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HMG-CoA Reductase Inhibitor
Aka: HMG-CoA Reductase Inhibitor, 3-Hydroxy-3-Methyl-Glutaryl Coenzyme A Reductase, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Statin, Lovastatin, Simvastatin, Pravastatin, Atorvastatin, Fluvastatin, Rosuvastatin, Zocor, Lipitor, Crestor
- See Also
- Hyperlipidemia
- Statin-Induced Myopathy
- Indications
- See Hyperlipidemia Management for formal criteria
- Coronary Artery Disease
- Diabetes Mellitus
- Age over 40 years old, comorbidities or long diabetes duration (20 years for DM 1, 10 years for DM 2)
- Chronic Kidney Disease
- Cerebrovascular Accident
- Peripheral Vascular Disease
- Hyperlipidemia
- Most Statins are approved down to age 10 years (age 8 years for Pravastatin)
- If used in children and teens, LDL Cholesterol above 190 is an indication for Statins (esp. with premature CAD FHx)
- Mechanism: Effects
- Lipid-related effects
- LDL decreased (20-40%)
- HDL Increased (5-15%)
- Triglycerides decreased
- Atorvastatin (40%)
- Simvastatin (30%)
- Other Statins (10-20%)
- Statin Benefit increases with 10 year ASCVD Risk
- ASCVD Risk 7.5%: NNT 40 to prevent one ASCVD event with moderate-dose Statin (NNT 26 if high-dose Statin)
- ASCVD Risk 10%: NNT 33 to prevent one ASCVD event with moderate-dose Statin (NNT 20 if high-dose Statin)
- ASCVD Risk 15%: NNT 20 to prevent one ASCVD event with moderate-dose Statin (NNT 13 if high-dose Statin)
- ASCVD Risk 20%: NNT 15 to prevent one ASCVD event with moderate-dose Statin (NNT 10 if high-dose Statin)
- ASCVD Risk 25%: NNT 12 to prevent one ASCVD event with moderate-dose Statin (NNT 8 if high-dose Statin)
- Grundy (2016) Pharmaceutical Journal
- http://www.pharmaceutical-journal.com/research/review-article/primary-prevention-of-cardiovascular-disease-with-statins-assessing-the-evidence-base-behind-clinical-guidance/20200568.article
- Other effects (related to decreased coronary events)
- Antiproliferation effect on Smooth Muscle Cells
- Antioxidant and anti-inflammatory effects
- Outcomes: Primary Prevention
- NNT taken four years to prevent one coronary event: 81
- NNT taken four years to prevent one cerebrovascular event: 81
- Outcomes: Secondaary Prevention
- NNT taken five years to prevent one death: 50
- NNT taken two years to prevent one fatal MI: 77
- Contraindications
- Drug Interactions (see below): Myopathy or hepatitis
- Pregnancy (Teratogen)
- Spontaneous Abortion and Stillbirth risk
- Birth defects in animal studies, but observational studies do not show increased risk
- In 2021, FDA allows for Statin use in high risk cardiovascular risks in pregnancy
- https://www.fda.gov/safety/medical-product-safety-information/statins-drug-safety-communication-fda-requests-removal-strongest-warning-against-using-cholesterol
- May consider use in prior MI, CVA or Homozygous familial Hypercholesterolemia
- Ensure reliable Contraception
- Stop Statin at least 1-2 months before planned pregnancy
- Do NOT use in Lactation (small amounts pass into Breast Milk)
- Acute Liver Failure or decompensated Cirrhosis
- As of 2012 Statins are considered safe in other chronic stable liver disease
- Chalasani (2004) Gastroenterology 126(5): 1287-92 [PubMed]
- Vuppalanchi (2005) Am J Med Sci 329(2):62-5 [PubMed]
- Beneficial in non-Alcoholic Steatohepatitis (NASH)
- Lowers cardiovascular risk
- Transaminases frequently improve on Statins
- Rallidis (2004) Atherosclerosis 174(1): 193-6 [PubMed]
- Efficacy
- Findings
- Reduces Myocardial Infarction risk (30%)
- Reduces need for Angioplasty (47 vs 20)
- Associated with regression on angiogram
