Improving Outcomes in Challenging Patient Populations Achieving Optimal

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Improving Outcomes in Challenging Patient Populations: Achieving Optimal Lipids While Maximizing Tolerability and Safety

Improving Outcomes in Challenging Patient Populations: Achieving Optimal Lipids While Maximizing Tolerability and Safety Eliot Brinton, MD, FAHA, FNLA Diplomate, American Board of Clinical Lipidology Director, Metabolism Section Cardiovascular Genetics Associate Professor (Adjunct) University of Utah School of Medicine Salt Lake City eliot. brinton@utah. edu

Why are Statins First-Line Rx for Most Dyslipidemias? • Most effective for our primary

Why are Statins First-Line Rx for Most Dyslipidemias? • Most effective for our primary lipid goals: ↓LDL-C & ↓Non-HDL-C • Best proven for CVD benefits • Generally safe and well tolerated • Cost-effective (esp. generics) • Excellent formulary/insurance coverage

US Statin Availability: 2001 -Present • Six statins available in US as of Jan

US Statin Availability: 2001 -Present • Six statins available in US as of Jan 2001 • Cerivastatin withdrawn mid-2011 due to myotoxicity • Rosuvastatin approved by FDA etc. 2003 • Pitavastatin – 2003 1 st approved/available in Asia – 2009 FDA approval – 2010 1 st available in US

Statin-Based LDL-C Lowering (n=473) Rosuvastatin (n=634) Atorvastatin (n=648) Simvastatin (n=485) Pravastatin (mg/day) LDL-C (±SE)

Statin-Based LDL-C Lowering (n=473) Rosuvastatin (n=634) Atorvastatin (n=648) Simvastatin (n=485) Pravastatin (mg/day) LDL-C (±SE) reduction (%) 10 * 20 † 40 10 20 40 80 10 20 40 ‡ Mean baseline LDL-C: 187 mg/d. L to 194 mg/d. L *P<0. 001 rosuvastatin vs atorvastatin 10 mg; simvastatin 10 mg, 20 mg, 40 mg; pravastatin 10 mg, 20 mg, 40 mg. †P<0. 002 rosuvastatin vs atorvastatin 20 mg, 40 mg; simvastatin 20 mg, 40 mg, 80 mg; pravastatin 20 mg, 40 mg. ‡P<0. 001 rosuvastatin vs atorvastatin 40 mg; simvastatin 40 mg, 80 mg; pravastatin 40 mg. 1. Jones PH, et al. Am J Cardiol. 2003; 92: 152 -160 , STELLAR trial.

Approximate Dose-Equivalency of Statin LDL-C Efficacy -----------dose of agent (mg/d)----------Rosuv Atorva Simva Pitava Lova

Approximate Dose-Equivalency of Statin LDL-C Efficacy -----------dose of agent (mg/d)----------Rosuv Atorva Simva Pitava Lova Prava Fluva Approx a* * ↓LDL-C 10 1 20 40** 80 5 10** 2** 40** 10** 20 40 4 80 *Atorva be more effective (½ and 1 doubling 20 and rosuva 40 may(80) **Most commonly used dose in US. Adapted from: Roberts WC. Am J Cardiol. 1997; 80: 106 -107. Stein E et al. J Cardiovasc Pharmacol Therapeut. 1997; 2: 7 -16. Rosuvastatin PI, Pitavastatin PI. 40 80 40 2834% 80** 3542% 3947% respectively). 4652% 51 -

Mean % change from baseline HDL-C Statin-Based HDL-C Raising Mean baseline HDL-C: 49 mg/d.

