Management of Lipids Beyond Statin Therapy

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

Disclosures/Conflict of Interest Neither speaker has a conflict of interest in relation to this presentation

Objectives Describe the pathophysiology of lipid disorders and the populations at risk for cardiovascular disease Compare and contrast currently available lipid management guidelines Discuss the efficacy and safety for FDA approved non-statin therapy and their role in current medical management for lipid disorders Evaluate and apply evidence based literature for novel drug classes new to lipid management

Pre-test Question #1 Which of the following is the cause for elevated cholesterol levels in patients with familial hypercholesterolemia? A. Being raised with poor dietary choices that cause increased consumption of high cholesterol foods as an adult B. Increased biosynthesis of cholesterol C. Decreased metabolism of LDL D. Decreased production of HDL

Pre-test Question #2 Which of the following medications has long term efficacy data showing reduction in cardiovascular events? (choose all that apply) A. Ezetimibe B. Fenofibrate C. Niacin D. Lomitapide E. Mipomersen F. Alirocumab

Meet Lydia Pre-test Case #1 62 yo female s/p MI and T2DM, HTN and hyperlipidemia/-triglyceridemia. Meds: ASA 81mg daily, Atorvastatin 10mg daily, Lisinopril 40mg daily, Metformin 1000mg twice daily, Metoprolol Succinate 100mg daily Labs: Chem 7 wnl; LFT wnl; A1c 7.5% Today : TC: 215, TG: 1,401, HDL:42, dldl: 86 (mg/dl) Results of Atorvastatin 10mg daily being added Question T-3 mo: TC: 215, TG: 1,589, HDL: 40, dldl: 126 (mg/dl) Options What is Lydia s indication for statin usage? A. MI B. Type 2 Diabetes C. Her age only D. Both A and B According to ACC/AHA and AACE lipid guidelines what other lipid parameter may warrant drug therapy? A. Hemoglobin A1c B. HDL cholesterol C. Triglycerides D. Total Cholesterol http://blogs-images.forbes.com/janetnovack/files/2012/02/07fueeudvoarl_4310.jpg

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) - 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 Which drug therapy had data to support Bob s current lipid situation (ie has been shown to improve LDL cholesterol levels in Familiar Hypercholesterolemia)? Options A. Niacin B. Gemfibrozil C. Fish oil D. Alirocumab http://blogs-images.forbes.com/janetnovack/files/2012/02/07fueeudvoarl_4310.jpg

BACKGROUND

Cardiovascular Disease (CVD) in the United States 1 in 3 deaths (~787,000/year) CAD = 1 in 6 deaths (~386,000/year) Total costs > $300 billion / year Go AS, et al. Circulation. 2013 Jan 1;127(1).

Populations at Risk for Cardiovascular Disease (CVD) Pre-existing CVD Age (male >45, female >55) Cholesterol Total, LDL, non-hdl HDL Hypertension 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. Circulation. 2014 Jun 24;129(25 Suppl 2):S49-73.

PATHOPHYSIOLOGY

Functions Cell membrane formation Hormone synthesis Bile salt production Source of free fatty acids Cholesterol 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 phospholipids B-100, E, C-I, C-II, C- III LDL VLDL catabolism Cholesterol esters, phospholipids, proteins B-100 HDL Diet & Liver Proteins, phospholipids, cholesterol esters A-I, A-II, E, C-I, C-II, 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.

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

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

Pathophysiology of Familial Hypercholesterolemia Castelli WP. Am J Cardiol. 1998 Nov 26;82(10B):60T-65T.

TREATMENT OPTIONS

Treatment Options Ezetimibe Inhibits absorption of cholesterol across GI tract Castelli WP. Am J Cardiol. 1998 Nov 26;82(10B):60T-65T.

Treatment Options Statins Inhibit HMG-CoA reductase Decreased hepatic cholesterol synthesis Upregulation of LDLR & increased clearance of LDL Castelli WP. Am J Cardiol. 1998 Nov 26;82(10B):60T-65T.

