Management of Lipids Beyond Statin Therapy

9/23/2015

Management of Lipids Disclosures/Conflict of Interest

Beyond Statin Therapy • Neither speaker has a conflict of interest in relation to this presentation

Jessica L. Kerr, PharmD, CDE Associate Professor SIUE School of Pharmacy Jared Sheley, PharmD, BCPS Clinical Assistant Professor SIUE School of Pharmacy

Pre‐test Question #1 Objectives

Which of the following is the cause for elevated cholesterol • Describe the pathophysiology of lipid disorders and the populations at risk for levels in patients with familial hypercholesterolemia? cardiovascular disease

• Compare and contrast currently available lipid management guidelines A. Being raised with poor dietary choices that cause increased consumption • Discuss the efficacy and safety for FDA approved non‐statin therapy and their of high cholesterol foods as an adult role in current medical management for lipid disorders B. Increased biosynthesis of cholesterol • Evaluate and apply evidence based literature for novel drug classes new to C. Decreased metabolism of LDL lipid management D. Decreased production of HDL

Pre‐test Question #2 Meet Lydia Pre‐test Case #1 Which of the following medications has long term efficacy • 62 yo female s/p MI and T2DM, HTN and hyperlipidemia/‐triglyceridemia. data showing reduction in cardiovascular events? • Meds: ASA 81mg daily, Atorvastatin 10mg daily, Lisinopril 40mg daily, Metformin 1000mg twice daily, Metoprolol Succinate 100mg daily (choose all that apply) • Labs: Chem 7 –wnl; LFT –wnl; A1c 7.5% Today : TC: 215, TG: 1,401, HDL:42, dLDL: 86 (mg/dl) A. Ezetimibe –Results of Atorvastatin 10mg daily being added T‐3 mo: TC: 215, TG: 1,589, HDL: 40, dLDL: 126 (mg/dl) B. Fenofibrate Question Options C. Niacin What is Lydia’s indication for statin usage? A. MI Lomitapide B. Type 2 Diabetes D. C. Her age only E. Mipomersen D. Both A and B According to ACC/AHA and AACE lipid guidelines A. Hemoglobin A1c F. Alirocumab what other lipid parameter may warrant drug B. HDL cholesterol therapy? C. Triglycerides D. Total Cholesterol

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Meet Bob Pre‐test Case #2 • 34 yo male with Heterozygous Familial Hypercholesterolemia, s/p STEMI 6 months ago. He comes today for repeat lab tests. • Meds: ASA 81mg daily,Clopidogel 75 mg daily, Metoprolol Tartrate 100mg BID, Lisinopril 20 mg PO daily, Atorvastatin 80mg daily, Ezetimibe 10mg daily, APAP prn migraine headaches

• Labs: Chem 7 –wnl; LFT –wnl; Today : TC: 231, TG: 132, HDL: 40, LDL: 165 (mg/dl) BACKGROUND ‐ T‐3 mo : TC: 251, TG: 128, HDL:37, LDL: 189 (mg/dl) –Results of starting atorvastatin to 80mg daily; added ezetimibe 10 mg at this time T‐6 mo : TC: 362, TG: 198, HDL: 31, LDL: 291 (mg/dl) ‐ Started on Atorvastatin 80mg based on these results

Question Options Which drug therapy had data to support Bob’s current A. Niacin lipid situation (ie has been shown to improve LDL B. Gemfibrozil cholesterol levels in Familiar Hypercholesterolemia)? C. Fish oil D. Alirocumab

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Cardiovascular Disease (CVD) in the United States Populations at Risk for Cardiovascular Disease (CVD)

• 1 in 3 deaths (~787,000/year) • Pre‐existing CVD • Age (male >45, female >55) • Cholesterol • CAD = 1 in 6 deaths (~386,000/year) • Total, LDL, non‐HDL • HDL • Hypertension • Total costs > $300 billion / year • Diabetes • Tobacco use • Family History of premature CVD (Male <55, Female <65) • Race • Elevated hs‐CRP (>2 mg/L) • CAC score (>300 Agatston units) • ABI (<0.9)

Goff DC, et al.;American College of Cardiology / American Heart Association Task Force on Practice Guidelines. Go AS, et al. Circulation. 2013 Jan 1;127(1). Circulation. 2014 Jun 24;129(25 Suppl 2):S49‐73.

Cholesterol • Functions • Cell membrane formation • Hormone synthesis • Bile salt production PATHOPHYSIOLOGY • Source of free fatty acids Class of Primary Source Primary Composition Apoproteins Lipoprotein Chylomicrons Diet Triglycerides B-48, E, A-I, A-IV, C-I, C-II, C-III VLDL Liver Triglycerides and B-100, E, C-I, C-II, C- phospholipids III LDL VLDL catabolism Cholesterol esters, B-100 phospholipids, proteins HDL Diet & Liver Proteins, phospholipids, A-I, A-II, E, C-I, C-II, cholesterol esters C-III

Marais AD. Clin Biochem Rev. 2004 Feb;25(1):49‐68. Castelli WP. Am J Cardiol. 1998 Nov 26;82(10B):60T‐65T.

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Cholesterol Pathophysiology Pathophysiology of Familial Hypercholesterolemia • Defect in LDL removal by liver • LDL receptor (LDLR) • Binds cholesterol and internalizes LDL/LDLR complex • 85% of cases

• Apolipoprotein B (ApoB) • Only receptor on LDL • Serves as ligand for LDL and LDLR • 5‐10% of cases

• Proprotein convertase subtilisin/kinexin type 9 (PCSK9) • Degradation of LDLR • Gain of function  increased LDLR degradation  fewer LDLR • <5% of cases

Kim Y, et al. Korean Circ J. 2013 Jun;43(6):363‐7. Hopkinds P, et al. J Clin Lipidol. 2011 Jun;5(3 Suppl):9‐17. Marais A,et al. Clin Biochem Rev. 2004 Feb;25(1):49‐68. Chin‐Dusting JP, et al.. Expert Opin Pharmacother. 2001 Mar;2(3):419‐30. Castelli WP. Am J Cardiol. 1998 Nov 26;82(10B):60T‐65T. Castelli WP. Am J Cardiol. 1998 Nov 26;82(10B):60T‐65T. Nordestgaard B, et al. Eur Heart J. 2013 Sep 12. [epub ahead of print]

Pathophysiology of Familial Hypercholesterolemia

TREATMENT OPTIONS

Castelli WP. Am J Cardiol. 1998 Nov 26;82(10B):60T‐65T.

