Safety and Tolerability of Maximizing Oral Hypocholesterolemic Agents in Treating Severe FH Zuhier Awan, MD, PhD, FAACC, FRCPC, FAHA, FACE Consultant and Associate Professor of Medicine, Clinical Biochemistry and Molecular Genetic. Conflict of Interest Advisory Board, Speaker’s Bureau Pfizer Amgen Amryt (Aegerion) Outline Presentation 1. Tolerability of Lipid Lowering Drugs 2. Safety and Tolerability of Statin 3. Safety of Maximizing and Combining 18 Y student No medical illness Hx of premature CAD BMI 18 LDL 8 mmol/L Oral Lipid Lowering Drugs Patient Therapy TC LDL-C HDL-C TG Tolerability Statins* 19 – 37% 25 – 60% 4 – 12% 14 – 29% Good Ezetimibe 13% 18% 1% 9% Good Bile acid 7 – 10% 10 – 18% 3% Neutral or Poor sequestrants Nicotinic acid 10 – 20% 10 – 20% 14 – 35% 30 – 70% Reasonable to poor Fibrates 19% 4 – 8% 11 – 13% 30% Good *Daily dose of 40 mg of each drug, excluding rosuvastatin Yeshurun D et al. South Med J 1995;88:379–391. | NCEP. Circulation 1994;89:1333–1445. | Knopp RH. N Engl J Med 1999;341:498–511. | Gupta EK et al. Heart Dis 2002;4:399–409. Mechanism of Action LDL Fibrate apoB100 Liver X Statin X VLDL apoB100 Ezetimibe X Bile acid sequestrants X CM Remnant CM apoB48 apoB48 Oral Lipid Lowering Drugs Drug Class Agents Side Effects Drug Interaction HMG CoA Rosuvastatin (2C9) and Myopathy, Atorvastatin and Protease Inhibitor reductase Atorvastatin (3A4) increased liver Rosuvastatin and Colchicine inhibitors LDL (18-60) enzymes Simvastatin and Ketoconazole (Statins) Pitavastatin and Pravastatin LDL (30-50) Inhibitor of Ezetimibe Headache, GI Bile acid sequestrants (4 hours NPC1L1 LDL( 14-18) distress spacing) and Fibric acids (Ezetimibe) PPAR alpha Gemfibrozil Dyspepsia, Gemfibrozil and Atorvastatin agonist, Fenofibrate gallstones, hydrolyzes TG TG (20-50) myopathy in lipoproteins (Fibrates) Doses of Currently Available Statins Required for a 30% to 50% LDL-C Reduction Lipophilic (CYP 3A4) O HO O • 20–40 mg simvastatin (Zocor) 35–41% O HO O OH • 40 mg lovastatin (Mevacor) 31% OH • 10 mg atorvastatin (Lipitor) 39% CH F 3 CH3 Lipophilic (CYP 2C9) N F CH 3 CH3 • 40–80 mg fluvastatin (Lescol) 25–35% O N N HN N H3C S CH3 Hydrophilic O O • 5–10 mg rosuvastatin (Crestor) 39–45% • 40 mg pravastatin (Pravachol) 34% Grundy SM, et al. Circulation. 2004;110:227–239. Intensity of Statin Therapy High Moderate Low LDL-C ≥50% LDL-C 30 to <50% LDL-C <30% Atorva 40-80 mg Atorva 10 mg Simva 10 mg Rosuva 20-40 mg Rosuva 10 mg Prava 10-20 mg Simva 20-40 mg Lova 20 mg Pravas 40 mg Fluva 20-40 mg Lova 40 mg Pitava 1 mg Fluva XL 80 mg Fluva 40 mg bid Pitava 2-4 mg Statins in bold were evaluated in randomized controlled trials; those in italics were not 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults, p 34 Atorvastatin vs. Rosuvastatin Rosuvastatin Dosing Considerations 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. Statin Drug Interactions: Labeled Contraindications for Lovastatin and Simvastatin Lovastatin and simvastatin are contraindicated with: • Erythromycin • Cyclosporine • Clarithromycin • HIV protease • Fluconazole (2C9) inhibitors • Ketoconazole • Warfarin • Amidiodarone • Grapefruit juice HIV = human immunodeficiency virus Mevacor® [package insert]; 2008. | Zocor® [package insert]; 2008. FDA Warning (March 2010 + May 2011) • No Simvastatin with itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, or nefazodone. • No simvastatin >10 mg with gemfibrozil, cyclosporine, or danazol • No simvastatin >20 mg with amiodarone or verapamil • No simvastatin >40 mg with diltiazem • Patients of Chinese descent should not receive simvastatin 80 mg with cholesterol-modifying doses of niacin-containing products. • caution when such patients are treated with simvastatin 40 mg or less in combination with cholesterol-modifying doses of niacin-containing products 18 Y student No medical illness Hx of premature CAD BMI 18 LDL 8 mmol/L Outline Presentation 1. Tolerability of Lipid Lowering Drugs 2. Safety and Tolerability of Statin 3. Safety of Maximizing and Combining Question: How safe are statins? Statin Associated Muscle Symptoms SAMS MYALGIA Pain MYOPATHY Weakness MYOSITIS CK >10X ULN RHABDOMYOLYSIS CK >40X ULN Statin Safety in Perspective Number Needed to Treat: for 1 year to Cause a GI Bleed1 Cause a Fatal GI Bleed1 Aspirin 248 2066 Cause Severe Myositis2 Cause Fatal Myositis2 Statins 100 , 000 1,000,000 1Derry S, Loke YK. 2000 2Thompson PD, et al. 2003 Fatal Rhabodmyolysis Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med 2002; 346: 539-40 In Summary…The Risk is Small! 