- Prevents one cardiovascular event in 5 years for 20 with CV disease and 50 at high risk for CV disease
- Reduces coronary death rate (42%)
- Reduces Cerebrovascular Accident risk (30%)
- Conflicting evidence on reducing Dementia risk
- Recent prospective articles do not suggest benefit
- Rea (2005) Arch Neurol 62:1047-51 [PubMed]
- Reduces C-Reactive Protein
- Inflammatory factors related to ACS pathogenesis
- May explain benefit to normolipidemic patients
- In age over 75 years without significant CAD risk, starting Statin may increase mortality without a decrease in CV risk
- Han (2017) JAMA Intern Med +PMID:28531241 [PubMed]
- References
- (1994) Lancet 344(8934):1383-9 [PubMed]
- (1997) FDC Reports 59(46):T&G6
- (2004) Lancet 363:757-67 [PubMed]
- Jick (2000) Lancet 356:1627-31 [PubMed]
- Jukema (1995) Circulation 91:2528-40 [PubMed]
- Ridker (2001) N Engl J Med 344:1959-65 [PubMed]
- Sacks (1996) N Engl J Med 335:1001-9 [PubMed]
- Precautions
- Do not stop Statins abruptly (worse CAD outcomes)
- Elderly (even over age 80) benefit from continued Statin use for CAD prevention
- Adverse Effects
- See Statin-Induced Myopathy
- Mild Gastrointestinal upset
- Rash
- Insomnia (seen more with lipophilic agents)
- May be reduced with Pravastatin or Fluvastatin
- Lupus-Like Syndrome
- Peripheral Neuropathy
- Concurrent use with Coumadin increases bleeding risk
- Cataract development
- Controversial - some early reports demonstrate Statin users might present 2-3 years earlier than their peers with Cataracts
- Fong (2012) Am J Ophthalmol 153(2):222-8 [PubMed]
- Cognitive Impairment
- Uncommon, and reversible on stopping Statin
- Subjective patient reports but not found in initial studies
- Statins may also protect cognitive function by affecting atherosclerosis
- Consider a water soluble Statin (e.g. Pravastatin) that does not cross blood-brain barrier
- Wagstaff (2003) Pharmacotherapy 23(7):871-80 [PubMed]
- Diabetes Mellitus
- Statins (especially at high dose) are associated with an increase in Hemoglobin A1C
- Affects 1-3 patients in 1000 who might be raised from Metabolic Syndrome to meeting criteria for Diabetes Mellitus
- Dormuth (2014) BMJ 348:g3244 [PubMed]
- Sattar (2010) Lancet 375(9716): 735-42 [PubMed]
- Liver Function Abnormalities (1-2% Incidence)
- AST and ALT may be increased 2-3x normal
- These effects are typically transient
- Serious liver injury is rare and idiosyncratic
- Liver failure occurs in 1 patient in one million on Statins
- Same Incidence in those not on a Statin
- FDA No longer recommends routine monitoring of Liver Function Tests as of 2012
- Obtain baseline Liver Function Test and then as clinically indicated
- Statins are safe in chronic stable liver disease
- Statins may actually improve Liver Function Tests (and lower CV risk) in NASH
- Adverse Effects: Compliance and Tolerance
- Discontinuation rate with Statins: 15%
- Discontinuation rate with other medications: 35%
- Pharmacokinetics
- First-pass metabolism in all Statins except Pravastatin
- Protein binding
- Most Statins are 90% Protein bound
- Pravastatin is 50% Protein bound
- Cytochrome P450 Metabolism
- CYP3A4 isoenzyme metabolizes most Statins (except Rosuvastatin and Pravastatin)
- CYP2C9 isoenzyme metabolizes Fluvastatin
- Pravastatin is not metabolized by P450 system
- Safer to use in combination with other drugs
- Renal elimination occurs most with Pravastatin
- Dosing
- Specific LDL and HDL targets have been replaced with high-intensity Statin if 10 year cardiovascular risk >20%
- High intensity Statin (age <75 years with 10 year cardiovascular risk >20%)
