HMG CoA reductase inhibitor (statin)

Classification

• high-intensity statin
  • atorvastatin 40-80 mg daily, rosuvastatin 20-40 mg daily
• medium intensity statin
  • atorvastatin 20 mg daily, pravastatin 40-80 mg daily rosuvastatin 5-10 mg daily, simvastatin 20-40 mg daily
• low intensity statin
  • atorvastatin 10 mg daily
  • fluvastatin 20-40 mg daily, lovastatin 20 mg daily, pitavastatin 1 mg daily, pravastatin 10-20 mg daily, simvastatin 10 mg daily

Epidemiology

• 25% of people > 45 years of age are on a statin

Indications

• treatment of hypercholesterolemia*
  • LDL cholesterol >= 190 mg/dL
  • may be coadministered with ezetimibe;
    • effects on LDL cholesterol additive, but clinical benefit does not correlate
    • may not be useful in patients > 80 year of age
• treatment of proteinuria in conjunction with ACE inhibitors
• Kidney Disease Improving Global Outcomes Lipid Work Group recommends statins for all patients with chronic kidney disease >= 50 years of age
  • may reduce all-cause mortality (RR=0.81) & cardiovascular mortality (RR=0.78) in patients with chronic renal failure [141, 249]
  • no benefit for dialysis patients
• may reduce risk of contrast nephropathy in patients undergoing coronary angiography (relative risk = 0.58)
• may reduce risk of liver disease, hepatocellular carcinoma & liver-related mortality
  • especially benificial in men with diabetes mellitus & high Fibrosis-4 index

primary prevention of cardiovascular disease

• meta-analysis used to promote statins for primary prevention
• primary prevention in low-risk patients may constitute low-value care
• low-to-moderate-dose statins for adults aged 40-75 without known cardiovascular disease with at least one risk factor (dyslipidemia, diabetes, hypertension, smoking) & a 10-year risk of >=10% (USPSTF) [200 241,242]
• AHA/ACC recommends moderate dose statin for adults 40-75 years with diabetes mellitus type 2 regardless of calculated ASCVD risk
  • atorvastatin, rosuvastatin & simvastatin best statins for lowering non-HDL cholesterol in patients with diabetes mellitus
  • estimated 10-year cardiovascular risk >= 7.5% (AHA/ACC)
    • benefits less likely with risk of 7.5-10%
  • benefits only begin to outweigh the risks when CVD risk is 14% for men age 40-49 years, 21% for men age 70-75 years, & 17-22% for women
  • USPSTF concludes statins of benefit for primary prevention in adults 40-75 years with at least on major risk factor (dyslipidemia, diabetes, hypertension, smoking) & a 10 year cardiovascular risk > 10% [304, 312]
    • benefit is small if 10 year cardiovascular risk is < 10% [304, 312]
  • evidence is insufficient to determine the balance of benefits & harms of statin use for the primary prevention of CVD events & mortality in adults >75 years
  • USPSTF recommendations of 10-year risk of >=10% would lead to 9 million fewer U.S. patients prescribed statins than AHA/ACC recommendations of 10-year risk of >=7.5%
  • 2021 European Society of Cardiology recommends statin for primary prevention if >= 7.5% 10-year cardiovascular risk & age 40-49 years & >= 10% 10-year cardiovascular risk & age 50-69 years
  • calculating 30 year risk of cardiovascular disease rather than 10 year risk would result in even more statin eligible persons (American College of Cardiology)
  • benefit for primary prevention confirmed, including primary prevention in the elderly (73 +/- 3 years)
  • no evidence of benefit for primary prevention in patients > 80 years of age
  • no benefit for <A30603>primary prevention of cardiovascular disease</A30603> or all-cause mortality among healthy adults over age 75 years
  • initiating statin therapy in elderly > 75 years without cardiovascular disease lowers 7 year cardiovascular mortality (RR=0.80) & all cause mortality (RR-0.75); retrospective study
  • no benefit of pravastatin 40 mg/day for primary prevention in patients > 65 years of age
  • diabetes mellitus in patients 40-75 years of age with LDL cholesterol > 70 mg/dL
    • no mortality benefit demonstrated in clinical trials
    • may reduce risk of diabetic retinopathy (11 v 12%)
  • benefit for primary prevention absent in patients without hypertension (see Jupiter study)
  • benefit for primary prevention in terms of mortality (RR=0.86), MI (RR= 0.75), stroke (RR=0.78); Cochrane review of 18 trials, 14 of which recruited participants with hyperlipidemia, diabetes mellitus, hypertension &/or microalbuminuria
  • in analyses adjusted substantially, risk for stroke reduced in elderly (>= 70 years) without known cardiovascular disease (RR=0.7)
  • no mortality benefit for primary prevention
  • harms exceed small benefit for primary prevention in elderly > 75 years of age
    • evidence is insufficient to weigh benefits vs harms in elderly > 75 years of age
    • discontinuation of statin associated with 33% increased risk of hospitalization for cardiovascular event in 75-year-old treated for primary prevention (French study)
  • no reduction in mortality
  • no benefit of statin for primary prevention in elderly >65-70 years of age in SPRINT trial
  • use for primary prevention controversial
  • benefits in patients with low cardiovascular risk (5 year risk < 10%) similar to benefits in high-risk patients
  • ~ 1/2 of patients taking statins don't experience a substantial lowering of LDL cholesterol
  • 5 year cardiovascular death reduction of 1.2% in elderly > 75 years, including elderly > 85 years, NNT=20 to avert 1 cardiovascular death
    • A meta-analysis of 28 randomized controlled treals did not find strong evidence of benefit in primary prevention among epderly > 75 years
  • suggestion is made that everyone over 50 years of age should take a statin: allegedly, benefits of statins outweigh risks, even in the healthiest patients
  • nearly all of 19 randomized controlled trials reviewed for guidelines were industry-sponsored
  • a global statin market of roughly US $20 billion annually drives much of the research & interest in statins for primary prevention