Treatment Options Niacin Reduced hepatic VLDL production Castelli WP. Am J Cardiol. 1998 Nov 26;82(10B):60T-65T.

Treatment Options Fibric Acid Derivatives Increased VLDL clearance

Treatment Options Bile acid sequestrants Bind bile acids in GI cause new bile acids to be produced from cholesterol Increased uptake via LDLR Castelli WP. Am J Cardiol. 1998 Nov 26;82(10B):60T-65T.

New Treatment Options Microsomal Triglyceride Transfer Protein (MTP) Inhibitors Prevents assembly of lipoproteins (VLDL) in the liver Castelli WP. Am J Cardiol. 1998 Nov 26;82(10B):60T-65T.

New Treatment Options ApoB synthesis Inhibitors Prevents formation of VLDL and LDL Castelli WP. Am J Cardiol. 1998 Nov 26;82(10B):60T-65T.

New Treatment Options Proprotein Convertase Subtilisin-Kexin Type 9 (PCSK-9) Inhibitors Prevents breakdown of LDL Receptor Castelli WP. Am J Cardiol. 1998 Nov 26;82(10B):60T-65T.

GUIDELINES

Why the Paradigm Shift? Critical questions to be answered: What is the evidence for LDLc and non-hdlc goals for secondary prevention of ASCVD? 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? Myocardial infarction Acute Coronary Syndrome (ACS) Transient Ischemic Attack (TIA) Peripheral Arterial Disease (PAD) * Includes Ankle/Brachial Index < 0.90 Criteria for classification of ASCVD Coronary Revascularization Procedure Other Revascularization Procedure Ischemic Stroke (CVA) Other Atherosclerotic Diseases: *Coronary atherosclerosis *Renal atherosclerosis *Aortic aneurysm *Carotid Plaque, > 50% stenosis 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

ACC/AHA 2013 Lipid Guidelines Group 1. Patient with Clinical ASCVD Group 2. Primary elevated LDLc > 190mg/dl Group 3. 45-75 years old with diabetes and LDLc 70-189mg/dl Group 4. 45-75 years old without diabetes or ASCVD with 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.

Selecting Intensity Dose of Statins High-Intensity LDL reduction of > 50% on average atorvastatin 80 mg rosuvastatin 20 mg atorvastatin 40 mg* rosuvastatin 40 mg* Moderate-Intensity LDL reduction of 30-50% on average atorvastatin 10 mg rosuvastatin 10 mg simvastatin 20-40 mg pravastatin 40 mg lovastatin 40 mg fluvastatin 40 mg BID atorvastatin 20 mg* rosuvastatin 5 mg* pravastatin 80 mg* fluvastatin XL 80 mg* pitavastatin 2-4 mg* Low-Intensity LDL reduction of < 30% pravastatin 10-20 mg lovastatin 20 mg simvastatin 10 mg* fluvastatin 20-40 mg* pitavastatin 1 mg* *Alternatives with FDA approval but not studied in RCTs reviewed by Expert Panel RULE OF THUMB: HIGH-intensity statin dosing starts at ½ the max prescribed dose and no HIGH-intensity drugs fall in the LOW-intensity category Stone N. J Am Coll Cardiol. 2014;63(25 Pt B)2889-934.

NLA Guidelines Targets of intervention in lipid management Non-HDL cholesterol LDL cholesterol Apo B Treatment Goals Risk Category Treatment Goals (mg/dl) Non-HDL-c LDL-c Apo B Very High <100 <70 <80 High <130 <100 <90 Moderate Low Jacobson TA, et al. Journal of Clinical Lipidology. 2014(8):473-488

ACC/AHA 2013 NLA 2014 Triglycerides per Guidelines Endocrine Society 2012 Comparison Between Guidelines *Primary objective: < 500mg/dl *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 *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.

