Lipid Update Family Medicine Review Conference Anschutz Medical Campus November 2, Robert H. Eckel, M.D.

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1 Lipid Update 2011 Family Medicine Review Conference Anschutz Medical Campus November 2, 2011 Robert H. Eckel, M.D. Professor of Medicine Division of Endocrinology, Metabolism and Diabetes Division of Cardiology Professor of Physiology and Biophysics Charles A. Boettcher II Chair in Atherosclerosis University of Colorado Denver School of Medicine Director Lipid Clinic, University Hospital The Lipid Patient Five Groups LDL cholesterol TG (Ø HDL cholesterol LDL cholesterol + TG Ø HDL cholesterol Lipoprotein (a) 1

2 Assessing Acquired Causes of Dyslipidemia Lifestyle Diet, inactivity, alcohol, tobacco Medications Steroids, diuretics, b-blockers, PIs, cis-ra Insulin resistance Thyroid disease Liver disease Kidney disease Proteinuria Ø GFR Revised NCEP ATP III LDL-C Goals CHD Risk Category LDL-C Goal Consider Drug Rx High (Very High) CHD or Risk Equivalent (>20%/10 yrs) <100 (<70) 100* Moderately High 2+ RF (10-20%/10 yrs) < * Moderate 2+ RF (<10%/10 yrs) < * Low 0 1 RF s < * Circulation 110:227, 2004 * Consider drug options if below goal, but above goal for next higher risk level 2

3 Revised NCEP ATP III Non-HDL Goals CHD Risk Category Non-HDL-C Goal Consider Drug Rx High (Very High) CHD or Risk Equivalent (>20%/10 yrs) <130 (<100) 130* Moderately High 2+ RF (10-20%/10 yrs) < * Moderate 2+ RF (<10%/10 yrs) < * Low 0 1 RF s < * Circulation 110:227, 2004 * Consider drug options if below goal, but above goal for next higher risk level NHLBI Clinical Guidelines for CVD Risk Reduc on: Organiza onal Structure NHLBI Director DARD Director Guideline Leadership Group SAIC Support Contract DARD Project Team Clinical Guidelines Executive Committee Cross-Cutting Workgroups Risk Assessment Lifestyle/Nutrition/PA Expert Panel for the Integrated CVD Guideline Development Expert Panel for Cholesterol Updates Expert Panel for Hypertension Updates Expert Panel for Obesity Updates Implementation/System/IT/ Informatics 3

4 Is It Lipids or Apolipoproteins & CVD Risk? The Emerging Risk Factors Collaboration 302,430 people without CVD from 68 long-term prospective studies Mostly Europe and North America 2.79 million person-years of follow-up 8857 non-fatal MIs 3928 CHD deaths 2534 ischemic strokes 513 hemorrhagic strokes 2536 unclassified strokes ERF Collaboration, JAMA 302:1993, 2009 CHD Risk: Non-HDL vs. HDL Cholesterol (n = 302,430) ERF Collaboration, JAMA 302:1993,

5 Apolipoprotein B One apo B molecule/particle Assesses potentially atherogenic particle number Helps to distinguish risk of CHD in patients with hypertriglyceridemia Highly correlated with non-hdl cholesterol 0.95 when TG < 300 mg/dl 0.80 when TG higher Epidemiological Studies in which Total Cholesterol or LDL cholesterol were Equal or Superior to Apo B as Markers of CVD Risk Graaf J et al. Nat Clin Pract Endo Metab ,

6 Epidemiological, Non-Invasive Studies and Clinical Trials which Show that LDL Particles or Apo B are Better Markers of CVD Risk then LDL Cholesterol Graaf J et al. Nat Clin Pract Endo Metab , 2008 Apo B May Predict Vascular Events Better than LDL Cholesterol Observational studies Quebec Cardiovascular Study LIPID (placebo) AMORIS Interventional studies AFCAPS/TexCAPS (lovastatin) LIPID (pravastatin) IDEAL (simvastatin, atorvastatin) TNT (atorvastatin) 6

7 In the ERF Collaboration, Lipids and Apolipoproteins Were Equal in Predicting CHD Risk (n = 91,307) ERF Collaboration, JAMA 302:1993, 2009 The real value of apo B is in patients without increases in LDL cholesterol, in patients with hypertriglyceridemia 7