73 cases of fatal rhabdomyolysis in 484,273,000 Statin prescriptions In 2014: 15 – 20 million statin users only 3 deaths Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med 2002; 346: 539-40 US population: ± 300 million Peanut allergy 1.4% of population: 4.2 million affected 150 fatalities/year Question: Will patients tolerate statins? Muscle Related Side Effects Statins Intolerance No serial measurement of CK Journal of Clinical Lipidology (2014) 8, STOMP Study 420 healthy statin naïve subjects Atorvastatin 80 mg vs. Placebo 6 months Criculation 2013; 127: 96 - 103 The Effect of Statins on Skeletal Muscle Function and Performance (STOMP) study Atorvastatin 80 mg vs. placebo 6 MONTHS n=420 • Exercise capacity No significant changes • Muscle strength No significant changes • Myalgia 19 vs 10 (p=0.05) • CK ≥10 x ULN none Myalgic subjects on atorvastatin or placebo had decreased muscle strength in 5 of 14 and 4 of 14 variables, respectively (P=0.69). Circulation. 2013;127:96-103 The Effect of Statins on Skeletal Muscle Function and Performance (STOMP) study Circulation. 2013;127:96-103 Ann Intern Med. 2013;158:526-534. Discontinuation of Statins in Routine Care Statin use 2000 - 2008 Brigham's And Women's hospital Boston 120000 %120 107835 100000 %100 80000 %80 60000 57292 %60 40000 %40 18778 20000 %20 0 %0 patients discontinued documented events Ann Intern Med. 2013;158:526-534. Discontinuation of Statins in Routine Care Statin use 2000 - 2008 Brigham's And Women's hospital Boston 3000 2721 %120 Re-challenge in 6 579 patients 2500 93% were on statin after 12 months %100 2000 %80 1500 1295 %60 996 1000 %40 500 %20 0 %0 same statin same dosage higher dosage Ann Intern Med. 2013;158:526-534. Lesson Learned Statin Myalgia Clinical Index Score Region Time De-challenge Statin Myalgia Clinical Index Score Probable 9-11 Possible 7-8 Re-challenge Unlikely <7 Risk Factors for Statin-Associated Muscle Symptoms • Anthropometric • Concurrent conditions/medications • Surgery • Related history • Genetics (muscular dystrophy) • Other risk factors Evaluate Drug Interactions symptoms Follow-Up http://www.acc.org/StatinIntoleranceApp Hepatic Safety of Statins United Network for Organ Sharing (UNOS) Database • From 1990 – 2002 in the US: 51 741 liver transplants • 3 cases of acute liver failure related to statins* • 2 Cerivastatin • 1 Simvastatin • These studies were retrospective analyses. • Formal causality assessment of DILI and confirmation that cases were bona-fide cases of DILI from statins were not performed! * Russo MW, Galanko JA, Shrestha R, et al. Liver transplantation from drug induced liver injury in the United States. Liver Transpl 2004; 10:1018– 1023. Lancet 2010; 367: 1916-1922 Enzyme Activity During 3-year Follow-up in Patients with Raised Liver Enzymes Patients on statin treatment (n=227) Patients not statin treatment (n=210) Athyros, V. et al., Lancet 2010;376:1916-22. Cardiovascular Events in Patients with Normal and Abnormal LFT’s 12 63 (30%) of 210 117 (23%) of 510 patients patients 10 68% RRR 10% 23% RRR 8 P<0.0001 p<0001 patient patient years 7,6% 6 22 (10%) of 227 90 (14%) of 653 Statin patients patients 100 Control 4 4,6% 2 3,2% 0 Event rate Event / Abn LFT Norm LFT Athyros, V. et al., Lancet 2010;376:1916-22. Cardiovascular Events in Patients with Normal and Abnormal LFT’s 12 63 (30%) of 210 117 (23%) of 510 patients patients 10 68% RRR 10% 23% RRR 8 P<0.0001 p<0001 patient patient years 7,6% 6 22 (10%) of 227 90 (14%) of 653 Statin patients patients 100 Control 4 4,6% 2 3,2% 0 Event rate Event / Abn LFT Norm LFT Athyros, V. et al., Lancet 2010;376:1916-22. NAFLD at Baseline and Follow up Risk reduction of moderate to severe hepatic steatosis: 70% ! 36 44 27 35 27 32 Am J Gastroenterol advance online publication, Summary of studies using statin therapy for NAFLD F, fibrosis; CT, computed tomography; IN, inflammation; N / A, not applicable; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steato hepatitis; RCT, randomized control trial; S, steatosis; US, ultrasound. Am J Gastroenterol advance online publication, Use of Atorvastatin or Pravastatin in Patients with NASH 5 patients with NASH 20 mg Prava for 6 months1 Normalization of liver enzymes in all patients Some improvement in hepatic inflammation and steatosis (liver biopsies) 7 patients with NASH 20 mg Atorvastatin 21 months (± 2 months)2 Well tolerated No increase in liver enzymes Significant improvement of hepatic histology in some patients 1. Rallidis LS, Drakoulis CK, Parasi AS. Pravastatin in patients with nonalcoholic steatohepatitis: results of a pilot study. Atherosclerosis 2004;174: 193-196. 2. Horlander JC, Kwo PY, Cummings OW. Atorvastatin for the treatment of NASH.