secondary prevention of cardiovascular disease

• clinical atherosclerotic cardiovascular disease
  • cardiovascular risk reduction {4-year}; (secondary prevention)
    • mortality risks decrease as statin doses increase
• lowers risk for vascular events in adults > 70 years of age,
  • benefit only in those with history of vascular disease
• coronary artery disease
  • preferential benefit for patients at high genetic risk
  • history of myocardial infarction
  • no significant benefit for patients > 80 years of age
• peripheral arterial disease
  • may reduce arterial inflammation
    • reduces carotid inflammation
  • reduces progression of arterial stiffness in Chinese as assessed by brachial-ankle pulse wave velocity
• ischemic cerebrovascular disease
  • history of transient ischemic attack or ischemic stroke
  • conflicting data on benefit/risk for hemorrhagic stroke [168-173,322]
• may attenuate risk associated with elevated CRP
  • after acute myocardial infarction
  • in prevention of unstable angina & myocardial infarction [6, 15,36]
  • even in those patients with low LDL cholesterol*
  • serum CRP does NOT predict response to statins
• may reduce risk of severe or fatal COVID-19 (30%)
• questionable benefit for patients with rheumatologic disease
• may or may not benefit elderly with heart failure
  • statin initiation in patients in HFpEF reduces major cardiovascular events, hospitalizations & all cause mortality in veterans without prevalent atherosclerotic cadiovascular disease
• cardiovascular benefits may be independent of LDL cholesterol, or total cholesterol
  • target for statin therapy may be non-HDL cholesterol
• benefit of secondary prevention for women with coronary artery disease may not extend to stroke or all-cause mortality
• long-term statin use associated with greater myocardial salvage in patients with STEMI after PCI

* ACC/AHA cardiovascular risk calculator overestimates risk

* may reduce non arterial inflammation

* may reduce risk of inflammatory bowel disease

* may diminish inflammatory-associated demyelination in multiple sclerosis

* may reduce inflammatory gum disease (periodontal disease)

