2. Clinical question: When do you get statin induced myopathy?

3. HMG-CoA Reductase Inhibitors 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)

4. www.knowledgeofhealth.com/statinsales

5. Number of adverse reactions associated with HMG CoA reductase inhibitors reported to the WHO International Information System Database AgentTNRArthralgia (%) Myalgia (%) PN (%) Neuropathy (%) Rhabdo (%) Myopathy (%) Atorvastatin Cerivastatin Fluvastatin Lovastatin Pravastatin Simvastatin 3188 387 2061 21541 6208 15149 1.3 3.1 1.6 1.3 1.4 1.7 7.6 14.4 9.1 6.2 6.4 8.4 0.0. NA 0.6 NA 0.0 0.1 NA 0.1 0.3 0.2 0.3 0.5 2.1 0.5 0.2 0.3 0.4 0.1 0.02 1.2 1.8 1.6 0.9 Drug Safety. June 2000; 22

6. 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.

7. 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.

8. Complicating Risk Factors for Statin Induced Myopathy Patient Characteristics Sex: F>M Age Patient size Hepatic dysfunction Renal insufficiency Hypothyroidism Diet (grapefruit juice) Statin Properties High systemic exposure High bioavailability Low protein binding Potential for drug- drug interactions, particularly those with CYP450 interactions American Journal of Medicine. 2004; Vol. 116: 408-416.

9. Drug Interactions Fold increase of statin AUC Simvastatin LovastatinAtorvastatinFluvastatinCerivastatinPravastatin Rosuvastatin Itraconazole 5-20 2-4-<1.5-- Erythromyin, clarithro 4-12 1.5-5-<1.5<2- Verapamil, diltiazem 3-8 ?-?-- Cylcosporine 6-8 5-206-152-445-10 Gemfibrozil2-3 <1.5-4-622 Grapefruit juice 2-10 1-4-<1.5-- Clinical Pharmacology & Therapeutics. December 2006. 80(6):565-581,

10. 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.

11. 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

12. 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