drug adverse effects of HMG CoA reductase inhibitors

Etiology

• 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

Adverse effects

• statin myopathy (most common)
  • increase in serum creatine kinase (mild to rhabdomyolysis)
  • myopathy may occur with normal serum creatine kinase
  • statin use attenuates substrate use during maximal exercise, induces muscle fatigue during repeated muscle contractions, & decreases muscle mitochondrial oxidative capacity
  • increased risk of exertional rhabdomyolysis (RR=3.0)
  • increased risk of hospitalization for acute renal failure with high-dose or potent statin
  • stop statin if
    • serum creatine > 10-fold upper reference value, or severe myalgias
  • CoQ10 may or may not help myalgias
    • CoQ10 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
  • transcriptional activity of a gene associated with statin-induced myopathy peaks in the middle of the day
  • 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
• 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 osteoarthrities & other arthropathies (7%)
  • not stastically significant
• memory impairment is 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
    • data limited, especially for high-dose statins
    • no definitive evidence of benefit or harm
  • 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) [4, 6]
  • increased liver function tests 1%
  • baseline serum ALT
    • further monitoring of LFTs no longer routinely required
    • up to 3 fold elevation in serum ALT acceptable to continue statin
  • 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
• erectile dysfunction?
  • not associated with erectile dysfunction
• aggressive statin therapy in the elderly, resulting in reductions of total cholesterol < 148 mg//dL may result in subtle affective changes.
• intracranial hemorrhage (ICH)
  • increased risk independent of LDL
    • increased risk of non-fatal hemorrhagic stroke, RR = 1.7
  • 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
  • discontinuation of statin after ICH is associated with increased risk of mortality (RR=3.9 within 30 days; RR=1.5 at 3 months
• diabetes mellitus type 2 (RR=1.12)
  • risk is inherent in inhibition of HMG CoA reductase
    • mediated by body weight or other modifiable metabolic factors
  • overall increase in risk varies dependent on dose, duration & source of data
    • increase is risk ~ 10%
    • risk of type 2 diabetes in statin users is 31% vs 19% in non users after 7 years; NNH=9
  • risk of diabetes increases with duration of statin therapy
  • statin use associated with diabetes progression in patients with diabetes
  • one additional case of diabetes for every 255 patients on statin for 4 years
  • 498 patients treated with high-dose for 1 year for 1 patient to develop diabetes; compare with 155 high-risk patients treated for one year to prevent 1 cardiovascular event
  • increased risk of diabetes with high dose rosuvastatin is 27%
  • benefits outweigh risks in secondary prevention & high-risk patients
  • risk higher for more potent statins (simvastatin, rosuvastatin, atorvastatin) than low potency statins (pravastatin, lovastatin, fluvastatin)
  • increased risk in patients with impaired glucose tolerance, (RR=1.5, number needed to harm = 12)
  • risk may be associated with increased expression of LDL receptor
  • unknown if type 2 diabetes resolves when statin is discontinued
• statin use may increase risk of pneumonia
• increased risk of acute renal failure
  • risk greatest in the 1st 120 days
  • risk higher for more potent statins
  • relative risk higher in patients without chronic kidney disease
  • also see myopathy (above)
• decreased energy & increased fatigue with exertion, especially among women
• statin use in older men is associated with a slight reduction in physical activity
• 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
• no consensus on statins & risk of cataracts
  • increased risk of cataracts (9%, 20% without corbidities)
• potentially teratogenic, risk may be small
  • statin use during the first trimester of pregnancy is not associated with increased risk for congenital malformations
• use of statins before diagnosis of incident diabetes is not associated with an increased risk of microvascular disease
• increased risk of gynecomastia (RR=1.4)
• immune-mediated necrotizing myopathy (IMNM)
• simvastatin & pravastatin score best in safety profile

More general terms

• drug adverse effect(s)