1. Slide Source: Lipids Online Slide Library www.lipidsonline.org Initiating and Monitoring Statin Therapy Kimberly K. Birtcher, MS, PharmD, BCPS (AQ Cardiology), CDE, CLS

2. Slide Source: Lipids Online Slide Library www.lipidsonline.org NCEP Report Suggests the Need for More Intensive Therapy Based on statin trials published since 2001 Key points: – Treat according to global risk level, not only cholesterol value – Achieve at least a 30% to 40% reduction in low- density lipoprotein cholesterol (LDL-C) – Initiate therapeutic lifestyle changes (TLC) in all patients with lifestyle-related risk factors regardless of LDL-C level NCEP = National Cholesterol Education Program Grundy SM, et al. Circulation. 2004;110:227-239. | NCEP ATP III. JAMA. 2001;285:2486-2497.

3. Slide Source: Lipids Online Slide Library www.lipidsonline.org Statin Dosing Strategies Start with dose needed to give appropriate LDL-C reduction (some patients will need more than 30% to 40% LDL-C reduction to achieve LDL-C goal) Doubling the statin dose provides up to 6% to 7% additional LDL-C reduction May need combination therapy to achieve goals Monitor for efficacy and safety Achieve AT LEAST a 30% to 40% LDL-C reduction, regardless of baseline LDL-C. Grundy SM, et al. Circulation. 2004;110:227–239. | Pasternak RC, et al. J Am Coll Cardiol. 2002;40:567–572. | Jones P, et al. Am J Cardiol. 1998;81:582–587. LDL–C = low-density lipoprotein cholesterol

4. Slide Source: Lipids Online Slide Library www.lipidsonline.org In clinical trials: 40 mg daily of lovastatin has shown an LDL-C reduction of 31% 40 mg daily of pravastatin has shown an LDL-C reduction of 34% 40–80 mg daily of fluvastatin has shown an LDL-C reduction of 25–35% 20–40 mg daily of simvastatin has shown an LDL-C reduction of 35–41% 10 mg daily of atorvastatin has shown an LDL-C reduction of 39% 5–10 mg daily of rosuvastatin has shown an LDL-C reduction of 39–45% Grundy SM, et al. Circulation. 2004;110:227–239. LDL-C = low-density lipoprotein cholesterol Doses of Currently Available Statins Required for a 30% to 40% LDL-C Reduction

5. Slide Source: Lipids Online Slide Library www.lipidsonline.org Secondary Primary LDL-C Reduction Significantly Reduces Coronary Events: Primary and Secondary Prevention in Early Statin Trials LaRosa JC, et al. JAMA. 1999;282:2340–2346. Risk Reduction in Major Coronary Events (%) −38 P<0.001 −31 P<0.001 −38 P<0.001 −25 P<0.001 −25 P=0.002 CARE 4159 −28% LIPID 9014 −25% 4S 4444 −36% WOSCOPS 6595 −26% AFCAPS/ TexCAPS 6605 −27% N LDL-C  LDL–C = low-density lipoprotein cholesterol

6. Slide Source: Lipids Online Slide Library www.lipidsonline.org Start With the Dose Needed to Give the Appropriate LDL-C Reduction Baseline LDL-C160 mg/dL Target LDL-C<70 mg/dL Needed LDL-C reduction160 − 69 = 91 mg/dL To achieve the target LDL-C, this patient needs a: 57% LDL-C reduction = (160−69 mg/dL)/160 mg/dL  100 Medications and doses that will achieve this reduction are: – Atorvastatin 80 mg – Rosuvastatin 20 mg – Ezitimibe/simvastatin 10/40 mg Some patients will need more than the initial starting dose: LDL–C = low-density lipoprotein cholesterol

7. Slide Source: Lipids Online Slide Library www.lipidsonline.org Jones PH, et al. Am J Cardiol. 2003;92:152–160. *P < 0.001 vs. atorvastatin 10 mg and simvastatin 20 mg and 40 mg † P = 0.026 vs. atorvastatin 20 mg Mean % Change in LDL-C from Untreated Baseline Value AtorvastatinRosuvastatinSimvastatin 14% with 3 titrations 9% with 2 titrations 18% with 3 titrations 10 mg 20 mg 30 mg 40 mg −28 −7 −4 −7 −46† −6* −3* −37 −6 −5 −3 LDL–C=low-density lipoprotein cholesterol The Initial Statin Dose Produces Most of the LDL-C Lowering