Treatment Options Treatment Options

Statins

Ezetimibe Inhibit HMG‐CoA reductase  Inhibits absorption Decreased hepatic of cholesterol cholesterol synthesis  across GI tract Upregulation of LDLR & increased clearance of LDL

Castelli WP. Am J Cardiol. 1998 Nov 26;82(10B):60T‐65T. Castelli WP. Am J Cardiol. 1998 Nov 26;82(10B):60T‐65T.

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Treatment Options Treatment Options

Fibric Acid Niacin Derivatives

Reduced hepatic VLDL production Increased VLDL clearance

Castelli WP. Am J Cardiol. 1998 Nov 26;82(10B):60T‐65T.

Treatment Options New Treatment Options

Bile acid Microsomal sequestrants Triglyceride Transfer Protein (MTP) Inhibitors Bind bile acids in GI  cause new bile acids to be produced from Prevents assembly cholesterol  of lipoproteins (VLDL) Increased uptake in the liver via LDLR

Castelli WP. Am J Cardiol. 1998 Nov 26;82(10B):60T‐65T. Castelli WP. Am J Cardiol. 1998 Nov 26;82(10B):60T‐65T.

New Treatment Options New Treatment Options

ApoB synthesis Proprotein Inhibitors Convertase Subtilisin‐Kexin Prevents formation Type 9 of VLDL and LDL (PCSK‐9) Inhibitors

Prevents breakdown of LDL Receptor

Castelli WP. Am J Cardiol. 1998 Nov 26;82(10B):60T‐65T. Castelli WP. Am J Cardiol. 1998 Nov 26;82(10B):60T‐65T.

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Why the Paradigm Shift?

• Critical questions to be answered: • What is the evidence for LDLc and non‐HDLc goals for secondary prevention of ASCVD? GUIDELINES • What is the evidence for LDLc and non‐HDLc goals for the primary prevention of ASCVD? • For primary and secondary prevention, what is the impact on lipid levels, effectiveness, safety of lipid management drugs?

Stone NJ, et al. Circulation. 2014;129(Suppl 2):S1‐45

What is Clinical ASCVD? ACC/AHA 2013 Lipid Guidelines

Group 1. Group 2.

Criteria for classification of ASCVD Patient with Clinical Primary elevated Myocardial infarction Coronary Revascularization Procedure ASCVD Acute Coronary Syndrome (ACS) Other Revascularization Procedure LDLc > 190mg/dl Transient Ischemic Attack (TIA) Ischemic Stroke (CVA) Peripheral Arterial Disease (PAD) Other Atherosclerotic Diseases: * Includes Ankle/Brachial Index < 0.90 *Coronary atherosclerosis Group 3. Group 4. *Renal atherosclerosis *Aortic aneurysm 45‐75 years old without *Carotid Plaque, > 50% stenosis 45‐75 years old with diabetes and diabetes or ASCVD with LDLc 70‐189mg/dl LDLc 70‐189mg/dl and 10yr ASCVD risk >7.5%

Group 1 and 2: HIGH‐intensity statin recommended (moderate if high intensity is contraindicated/not tolerated Group 3: MODERATE‐intensity or HIGH‐intensity if 10 yr risk >7.5% Group 4: MODERATE or HIGH‐intensity if 10 yr risk >7.5%

Stone N. J Am Coll Cardiol. 2014;63(25 Pt B)2889‐934. Jacobson TA, et al. Journal of Clinical Lipidology. 2014(8):473‐488 Stone N. J Am Coll Cardiol. 2014;63(25 Pt B)2889‐934.

Selecting Intensity Dose of Statins NLA Guidelines

• Targets of intervention in lipid management High‐Intensity Moderate‐Intensity Low‐Intensity LDL reduction of >50% on LDL reduction of 30‐50% on LDL reduction of < 30% • Non‐HDL cholesterol average average LDL cholesterol atorvastatin 80 mg atorvastatin 10 mg pravastatin 10‐20 mg • rosuvastatin 20 mg rosuvastatin 10 mg lovastatin 20 mg • Apo B simvastatin 20‐40 mg pravastatin 40 mg lovastatin 40 mg fluvastatin 40 mg BID Treatment Goals atorvastatin 40 mg* atorvastatin 20 mg* simvastatin 10 mg* rosuvastatin 40 mg* rosuvastatin 5 mg* fluvastatin 20‐40 mg* Risk Category Treatment Goals (mg/dl) pravastatin 80 mg* pitavastatin 1 mg* Non‐HDL‐cLDL‐cApo B fluvastatin XL 80 mg* pitavastatin 2‐4 mg* Very High <100 <70 <80 *Alternatives with FDA approval but not studied in RCTs reviewed by Expert Panel High <130 <100 <90 RULE OF THUMB: HIGH‐intensity statin dosing starts at ½ the max Moderate prescribed dose and no HIGH‐intensity drugs fall in the LOW‐intensity Low category Stone N. J Am Coll Cardiol. 2014;63(25 Pt B)2889‐934.