- Atorvastatin 40-80 mg orally daily
- Rosuvastatin 20-40 mg orally daily
- Low intensity Statin (age >75 years, or Statin intolerant)
- Atorvastatin 10-20 mg orally daily
- Rosuvastatin 25-10 mg orally daily
- Simvastatin 20-40 mg orally daily
- Pravastatin 40-80 mg orally daily
- Lovastatin 40 mg orally daily
- Preparations (from least to most potent)
- Fluvastatin (Lescol, generic)
- Dose 20 mg lowers LDL 17% (recommended starting dose)
- Dose 40 mg lowers LDL 23%
- Dose 80 mg lowers LDL 33%
- Pravastatin (Pravachol, generic)
- Dose 10 mg lowers LDL 19%
- Dose 20 mg lowers LDL 24% (recommended starting dose)
- Dose 40 mg lowers LDL 34%
- Dose 80 mg lowers LDL 40%
- Lovastatin (Mevacor, generic)
- Starting Dose: 20 mg qd
- Dose 20 mg lowers LDL 29% (recommended starting dose)
- Dose 40 mg lowers LDL 31%
- Dose 80 mg lowers LDL 48%
- Cerivastatin (Baycol, not available in US)
- Cerivastatin recalled in United States (August 2001)
- Dose 0.2 mg lowers LDL 25% (start if Renal Failure)
- Dose 0.3 mg lowers LDL 30% (recommended start dose)
- Dose 0.4 mg lowers LDL 36%
- Dose 0.8 mg lowers LDL 44%
- Simvastatin (Zocor, generic)
- Dose 10 mg lowers LDL 28%
- Dose 20 mg lowers LDL 35% (recommended starting dose)
- Dose 40 mg lowers LDL 40% (maximum dose recommended in U.S. as of 2011)
- Dose 80 mg lowers LDL 48% (dose no longer recommended due to complications)
- Atorvastatin (Lipitor, generic)
- Dose 10 mg lowers LDL 38% (recommended starting dose)
- Dose 20 mg lowers LDL 46%
- Dose 40 mg lowers LDL 51%
- Dose 80 mg lowers LDL 54%
- Triglycerides lowered 40%
- Rosuvastatin (Crestor, generic but still >$200/month as of summer 2016)
- Dose 5 mg lowers LDL 45%
- Dose 10 mg lowers LDL: 52%
- Dose 20 mg lowers LDL 55%
- Dose 40 mg lowers LDL: 63%
- Indications to start at lower dose (5 mg)
- Asians
- Higher drug levels leads to higher toxicity risk
- Renal Insufficiency (max 10 mg if CrCl < 30 ml/min)
- Hypothyroidism (uncontrolled)
- Age over 65 years
- Cyclosporine use (max dose 5 mg daily)
- Concurrent Gemfibrozil (max dose 10 mg daily)
- Management: Statin choices if special concerns
- Preferred agents if risk of Drug Interactions
- Pravastatin (no CYP 450 METABOLISM)
- Fluvastatin
- Preferred agents if Renal Function impaired
- Atorvastatin
- Fluvastatin
- Avoid Pravastatin if Creatinine Clearance <60 ml/min
- If used, start dosing at 10 mg and titrate slowly
- Monitoring: Liver transaminase testing (AST,ALT)
- Protocols below are no longer routinely indicated as of March 2012
- FDA recommends only obtaining baseline Liver Function Test and then as clinically indicated
- Statins are contraindicated in Acute Liver Failure or decompensated Cirrhosis
- Statins should be discontinued if symptoms of liver injury and elevated Serum Bilirubin
- No history of liver disease (old pre-2012 guidelines, listed for historical purposes only)
- Stop Statin if >3x over baseline
- Liver Transaminase testing (AST, ALT) schedule
- Baseline
- Obtain only as clinically indicated
- Previously was routinely scheduled at week 6, month 3 and then every 6-12 months
- Chronic Liver Disease history (old pre-2012 guidelines, listed for historical purposes only)
- Start with lower initial Statin dose
- Stop Statin if transaminase >2x over baseline
- Liver Transaminase testing (AST or ALT) schedule (adjust per clinical discretion, FDA does not mandate any schedule as of 2012)
- Baseline
- Two weeks
- One month
- Two months
- Three months
-
Drug Interactions (See Contraindications above)
- CYP3A4 Inhibitors