8. Slide Source: Lipids Online Slide Library www.lipidsonline.org Combination Drug Strategies May Be an Option for Some Patients Consider combination therapy if: – Higher statin doses are not well tolerated – Lipid goals are not met Statins + bile acid resins or ezetimibe: – ↓ LDL-C >50% Fibrates, niacin, omega-3 fatty acids: – ↓ Triglycerides and nonHDL-C – ↑ HDL-C Combination therapy may increase risk for drug interactions Vasudevan AR, Jones PH. Curr Cardiol Rep. 2005;7:471–479. LDL-C = low-density lipoprotein cholesterol HDL-C = high-density lipoprotein cholesterol

9. Slide Source: Lipids Online Slide Library www.lipidsonline.org Statin Drug Interactions: Labeled Contraindications for Lovastatin and Simvastatin Erythromycin Clarithromycin Itraconazole Ketoconazole Telithromycin Mevacor ® [package insert]; 2008. | Zocor ® [package insert]; 2008. Lovastatin and simvastatin are contraindicated with: Nefazodone HIV protease inhibitors Grapefruit juice >1 quart/day HIV = human immunodeficiency virus

10. Slide Source: Lipids Online Slide Library www.lipidsonline.org Lovastatin 20 mg/day maximum with cyclosporine, danazol, fibrates, niacin >1 g/day 40 mg/day maximum with amiodarone, verapamil Simvastatin 10 mg/day maximum with cyclosporine, danazol, gemfibrozil 20 mg/day maximum with amiodarone, verapamil Use with caution with other fibrates, niacin > 1 g/day Statin Drug Interactions: Labeled Dosing Restrictions for Lovastatin and Simvastatin Mevacor® [package insert]; 2008. | Zocor® [package insert]; 2008.

11. Slide Source: Lipids Online Slide Library www.lipidsonline.org Statin Dosing Considerations: Use of Rosuvastatin in Specific Populations Asians – May have higher blood concentrations and more risk of side effects than Caucasians – Start with 5 mg daily; maximum of 20 mg daily Patients with renal impairment – Start with 5 mg daily; maximum of 10 mg daily Patients who are predisposed to myopathy – Start with 5 mg daily Crestor ® [package insert]; 2008.

12. Slide Source: Lipids Online Slide Library www.lipidsonline.org Give a 10 mg/day maximum dose when taken with gemfibrozil or with lopinavir/ritonavir Give a 5 mg/day maximum dose when taken with cyclosporine Give antacids containing aluminum or magnesium >2 hours after rosuvastatin Remember that this statin may increase the levels of ethinyl estradiol and norgestrel Remember that this statin may increase the effects of warfarin; monitor international normalized ratio Use cautiously with other drugs that may decrease the levels or activity of endogenous steroid hormones (i.e., ketoconazole, spironolactone, cimetidine) Statin Drug Interactions: Rosuvastatin Crestor ® [package insert]; 2008.

13. Slide Source: Lipids Online Slide Library www.lipidsonline.org Statins: Monitoring Headache or Dyspepsia Initially 6–8 weeks after starting therapy At each follow- up visit Muscle Soreness, Tenderness, or Pain Initially 6–12 weeks after starting therapy At each follow- up visit Pasternak RC, et al. J Am Coll Cardiol. 2002;40:567–572.