NON-STATIN UPDATES

Fibrates Role in Therapy Gemfibrozil: ohelsinki Heart Study (HHS) vs. placebo ova-hit secondary prevention - vs. placebo Fenofibrate: ofield vs. placebo Combination statins + fibrates: 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. Tonkin, A. et al. Am Heart J. 2012 Mar;163(3):508-14. PMID: 22424024

Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus The ACCORD Study Group Interventions SBP <120 SBP <140 Simvastatin + fenofibrate Simvastatin + placebo Totals A1C<6% 1,050 1,050 1,450 1,450 5,000 A1C 7.0-7.9% 1,050 1,050 1,450 1,450 5,000 Subtotals 2100 2100 2900 2900 Totals 4,200 5,800 10,000 ACCORD study group. N Engl J Med. 2010 Apr 29;362(17):1563-74.

ACCORD Results Treatment arm Primary outcome event rate Hazard ratio (95% CI) Simvastatin + Placebo 2.4% 1 Simvastatin + Fenofibrate 2.2% 0.92 (0.79-1.08) Sub-population Control primary outcome rate Experimental primary outcome rate P value of inter-group interaction Male 13.3% 11.2% Female 6.6% 9.1% Dyslipidemia subpopulation (TG >204mg/dL, HDL (<34mg/dL) 17.3% 12.4% 0.01 0.057 Remaining population 10.1% 10.1% ACCORD study group. N Engl J Med. 2010 Apr 29;362(17):1563-74.

ACCORD Secondary Outcomes Outcome Primary + revasc./chf hospitalization Major coronary disease event Fenofibrate + statin # events (%) Placebo + statin # events (%) HR (95% CI) P value 641 (5.35) 667 (5.64) 0.94 (0.85-1.05) 0.30 332 (2.58) 353 (2.79) 0.92 (0.79-1.07) 0.26 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 Nonfatal stroke 47 (0.35) 40 (0.30) 1.17 (0.76-1.78) 0.48 All deaths 203 (1.47) 221 (1.61) 0.91 (0.75-1.10) 0.33 CV deaths 99 (0.72) 114 (0.83) 0.86 (0.66-1.12) 0.26 Fatal or nonfatal CHF 120 (0.90) 143 (1.09) 0.82 (0.65-1.05) 0.10 ACCORD study group. N Engl J Med. 2010 Apr 29;362(17):1563-74.

ACCORD Safety Data Adverse event Fenofibrate + statin # reports (%) Placebo +statin # reports (%) P value Myalgia 1140 (40.1%) 1115 (40.5%) 0.79 Myopathy/Myositis/Rha bdomyolysis 4 (0.1%) 3 (0.1%) 1.00 ALT > 3x ULN 52 (1.9%) 40 (1.5%) 0.21 ALT >5 x ULN 16 (0.6%) 6 (0.2%) 0.03 Female SCr ever >1.3mg/dL Male SCr ever >1.5mg/dL Post randomization microalbuminuria ( 30 to <300mg/g) Post randomization macroalbuminuria ( 300 mg/g) 235 (27.9%) 157 (18.7%) <0.001 698 (36.7%) 350 (18.5%) <0.001 1050 (38.2%) 1137 (41.6%) 0.01 289 (10.5%) 337 (12.3%) 0.04 ACCORD study group. N Engl J Med. 2010 Apr 29;362(17):1563-74.

