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 http://blogs‐images.forbes.com/janetnovack/files/2012/02/07FUeEudVoarl_4310.jpg 1 9/23/2015 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 http://blogs‐images.forbes.com/janetnovack/files/2012/02/07FUeEudVoarl_4310.jpg 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. 2 9/23/2015 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. 3 9/23/2015 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. 4 9/23/2015 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 5 9/23/2015 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.