Transcript Clinical question: When do you get statin induced myopathy?

Clinical question:
When do you get statin induced
myopathy?
HMG-CoA Reductase Inhibitors
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1987: first approved for the treatment of
hypercholesterolemia
Prevention of primary and secondary CHD
First generation:
-simvastatin (Zocor), lovastatin (Mevacor),
pravastatin (Pravachol)
Second generation:
-fluvastatin (Lescol)
Third generation:
-atorvastatin (Lipitor), rosuvastatin (Crestor),
cerivastatin (Baycol)
www.knowledgeofhealth.com/statinsales
Number of adverse reactions associated with HMG
CoA reductase inhibitors reported to the WHO
International Information System Database
Agent
TNR
Arthralgia
(%)
Myalgia
(%)
PN
(%)
Neuropathy
(%)
Rhabdo
(%)
Myopathy
(%)
Atorvastatin
3188
1.3
7.6
0.0.
0.1
0.5
0.1
Cerivastatin
387
3.1
14.4
NA
NA
2.1
0.02
Fluvastatin
2061
1.6
9.1
0.6
0.1
0.5
1.2
Lovastatin
21541
1.3
6.2
NA
0.3
0.2
1.8
Pravastatin
6208
1.4
6.4
NA
0.2
0.3
1.6
Simvastatin
15149
1.7
8.4
0.0
0.3
0.4
0.9
Drug Safety. June 2000; 22
Symptoms/Duration of Onset of
Myopathy
• diffuse muscle weakness, weakness of the limbs,
weakness after exertion
• Onset is usually within weeks to months but may
occur at any time during therapy
• Review: mean duration before symptom onset=6.3
months (range 0.25-48 months), 2/3 had onset
within six months
• mean time to resolution of symptoms after statin
discontinuation=2.3 months (0.25-14 months)
Archives of Internal Medicine. December 2005; Vol. 165(22): 2671-6.
Mechanism of Statin Induced
Myotoxicity
• Depletion of secondary metabolites of Mevalonate
pathway (Ubiquinone or coenzyme 10)-Ubiquinone is
involved in mitochondrial electron transfer and serves as
an important intermediary in the oxidative
phosphorylation pathway:
less CoQ10=less recovery=more weakness
• Inconclusive: decrease in serum ubiquinone does not
necessarily =decrease in intracellular ubiquinone
• More research is needed
• Other theories: Induction of apoptotic cell death or
Changes in the Cl- channel conductance within the
myocyte, which leads to alteration in muscle cell
membrane properties
American Journal Of Health System Pharmacy. March 2004. Vol 61(5): 515-519.
Complicating Risk Factors for
Statin Induced Myopathy
Patient Characteristics
Sex: F>M
Age
Patient size
Hepatic dysfunction
Renal insufficiency
Hypothyroidism
Diet (grapefruit juice)
American Journal of Medicine. 2004; Vol. 116: 408-416.
Statin Properties
High systemic
exposure
High bioavailability
Low protein binding
Potential for drugdrug interactions,
particularly those with
CYP450 interactions
Drug Interactions
Fold
increase of
statin AUC
Simvastatin
Lovastatin
Atorvastatin
Fluvastatin
Cerivastatin
Pravastatin
Rosuvastatin
Itraconazole
5-20
5-20
2-4
-
<1.5
-
-
Erythromyin,
clarithro
4-12
4-12
1.5-5
-
<1.5
<2
-
Verapamil,
diltiazem
3-8
3-8
?
-
?
-
-
Cylcosporine
6-8
5-20
6-15
2-4
4
5-10
5-10
Gemfibrozil
2-3
2-3
<1.5
-
4-6
2
2
Grapefruit
juice
2-10
2-10
1-4
-
<1.5
-
-
Clinical Pharmacology & Therapeutics. December 2006. 80(6):565-581,
Clinical evaluation
• Evaluate extent of muscle soreness/weakness-compared
to baseline or prior to initiation of therapy
• Obtain serum CK level and compare to baseline
– If normal or moderately elev. CK levels (3-10 times the ULN),
symptoms and CK values may be monitored without
discontinuation of drug
– If serum CK levels continue to increase, a reduction in dose or
temporary discontinuation of the drug is necessary
– If serum CK levels exceed 10x the ULN, both the statin and any
other precipitating agent should be discontinued regardless of the
patient’s symptoms
American Journal Of Health System Pharmacy. March 2004. Vol 61(5): 515-519.
CK analysis
• Other cause of muscle soreness/pain:
– Exercise or strenuous work
– Muscle damage resulting from trauma, sepsis, inflammatory
diseases
– Hypothyroidism-obtain a TSH level
• Recent literature suggests that CK elevations do not always
correlate with muscle damage
• If all other etiologies are excluded, the possiblility of statin induced
myopathy in the presence of normal CK values should be
considered.
American Journal Of Health System Pharmacy. March 2004. Vol 61(5): 515-519
Final Analysis
• Since the mechanism of statin induced myopathy is not well defined,
no preventative measure is available
• Important to recognize factors that place patients at increased risk,
for example, the risk is substantially increased for most statins when
used concurrently with drugs that interfere with CYP450 hepatic
metabolism
• Initiate therapy at lowest therapeutic dose
• Patient education-awareness of potential myotoxic effects and the
signs of myopathy
• Routine monitoring of CK levels has not been shown to be
necessary, but a baseline CK level prior to initiating therapy can be
useful for reference purposes.
• Until further evidence is available, widespread use of ubiquinone is
not warranted