Niacin s Role in Therapy Niacin Formulations Conjugation pathway Low-affinity, high-capacity FLUSHING Niacin Amidation pathway High-affinity Low capacity HEPATOTOXIC Metabolism: Rate of release of the various niacin formulations determines the pathway NUA Immediate release Extended Release NIASPAN NAM Sustained release Depending on pathway metabolized you can know the side effects of the drug Niaspan (niacin) tablet, extended release [Internet]. US National Library of Medicine; 2008 Jan. Available from http://dailymed.nlm.nih.gov/dailymed/archives/

AIM-HIGH Trial RDBPC Trial = 92 centers in US/Canada n = 3,414 Purpose: Does improving HDL and TGs parameters = better cardiac outcomes in patients with heart/vascular disease with well controlled LDL Study intervention: Treatment group: niacin ER 1500-2000mg + simvastatin Placebo group: simvastatin + placebo (+50mg niacin IR) Both groups: +/- ezetimibe 10mg/d to achieve target LDL Primary endpoint: composite of first event of death from CHD, non-fatal MI, ischemic stroke, hospitalization (>23 hours) for ACS, or symptom-driven coronary/cerebral revascularization RDBPC = Randomized, double blind, placebo controlled trial 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 Supplement to Niacin in Patients with Low HDL Cholesterol Levels Receiving Intensive Statin Therapy. N Engl J Med 2011; 365:2255-67. Available from http://www.natap.org/2012/hiv/nejmoa1107579_appendix.pdf

Endpoint Placebo + statin n = 1696 AIM-HIGH Trial ER Niacin +statin N = 1718 HR with Niacin (95% CI) P value Primary 274(16.2%) 282(16.4%) 1.02 (0.87-1.21) 0.80 Death from CHD 26(1.5%) 20(1.2%) Nonfatal MI 80(4.7%) 92(5.4%) Ischemic CVA 15(0.9%) 27(1.6%) Hospitalization ACS 67(4%) 63(3.7%) Symptom driven revasc. 86(5.1%) 80(4.7%) Steering committed decided to halt blinded treatment phase 18 months earlier = lack of benefit of niacin beyond statin therapy 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/ 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. Largest ever randomized trial of ER niacin treatment, n=25, 673 Purpose: Does adding Extended Release Niacin to already background statin therapy improve cardiovascular reduction in high risk patient populations Hx of MI CVA PAD DM with evidence of symptomatic CHD Study intervention: Treatment group: niacin ER 2g, laropiprant 40mg Control group: matching placebo Both groups received simvastatin 40mg (+/- ezetimibe 10mg) CONCLUSION: Indicated addition of niacin was not better in combination vs. background statin therapy in reduction of CV events. (p = 0.29; CI [0.9-1.03]) HPS2-THRIVE Collaborative Group. N Engl J Med 2014;371:203-12.

HPS2-THRIVE Trial Event Type Niacin-L (n = 12,838) Placebo ERN/LRPT (n = 12,835) Absolute Excess Placebo with P value P(CI) value # randomized 12,838 Niacin-L 12,835 (%) Abnormal Alanine Serious transaminase ADE - # (%) at Routine visits GI Any >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) Any >3x ULN c/o muscle 124(0.27%) 65(0.14%) <0.001 Bleeding damage 326 (2.5) 238 (1.9) 0.7 +/- 0.2 <0.001 (1.17-1.62) All Results Musculoskeletal 481 (3.7) 385 (3.0) 0.7 +/- 0.2 <0.001 Any >3x ULN 315(0.68%) 133(0.29%0 (1.10-1.44) <0.001 New Any onset >3x ULN DMc/o muscle 494/8704 (5.7) 234(0.51%0 376/8670 (4.3) 1.3+/-0.3 119(0.26%) <0.001 <0.001 damage (1.16-1.51) Disturbed DM control 460/4134 (11.1) 311/4135 (7.5) 3.7 +/- 0.6 <0.001 (1.37-1.78) European Heart Journal [Internet]. 2013 Jan; Available from http://eurheartj.oxfordjournals.org/content/early/2013/02/26/eurheartj.eht055.full.pdf+html HPS2-THRIVE Collaborative Group. N Engl J Med 2014;371:203-12.

Ezetimibe s Role in Therapy ENHANCE Trial RBDMC Trial = 24 months Purpose: Does combination therapy of simvastatin and ezetimibe improve surrogate markers by reducing mean intima-media thickness [IMT]? Study Intervention: Familial Hypercholesterolemia 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.

