Pharmacology Challenges: Managing Statin Myalgia

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1 Clinical Case: RM is a 50 year-old African American woman with a past medical history of type diabetes, dyslipidemia, hypertension and peripheral arterial disease. She had been prescribed simvastatin 80 mg po daily and atorvastatin 40 mg po daily in the past but could not tolerate them due to muscle pain in her legs and back (CK measurements were slightly elevated at iu/ml [normal 0-00], no weakness). Currently, she is on no lipid-lowering therapy. She has seen a dietician several times in the past and is adherent with lifestyle modifications that are appropriate for her diabetes. She has tried to lose weight, but has not been successful in losing more than 0 pounds over the past several years. She exercises every day by walking briskly for minutes. Meds: amlodipine 0 mg po daily lisinopril 40 mg po daily aspirin 8 mg po daily cilostazole 00 mg po twice daily insulin glargine 40 units sq daily metformin 000 mg po twice daily Vital Signs: BP = 36/88, 34/86 mm Hg HR = 70 beats/min Wt = 90 lbs ht = 63" Labs: TC = 95 mg/dl AC 7.4% 30 HDL-C = 45 mg/dl TG = 50 mg/dl LDL-C = 0 mg/dl egfr = 75 ml/min/.73m Spot microalbulmin = 0 mg:g Does this patient need statin therapy? How would you answer change if she did not have a history of diabetes and/or peripheral arterial disease? How you categorize her previous reaction to statin therapy? Myalgia, myopathy, myonecrosis and/or clinical rhabdomyolysis What are treatment options for implementing lipid-lowering therapy in this patient? Page

2 03 ACC/AHA Blood Cholesterol Guidelines High-Intensity Moderate-Intensity Low-Intensity by 50% by ~ 30 to 49% by <30% Atorvastatin mg Rosuvastatin 0-40 mg Atorvastatin 0-0 mg Rosuvastatin 5-0 mg Simvastatin 0 40 mg Pravastatin mg Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40 mg bid Pitavastatin 4 mg Simvastatin 0 mg Pravastatin 0 0 mg Lovastatin 0 mg Fluvastatin 0 40 mg Pitavastatin mg Page

3 NATIONAL LIPID ASSOCIATION (NLA) Statin-associated muscle adverse events Myalgia unexplained muscle discomfort, often described as flu-like symptoms, with normal CK level. Spectrum of myalgia complaints includes: muscle aches, muscle soreness, muscle stiffness, muscle tenderness, and muscle cramps with or shortly after exercise (not nocturnal cramping) Myopathy muscle weakness (not attributed to pain and not necessarily associated with elevated CK) Myositis muscle inflammation Myonecrosis muscle enzyme elevation or hyperckemia Mild >3-fold greater than untreated baseline CK levels or normative upper limit that are adjusted for age, race and sex. Moderate 0-fold greater than untreated baseline CK levels or normative upper limit that are adjusted for age, race and sex. Severe 50-fold greater than untreated baseline CK levels or normative upper limit that are adjusted for age, race and sex. Myonecrosis with myoglobuminuria or acute renal failure (increase in S.Cr 0.5 mg/dl clinical rhabdomyolysis) Definition of Statin intolerance: Clinical syndrome characterized by the inability to tolerate at least statins, one statin at the lowest starting daily dose AND another statin at any daily dose, due to either objectionable symptoms (real or perceived) or abnormal lab determinations, which are temporally related to statin treatment and reversible upon statin discontinuation, but reproducible by re-challenge with other known determinants being excluded (such as hypothyroidism, interacting drugs, concurrent illnesses, significant changes in physical activity or exercise, and underlying muscle disease) NLA Statin Intolerance Expert Panel: Recommendations to Clinicians. Acknowledge that statin intolerance is real, manifesting as an array of muscle-related symptoms including aching, stiffness, proximal motor weakness, fatigue, and back pain. Estimated frequency of muscle symptoms related to statin use range from -0%. Severe myopathy with weakness and/or markedly elevated muscle enzymes is rare.. Attempt to maintain statin treatment in some form in almost every case of statin intolerance. Patients can be continued on statin treatment, commonly with doses and/or alternative statins that achieve less LDL-C lowering. Atorvastatin or rosuvastatin at doses of 5 0 mg taken once or twice a week may reduce LDL-C by 6 6%. 3. Clinicians may optionally pursue nonstatin LDL-C lowering treatments in statin-intolerant patients, with or without concomitant statin therapy (bile acid sequestrants, niacin, ezetimibe, fibrates, plant sterol esters or stanol esters, viscous fiber) Page 3

4 NLA Muscle Safety Task Force: Page 4

5 Proposed Myalgia Index Score Clinical Symptoms Point value new or increased unexplained muscle symptoms Regional Distribution Symmetric hip flexors.thigh aches 3 Symmetric calf aches Symmetric upper proximal aches Non-specific asymmetric, intermittent Temporal pattern based on symptoms onset < 4 weeks 3 4- weeks < weeks De-challenge Improves upon withdrawal (< weeks) Improves upon withdrawal (-4 weeks) Does not improve upon withdrawal (> 4weeks) 0 Challenge Same symptoms reoccur upon rechallenge < 4 weeks 3 Same symptoms reoccur upon rechallenge 4- weeks Score: Probable = 9- points, Possible = 7-8 points, Unlikely < 7 points Half-life (hr) CYP450 Metabolism Solubility Lovastatin -3 3A4 Lipophillic Simvastatin 3A4 Lipophillic Pravastatin.5- none Hydrophilic Fluvastatin C9 Hydrophilic Atorvastatin 4 3A4 Lipophillic Rosuvastatin 0 C9 Hydrophilic Pitavastatin C9, C8 Slightly Hydrophilic Page 5