* may prevent sepsis in elderly with atherosclerosis

* may provide benefit for osteoporosis

* may diminish risk of fractures

* may diminish risk of macular degeneration

* may diminish risk of glaucoma & cataracts*

* might be associated with reduction in cancer risk [55-57]

• statins reduce cancer risk in patients with heart failure (RR=0.84)
• statins reduce risk of cancer deaths in patients with heart failure (RR=0.64)

* may diminish risk of prostate cancer & colon cancer

* may diminish risk of metastatic, but not localized prostate cancer

* post-diagnosis statin may diminish risk of prostate cancer-specific mortality (RR=0.81) & all-cause mortality (RR=0.85)

• benefit may be restricted to men on androgen-deprivation therapy

* may reduce risk of liver cancer

* lipophilic statins (atorvastatin, simvastatin) may reduce risk of hepatocellular carcinoma (3% vs 8%) in patients with chronic viral hepatitis

* 15% reductions observed in risk for 13 types of cancer with similar reduction in all-cause mortality

* no reduction in cancer risk

* may reduce mortality from ischemic stroke

* may diminish risk of stroke in women > 55 years of age

* may reduce cardiovascular mortality (RR=0.8) & all-cause mortality in women (RR=0.9)

* may reduce mortality in nursing home residents with or without dementia

* equally effective in men & women

* may diminish perioperative mortality

* may reduce risk of postoperative acute renal failure (RR = 0.81)

* rosuvastatin & other statins may reduce risk of venous thromboembolism

* may reduce risk of venous thromboembolism in women on hormone replacement therapy

• no plausible mechanism is apparent

* may diminish risk of mortality associated with pneumonia

* may slow brain atrophy in patients with secondary progressive multiple sclerosis

* statin use after concussion may be associated with a lower risk for dementia the elderly (37 vs 43 cases per 1000 annually)

* may be of benefit in treatment of venous stasis ulcers

* statins may reduce risk of osteoarthritis

* statin therapy may be ineffective in the setting of untreated hypothyroidism, diabetes mellitus, biliary disease, or nephrotic syndrome

Contraindications

• hemorrhagic stroke (data are conflicting) [168-173]
• liver disease
• rhabdomyolysis
• pregnancy
• lactation
• myositis
• patients on renal dialysis
• limited prognosis
  • stopping statins in patients with limited prognosis is not associated with increased risk of cardiovascular events or increased mortality & may improve quality of life, reduce use of other useless medications & lower overall costs

* data are conflicting on use of statins after hemorrhagic stroke [81,168-173,182,322]

• caution recommended in use of statins in patients with previous haemorrhagic stroke & in patients with poorly controlled hypertension

* not a contraindication for hormone replacement therapy in post-menopausal women

* probably does not diminish risk of dementia

* not useful for treatment of dementia (see Statins & the risk of dementia ..)

* may not benefit patients > 80 years of age#

* does not lower risk of infection

* no benefit to starting statin within 14 days of MI

* peroperative statin does not prevent postoperative delirium

* no benefit of statins in patients with aneurysmal subarachnoid hemorrhage

* no benefit for COPD

* no benefit for ARDS

* as an alternative to exercise to reduce cardiovascular risk through improving physical fitness

* as an alternative to a heart healthy diet

• 4 of 5 MIs in men are preventable through healthy diet & lifetyle
• this translates to a number needed to treat of 1.25

* no study has has compared statins with beneficial lifestyle changes & found that statins had a superior or additive effect on clinical outcomes

# benefits in elderly (see PROSPER study,)

# benefits in elderly shown in meta-analysis

# insufficient evidence to assess net harms & benefits of initiating statins in adults >=76 years, regardless of estimated 10-year cardiovascular risk

# benefits in elderly with coronary artery disease > 80 years

# no reduction in mortality after MI in the elderly (> 80)

# insufficient data to recommend initiation or continuation of statins in patients with known cardiovascular disease >= 80 years of age

# discontinuation of statin in palliative care patients may improve quality of life.

Pregnancy category: X

• potentially teratogenic, risk may be small
• statin use during the first trimester of pregnancy is not associated with increased risk for congenital malformations
• FDA is removing contraindication against using statins in all pregnant patients