Ezetimibe s Role in Therapy IMPROVE-IT Trial RBDMC Trial = 6 year follow up trial Purpose: Does combination therapy of simvastatin and ezetimibe improve cardiovascular outcomes (composite of cardiovascular death, nonfatal MI, unstable angina requiring hospitalization, revascularization or nonfatal stroke? Study Intervention: Hospitalization with 10 day for ACS Simvastatin 40mg with placebo simvastatin 40mg PLUS ezetimibe 10mg daily IMPROVE-IT Investigators. N Eng J Med 2015;372;2387-97. http://www.medscape.com/viewarticle/835030_print Accessed 7/2/2015

New FDA Approved Therapies Agent Mechanism FDA Approval Lomitapide (Juxtapid TM ) Mipomersen (Kynamro TM ) Alirocumab (Praluent ) Evolocumab (Repatha TM ) Microsomal Triglyceride Transfer Protein (MTP) Inhibitor Antisense Oligonucleotide for Apolipoprotein B-100 Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) Inhibitor December 2012 January 2013 July 2015 August 2015 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 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 (Juxtapid TM ) Indication Dosing Homozygous Familial Hypercholesterolemia (HoFH) (Adjunct to diet &other lipid-lowering therapy, including LDL apheresis where available) Begin at 5 mg PO, titrate every 2-4 weeks to 60 mg PO daily Renal Dosing: End-stage renal disease on hemodialysis: Do no exceed 40 mg daily Hepatic Dosing: Child-Pugh A: Do not exceed 40 mg daily Drug Interactions: CI with strong CYP3A4 inhibitors Max dose 30 mg daily with weak CYP3A4 inhibitors (eg atorvastatin, amiodarone, amlodipine, OC, etc.) Mechanism Binds to and inhibits microsomal triglyceride transfer protein (MTP) Juxtapid Package Insert. Aergeion Pharmaceuticals, 2015. http://www.juxtapidremsprogram.com/_pdf/juxtapid_prescribing_information_final_05-15.pdf

Lomitapide Microsomal Triglyceride Transfer Protein (MTP) Inhibitors Prevents assembly of lipoproteins (VLDL) in the liver Castelli WP. Am J Cardiol. 1998 Nov 26;82(10B):60T-65T.

Lomitapide (Juxtapid TM ) Contraindications Pregnancy Concurrent use with moderate or strong CYP3A4 inhibitors Child-Pugh B or C hepatic impairment Black Box Warning REMS program Risk of Hepatotoxicity Elevation in transaminases Increased hepatic steatosis Juxtapid REMS program: Pharmacy and prescriber must be enrolled Juxtapid Package Insert. Aergeion Pharmaceuticals, 2013. http://www.aegerion.com/collateral/documents/english-us/prescribing_information%20june%202013.pdf

Phase 3 Homozygous FH Study Open-label, Single arm Started lomitapide 5 mg daily, to max 60 mg daily Primary Endpoint: Change in LDL from baseline to week 26 Baseline (n=29) Week 26 (Efficacy) (n=23) Level Level Change from baseline LDL (mg/dl) 336 166-50% (-39 to -62%) Cuchel M, et al. Lancet 2013;381:40-46.

Safety Outcomes Most common adverse events: Diarrhea (79%) Nausea (65%) Dyspepsia (38%) Vomiting (35%) Abdominal pain (28%) Weight loss (24%) Study discontinuation 6 patients 3 due to side effects (GI) ALT or AST elevation > 3 X ULN: 34% > 5 X ULN: 14% >10 X ULN: 0% No patients discontinued due to elevated ALT/AST Hepatic fat Increased from 1% to 8.6% Cuchel M, et al. Lancet 2013;381:40-46.