8 Impact of TG Levels on Relative Risk of CHD: Framingham Heart Study Men Women 2.0 R R TG (mg/ dl) Castelli WP. Can J Cardiol. 4:5A, 1988 Hypertriglyceridemia (1 mm ) and CHD: A Meta-Analysis (21 studies) Relative Risk MEN (65,863): 1.30 ( ) WOMEN (11,089): 1.69 ( ) Adjusted for HDL cholesterol (9 studies): MEN (29,105): 1.17 ( ) WOMEN (6,345): 1.37 ( ) Abdul-Maksoud M and Hokanson J.E., J Vasc Med,

9 Risk of CHD in the Top vs. Bottom Tertile of Usual Log-TG by Study Characteristics Sarwar, N. et al. Circulation 2007;115: Sarwar N et al, Circulation 115:450, 2007 Apo B and CHD Risk: MetaAnalysis Thompson A and Danesh J, Journal of Internal Medicine, 259:481,

10 CHD and Ischemic CVA Risk: Emerging Risk Factors Collaboration Meta-Analysis CHD (n = 302,430 people) CVA ERF Collaboration, JAMA 302:1993, 2009 Odds Ratios for the Development of CHD: Lipid and Lipoprotein Phenotypes Odds are adjusted for age, smoking, alcohol, blood pressure, gender, and medications OR 1.0 (0.001) (0.005) 2.7 (0.001) 3.1 (0.01) 2.1 Normal IIA IIB IV Nl TG TG Ø HDL HyperapoB Lamarche B et al, Am J Card 75:1189,

11 Management of Triglycerides Goal: Is it TG? No, it s non-hdl cholesterol! Then isn t it TG < 150 mg/dl? Or should it be apo B? Correlations Between Apo B, Cholesterol, LDL Cholesterol and Non-HDL Cholesterol Sniderman AS et al, Am J. Card 91:1173,

12 ACC/ADA Lipid Goals LDL-C Non- HDL-C Apo B CHD or DM + 1 RF < 70 mg/ dl < 100 mg/dl < 80 mg/ dl 2 RFs or DM < 100 mg/dl < 130 mg/dl < 90 mg/ dl Brunzell JD et al, JACC 51:1512,

13 LDL-C Reduction in Statin Trials 35 Event Rate (%) Clinical statin trial data ie max model, r 2 = 0.82, p=0.01 4S Tx LIPID Tx LIPID P CARE Tx CARE P HPS Tx HPS P TNT 80 mg TNT 10 mg 4S P LDL-C (mg/dl) Charland SL, et al. Circulation 2005; 112:II-816 Statins: The Down Side Abnormal AST and ALT < 3X ULN: ~1.3% > 3X ULN: <1.0% Dose related Myopathy: Any disease of muscles Myalgias: pain in a muscle of group of muscles ~10% Myositis: muscle symptoms with CK ~2.5% Rhabdomyolysis: > 50 fold in CK + renal impairment <0.1% Bruckert E et al, Cardiov Drugs 19:403, 2005 Brown WV, Curr Opin Lipid 19:558, 2008 Onusko E, J Fam Pract 57:449,

14 What the Clinician Needs to Consider Hypothyroidism Other drugs Fibrates, azole anti-fungals, cyclosporine, macrolides, diltiazem, HIV protease inhibitors Genetic differences in drug-metabolizing enzymes, e.g. OATP1B1 SLCO1B1, CYP2D2, 3A4 Neuromuscular diseases Mitochondrial myopathy, McArdles disease, myotonic dystrophy, polymyositis Patient Types Diagnostic Strategies Therapeutic Options Asymptomatic Mildly Symptomatic CK in high risk patients only CK measured: < 5 x normal Symptoms worse: repeat CK & Stop or Reduce Statin Dose Titrate Statin Dose to reach LDL and non- HDL-C goals Ezetimibe and/or BAS Fluvastatin or pravastatin, 20 mg per night or every other night Moderate to Severely Symptomatic Stop Statin: CK measured, hydrate if creatinine Symptoms gone: CK & creat Fluvastatin XL 80 mg per night Rosuvastatin 5 mg daily, every other day, or weekly Eckel RH, JCEM 95:2015, 2010 Red yeast rice, bid 14