Benefit/risk

• subjects without known cardiovascular disease
  • number needed to treat (NNT)
    • 104 for 5 years to prevent 1 MI*
    • 154 for 5 years to prevent 1 stroke
    • 144 for 9 years to prevent 1 stroke (elderly >= 70 years)
    • 50-200 for 5 years prevent 1 major cardiovascular event
    • 145 for 5 years to prevent 1 MI & 88 to prevent 1 cardiovascular event (elderly 70-79 years with moderate intensity statin)
    • 80 for 5 years to prevent 1 MI & 42 to prevent 1 cardiovascular event (elderly 80-100 years with moderate intensity statin)
    • no mortality benefit
    • 66 for 10 years to prevent 1 cardiovascular event in subjects at low genetic risk (Jupiter trial)
      • industry-sponsored study stopped early after median follow-up of 1.9 years (Jupiter trial)
  • 25 for 10 years to prevent 1 cardiovascular event in subjects at high genetic risk
  • eligibility for guideline-directed statin use between 1987 & 2016 in Ireland increased eligible patients from 8% to 61%, resulting in number needed to treat to prevent one major cardiovascular event from 40 to 400
  • may reduce cardiac events for some adults aged 50-75 years with life expectancy >=2.5 years; no data suggest a mortality benefit
• subjects with known heart disease
  • number needed to treat (NNT)
    • 39 for 5 years for prevent 1 non-fatal MI
      • 24 for 1 year to prevent 1 MI (pravastatin in Prosper trial
      • 125 for 5 years for prevent 1 stroke
      • 83 for 5 years to prevent 1 death
• number needed to harm (5 years of treatment)
  • diabetes mellitus = 50
  • mypopathy = 10, ranges of 5-minimal risk
• according to the American Heart Association
  • primary prevention in 5% of patients treated for 5 years (who achieve a 77-mg/dL reduction in LDL)
  • secondary prevention in 10% of those treated
  • risk of myopathy, including rhabdomyolysis < 0.1%
• absolute risk reductions for all-cause mortality, myocardial infarction, & stroke of treatment with statins are modest compared with the relative risk reductions
• significant heterogeneity further reduces the certainty of the evidence
• conclusive association between absolute reductions in LDL-C levels & individual clinical outcomes is not established

* compare to diet & lifestyle behaviors

• can prevent 4 out of 5 MIs

* compare to a Mediterranean diet:

• NNT = 61 for 5 years to prevent 1 stroke, MI or death in subjects without known heart disease
• 30 for 5 years to prevent 1 death or 1 cancer after MI

* nearly all of 19 randomized controlled trials used to establish guidelines for statin use were industry-sponsored

• raw data from these trials has not been made available for peer review

* global market of US $20 billion annually fuels guidelines for statin use & further research

Dosage

• QD or QOD dosing may be equivalent
• most of benefit obtained at usual starting dose
• combination of low-dose statin plus either a bile acid sequestrant or ezetimibe reduces LDL cholesterol more than high-dose statin monotherapy
  • long-term clinical benefits uncertain
• high-intensity statin
  • atorvastatin 40-80 mg QD, rosuvastatin 20-40 mg QD
  • indications
    • known cardiovascular disease
    • LDL cholesterol > 190 mg/dL
    • diabetes mellitus & 10 year cardiovascular risk >= 7.5%
  • treat-to-target LDL cholesterol 50-70 mg/dL non-inferior to high-intensity statins for patients with coronary artery disease
• moderate dose statins
  • atorvastatin 10-20 mg QD, rosuvastatin 5-10 mg QD, simvastatin 20-40 mg QD, provastatin 40-80 mg QD, lovastatin 40 mg QD, fluvastatin 40 mg BID
  • indications
    • LDL-cholesterol > 70 mg/dL AND
      • diabetes mellitus OR
      • 10 year cardiovascular risk >= 7.5%
    • high-dose statin otherwise indicated, but
      • age > 75
      • renal insufficiency
      • coadministration of drug that interferes with statin metabolism
• high dose statins might be warranted for patients with ischemic stroke with evidence of atherosclerosis
• QHS dosing of short-acting statin may have benefit