Conclusions Lomitapide provided additional 50% LDL reduction Surrogate outcome (LDL) Side effects common Dose titration limited by side effects (GI and LFT) Lomitapide should be considered as add on therapy for patients with HoFH not able to reach target LDL with other therapies

Mipomersen (Kynamro TM ) Indication Dosing Mechanism Homozygous Familial Hypercholesterolemia (HoFH) (Adjunct to diet &other lipid-lowering therapy) 200 mg subcutaneously once weekly 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

Mipomersen ApoB synthesis Inhibitors Prevents formation of VLDL and LDL Castelli WP. Am J Cardiol. 1998 Nov 26;82(10B):60T-65T.

Mipomersen (Kynamro TM ) Contraindications Moderate or severe hepatic impairment (Child-Pugh B or C) Active liver disease Pregnancy Category B Black Box Risk of Hepatotoxicity Warning Elevation in transaminases Increased hepatic steatosis REMS program Kynamro REMS: Only certified healthcare providers may prescribe Kynamro Package Insert. Genzyme Corporation, 2013. http://www.kynamro.com/~/media/kynamro/files/kynamro-pi.pdf

Mipomersen in Homozygous FH Randomized, double-blind, placebo-controlled Mipomersen 200 mg or placebo subq once weekly x 26 weeks Primary Outcome: LDL change from baseline (%) Placebo (n=17) Mipomersen (n=34) Difference (95% CI) LDL (% change from baseline) -3.3% (5.5 to -12.1%) -24.7% (-17.7 to -31.6%) -21.3%* (-9.8 to -32.9%) Raal F, et al. Lancet 2010;375:998-1006.

Safety Outcomes Placebo (n=17) Mipomersen (n=34) Adverse events 76% 88% Injection-site reaction 24% 76% Influenza-like symptoms 24% 29% Nausea 6% 18% Headache 12% 15% Chest Pain 0% 12% Laboratory Abnormalities ALT 1 - <2 X ULN 41% 35% ALT 2 - <3 X ULN 12% 15% ALT 3 - <8 X ULN 0% 12% ALT > 8 X ULN 0% 0% Raal F, et al. Lancet 2010;375:998-1006.

Conclusions Mipomersen is a promising therapy for uncontrolled Homozygous FH Surrogate outcome (LDL) Well tolerated Additional data needed in other patient populations

Mipomersen in Heterozygous FH Randomized, double-blind, placebo-controlled Mipomersen 200 mg vs. placebo subq weekly x 26 weeks Primary Endpoint: LDL change from baseline (%) LDL (% change from baseline)) Placebo (n=41) 5.2% (10.9 to -0.5%) Mipomersen p-value (n=82) -28.0% (-22.1 to -34.0%) <0.001 Achieved LDL < 100 mg/dl: 5% vs. 45% Stein E, et al. Circulation 2012;126:2283-2292.

Safety Outcomes Placebo (n=41) Mipomersen (n=83) Adverse events 93% 100% Injection-site reaction 42% 93% Influenza-like symptoms 32% 49% Nausea 15% 17% Headache 17% 18% Diarrhea 12% 11% Nasopharyngitis 7% 11% Cough 5% 11% Laboratory Abnormalities 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.

Conclusions Mipomersen is effective for reducing LDL in HeFH when patients fail to reach LDL goals with traditional therapies All patients had history of CAD 40% more patients able to achieve goal LDL Surrogate outcome (LDL) Common ADR: Injection reactions & ALT

Alirocumab (Praluent ) Indication Dosing Mechanism Heterozygous Familial Hypercholesterolemia (HeFH) Clinical ASCVD (Adjunct to diet & maximally tolerated statin therapy in adults who require additional LDL-C lowering) 75 mg subcutaneously every 2 weeks (may increase to 150 mg if additional LDL-C lowering needed) Monoclonal antibody, binds to PCSK9 Inhibits PCSK9 increased LDLR increased clearance of LDL from blood Praluent Package Insert. Sanofi-Aventis, 2015. http://products.sanofi.us/praluent/praluent.pdf

New Treatment Options Proprotein Convertase Subtilisin-Kexin Type 9 (PCSK-9) Inhibitors Prevents breakdown of LDL Receptor Castelli WP. Am J Cardiol. 1998 Nov 26;82(10B):60T-65T.