Mean % change from baseline HDL-C Statin-Based HDL-C Raising Mean baseline HDL-C: 49 mg/d. L to 51 mg/d. L † ‡ * (mg/day) Rosuvastatin (n=473) Atorvastatin (n=634) Simvastatin (n=648) Pravastatin (n=485) * P<0. 002 rosuvastatin 10 mg vs pravastatin 10 mg. †P<0. 002 rosuvastatin 20 mg vs atorvastatin 20 mg, 40 mg, 80 mg; simvastatin 40 mg; pravastatin 20 mg, 40 mg. ‡P<0. 002 rosuvastatin 40 mg vs atorvastatin 40 mg, 80 mg; simvastatin 40 mg; pravastatin 40 mg. 1. Jones PH, et al. Am J Cardiol. 2003; 92: 152 -160, STELLAR trial.

HDL-C Increase Pitavastatin vs. Atorvastatin and Simvastatin Mean % Change in HDL-C (mg/d. L)

HDL-C Increase Pitavastatin vs. Atorvastatin and Simvastatin Mean % Change in HDL-C (mg/d. L) Patients With Primary Hyperlipidemia/Mixed Dyslipidemia: 12 -week Trials Pitava 2 mg Atorva 10 mg Pitava 4 mg Atorva 20 mg Pitava 2 mg Simva 20 mg Pitava 4 mg Simva 40 mg (n=315) (n=102) (n=298) (n=102) (n=307) (n=107) (n=319) (n=110) Note: HDL-raising by statins not proven beneficial Budinski D et al: Clin Lipidol; 4 (3); 2009: 1 -12 Ose L, et al: Curr Med Res Opin 25 (11), 2009, 2755– 2764 Pitavastatin [package insert]. Kowa Pharmaceuticals America, Inc; 2009.

Challenges with Statin Safety: ↑↑DDI Risk with Polypharmacy • DDI risk ↑exponentially w/ ↑#

Challenges with Statin Safety: ↑↑DDI Risk with Polypharmacy • DDI risk ↑exponentially w/ ↑# meds • Highest-risk pts are most in need of statins, but: – Prior CVD event (usu associated w/ polypharmacy) – High-risk co-morbidities (all assoc. w/ polypharm) • Diabetes Mellitus • Hypertension • Older patients • Among older/complicated patients: * – ~1/4 take > 5 daily medications – ~12% take > 10 daily meds • DDI a factor in ~60% of statin-rhabdomyolysis** DDI=drug-drug interaction • Masoodi NA. BJMP 2008; 1: 6 -9. • ** Bottorff MB. Prevent. Med. in Managed Care 2004; 4: S 30 -S 37.

Metabolic Pathways of Statins Pathway Inhibitors Hepatic Uptake & Excretion Intestinal Uptake & Excretion

Metabolic Pathways of Statins Pathway Inhibitors Hepatic Uptake & Excretion Intestinal Uptake & Excretion CYP=Cytochrome P 450 system, OATP= Organic anion transporting polypeptide, MDR= multidrug resistance protein, MRP=multidrug resistance-related protein. Neuvonen, PJ, et al. Clin. Pharm. & Ther 2006; 80 : 565 -81

Statin Metabolism: Many Similarities, Some Key Differences Factor Pitava Rosuv Atorv Simv a a

Statin Metabolism: Many Similarities, Some Key Differences Factor Pitava Rosuv Atorv Simv a a a Lov Prava Fluv a a Absorp (%) 80 50 30 60 -85 30 35 98 Bioav (%) 60 20 12 <5 5 18 30 T ½ (h) 10 -13 20 7 -20 2 -5 1 -3 CYP +/- 3 A 4 - 2 C 9 OATP 1 B 1 + + + + “+/-” = minimal metabolism by by pathway MDR 1 + - pathway. “-” + = no metabolism + + + ? Adapted from : Neuvonen, PJ et al, Clin. Pharm & Ther. 2006; 80: 565 -81

CYP Inhibitors ↑Levels & ↑DDI Risk ISOENZYME INHIBITORS CYP 3 A 4 Antibiotic agents:

CYP Inhibitors ↑Levels & ↑DDI Risk ISOENZYME INHIBITORS CYP 3 A 4 Antibiotic agents: ciprofloxacin, clarithromycin, erythromycin, norfloxacin Antidepressant agents: fluvoxamine, nefazodone Antidysrhythmic agent: amiodarone Antifungal agents: fluconazole, itraconazole, ketoconazole Calcium-channel blockers: diltiazem, verapamil Food product: grapefruit juice H 2 receptor blocker: cimetidine HIV protease inhibitors: indinavir, nelfinivir, ritonavir, saquinavir CYP 2 D 6 Antidepressant agents: fluoxetine, paroxetine, sertraline Antidysrhythmic agents: amiodarone, quinidine H 1 receptor blockers: chlorpheniramine, hydroxyzine, promethazine H 2 receptor blockers: cimetidine, ranitidine NSAID: celecoxib Recreational drug: cocaine CYP 2 C 9 Antibiotic agents: isoniazid, metronidazole, sulfamethoxazole, trimethoprim Antidepressant agents: fluvoxamine, paroxetine, sertraline Antidysrhythmic agent: amiodarone Antifungal agents: fluconazole, miconazole CYP 2 C 19 Anticonvulsant agent: felbamate Antidepressant agents: fluoxetine, fluvoxamine, paroxetine Antifungal agent: ketoconazole Antiplatelet agent: ticlopidine Proton pump inhibitors: lansoprazole, omeprazole

Challenges with Statin Safety: Patients at Metabolic Risk • Age-related: impaired hepatic and/or renal

Challenges with Statin Safety: Patients at Metabolic Risk • Age-related: impaired hepatic and/or renal drug metabolism common in elderly • Ethnic-related impairment of CYP 2 D 6 metabolism* – Chinese/Japanese: 40 -70% low funct, ~6% none – Caucasian: 12 -23% low function – African: 15 -34% low function • OATP 1 B 1 statin transport system** – – Coded by SLCO 1 B 1 gene Hypofunctional variants common Up to 17 x ↑ risk statin myopathy Major cause of high-dose simvastatin toxicity * Zhou SF. Clin Pharmacokinet. 2009; 48: 689 -723. **SEARCH Collab. Grp. NEJM, 2008; 359; 789 -99.

Statin Safety Update: Focus on Simvastatin and Pitavastatin

Statin Safety Update: Focus on Simvastatin and Pitavastatin

Simvastatin Label Change 6/8/11: New Restrictions on 80 mg/d Dose Already Patient Situation on

Simvastatin Label Change 6/8/11: New Restrictions on 80 mg/d Dose Already Patient Situation on Simva: Recommended Change 5 -20 mg/d Needs more LDL-C↓ ↑ Simva (40 mg/d max) or Switch to stronger statin 40 mg/d Switch to stronger statin ↓ Simva dose or Switch to other statin None 80 mg/d Needs more LDL-C↓ < 1 year Rx or w/ muscle Sx > 1 year Rx and no muscle Sx Merck Healthcare Provider letter June 8, 2011 http: //www. simvastatininfocenter. com/documents/hcpletter. pdf

Simvastatin Label Change 6/8/11: New Interacting-Drug Contraindications Interacting Drug Label Class Agent Itraconazole Ketoconazole

Simvastatin Label Change 6/8/11: New Interacting-Drug Contraindications Interacting Drug Label Class Agent Itraconazole Ketoconazole Azole antifungals Posaconazole HIV protease inhibitors (all) Erythromycin Clarithromycin Macrolide antibiotics Telithromycin Antidepressant Nefazodone Fibrate Gemfibrozil Transplant Cyclosporine Androgen Danazol Old Avoid “ “ “ “ 10 mg max “ “ Merck Healthcare Provider letter June 8, 2011 http: //www. simvastatininfocenter. com/documents/hcpletter. pdf New Contraindicated “ “ “ “ “

Simvastatin Label Change 6/8/11: New Maximum Doses by Interacting Drugs Interacting Drug Class Anti-arrhythmic