Dosage adjustment in renal failure

• not required for atorvastatin, fluvastatin

Pharmacokinetics

• most statins are metabolized by cyt P450 3A4, except
  • pravastatin is isomerized to inactive metabolite
  • rosuvastatin (Crestor) & fluvastatin (Lescol) are metabolized by cyt P450 2C9
• lovastatin bioavailability increased by food
  • others may be taken without food
• most statins cross the blood brain barrier
  • the CNS has its own cholesterol metabolism
  • pravastatin does not penetrate the blood brain barrier,; rosuvastatin probably doesn't either
• transcriptional activity of the HMG-CoA reductase gene in the liver peaks in the middle of the night
  • activity of a gene associated with statin-induced myopathy peaks in the middle of the day

Monitor

• liver function tests no longer routinely indicated
  • check LFTs prior to initiation of statin
  • check LFTs again only if symptomatic
  • slight difference in recommendations for each statin
  • discontinue if serum ALT or serum AST > 3x upper limit of normal
  • increased liver function tests (< 10-fold normal) NOT associated with increased risk of hepatotoxicity
• creatine kinase
  • baseline levels on ALL patients (former recommendation)
    • not indicated in the absence of myalgias
  • recheck patients who develop myalgias or brown urine
  • discontinue if 10x upper limit of normal
  • monitor elevated levels < 10x normal weekly
  • routine monitoring NOT recommended
• lipid panel baseline, at 1-3 months, thereafter every 3-12 months*

* no reason given except for assessment of medication compliance; no suggestion given how results of testing would change management

• monitor with HMG CoA reductase inhibitors (statins)