Jacobson TA, et al. Journal of Clinical Lipidology. 2014(8):473‐488

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Triglycerides per Guidelines

Comparison Between Guidelines ACC/AHA 2013 *Primary objective: < 500mg/dl NLA 2014 *Primary objective: < 500mg/dl 200‐499mg/dl ‐ statins preferred + LSM 500‐999mg/dl ‐TG lowering agent or statin (if no h/o pancreatitis) is acceptable >1000mg/dl ‐TG lowering agent should be DOC NON‐STATIN UPDATES Endocrine Society 2012 *Primary objective: Varies If > 2000mg/dl –treatment is to prevent pancreatitis with an initial goal of < 1000mg/dl (v. severe) Once < 1000mg/dl then to prevent premature CHD >1000mg/dl ‐ strongly consider Fibrates

CHD = coronary heart disease; DOC = drug of choice; LSM = Lifestyle Modifications –weight loss, loss of 5‐10% of body weight, physical activity > 150min/wk, restriction of alcohol and sugar/refined carb intake

Stone N. J Am Coll Cardiol. 2014;63(25 Pt B)2889‐934. Jacobson TA, et al. Journal of Clinical Lipidology. 2014(8):473‐488. Berglund, et al. J Clin Endocrinol Metab 2012. 97;2969‐89.

Effects of Combination Lipid Therapy in Type 2 Diabetes Fibrates’ Role in Therapy Mellitus The ACCORD Study Group Gemfibrozil: Interventions SBP <120 SBP <140 Simvastatin Simvastatin Totals oHelsinki Heart Study (HHS) – vs. placebo +fenofibrate + placebo VA‐HIT secondary prevention ‐ vs. placebo o A1C<6% 1,050 1,050 1,450 1,450 5,000

Fenofibrate: A1C 7.0‐7.9% 1,050 1,050 1,450 1,450 5,000 oFIELD –vs. placebo Subtotals 2100 2100 2900 2900

Combination statins + fibrates: Totals 4,200 5,800 10,000 oACCORD

Huttunen, JK et al. Helsinki Heart Study. Drugs. 1988;36 Suppl 3:32‐6. Robins, SJ et al. JAMA. 2001 Mar 28;285(12):1585‐91. ACCORD study group. N Engl J Med. 2010 Apr 29;362(17):1563‐74. Tonkin, A. et al. Am Heart J. 2012 Mar;163(3):508‐14. PMID: 22424024

ACCORD Results ACCORD Secondary Outcomes

Treatment arm Primary outcome event rate Hazard ratio (95% CI) Outcome Fenofibrate Placebo HR (95% CI) P value + statin + statin Simvastatin + Placebo 2.4% 1 #events (%) # events (%) Primary + 641 (5.35) 667 (5.64) 0.94 (0.85‐1.05) 0.30 Simvastatin + Fenofibrate 2.2% 0.92 (0.79‐1.08) revasc./CHF hospitalization Major coronary 332 (2.58) 353 (2.79) 0.92 (0.79‐1.07) 0.26 disease event Sub‐population Control primary outcome Experimental primary P value of inter‐group rate outcome rate interaction Nonfatal MI 173 (1.32) 186 (1.44) 0.91 (0.74‐1.12) 0.39 All strokes 51 (0.38) 48 (0.36) 1.05 (0.71‐1.56) 0.80 Male 13.3% 11.2% 0.01 Nonfatal stroke 47 (0.35) 40 (0.30) 1.17 (0.76‐1.78) 0.48 Female 6.6% 9.1% All deaths 203 (1.47) 221 (1.61) 0.91 (0.75‐1.10) 0.33 Dyslipidemia sub‐ 17.3% 12.4% population CV deaths 99 (0.72) 114 (0.83) 0.86 (0.66‐1.12) 0.26 (TG >204mg/dL, HDL (<34mg/dL) 0.057 Fatal or nonfatal 120 (0.90) 143 (1.09) 0.82 (0.65‐1.05) 0.10 CHF

Remaining population 10.1% 10.1%

ACCORD study group. N Engl J Med. 2010 Apr 29;362(17):1563‐74. ACCORD study group. N Engl J Med. 2010 Apr 29;362(17):1563‐74.

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ACCORD Safety Data ACCORD Take‐home Points

Adverse event Fenofibrate Placebo P value + statin +statin Adding fenofibrate to statin therapy in T2DM patients is # reports (%) # reports (%) not recommended for all patients. Myalgia 1140 (40.1%) 1115 (40.5%) 0.79 Myopathy/Myositis/Rha 4 (0.1%) 3 (0.1%) 1.00 bdomyolysis Fenofibrate caused mild elevations in SCr (0.06mg/dL) ALT > 3x ULN 52 (1.9%) 40 (1.5%) 0.21 but did not increase dialysis or ESRD rates. ALT >5 x ULN 16 (0.6%) 6 (0.2%) 0.03 Female SCr ever 235 (27.9%) 157 (18.7%) <0.001 >1.3mg/dL The fenofibrate group had lower rates of micro‐ and Male SCr ever 698 (36.7%) 350 (18.5%) <0.001 macro‐albuminuria suggesting possible renal protection. >1.5mg/dL Post randomization 1050 (38.2%) 1137 (41.6%) 0.01 microalbuminuria (≥30 to <300mg/g) No increased risk of myositis/rhabomyolysis noted with Post randomization 289 (10.5%) 337 (12.3%) 0.04 fenofibrate + statin. macroalbuminuria (≥300 mg/g) Genuth S, Ismail‐Beigi F. J Clin Endocrinol Metab. 2012 Jan;97(1):41‐8 ACCORD study group. N Engl J Med. 2010 Apr 29;362(17):1563‐74.

Niacin’s Role in Therapy Niacin’s Role in Therapy Niacin Formulations • FDA‐approved indications Niacin • Treatment of dyslipidemias as monotherapy or • Metabolism: adjunctively Conjugation Amidation pathway pathway • Rate of release of the • Prophylaxis of recurrent MI various niacin Low‐affinity, High‐affinity formulations determines • Slow progression or promote regression of CAD high‐capacity Low capacity FLUSHING HEPATOTOXIC the pathway • Treatment of hyperlipidemia • Current formulations NUA NAM • Depending on pathway • Niaspan (ER) [Rx] Immediate release Sustained release metabolized you can • Niacor (IR) [Rx] know the side effects of Extended Release the drug • Niacin (IR, ER, SR) [OTC] NIASPAN

Lexicomp Online [Online]. Lexicomp, inc. 2013. Available from http://www.lexicomp.com Niaspan (niacin) tablet, extended release [Internet]. US National Library of Medicine; 2008 Jan. Available from http://dailymed.nlm.nih.gov/dailymed/archives/ Allen L, Ansel H, Popovich N. Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. 9th ed. Baltimore: Lippincott Williams & Wilkins; 2009.