14. Slide Source: Lipids Online Slide Library www.lipidsonline.org Statins: Monitoring (Continued) Pasternak RC, et al. J Am Coll Cardiol. 2002;40:567– 572. | McKenney JM, et al. Am J Cardiol. 2006;97:89C– 94C. Lipid Panel Baseline6 weeks3 monthsEvery 6 months Liver Function Tests Baseline 12 weeks after starting/increasing therapy Annually, as needed (when the patient reports liver symptoms) Creatine Kinase Test Baseline As needed (when patient reports muscle soreness, tenderness, or pain)

15. Slide Source: Lipids Online Slide Library www.lipidsonline.org Statins are well tolerated by most people Some people experience problems with liver function. Elevations in liver transaminases: – Occur in 0.5% to 2.0% of statin users – Are dose-dependent – Are usually reversed with a lowered statin dose – Usually do not recur with rechallenge or use of another statin – Rarely progress to liver failure Statins: Liver Issues Pasternak RC, et al. J Am Coll Cardiol. 2002;40:567–572.

16. Slide Source: Lipids Online Slide Library www.lipidsonline.org Initiate statins Continue statins Increase the dose of statins Statins: Liver Issues (Continued) Pasternak RC, et al. J Am Coll Cardiol. 2002;40:567–572. | McKenney JM, et al. Am J Cardiol. 2006;97:89C–94C. Modest increases* in liver transaminases are not a contraindication to: *Increases <3  the upper limits of normal.

17. Slide Source: Lipids Online Slide Library www.lipidsonline.org Repeat liver function tests – If values are still high, rule out other causes Based on clinical judgment, consider: – Continuing the statin – Reducing the dose of the statin – Discontinuing statin therapy Statins: Liver Issues (Continued) *Increased <3  the upper limits of normal. Reprinted from McKenney JM, et al. Am J Cardiol. 2006; 97:89C–94C, with permission from Elsevier. When an elevation* in liver transaminases is isolated and asymptomatic:

18. Slide Source: Lipids Online Slide Library www.lipidsonline.org Statins: Liver Issues (Continued) Reprinted from McKenney JM, et al. Am J Cardiol. 2006;97: 89C–94C, with permission from Elsevier. | Pasternak RC, et al. J Am Coll Cardiol. 2002;40:567–572. Patients with these conditions may receive statins: Chronic liver disease Nonalcoholic fatty liver disease Nonalcoholic steatohepatitis

19. Slide Source: Lipids Online Slide Library www.lipidsonline.org Teach patients to report jaundice, malaise, fatigue, and lethargy Suspect hepatotoxicity when jaundice, hepatomegaly, increased indirect bilirubin, or increased prothrombin time occur Discontinue statin therapy with objective evidence of significant liver injury – Seek cause – Consider referral to a gastroenterologist or hepatologist Statins: Liver Issues (Continued) Reprinted from McKenney JM, et al. Am J Cardiol. 2006; 97:89C–94C, with permission from Elsevier.

20. Slide Source: Lipids Online Slide Library www.lipidsonline.org Myopathy – Patient reports muscle pain, soreness, weakness, and/or cramps with elevated creatine kinase (>10  ULN) Rhabdomyolysis – Creatine kinase >10,000 IU/L, or – Creatine kinase >10  ULN with an elevation in serum creatinine or requiring medical intervention with IV hydration therapy Statins: Muscle Issues IV = intravenous; ULN = upper limits of normal Reprinted from McKenney JM, et al. Am J Cardiol. 2006; 97:89C–94C, with permission from Elsevier.

21. Slide Source: Lipids Online Slide Library www.lipidsonline.org The risk of myopathy increases with respect to: Age (>80 years; especially in women) Multisystem diseases (chronic renal failure, especially due to diabetes) Multiple medications Perioperative periods Alcohol abuse Grapefruit juice >1 quart/day Statins: Muscle Issues (Continued) Pasternak RC, et al. J Am Coll Cardiol. 2002;40:567–572.