Adverse effects

• adverse effects occur in 17% of patients, mostly myopathy
  • widely different reported incidence of adverse effects
  • adverse effects occur in 13% of patients after rechallange with a different statin
  • simvastatin & pravastatin score best in safety profile
• statin myopathy [49, 115]
  • increase in creatine kinase (mild to rhabdomyolysis)
  • myopathy may occur with normal serum creatine kinase
  • risk factors
    • older age
    • female gender
    • renal insufficiency
    • coadministration of fibrates, niacin, macrolides
    • coadministration of antiarrhythmic agents
    • hypothyroidism
    • alcoholism
    • obesity
    • exertion
      • increased risk of exertional rhabdomyolysis (RR=3.0)
    • LILRB5 variant rs12975366: T > C Asp247Gly may predispose to statin myopathy
    • genetic variants in SLCO1B1 may predispose to statin myopathy
  • statin use attenuates substrate use during maximal exercise, induces muscle fatigue during repeated muscle contractions, & decreases muscle mitochondrial oxidative capacity
  • genetic variants in SLCO1B1 gene may predispose to statin myopathy
  • uncertain benefit of CoQ supplements
    • CoQ supplements of no benefit
  • symptoms usually subside within a month or two after stopping the statin, but they sometimes persist longer
  • hydrophilic statins (fluvastatin, pravastatin, & rosuvastatin) less likely to cause statin myopathy than lipophilic statins
  • conflicting reports regarding frequency of statin myopathy
    • atorvastatin 10 mg QD in patients at high cardiovascular risk not associated with myopathy unless patients knew they were taking statin
    • no overall effect of atorvastatin 20 mg on muscle symptoms compared with placebo
    • > 90% of muscle symptoms in patients taking statins not due to statin
    • 31% of new statin users complain of muscle symptoms; 13% discontinue use
      • vitamin D not helpful
  • a statin-associated autoimmune-necrotizing myopathy with autoantibody directed against HMG-CoA reductase, the pharmacologic target of statins
    • occurs in a minority of patients with statin-induced myopathy
  • inflammatory myositis (inclusion body myositis)
• increased risk of musculoskeletal injuries (19%)
  • sprains, muscle strain
• increased risk of musculoskeletal pain (9%)
  • increased risk of generalized pain in cancer patients > 80 years of age
• increase risk of osteoarthritis & other arthropathies (7%)
  • not stastically significant
  • increased risk of back disorders, including
    • spondylosis, intervertebral disc disorders, herniated discs spinal stenosis
    • <A396232>NNH</A396232>=17, RR=1.5-1.7 (4 years use)
• memory impairment is the 2nd most common complaint
  • reversible cognitive impairment
  • most statins cross the blood brain barrier
    • the CNS has its own cholesterol metabolism
    • pravastatin does not cross the blood brain barrier
      • rosuvastatin probably does not either
  • no increase in risk of cognitive impairment
    • no robust association between lipid levels or statin use & cognitive impairment
    • data limited, especially for high-dose statins
    • no definitive evidence of benefit or harm
  • no adverse affects on memory, cognition, or brain volumes in elderly >= 70 years
  • acute memory impairment within 30 days (RR=4.4, all antihyperlipidemic agents)
  • no increased risk of dementia or mild cognitive impairment whether lipophilic or hydrophilic statin
    • risk of Alzheimer's disease may be elevated in persons in lowest quartile of baseline cognitive function
    • no increased risk for dementia in patients with familial hypercholesterolemia taking high-intesity statins over most if not all of adult life
• may increase incidence of postoperative delirium
• hepatotoxicity (rare)
  • increased serum transaminases 3-10 fold 1.4%
    • up to 3-fold is acceptable to continue statin
  • increased liver function tests (> 10-fold) 1%
  • statins reduce cardiovascular events in patients with moderately abnormal liver function tests [[[A12210|LFTs]]]
  • statins more beneficial in patients with abnormal LFTs than with normal LFTs
  • patients with abnormal LFTs who receive statins tend to have improvements in LFTs
  • no particular statin is more or less likely to cause LFT abnormalities
  • statins account for 2% of drug-related hepatotoxicity
  • 18% of patients with statin-induced hepatotoxicity develop chronic liver disease
• increased risk of renal failure
  • acute renal failure (RR=1.3)
  • chronic renal failure (RR=1.4-1.5)
• peripheral neuropathy (< 0.1%/year)
  • no evidence that CoQ supplements help
  • may take 3-12 months for neuropathy to improve after discontinuing statin
  • statins do not increase risk of peripheral neuropathy
• statin use may increase risk of pneumonia
• intracranial hemorrhage (ICH)
  • increased risk independent of LDL
  • no increased risk of intracerebral hemorrhage
  • decreased risk of intracerebral hemorrhage (RR=0.68)
  • pre-ICH statin use not associated with improved ICH functional outcome or mortality
  • post-ICH statin use is not associated with an increased risk of ICH recurrence
  • statins may reduce risk of intracranial hemorrhage
  • discontinuation of statin after ICH is associated with increased risk of mortality (RR=3.9 within 30 days; RR=1.5 at 3 months
• statins may increase risk of type 2 diabetes (RR=1.12)
  • risk is inherent in inhibition of HMG CoA reductase
    • mediated by body weight or other modifiable metabolic factors
    • impaired pancreatic beta-cell function
    • increased peripheral insulin resistance
  • atorvastatin & rosuvastatin (evidence-base)
  • risk may be dose-related
  • benefits outweigh risks in secondary prevention & high-risk patients
  • overall increase in risk varies dependent on dose, duration & source of data
    • ~ 10%
    • risk of type 2 diabetes in statin users is 31% vs 19% in non users after 7 years; NNH=9
  • higher dose statins & rosuvastatin, 10 mg & up; atorvastatin, 20 mg & up; simvastatin, 40 mg & up) with 15% higher rate of new diabetes diagnoses than lower-dose statin users
  • increased risk in patients with impaired glucose tolerance, (RR=1.5, number needed to harm = 12)
  • new-onset diabetes more common in patients with baseline HgbA1c) in the prediabetes range than in patients with lower HgbA1c
  • incidence of new-onset diabetes highest in 1st 4 months of statin use
  • 46% increase in risk for type 2 diabetes in statin users
  • statin use associated with diabetes progression in patients with diabetes
  • among patients with known diabetes at baseline, glycemia worsens slightly with statin therapy compared with placebo
  • risk may be associated with increased expression of LDL receptor
  • unknown if type 2 diabetes resolves when statin is discontinued
• NO evidence of increased cancer risk within 10 years
• decreased energy & increased fatigue with exertion, especially among women
• statin use in older men is associated with a slight reduction in physical activity
• increased risk of cataracts (9%, 20% without comorbidities)
• increased caloric intake (10%), including dietary fat (14%) with resultant increase in BMI (1.3 vs 0.4) for non-users
• statin use may increase risk of Parkinson's disease (RR=1.6-1.7)
  • statin use associated with worse baseline nigrostriatal dopamine degeneration
  • statin use prior to diagnosis of Parkinson's disease associated with increased risk of dementia
• not associated with increased risk of pancreatitis
• not associated with increased risk of erectile dysfunction
• accelerated coronary plaque calcification
  • slower progression of coronary atherosclerosis volume
  • reduction of high-risk plaque features
  • no protection against progression of coronary lesions to high-grade stenoses
• increased risk of gynecomastia (RR=1.4)
• immune-mediated necrotizing myopathy (IMNM)