AIM‐HIGH Trial AIM‐HIGH Trial Endpoint Placebo ER Niacin +statin HR with Niacin Pvalue + statin N = 1718 (95% CI) • RDBPC Trial = 92 centers in US/Canada n = 3,414 n = 1696 Primary 274(16.2%) 282(16.4%) 1.02 (0.87‐1.21) 0.80 • Purpose: Does improving HDL and TGs parameters = better cardiac outcomes in patients with heart/vascular disease with well controlled LDL Death from CHD 26(1.5%) 20(1.2%)

Nonfatal MI 80(4.7%) 92(5.4%) • Study intervention: Ischemic CVA 15(0.9%) 27(1.6%) • Treatment group: niacin ER 1500‐2000mg + simvastatin Hospitalization ACS 67(4%) 63(3.7%) • Placebo group: simvastatin + placebo (+50mg niacin IR) Symptom driven 86(5.1%) 80(4.7%) • Both groups: +/‐ ezetimibe 10mg/d to achieve target LDL revasc.

• Primary endpoint: composite of first event of death from CHD, non‐fatal MI, ischemic stroke, hospitalization (>23 hours) for ACS, or symptom‐driven • Steering committed decided to halt blinded treatment phase 18 months coronary/cerebral revascularization earlier = lack of benefit of niacin beyond statin therapy

RDBPC = Randomized, double blind, placebo controlled trial • Noted unexplained  in ischemic strokes with niacin group

AI‐HIGH Investigators. N Engl J Med 2011;365:2255‐67. AIM‐HIGH Cholesterol Management Program [Internet]. Available from http://www.aimhigh‐heart.com/ AI‐HIGH Investigators. N Engl J Med 2011;365:2255‐67. Nicholls SJ. Cleveland Clinic Journal of Medicine [Internet] 2012 Jan; 79(1):38‐43. Available from http://www.ccjm.org/content/79/1/38.full.pdf+html AIM‐HIGH Cholesterol Management Program [Internet]. Available from http://www.aimhigh‐heart.com/ Supplement to Niacin in Patients with Low HDL Cholesterol Levels Receiving Intensive Statin Therapy. N Engl J Med 2011; 365:2255‐67. Available from Nicholls SJ. Cleveland Clinic Journal of Medicine [Internet] 2012 Jan; 79(1):38‐43. Available from http://www.ccjm.org/content/79/1/38.full.pdf+html http://www.natap.org/2012/HIV/nejmoa1107579_appendix.pdf

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AIM‐HIGH Trial AIM‐HIGH Trial • The AIM‐HIGH trial may have had methodological flaws

o Statin use between the two treatment arms was not uniform

oThe placebo control group received niacin (low dose)

oThe study may have been halted too soon

AI‐HIGH Investigators. N Engl J Med 2011;365:2255‐67. AIM‐HIGH Cholesterol Management Program [Internet]. Available from http://www.aimhigh‐heart.com/ Nicholls SJ. Cleveland Clinic Journal of Medicine [Internet] 2012 Jan; 79(1):38‐43. Available from http://www.ccjm.org/content/79/1/38.full.pdf+html

HPS2‐THRIVE Trial • RDBMC Trial = 245 sites in the United Kingdom, Scandinavia and China. HPS2‐THRIVE Trial Largest ever randomized trial of ER niacin treatment, n=25, 673 Event Type Niacin‐L Placebo Absolute P value • Purpose: Does adding Extended Release Niacin to already background statin (n = 12,838) ERN/LRPT(n = 12,835) Excess Placebo with P(CI) value therapy improve cardiovascular reduction in high risk patient populations # randomized 12,838Niacin 12,835‐L (%) • Hx of MI Abnormal AlanineSerious transaminase ADE ‐ # (%) at Routine visits • CVA GIAny >3x ULN 620(4.8) 140(0.30%) 491(3.8) 1.0 67(0.14%) +/‐0.3 <0.001 <0.001 (1.113‐1.44) • PAD Any >3x ULN c/o muscle 124(0.27%) 65(0.14%) <0.001 Bleedingdamage 326 (2.5) 238 (1.9) 0.7 +/‐ 0.2 <0.001 • DM with evidence of symptomatic CHD (1.17‐1.62) All Results Musculoskeletal 481 (3.7) 385 (3.0) 0.7 +/‐ 0.2 <0.001 • Study intervention: Any >3x ULN 315(0.68%) 133(0.29%0(1.10 <0.001‐1.44) • Treatment group: niacin ER 2g, laropiprant 40mg NewAny onset>3x ULN DM c/o muscle 494/8704 (5.7)234(0.51%0 376/8670 (4.3) 1.3+/ 119(0.26%)‐0.3 <0.001 <0.001 damage • Control group: matching placebo (1.16‐1.51) • Both groups received simvastatin 40mg (+/‐ ezetimibe 10mg) Disturbed DM 460/4134 (11.1) 311/4135 (7.5) 3.7 +/‐ 0.6 <0.001 control (1.37‐1.78) CONCLUSION: Indicated addition of niacin was not better in combination vs. background statin therapy in reduction of CV European Heart Journal [Internet]. 2013 Jan; Available from http://eurheartj.oxfordjournals.org/content/early/2013/02/26/eurheartj.eht055.full.pdf+html events. (p = 0.29; CI [0.9‐1.03]) HPS2‐THRIVE Collaborative Group. N Engl J Med 2014;371:203‐12. HPS2‐THRIVE Collaborative Group. N Engl J Med 2014;371:203‐12.