22. Slide Source: Lipids Online Slide Library www.lipidsonline.org Statins: Muscle Issues (Continued) Fibrates, especially gemfibrozil Niacin Cyclosporine Erythromycin Clarithromycin Itraconazole Ketoconazole Protease inhibitors Verapamil Amiodarone Nefazodone Pasternak RC, et al. J Am Coll Cardiol. 2002;40:567–572. The risk of myopathy increases with certain medications:

23. Slide Source: Lipids Online Slide Library www.lipidsonline.org Teach patients to report muscle symptoms When muscle symptoms or elevations in creatine kinase occur, the clinician should rule out common causes: – Exercise, trauma, falls, accidents, seizures, shaking chills, hypothyroidism, infections, carbon monoxide poisoning, polymyositis, dermatomyositis, alcohol abuse, illicit drug abuse (cocaine, amphetamines, heroin, PCP) – A patient will be at increased risk when starting vigorous, sustained endurance-exercise or when undergoing surgery Statins: Muscle Issues (Continued) Reprinted from McKenney JM, et al. Am J Cardiol. 2006; 97:89C–94C, with permission from Elsevier. PCP = phencyclidine hydrochloride

24. Slide Source: Lipids Online Slide Library www.lipidsonline.org When there are tolerable muscle symptoms or creatine kinase is elevated (<10  the upper limits of normal) in the absence of such symptoms: – Continue statin therapy at the same or a reduced dose – Use the patient’s symptoms to guide statin therapy When there are intolerable muscle symptoms that cannot be attributed to other causes and may or may not be accompanied by an elevation in creatine kinase: – Discontinue statin therapy – Restart the (same or different) statin at the same or a reduced dose when a patient is asymptomatic – Try other lipid-lowering medications when muscle symptoms recur after treatment with various statins Statins: Muscle Issues (Continued) Reprinted from McKenney JM, et al. Am J Cardiol. 2006; 97:89C–94C, with permission from Elsevier.

25. Slide Source: Lipids Online Slide Library www.lipidsonline.org When rhabdomyolysis occurs: Stop statin therapy Provide intravenous hydration After recovery, weigh the risks and benefits of restarting statin therapy Statins: Muscle Issues (Continued) Reprinted from McKenney JM, et al. Am J Cardiol. 2006; 97:89C–94C, with permission from Elsevier.

26. Slide Source: Lipids Online Slide Library www.lipidsonline.org Assess renal function before initiating statin therapy Statin therapy may be used in patients with chronic kidney disease (some statins may need dose adjustments) No need to routinely monitor serum creatinine or proteinuria Statins: Kidney Issues Reprinted from McKenney JM, et al. Am J Cardiol 2006; 97:89C–94C, with permission from Elsevier.

27. Slide Source: Lipids Online Slide Library www.lipidsonline.org Routine neurologic monitoring is not needed With symptoms consistent with peripheral neuropathy, the clinician should rule out common causes: – Diabetes– Cancer – Renal insufficiency– Hypothyroidism – Alcohol abuse– AIDS – Vitamin B12 deficiency– Lyme disease – Heavy metal intoxication Statins: Neurology Issues AIDS = acquired immunodeficiency syndrome Reprinted from McKenney JM, et al. Am J Cardiol. 2006; 97:89C–94C, with permission from Elsevier.

28. Slide Source: Lipids Online Slide Library www.lipidsonline.org Statins: Neurology Issues (Continued)   With symptom improvement Without symptom improvement  Consider diagnosis of statin-induced neuropathy Rule out statin-induced neuropathy  Consider using a different statin Restart statin therapy, weighing risks and benefits If no other cause is found for peripheral neuropathy symptoms, stop statin use for 3 to 6 months  Reprinted from McKenney JM, et al. Am J Cardiol. 2006; 97:89C–94C, with permission from Elsevier.

29. Slide Source: Lipids Online Slide Library www.lipidsonline.org Rule out common causes Stop statin therapy for 1 to 3 months if no other cause of the impairment is found Restart statin therapy if there is no symptom improvement, weighing the risks and benefits Statins: Neurology Issues (Continued) Reprinted from McKenney JM, et al. Am J Cardiol. 2006; 97:89C–94C, with permission from Elsevier. When a patient has impaired cognition, the clinician should:

30. Slide Source: Lipids Online Slide Library www.lipidsonline.org Summary Treat according to the patient’s global risk, not only cholesterol value Statins are safe and effective Achieve at least a 30% to 40% reduction in low-density lipoprotein cholesterol (LDL-C) with initial statin therapy May need to use higher initial doses of statins or combination therapy in some patients to reach LDL-C goals Use established guidelines to monitor for and manage potential adverse drug reactions