• drug adverse effects of HMG CoA reductase inhibitors
• drug adverse effects of anti-hyperlipidemic agents

Drug interactions

• inhibitors of cyt P450 3A4 inhibit metabolism of statins
  • simvastatin (Zocor), lovastatin (Mevacor) > atorvastatin (Lipitor)
  • pravastatin (Pravachol), rosuvastatin (Crestor), fluvastatin (Lescol) are safe to use with cyt P450 3A4 inhibitors
  • pravastatin allegedly has least interaction
  • cyt P450 3A4 inhibitors that may interact with statins
    • antibiotics:
      • erythromycin, clarithromycin, telithromycin, isoniazid
      • azithromycin ok
    • antifugals:
      • itraconazole, ketoconazole
      • terbinafine ok
    • Ca+2 channel blockers: diltiazem, nifedipine, verapamil
    • antiretrovirals: delavirdine, efavirenz, indinavir, ritonavir, saquinavir
    • others, see cyt P450 3A4
• increased risk of myopathy when statin is combined with:
  • fibrates, cyclosporine, niacin
  • use fenofibrate rather than gemfibrozil with statin
  • fluvastatin may be safest to use with cyclosporine
• diminished response to vitamin D
• statin drug interaction summaries

• drug interaction(s) anticonvulsants with statins
• drug interaction(s) of statins with vitamin D
• drug interaction(s) of statins with SSRIs
• drug interaction(s) of statins with influenza virus vaccines
• drug interaction(s) of statins with macrolide
• drug interaction(s) of statins with antiviral protease inhibitors
• drug interaction(s) of statins with fibrates

Laboratory

• baseline serum ALT; further monitoring unnecessary if normal
• routine serum creatine kinase unnecessary
• serum C-reactive protein does not predict response to statins
• elevated fasting serum triglyceride in patients on statins is associated with an increased risk of cardiovascular events (when >175 mg/dL, RR=1.6 relative to < 80 mg/dL)