Take‐home Points on Niacin Ezetimibe’s Role in Therapy ENHANCE Trial • RBDMC Trial = 24 months

 Practitioners should provide risk vs. benefit assessment when starting dual therapy of • Purpose: Does combination therapy of simvastatin and statin and niacin formulations. ezetimibe improve surrogate markers by reducing mean intima‐media thickness [IMT]?  Advanced clinical decision: • Clinicians may elect to utilize niacin therapy for patients who need: • Non‐LDL control • Study Intervention: • TG control to decrease risk of pancreatitis • Familial Hypercholesterolemia • Avoidance of fibric acid drug interactions/ADEs with statins • Simvastatin 80mg with placebo • simvastatin 80mg PLUS ezetimibe 10mg daily • Evaluated by B‐mode ultrasonography (IMT) ENHANCE Investigators. N Engl J Med 20088;358;1431‐43.

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Ezetimibe’s Role in Therapy New FDA Approved Therapies IMPROVE‐IT Trial • RBDMC Trial = 6 year follow up trial Agent Mechanism FDA Approval Lomitapide Microsomal Triglyceride Transfer December 2012 • Purpose: Does combination therapy of (JuxtapidTM) Protein (MTP) Inhibitor simvastatin and ezetimibe improve cardiovascular outcomes Mipomersen Antisense Oligonucleotide for January 2013 • (composite of cardiovascular death, TM nonfatal MI, unstable angina requiring (Kynamro ) Apolipoprotein B‐100 hospitalization, revascularization or nonfatal stroke? Alirocumab July 2015 (Praluent ®) Proprotein Convertase • Study Intervention: Subtilisin/Kexin type 9 (PCSK9) Evolocumab August 2015 • Hospitalization with 10 day for ACS Inhibitor (RepathaTM) • Simvastatin 40mg with placebo • simvastatin 40mg PLUS ezetimibe 10mg daily

Juxtapid Package Insert. Aergeion Pharmaceuticals, 2013. http://www.aegerion.com/Collateral/Documents/English‐US/Prescribing_Information%20june%202013.pdf Kynamro Package Insert. Genzyme Corporation, 2013. http://www.kynamro.com/~/media/Kynamro/Files/KYNAMRO‐PI.pd IMPROVE‐IT Investigators. N Eng J Med 2015;372;2387‐97. http://www.medscape.com/viewarticle/835030_print Accessed 7/2/2015 Praluent Package Insert. Sanofi‐Aventis, 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125559Orig1s000lbl.pdf Repatha Package Insert. Amgen, Inc., 2015. http://pi.amgen.com/united_states/repatha/repatha_pi_hcp_english.pdf

Lomitapide (JuxtapidTM) Lomitapide

Indication Homozygous Familial Hypercholesterolemia (HoFH) (Adjunct to diet &other lipid‐lowering therapy, including LDL apheresis where available) Dosing Begin at 5 mg PO, titrate every 2‐4 weeks to 60 mg PO daily Microsomal Triglyceride Renal Dosing: End‐stage renal disease on hemodialysis: Do no exceed 40 mg daily Transfer Protein Hepatic Dosing: Child‐Pugh A: Do not exceed 40 mg daily (MTP) Inhibitors Drug Interactions: CI with strong CYP3A4 inhibitors Max dose 30 mg daily with weak CYP3A4 inhibitors (eg atorvastatin, amiodarone, amlodipine, OC, etc.) Prevents assembly Mechanism Binds to and inhibits microsomal triglyceride transfer protein (MTP) of lipoproteins (VLDL) in the liver

Juxtapid Package Insert. Aergeion Pharmaceuticals, 2015. http://www.juxtapidremsprogram.com/_pdf/Juxtapid_Prescribing_Information_final_05‐15.pdf Castelli WP. Am J Cardiol. 1998 Nov 26;82(10B):60T‐65T.

TM Lomitapide (Juxtapid ) Phase 3 Homozygous FH Study Contraindications Pregnancy • Open‐label, Single arm Concurrent use with moderate or strong CYP3A4 inhibitors Started lomitapide 5 mg daily, to max 60 mg daily Child‐Pugh B or C hepatic impairment • Black Box Risk of Hepatotoxicity Elevation in transaminases • Primary Endpoint: Change in LDL from baseline to week 26 Warning Increased hepatic steatosis Baseline Week 26 (Efficacy) REMS program Juxtapid REMS program: Pharmacy and prescriber must be enrolled (n=29) (n=23) Level Level Change from baseline

LDL (mg/dl) 336 166 ‐50% (‐39 to ‐62%)

Juxtapid Package Insert. Aergeion Pharmaceuticals, 2013. http://www.aegerion.com/Collateral/Documents/English‐US/Prescribing_Information%20june%202013.pdf Cuchel M, et al. Lancet 2013;381:40‐46.

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Patients Secondary Efficacy Outcomes Baseline (n=29) Week 26 (Efficacy) Baseline Characteristics (n=29) (n=23) Level Level Change from Age (years) 30.7 +/- 10.6 baseline Genetic diagnosis 100% Total cholesterol 429 236 ‐46%* (mg/dl) (‐35 to ‐56%) Cardiovascular disease 93% VLDL 19 12 ‐45%* Current therapy (mg/dl) (‐29 to ‐61%) Non‐HDL 387 197 ‐50%* Statin 93% (mg/dl) (‐39 to ‐61%) Ezetimibe 76% HDL 43 39 ‐12%* Niacin 10% (mg/dl) (‐4 to ‐20%) Triglycerides 89 45 ‐45%* Fibrate 3% (mg/dl) (‐11 to ‐47%) Bile Acid Sequestrant 3% ApoB 2.6 1.3 ‐49%* Apheresis 62% (g/L) (‐38 to ‐60%) Lipoprotein(a) 2.4 1.7 ‐15%* (mcmol/L) (‐1 to ‐30%) ApoA 1.2 1.0 ‐14%* (g/L) (‐4 to ‐17%) Cuchel M, et al. Lancet 2013;381:40‐46. *statistically significant Cuchel M, et al. Lancet 2013;381:40‐46.