Simvastatin Label Change 6/8/11: New Maximum Doses by Interacting Drugs Interacting Drug Class Anti-arrhythmic Agent Amiodarone Verapamil Antihypertensive Diltiazem Amlodipine Anti-anginal Ranolazine Label Old 20 mg max “ 40 mg max 80 mg max “ Merck Healthcare Provider letter June 8, 2011 http: //www. simvastatininfocenter. com/documents/hcpletter. pdf New 10 mg max “ “ 20 mg max “

Simvastatin Label Change 6/8/11: New Dose Restrictions Current Interacting drug? Recommended Change Simva dose

Simvastatin Label Change 6/8/11: New Dose Restrictions Current Interacting drug? Recommended Change Simva dose No None 5 -40 mg/d Yes* Decrease/stop simva if needed* No None (if >1 year w/o myopathy) 80 mg/d Yes* Stop interacting drug or Reduce simva or Switch to other statin *See new maximum doses w/ each interacting drug Merck Healthcare Provider letter June 8, 2011 http: //www. simvastatininfocenter. com/documents/hcpletter. pdf

Effect of Co-Administered Drugs on Pitavastatin Systemic Exposure : Co-administered drug Change in AUC*

Effect of Co-Administered Drugs on Pitavastatin Systemic Exposure : Co-administered drug Change in AUC* Change in Cmax* Pitavastatin Dose Recommendation Cyclosporine 4. 6 fold¶ 6. 6 fold¶ Contraindicated Erythromycin 2. 8 fold¶ 3. 6 fold¶ Limit pitava dose to 1 mg/d Rifampin 29% 2. 0 fold Limit pitava dose to 2 mg/d Atazanavir 31% 60% No dosage adjustment Lopinavir ND ND Not studied, should not be used Ritonavir ND ND Not studied, should not be used *Data as fold change = the ratio between co-administration and pitavastatin alone (i. e. , 1 -fold = no change). Data as % change = % difference relative to pitavastatin alone (i. e. , 0% = no change). ¶ Considered clinically significant [see Dosage and Administration (2) and Drug Interactions (1)] Pitavastatin PI [package insert]. Kowa Pharmaceuticals America, Inc; 2009

Effect of Co-Administered Drugs on Pitavastatin Systemic Exposure, Minimal Effects From: Co-administered drug Change

Effect of Co-Administered Drugs on Pitavastatin Systemic Exposure, Minimal Effects From: Co-administered drug Change in AUC* Change in Cmax* Pitavastatin Dose Recommendation Enalapril 6% 7% No dosage adjustment Digoxin 4% 9% No dosage adjustment Grapefruit juice 15% 12% No dosage adjustment Itraconazole 23% 22% No dosage adjustment Gemfibrozil 45% 31% No dosage adjustment** Fenofibrate 18% 11% No dosage adjustment** Ezetimibe 2% 0. 2% No dosage adjustment *Data as fold change = the ratio between co-administration and pitavastatin alone (i. e. , 1 -fold = no change). Data as % change = % difference relative to pitavastatin alone (i. e. , 0% = no change). ¶ Considered clinically significant [see Dosage and Administration (2) and Drug Interactions (1)] **Use with fibrate products may increase risk of adverse skeletal muscle effects Pitavastatin PI [package insert]. Kowa Pharmaceuticals America, Inc; 2009

Adverse Reactions In ≥ 2% of Pitavastatin Patients and Greater than Placebo: Suggestion of

Adverse Reactions In ≥ 2% of Pitavastatin Patients and Greater than Placebo: Suggestion of myalgia dose-response Adverse Reactions* Placebo N=208 Pitava 1 mg N=309 Pitava 2 mg N=951 Pitava 4 mg N=1540 Back Pain 2. 9% 3. 9% 1. 8% 1. 4% Constipation 1. 9% 3. 6% 1. 5% 2. 2% Diarrhea 1. 9% 2. 6% 1. 5% 1. 9% Myalgia 1. 4% 1. 9% 2. 8% 3. 1% Pain in Extremity 1. 9% 2. 3% 0. 6% 0. 9% NA 3. 9% 3. 3% 3. 7% D/C for AR** *Adverse reactions (AR) by Med. DRA preferred term. **D/C = discontinued. Data from short-term controlled trials. Pitavastatin PI [package insert]. Kowa Pharmaceuticals America, Inc; 2009