- Azole Antifungals (Intraconazole, Ketoconazole - 10-20 fold increase in Statin serum levels)
- Increased risk of Statin Myopathy (esp. with age >65, Obesity, renal or liver Impairment)
- Avoid with Lovastatin or Simvastatin
- Avoid with Atorvastatin over 20 mg daily
- Fluconazole is less risky, especially with single dose, but Exercise caution with prolonged course
- Calcium Channel Blocker
- Diltiazem (limit to 240 mg daily)
- Avoid with Lovastatin over 20 mg daily
- Avoid with Simvastatin over 10 mg daily
- Remain alert for Statin Myopathy with Atorvastatin
- Verapamil (6-10 fold increase in Statin serum levels)
- Avoid with Lovastatin over 40 mg daily
- Avoid with Simvastatin over 10 mg daily
- Remain alert for Statin Myopathy with Atorvastatin
- Amlodipine (Norvasc)
- Avoid with Simvastatin over 20 mg daily
- Grapefruit juice increases some Statin levels
- Drugs most affected: Simvastatin,Lovastatin
- Avoid with any Grapefruit juice (or minimal use)
- Drugs affected moderately: Atorvastatin
- Limit Grapefruit juice to 8-16 ounces daily (effects more likely to manifest at 32 ounces)
- Limit juice timing to opposite Statin dose
- Take juice at night, if Statin taken in morning
- Drugs not affected: Pravachol, Crestor, Lescol
- References
- (2016) Presc Lett 23(3):18
- Reamy (2007) Am Fam Physician 76:190-1 [PubMed]
- CYP3A4/oragnic anion transporting polypeptide inhibitors
- Cyclosporine (10-20 fold increase in Statin serum levels)
- Avoid with Atorvastatin over 10 mg daily
- Avoid with Lovastatin over 20 mg daily
- Avoid with Rosuvastatin over 5 mg daily
- Avoid with pitavastatin, Pravastatin
- Avoid with Fluvastatin
- Macrolides (Erythromycin, Clarithromycin - 6-10 fold increase in Statin serum levels)
- Avoid while on Lovastatin and Simvastatin (or stop Statin while on Macrolide)
- Avoid with pitavastatin over 1 mg daily
- Avoid with Atorvastatin over 20 mg daily
- Azithromycin appears to be safe with Statins
- Protease inibitors (Atazanavir, Ritonavir, Lopinavir/Ritonavir)
- Avoid with Lovastatin, pitavastatin, and Simvastatin
- Avoid with Atorvastatin over 20 mg daily
- Avoid with Rosuvastatin over 10 mg daily
- CYP3A4/CYP2C9 Inhibitor
- Amiodarone
- Increased risk of Statin Myopathy (esp. with age >65, Obesity, renal or liver Impairment)
- Avoid with Lovastatin over 40 mg daily
- Avoid with Simvastatin over 20 mg daily
- Caution with Fluvastatin and Atorvastatin (consider dose adjustment)
- Warfarin (Increased INR and bleeding risk)
- Highest risk: Fluvastatin, Lovastatin, Rosuvastatin, Simvastatin
- Lowest risk: Atorvastatin, Pravastatin
- CYP2C9, CYP2C19/oragnic anion transporting polypeptide inhibitors
- Gemfibrozil (2-3 fold increase in Statin serum levels, >13 fold increase in Rhabdomyolysis risk)
- Avoid with Simvastatin over 10 mg daily
- Avoid with Rosuvastatin over 10 mg daily
- Avoid with Lovastatin over 20 mg daily
- Avoid with Pravastatin
- Caution with Fluvastatin or pitavastatin
- CYP2C9 Inhibitor
- Fluconazole (Diflucan)
- Caution with Fluvastatin
- Other interactions
- Mibefradil (Posicor)
- Niacin
- Alcohol
- Increases risk of liver enzyme elevations
- Resources
- FDA Safety information on Statins (March 2012)
- http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm
- References
- (2017) Presc Lett 24(11): 62
- (2012) Presc Lett 19(5): 25
- Carpenter (2019) Am Fam Physician 99(9):558-64 [PubMed]
- Chong (2001) Am J Med 111:390-400 [PubMed]
- Crouch (2001) Am Fam Physician 63(2):309-20 [PubMed]
- Gillett (2011) Am Fam Physician 83(6): 711-6 [PubMed]
- Jones (1998) Am J Cardiol 81:582-7 [PubMed]
- Sasaki (1998) Clin Ther 20:539-48 [PubMed]