Safety Outcomes Conclusions • Most common adverse events: • Diarrhea (79%) • ALT or AST elevation • Lomitapide provided additional 50% LDL reduction • Nausea (65%) • > 3 X ULN: 34% Surrogate outcome (LDL) • Dyspepsia (38%) • > 5 X ULN: 14% • • >10 X ULN: 0% • Vomiting (35%) • Side effects common • No patients discontinued due to elevated ALT/AST • Abdominal pain (28%) • Hepatic fat • Dose titration limited by side effects (GI and LFT) • Weight loss (24%) • Increased from 1% to 8.6% • Lomitapide should be considered as add on therapy for patients with HoFH not able to reach target LDL with other therapies • Study discontinuation • 6 patients • 3 due to side effects (GI)

Cuchel M, et al. Lancet 2013;381:40‐46.

Mipomersen (KynamroTM) Mipomersen

Indication Homozygous Familial Hypercholesterolemia (HoFH) ApoB synthesis (Adjunct to diet &other lipid‐lowering therapy) Inhibitors Dosing 200 mg subcutaneously once weekly Prevents formation of VLDL and LDL Mechanism Antisense oligonucleotide binds to messenger ribonucleic acid (mRNA) of apo B‐ 100  degradation of mRNA  reduced Apo B‐100 formation

Kynamro Package Insert. Genzyme Corporation, 2015. https://www.kynamro.com/families/product‐information.aspx Castelli WP. Am J Cardiol. 1998 Nov 26;82(10B):60T‐65T.

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Mipomersen (KynamroTM) Mipomersen in Homozygous FH

• Randomized, double‐blind, placebo‐controlled Contraindications Moderate or severe hepatic impairment (Child‐Pugh B or C) • Mipomersen 200 mg or placebo subQ once weekly x 26 weeks Active liver disease Pregnancy Category B Black Box Risk of Hepatotoxicity • Primary Outcome: LDL change from baseline (%) Warning Elevation in transaminases Placebo Mipomersen Difference Increased hepatic steatosis (n=17) (n=34) (95% CI) REMS program Kynamro REMS: Only certified healthcare providers may prescribe LDL ‐3.3% ‐24.7% ‐21.3%* (% change from (5.5 to ‐12.1%) (‐17.7 to ‐31.6%) (‐9.8 to ‐32.9%) baseline)

Kynamro Package Insert. Genzyme Corporation, 2013. http://www.kynamro.com/~/media/Kynamro/Files/KYNAMRO‐PI.pdf Raal F, et al. Lancet 2010;375:998‐1006.

Patients Safety Outcomes

Placebo Mipomersen Baseline Characteristics Baseline Lipid Profile (n=17) (n=34) Placebo Mipomersen Placebo Mipomersen Adverse events 76% 88% (n=17) (n=34) Injection‐site reaction 24% 76% (n=17) (n=34) Influenza‐like symptoms 24% 29% Genetic LDL (mg/dl) 402 441 Nausea 6% 18% 82% 88% confirmation Total cholesterol 460 503 Headache 12% 15% Age (years) 33.0 30.4 Non‐HDL cholesterol 422 464 Chest Pain 0% 12% Laboratory Abnormalities < 18 years 24% 9% HDL cholesterol 39 43 ALT 1 ‐ <2 X ULN 41% 35% Clinical ASCVD 65% 56% Lipoprotein(a) 70 60 ALT 2 ‐ <3 X ULN 12% 15% Lipid Lowering Therapies Triglycerides 89 80 ALT 3 ‐ <8 X ULN 0% 12% ALT > 8 X ULN 0% 0% Statin 100% 97% VLDL cholesterol 19 15 Statin + other drug 64% 79%

Raal F, et al. Lancet 2010;375:998‐1006. Raal F, et al. Lancet 2010;375:998‐1006.

Conclusions Mipomersen in Heterozygous FH

• Randomized, double‐blind, placebo‐controlled • Mipomersen 200 mg vs. placebo subQ weekly x 26 weeks • Mipomersen is a promising therapy for uncontrolled Homozygous FH • Primary Endpoint: LDL change from baseline (%) • Surrogate outcome (LDL) Placebo Mipomersen p‐value • Well tolerated (n=41) (n=82) LDL 5.2% ‐28.0% • Additional data needed in other patient populations (% change from baseline)) (10.9 to ‐0.5%) (‐22.1 to ‐34.0%) <0.001

• Achieved LDL < 100 mg/dl: 5% vs. 45%

Stein E, et al. Circulation 2012;126:2283‐2292.

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Patients Safety Outcomes Placebo Mipomersen Baseline Characteristics Baseline Lipid Profile (n=41) (n=83) Adverse events 93% 100% Placebo Mipomersen Placebo Mipomersen Injection‐site reaction 42% 93% (n=41) (n=83) (n=41) (n=82) Influenza‐like symptoms 32% 49% Age (years), mean 56 56 LDL (mg/dl) 143 153 Nausea 15% 17% Previous CABG 54% 44% Total 213 225 Headache 17% 18% Previous PCI 32% 30% cholesterol Diarrhea 12% 11% Lipid Lowering Therapies Non‐HDL 165 176 Statin 100% 99% Nasopharyngitis 7% 11% HDL 48 47 Maximal statin 65% 65% Cough 5% 11% Triglycerides 100 107 Statin + ezetimibe 85% 78% Laboratory Abnormalities Statin + ezetimibe + other 46% 32% VLDL 20 21 ALT 1 ‐ <2 X ULN 34% 41% ALT 2 ‐ <3 X ULN 5% 23% ALT 3 ‐ < 5 X ULN 2% 11% ALT 5 ‐ < 10 X ULN 0% 2% ALT > 10 X ULN 0% 1% ALT > 3 X ULN for 2 readings 0% 6% Stein E, et al. Circulation 2012;126:2283‐2292. Stein E, et al. Circulation 2012;126:2283‐2292.