Alirocumab (Praluent ) Warnings & Precautions Hypersensitivity Reactions Praluent Package Insert. Sanofi-Aventis, 2015. http://products.sanofi.us/praluent/praluent.pdf

Alirocumab in Heterozygous FH Double-blind placebo controlled trial Alirocumab 150 mg subq vs. placebo every 2 weeks Patients w/ HeFH and LDL > 160 mg/dl despite maximally tolerated statin therapy +/- other therapy Primary Outcome: % LDL reduction (week 24) 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

Alirocumab in Heterozygous FH Baseline LDL:196 mg/dl vs. 201 mg/dl Prmary Outcome: LDL (% change from baseline)) Alirocumab (n=72) Placebo (n=35) Difference -45.7% -6.6% -39.1% (p<0.0001) Reached LDL goal: 41% vs. 6% 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

ODYSSEY LONG TERM Trial Randomized, placebo-controlled Alirocumab 150 mg subq every 2 weeks vs. placebo x 78 weeks Patients w/ HeFH or established CHD or CHD risk equivalent + LDL > 70 mg/dl Must be on maximum tolerated statin Primary outcome: % change in LDL at week 24 Robinson JG, et al.odyssey LONG TERM Investigators.. N Engl J Med. 2015 Apr 16;372(16):1489-99.

ODYSSEY LONG TERM Trial Patients: 18% HeFH 99.99% on statin Baseline LDL = 122 mg/dl Primary outcome: % change in LDL at week 24-61.0% vs. 0.8% (p<0.001) 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.

ODYSSEY LONG TERM Trial Other Outcomes: Outcome Alirocumab Placebo p-value Positively adjudicated CV events 4.6% 5.1% 0.68 CHD or unknown death 0.3% 0.9% 0.26 Nonfatal MI 0.9% 2.3% 0.01 Ischemic Stroke 0.6% 0.3% 0.35 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.

ODYSSEY LONG TERM Trial Conclusions: Significant LDL reduction More patient reach goal LDL Well tolerated Decrease events?? Robinson JG, et al.odyssey LONG TERM Investigators.. N Engl J Med. 2015 Apr 16;372(16):1489-99.

Evolocumab (Repatha ) Indication Dosing Mechanism Warnings & Precautions Heterozygous Familial Hypercholesterolemia (HeFH) Clinical ASCVD (Adjunct to diet & maximally tolerated statin therapy in adults who require additional LDL-C lowering) Homozygous Familial Hypercholesterolemia (HoFH) (Adjunct to diet & other lipid lowering therapies) HeFH / Clinical ASCVD: 140 mg subq ever 2 weeks or 420 mg monthly HoFH: 420 mg subq monthly Monoclonal antibody, binds to PCSK9 Inhibits PCSK9 increased LDLR increased clearance of LDL from blood Hypersensitivity Reactions Repatha Package Insert. Amgen, Inc., 2015. http://pi.amgen.com/united_states/repatha/repatha_pi_hcp_english.pdf

Evolucumab in Heterozygous FH (RUTHERFORD-2 Trial) Randomized, placebo-controlled Evolocmab 140 mg subq Q2weeks, placebo Q2weeks Evolocumab 420 mg Q4weeks, Placebo Q4 weeks Patients: HeFH by clinical diagnosis Already on statin 87% on high-intensity statin Average baseline LDL: 151-162 mg/dl Primary Outcome: % LDL change (week 12) Raal FJ, et al; RUTHERFORD-2 Investigators. Lancet. 2015 Jan 24;385(9965):331-40.