Pitavastatin Safety/Tolerability in Complicated Patients Adverse Event Mixed 1 Highrisk 2 DM-22 Subjects 1,

Pitavastatin Safety/Tolerability in Complicated Patients Adverse Event Mixed 1 Highrisk 2 DM-22 Subjects 1, 353 121 143 539 95 19, 925 Serious AE* 3. 6% 3. 3% 5. 6% 9. 5% 7. 4% 0. 13% TRAE* 12. 0% 10. 7% 3. 5% 13. 5% 4. 2% 12% AE→D/C* 4. 1% 5. 8% 2. 1% 5. 6% 7. 4% Elderly LIVES (2 mg) 2 (4 mg) 2 (1, 2, & 4 mg) 3 All doses 4 mg/d except subgroup of elderly and LIVES (as noted). *AE= adverse event. Serious AE= AE requiring physician intervention. TRAE= treatment –related adverse event. AE-D/C= discontinuation due to adverse event. 1. Ose L, et al. Atherosclerosis 2010. 210: 202– 208. 2. Data on file. Kowa Pharmaceuticals America, Inc. 3. Kurihara Y et al. Jpn Pharmacol Ther 2008; 36: 709 -731.

Statin Safety and Tolerability • Common safety concerns – – Myopathy, rhabdomyolysis Hepatotoxicity New-onset

Statin Safety and Tolerability • Common safety concerns – – Myopathy, rhabdomyolysis Hepatotoxicity New-onset diabetes (not all statins? ) Other (arthritis/tendonitis, insomnia, ↓cognition, etc. ) • Unique problems – Hematuria, etc. w/ rosuva? – Other? • Problems generally highest with simvastatin, lovastatin and atorvastatin • Intermediate with rosuva and pitava? • Lowest with fluva and prava? Kurihara, Y, et al. Jpn Pharmac Ther, 2007; 35: 9 -40. Komano, N, et al. Prog Med, 2005; 25: 131 -142.

Metabolic Pathways of Statins Less Prone to DDI • Fluvastatin: mainly CYP 2 C

Metabolic Pathways of Statins Less Prone to DDI • Fluvastatin: mainly CYP 2 C 9 (less common CYP) +/- via 3 A 4 & 2 D 6 • Rosuvastatin little CYP, +/- via 2 C 9 & 2 C 19 • Pitavastatin little CYP, +/- via 2 C 8 & 2 C 9 • Pravastatin avoids CYP 450 system altogether These four statins are recommended most often for DDI issues, see Pharmacist’s Ltr/Prescriber’s Ltr. Aug 2009; 250812. All statins have potential DDI via glucuronidation (fluvastatin less commonly).

Statin Use in Complex Patients: Program Summary/Conclusions 1 • As of 2011, we have

Statin Use in Complex Patients: Program Summary/Conclusions 1 • As of 2011, we have many excellent statin choices: – Very high-efficacy (high-dose rosuva & atorva + fixed-dose combos) – High safety/tolerability* (prava & fluva) – Mixed safety/efficacy* (low-dose rosuva, high-dose pitava) – Variety of inexpensive generics (atorva newly generic end-2011) *Especially useful in complicated and challenging patients

Statin Use in Complex Patients: Program Summary/Conclusions 2 Unmet needs, however, remain: • How

Statin Use in Complex Patients: Program Summary/Conclusions 2 Unmet needs, however, remain: • How to optimally treat complex patients? – – – 2 o prevention Diabetes Mellitus-2 and other CHD-Risk Equiv. Low-HDL-C (AIM-HIGH? ? ) Other mixed dyslipidemia/insulin resistance Elderly patients (1/2 dose, other? ) • How to predict/prevent statin intoler. /AEs? • How to predict statin responsiveness? – Lipid benefits – ↓CVD