Conclusions Alirocumab (Praluent™)

• Mipomersen is effective for reducing LDL in HeFH when patients fail Indication Heterozygous Familial Hypercholesterolemia (HeFH) to reach LDL goals with traditional therapies Clinical ASCVD (Adjunct to diet & maximally tolerated statin therapy in adults who require • All patients had history of CAD additional LDL‐C lowering) • 40% more patients able to achieve goal LDL Dosing 75 mg subcutaneously every 2 weeks • Surrogate outcome (LDL) (may increase to 150 mg if additional LDL‐C lowering needed) Mechanism Monoclonal antibody, binds to PCSK9 Inhibits PCSK9  increased LDLR  increased clearance of LDL from blood • Common ADR: Injection reactions &  ALT

Praluent Package Insert. Sanofi‐Aventis, 2015. http://products.sanofi.us/praluent/praluent.pdf

New Treatment Options Alirocumab (Praluent™)

Proprotein Warnings & Hypersensitivity Reactions Convertase Precautions Subtilisin‐Kexin Type 9 (PCSK‐9) Inhibitors

Prevents breakdown of LDL Receptor

Praluent Package Insert. Sanofi‐Aventis, 2015. http://products.sanofi.us/praluent/praluent.pdf Castelli WP. Am J Cardiol. 1998 Nov 26;82(10B):60T‐65T.

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Alirocumab in Heterozygous FH Alirocumab in Heterozygous FH

• Baseline LDL:196 mg/dl vs. 201 mg/dl • Double‐blind placebo controlled trial • Alirocumab 150 mg subQ vs. placebo every 2 weeks • Prmary Outcome:

• Patients w/ HeFH and LDL > 160 mg/dl despite maximally tolerated statin Alirocumab Placebo Difference therapy +/‐ other therapy (n=72) (n=35) LDL ‐45.7% ‐6.6% ‐39.1% (% change from baseline)) • Primary Outcome: % LDL reduction (week 24) (p<0.0001)

• Reached LDL goal: 41% vs. 6%

Praluent Package Insert. Sanofi‐Aventis, 2015. http://products.sanofi.us/praluent/praluent.pd Praluent Package Insert. Sanofi‐Aventis, 2015. http://products.sanofi.us/praluent/praluent.pd http://my.americanheart.org/idc/groups/ahamah‐public/@wcm/@sop/@scon/documents/downloadable/ucm_469616.pdff http://my.americanheart.org/idc/groups/ahamah‐public/@wcm/@sop/@scon/documents/downloadable/ucm_469616.pdff

ODYSSEY LONG TERM Trial ODYSSEY LONG TERM Trial

• Randomized, placebo‐controlled • Patients: • Alirocumab 150 mg subQ every 2 weeks vs. placebo x 78 weeks • 18% HeFH • 99.99% on statin • Patients w/ HeFH or established CHD or CHD risk equivalent + LDL > 70 mg/dl • Baseline LDL = 122 mg/dl • Must be on maximum tolerated statin • Primary outcome: % change in LDL at week 24 • ‐61.0% vs. 0.8% (p<0.001) • Primary outcome: % change in LDL at week 24 • LDL < 70 mg/dl • 79% vs. 8%

Robinson JG, et al.ODYSSEY LONG TERM Investigators.. N Engl J Med. 2015 Apr 16;372(16):1489‐99. Robinson JG, et al.ODYSSEY LONG TERM Investigators.. N Engl J Med. 2015 Apr 16;372(16):1489‐99.

ODYSSEY LONG TERM Trial ODYSSEY LONG TERM Trial

• Other Outcomes: • Conclusions: Outcome Alirocumab Placebo p‐value • Significant LDL reduction Positively adjudicated CV events 4.6% 5.1% 0.68 • More patient reach goal LDL CHD or unknown death 0.3% 0.9% 0.26 Nonfatal MI 0.9% 2.3% 0.01 • Well tolerated Ischemic Stroke 0.6% 0.3% 0.35 • Decrease events ?? Unstable Angina Hospitalization 0% 0.1% 0.34 CHF Hospitalization 0.6% 0.4% 0.76 Coronary Revascularization 3.1% 3.0% 0.68 Post‐hoc analysis adjudicated major CV event 1.7% 3.3% 0.02

• Myalgia: 5.4% vs. 2.9% (p=0.006)

Robinson JG, et al.ODYSSEY LONG TERM Investigators.. N Engl J Med. 2015 Apr 16;372(16):1489‐99. Robinson JG, et al.ODYSSEY LONG TERM Investigators.. N Engl J Med. 2015 Apr 16;372(16):1489‐99.

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Evolocumab (Repatha®) Evolucumab in Heterozygous FH

Indication Heterozygous Familial Hypercholesterolemia (HeFH) (RUTHERFORD‐2 Trial) Clinical ASCVD • Randomized, placebo‐controlled (Adjunct to diet & maximally tolerated statin therapy in adults who require additional LDL‐C lowering) • Evolocmab 140 mg subQ Q2weeks, placebo Q2weeks Homozygous Familial Hypercholesterolemia (HoFH) • Evolocumab 420 mg Q4weeks, Placebo Q4 weeks (Adjunct to diet & other lipid lowering therapies) Dosing HeFH / Clinical ASCVD: 140 mg subQ ever 2 weeks or 420 mg monthly • Patients: HoFH: 420 mg subQ monthly 87% on high‐intensity statin Mechanism Monoclonal antibody, binds to PCSK9 • HeFH by clinical diagnosis Average baseline LDL: 151‐162 mg/dl Inhibits PCSK9  increased LDLR  increased clearance of LDL from blood • Already on statin Warnings & Hypersensitivity Reactions Precautions • Primary Outcome: % LDL change (week 12)

Repatha Package Insert. Amgen, Inc., 2015. http://pi.amgen.com/united_states/repatha/repatha_pi_hcp_english.pdf Raal FJ, et al; RUTHERFORD‐2 Investigators. Lancet. 2015 Jan 24;385(9965):331‐40.