Evolucumab in Heterozygous FH (RUTHERFORD-2 Trial) Primary Outcome: % LDL change (week 12) Evolocumab Placebo Difference Q2 week LDL (% change from baseline)) -61.3% -2.0% -59.2% (-65.1 to -53.4%) Evolocumab Placebo Difference Q4 week LDL (% change from baseline)) -55.7% 5.5% -61.3% (-69.0 to -53.6%) Raal FJ, et al; RUTHERFORD-2 Investigators. Lancet. 2015 Jan 24;385(9965):331-40.

Evolucumab in Homozygous FH (TESLA Part B Trial) Randomized, placebo-controlled Evolocumab 420 mg Q4weeks, Placebo Q4 weeks Patients: HoFH Already on high-intensity statin (+ 92% on ezetimibe) Average baseline LDL: 360 mg/dl Primary Outcome: % LDL change (week 12) LDL (% change from baseline)) Evolocumab Placebo Difference -23.1% 7.9% -30.9% (-18.0 to -43.9%) Raal FJ, et al; TESLA Investigators. Lancet. 2015 Jan 24;385(9965):341-50.

OSLER-1 & OSLER-2 Open-label extension trials of evolocumab vs. placebo Primary endpoint: Incidence of adverse events Secondary endpoint: % change in LDL 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.

OSLER-1 & OSLER-2 Primary endpoint: Incidence of adverse events Adverse Event Evolocumab (n=2,976) Secondary endpoint: % change in LDL 58% reduction vs. standard therapy at 12 months Standard Therapy (n=1,489) Muscle related 6.4% 6.0% Injection-site related 4.3% Leading to discontinuation 2.4% Neurocognitive 0.9% 0.3% Arthralgia 4.6% 3.2% Fatigue 2.8% 1.0% 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.

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.

OSLER-1 & OSLER-2 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.

Evolocumab generally well tolerated Few serious ADR s Maintains efficacy at 1 year Clinical Event Reduction?? Conclusions

Looking to the Future Limitations of use: The effects of Praluent on cardiovascular morbidity and mortality have not been determined Limitations of use: The effects of Repatha on cardiovascular morbidity and mortality have not been determined ODYSSEY OUTCOMES = Alirocumab CV Outcomes Study FOURRIER = Evolocumab CV Outcomes Study

Post-test Question #1 Which of the following is the cause for elevated cholesterol levels in patients with familial hypercholesterolemia? A. Being raised with poor dietary choices that cause increased consumption of high cholesterol foods as an adult B. Increased biosynthesis of cholesterol C. Decreased metabolism of LDL D. Decreased production of HDL

Post-test Question #2 Which of the following medications has long term efficacy data showing reduction in cardiovascular events? (choose all that apply) A. Ezetimibe B. Fenofibrate C. Niacin D. Lomitapide E. Mipomersen F. Alirocumab

Meet Lydia Post-test Case #1 62 yo female s/p MI and T2DM, HTN and hyperlipidemia/-triglyceridemia. Meds: ASA 81mg daily, Atorvastatin 10mg daily, Lisinopril 40mg daily, Metformin 1000mg twice daily, Metoprolol Succinate 100mg daily Labs: Chem 7 wnl; LFT wnl; A1c 7.5% Today : TC: 215, TG: 1401, HDL:42, dldl: 86(mg/dl) Results of Atorvastatin 10mg daily being added Question T-3 mo: TC: 215, TG: 1589, HDL: 40, dldl: 126 (mg/dl) Options What is Lydia s indication for statin usage? A. MI B. Type 2 Diabetes C. Her age only D. Both A and B According to ACC/AHA and AACE lipid guidelines what other lipid parameter may warrant drug therapy? A. Hemoglobin A1c B. HDL cholesterol C. Triglycerides D. Total Cholesterol http://blogs-images.forbes.com/janetnovack/files/2012/02/07fueeudvoarl_4310.jpg

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