Mechanism of action

• inhibition of HMG CoA reductase
  • inhibition to cholesterol biosynthesis
    • response to lipid-lowering effects dependent on genotype: apo E2 > apo E3 > apo E4
  • also inhibits biosynthesis of isopentenyl pyrophosphate derivatives, including:
    • ubiquinone CoQ
    • dolichol phosphate
    • prenyl proteins
  • inhibition of HMG CoA reductase in the liver stimulates LDL-receptors, which results in an increased clearance of LDL from the bloodstream & a decrease in blood cholesterol & LDL cholesterol levels
• statin use associated with transformation of coronary atherosclerosis toward high-density calcification but does not slow plaque progression on serial coronary CT angiography
• anti-inflammatory properties
  • reduction of plasma levels of C-reactive protein
  • lowers mortality associated with sepsis
    • Gram negative bacteria
    • Staphylococcus aureus
      • reduces risk of community-acquired sepsis due to S aureus
  • improves renal tubule function; reduces proteinuria
• reduction in autoimmunity
  • reduction in MHC class II molecules
  • increased production of Th2 cells
  • decreased production of Th1 cells
• anti-platelet effects
• enhancement of nitric oxide synthase activity
• inhibition of endothelin-1
• inhibits proliferation of endothelial cells
  • effects observed at somewhat higher level than achieved with clinical dose
• may have antithrombotic effects & fibrinolytic effects & may enhance the activity of other fibrinolytic agents
  • statins inhibit expression of tissue factor which downregulates the coagulation cascade extrinsic pathway
  • statins increase thrombomodulin expression on endothelial cells, thus may facilitate anticoagulation via protein C
  • most of the antithrombotic effects of statins are attributed to the inhibition of isoprenylation of signaling proteins
• reduces risk of myocardial infarction & stroke in diabetics regardless of cholesterol levels
• continuation of prescribed statin therapy lowers risk for all-cause mortality among patients with & without coronary heart disease (mean age, 58 years; 51% female)
• pravastatin does not lower blood pressure; it is not likely that other statin do either
• high doses of rosuvastatin & atorvastatin result in similar atherosclerosis regression, despite greater reductions in LDL cholesterol with rosuvastatin
• enhancement of osteoblast activity
• not much of an effect on non-cardiovascular outcomes

Notes

• for comparison of different statins (see)
• PCSK9 inhibitors may enhance LDL-lowering effect of statins
• exercise & improved fitness [7 METS] as adjunct treatment to statins may further diminish risk of mortality in patients with dyslipidemia
• advertisements increase statin use only in patients for whom a statin is not indicated
• 2013 AHA & ACC guidelines increase number of Americans eligible for statins
  • most of increase is for primary prevention
  • 48% of population eligible for statins
  • 87% of men 60-75 years of age eligible for statins
  • according to industry-sponsored study, not being offered a statin was the most common reason for non-use
  • for secondary prevention, not being offered a statin & discontuing use of a statin were equally common
  • most patients who discontinued statins did so because of adverse effects
• 1/3 of elderly (>= 80 years) without vascular disease prescribed statins
• generic statins associated with
  • better medication compliance (77% vs 71%)
  • slightly better outcomes
    • 8% fewer cardiovascular events
    • 1.5 fewer cardiovascular events per 100 patient years
  • improved affordablility
• patients with serious cardiovascular risk least likely to stop statin
• stopping statin therapy may be associated with increased cardiovascular risk 13.9% vs 12.2%
  • a higher medication possession ratio among veterans with cadiovascular disease associated with fewer hospitalizations for ischemic heart disease & stroke & lower mortality
  • in contrast, a statin controversy in 2013 in France led to discontinuation of statin use for primary prevention by 50% & all-cause mortality & cardiovascular mortality declined rather than increased
• nearly all of 19 randomized controlled trials reviewed for guidelines were industry-sponsored

a global statin market of roughly US $20 billion annually drives much of the research & interest in statins for primary prevention

women & men of color are less likely to receive appropriate statin therapy than non-Hispanic white men

More general terms

• enzyme inhibitor
• anti-hyperlipidemic agent

More specific terms

• hydrophilic statin
• lipophilic statin
• statins in the elderly

Additional terms

• cholesterol biosynthesis
• high-intensity statin therapy
• hydroxymethylglutaryl [HMG] CoA reductase (HMGCR)
• statin clinical trials
• statin deprescribing
• statin intolerance
• statin myopathy
• statin therapy in children
• Statins & the risk of dementia

Component of

• aspirin/HMG CoA reductase inhibitor
• HMG CoA reductase inhibitor/nicotinic acid
• calcium channel blocker/HMG CoA reductase inhibitor
• polypill (Polycap)

Patient information

Statin patient information