1. Stop Statin if >3x over baseline
    2. Liver Transaminase testing (AST, ALT) schedule
      1. Baseline
      2. Obtain only as clinically indicated
      3. Previously was routinely scheduled at week 6, month 3 and then every 6-12 months
  3. Chronic Liver Disease history (old pre-2012 guidelines, listed for historical purposes only)
    1. Start with lower initial Statin dose
    2. Stop Statin if transaminase >2x over baseline
    3. Liver Transaminase testing (AST or ALT) schedule (adjust per clinical discretion, FDA does not mandate any schedule as of 2012)
      1. Baseline
      2. Two weeks
      3. One month
      4. Two months
      5. Three months

XIV. Drug Interactions (See Contraindications above)

  1. CYP3A4 Inhibitors
    1. Azole Antifungals (Intraconazole, Ketoconazole - 10-20 fold increase in Statin serum levels)
      1. Increased risk of Statin Myopathy (esp. with age >65, Obesity, renal or liver Impairment)
      2. Avoid with Lovastatin or Simvastatin
      3. Avoid with Atorvastatin over 20 mg daily
      4. Fluconazole is less risky, especially with single dose, but Exercise caution with prolonged course
    2. Calcium Channel Blocker
      1. Diltiazem (limit to 240 mg daily)
        1. Avoid with Lovastatin over 20 mg daily
        2. Avoid with Simvastatin over 10 mg daily
        3. Remain alert for Statin Myopathy with Atorvastatin
      2. Verapamil (6-10 fold increase in Statin serum levels)
        1. Avoid with Lovastatin over 40 mg daily
        2. Avoid with Simvastatin over 10 mg daily
        3. Remain alert for Statin Myopathy with Atorvastatin
      3. Amlodipine (Norvasc)
        1. Avoid with Simvastatin over 20 mg daily
    3. Grapefruit juice increases some Statin levels
      1. Drugs most affected: Simvastatin,Lovastatin
        1. Avoid with any Grapefruit juice (or minimal use)
      2. Drugs affected moderately: Atorvastatin
        1. Limit Grapefruit juice to 8-16 ounces daily (effects more likely to manifest at 32 ounces)
        2. Limit juice timing to opposite Statin dose
          1. Take juice at night, if Statin taken in morning
      3. Drugs not affected: Pravachol, Crestor, Lescol
      4. References
        1. (2016) Presc Lett 23(3):18
        2. Reamy (2007) Am Fam Physician 76:190-1 [PubMed]
  2. CYP3A4/organic anion transporting polypeptide inhibitors
    1. Cyclosporine (10-20 fold increase in Statin serum levels)
      1. Avoid with Atorvastatin over 10 mg daily
      2. Avoid with Lovastatin over 20 mg daily
      3. Avoid with Rosuvastatin over 5 mg daily
      4. Avoid with Pitavastatin, Pravastatin
      5. Avoid with Fluvastatin
    2. Macrolides (Erythromycin, Clarithromycin - 6-10 fold increase in Statin serum levels)
      1. Avoid while on Lovastatin and Simvastatin (or stop Statin while on Macrolide)
      2. Avoid with Pitavastatin over 1 mg daily
      3. Avoid with Atorvastatin over 20 mg daily
      4. Azithromycin appears to be safe with Statins
    3. Protease inibitors (Atazanavir, Ritonavir, Lopinavir/Ritonavir)
      1. Avoid with Lovastatin, Pitavastatin, and Simvastatin
      2. Avoid with Atorvastatin over 20 mg daily
      3. Avoid with Rosuvastatin over 10 mg daily
  3. CYP3A4/CYP2C9 Inhibitor
    1. Amiodarone
      1. Increased risk of Statin Myopathy (esp. with age >65, Obesity, renal or liver Impairment)
      2. Avoid with Lovastatin over 40 mg daily
      3. Avoid with Simvastatin over 20 mg daily
      4. Caution with Fluvastatin and Atorvastatin (consider dose adjustment)
    2. Warfarin (Increased INR and bleeding risk)
      1. Highest risk: Fluvastatin, Lovastatin, Rosuvastatin, Simvastatin
      2. Lowest risk: Atorvastatin, Pravastatin
  4. CYP2C9, CYP2C19/oragnic anion transporting polypeptide inhibitors
    1. Gemfibrozil (2-3 fold increase in Statin serum levels, >13 fold increase in Rhabdomyolysis risk)
      1. Avoid with Simvastatin over 10 mg daily
      2. Avoid with Rosuvastatin over 10 mg daily
      3. Avoid with Lovastatin over 20 mg daily
      4. Avoid with Pravastatin
      5. Caution with Fluvastatin or Pitavastatin
  5. CYP2C9 Inhibitor
    1. Fluconazole (Diflucan)
      1. Caution with Fluvastatin
  6. Other interactions
    1. Mibefradil (Posicor)
    2. Niacin
    3. Alcohol
      1. Increases risk of liver enzyme elevations

XV. Resources

  1. Statin Decision Aid (Mayo)
    1. https://statindecisionaid.mayoclinic.org/
  2. FDA Safety information on Statins (March 2012)
    1. http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm

XVI. References

  1. (2017) Presc Lett 24(11): 62
  2. (2012) Presc Lett 19(5): 25
  3. Carpenter (2019) Am Fam Physician 99(9):558-64 [PubMed]
  4. Chong (2001) Am J Med 111:390-400 [PubMed]
  5. Crouch (2001) Am Fam Physician 63(2):309-20 [PubMed]
  6. Gillett (2011) Am Fam Physician 83(6): 711-6 [PubMed]
  7. Jones (1998) Am J Cardiol 81:582-7 [PubMed]
  8. Sasaki (1998) Clin Ther 20:539-48 [PubMed]

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