Evolucumab in Heterozygous FH Evolucumab in Homozygous FH (RUTHERFORD‐2 Trial) (TESLA Part B Trial)

• Primary Outcome: % LDL change (week 12) • Randomized, placebo‐controlled Evolocumab Placebo Difference • Evolocumab 420 mg Q4weeks, Placebo Q4 weeks • Patients: Q2 week LDL Average baseline LDL: 360 mg/dl ‐59.2% • HoFH (% change from ‐61.3% ‐2.0% (‐65.1 to ‐53.4%) baseline)) • Already on high‐intensity statin (+ 92% on ezetimibe)

Evolocumab Placebo Difference • Primary Outcome: % LDL change (week 12)

Q4 week LDL Evolocumab Placebo Difference ‐61.3% (% change from ‐55.7% 5.5% LDL (‐69.0 to ‐53.6%) ‐30.9% baseline)) (% change from ‐23.1% 7.9% (‐18.0 to ‐43.9%) baseline)) Raal FJ, et al; RUTHERFORD‐2 Investigators. Lancet. 2015 Jan 24;385(9965):331‐40. Raal FJ, et al; TESLA Investigators. Lancet. 2015 Jan 24;385(9965):341‐50.

OSLER‐1 & OSLER‐2 OSLER‐1 & OSLER‐2

• Open‐label extension trials of evolocumab vs. placebo • Primary endpoint: Incidence of adverse events Adverse Event Evolocumab Standard Therapy (n=2,976) (n=1,489) • Primary endpoint: Incidence of adverse events Muscle related 6.4% 6.0% Injection‐site related 4.3% Leading to discontinuation 2.4% • Secondary endpoint: % change in LDL Neurocognitive 0.9% 0.3% Arthralgia 4.6% 3.2% Fatigue 2.8% 1.0%

• Secondary endpoint: % change in LDL • 58% reduction vs. standard therapy at 12 months

Sabatine MS, et al. Open‐Label Study of Long‐Term Evaluation against LDL Cholesterol (OSLER) Investigators. Sabatine MS, et al. Open‐Label Study of Long‐Term Evaluation against LDL Cholesterol (OSLER) Investigators. N Engl J Med. 2015 Apr 16;372(16):1500‐9. N Engl J Med. 2015 Apr 16;372(16):1500‐9.

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OSLER‐1 & OSLER‐2 OSLER‐1 & OSLER‐2

• Exploratory Analysis‐ Cardiovascular Events: • 0.95% vs. 2.18%; HR 0.47 (0.28‐0.78)

Sabatine MS, et al. Open‐Label Study of Long‐Term Evaluation against LDL Cholesterol (OSLER) Investigators. N Engl J Med. 2015 Apr 16;372(16):1500‐9. Sabatine MS, et al. Open‐Label Study of Long‐Term Evaluation against LDL Cholesterol (OSLER) Investigators. N Engl J Med. 2015 Apr 16;372(16):1500‐9.

Conclusions Looking to the Future

• Evolocumab generally well tolerated • “Limitations of use: The effects of Praluent on cardiovascular morbidity and • Few serious ADR’s mortality have not been determined” • Maintains efficacy at 1 year • “Limitations of use: The effects of Repatha on cardiovascular morbidity and mortality have not been determined” • Clinical Event Reduction ?? • ODYSSEY OUTCOMES = Alirocumab CV Outcomes Study • FOURRIER = Evolocumab CV Outcomes Study

Post‐test Question #1 Post‐test Question #2

Which of the following is the cause for elevated cholesterol Which of the following medications has long term efficacy levels in patients with familial hypercholesterolemia? data showing reduction in cardiovascular events? (choose all that apply) A. Being raised with poor dietary choices that cause increased consumption A. Ezetimibe of high cholesterol foods as an adult B. Fenofibrate B. Increased biosynthesis of cholesterol C. Niacin C. Decreased metabolism of LDL D. Lomitapide Decreased production of HDL D. E. Mipomersen F. Alirocumab

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Meet Lydia Meet Bob Post‐test Case #1 Post‐test Case #2 • 34 yo male with Heterozygous Familial Hypercholesterolemia, s/p STEMI 6 months ago. He comes • 62 yo female s/p MI and T2DM, HTN and hyperlipidemia/‐triglyceridemia. today for repeat lab tests. • Meds: ASA 81mg daily, Atorvastatin 10mg daily, Lisinopril 40mg daily, • Meds: ASA 81mg daily,Clopidogel 75 mg daily, Metoprolol Tartrate 100mg BID, Lisinopril 20 mg PO Metformin 1000mg twice daily, Metoprolol Succinate 100mg daily daily, Atorvastatin 80mg daily, Ezetimibe 10mg daily, APAP prn migraine headaches • Labs: Chem 7 –wnl; LFT –wnl; A1c 7.5% Today : TC: 215, TG: 1401, HDL:42, dLDL: 86(mg/dl) • Labs: Chem 7 –wnl; LFT –wnl; –Results of Atorvastatin 10mg daily being added Today : TC: 231, TG: 132, HDL: 40, LDL: 165 (mg/dl) ‐ T‐3 mo: TC: 215, TG: 1589, HDL: 40, dLDL: 126 (mg/dl) T‐3 mo : TC: 251, TG: 128, HDL:37, LDL: 189 (mg/dl) –Results of starting atorvastatin to 80mg daily; added ezetimibe 10 mg at this time Question Options T‐6 mo : TC: 362, TG: 198, HDL: 31, LDL: 291 (mg/dl) What is Lydia’s indication for statin usage? A. MI ‐ Started on Atorvastatin 80mg based on these results B. Type 2 Diabetes C. Her age only Question Options D. Both A and B Which drug therapy had data to support Bob’s current A. Niacin According to ACC/AHA and AACE lipid guidelines A. Hemoglobin A1c lipid situation (ie has been shown to improve LDL B. Gemfibrozil what other lipid parameter may warrant drug B. HDL cholesterol cholesterol levels in Familiar Hypercholesterolemia)? C. Fish oil therapy? C. Triglycerides D. Alirocumab D. Total Cholesterol

http://blogs‐images.forbes.com/janetnovack/files/2012/02/07FUeEudVoarl_4310.jpg http://blogs‐images.forbes.com/janetnovack/files/2012/02/07FUeEudVoarl_4310.jpg

Management of Lipids Beyond Statin Therapy

Jessica L. Kerr, PharmD, CDE Associate Professor SIUE School of Pharmacy Jared Sheley, PharmD, BCPS Clinical Assistant Professor SIUE School of Pharmacy