15 LIPOSORBER SYSTEM LIPOSORBER SYSTEM Heparin Pump Re-Priming Solution Regeneration Solution Blood Withdrawal Blood Pump Plasma Pump Regeneration Pump Plasma Separator LIPOSORBER Column s Blood Return Plasma Line Waste Line 15

16 LIPOSORBER SYSTEM LDL-C Diet Therapy Diet & Drug Therapy LIPOSORBER Treatment Pre Time Average Post Time LIPOSORBER SYSTEM 16

17 LONG TERM EFFICACY OF LDL APHERESIS ON CHD IN Familial Hypercholesterolemia Patients Heterozygous FH with CHD Treatment LDL-Apheresis and Medication (n = 43) (Average LDL-Apheresis Interval = 14 days) Medication Only (n = 87) Follow-Up 6 Year Observation of Coronary Events (Non-Fatal MI, PTCA, CABG, CHD Death) Results 72% reduction in Coronary Events for apheresis patients Mabuchi H et al. Am J Card 82:1489, 1998 What about nonstatin approaches in the reduction of LDL cholesterol and CHD? 17

18 Maintain an Overall Healthy Diet! Dietary Patterns and MI Risk in 52 Countries: INTERHEART 5761 cases 10,646 controls Iqbal R et al, Circulation 118:1929,

19 Dietary Risk Score (7 components) and MI Risk in 52 Countries: INTERHEART Iqbal R et al, Circulation 118:1929, 2008 Range of LDL Cholesterol Lowering with Drugs Statins 15-60% And don t forget the 6% rule! 19

20 Range of LDL Cholesterol Lowering with Drugs Statins 15-60% Bile Acid Sequestrants 5-35% Ezetimibe 15-20% Fibrates 10-25% Nicotinic acid 0-20% Randomized Intervention Trials: Relationship Between LDL-C Reduction and Major Coronary Events Major coronary event rate (%) HPS CARE LIPID Post-CABG 5 AFCAPS/ 0 TexCAPS S LDL-C during trial (active treatment and placebo) Secondary prevention trials Primary prevention trials LRC-CPPT WOSCOPS Modified from Waters DD and Azar RR. Am J Cardiol. 86:35J-43J, Fox R. Circulation. 2001;104:e9051; Schwartz GG et al. JAMA. 285:1711,

21 Where are we at on ezetimibe? 21

22 ARBITER 6-HALTS HALTS : HDL And LDL Treatment Strategies Purpose Compare the effectiveness of combination lipid lowering therapy with either extended-release niacin or ezetimibe added to long-term statin therapy for the endpoint of carotid intima-media thickness over 14 months PROBE Design Prospective, randomized, parallel-group, open-label study involving blinded evaluation of endpoints Walter Reed Army Medical Center- Washington, D.C. Washington Adventist Hospital- Takoma Park, MD Overall Baseline Characteristics N = % male Age: 65 ± 11 years All on statins 42 ± 25 mg/d 6 ± 5 years duration 95% simvastatin or atorvastatin Baseline measured variables TC 147 ± 26 mg/dl LDL-C 82 ± 23 mg/dl HDL-C 42 ± 8.5 mg/dl TG 134 ± 68 mg/dl CIMT Mean ± mm Max ± mm Baseline characteristics balanced in the 2 treatment groups. Baseline statin dose: Little room for additional statin titration. 22

23 Results: Lipid Concentrations Niacin Niacin: HDL increased by 18.4% to 50 mg per deciliter Ø LDL and TG P < Ezetimibe Niacin P = 0.01 Ezetimibe Ezetimibe: LDL decreased by 19.2%, to 66 mg per deciliter P = 0.01 Niacin Ezetimibe Ezetimibe P = Niacin Δ LDL-C Δ HDL-C Δ TG (median) Ezetimibe 17.6±20.1 mg/dl 2.8±5.7 mg/dl -9 mg/dl Niacin 10.0±24.5 mg/dl +7.5±9.2 mg/dl -36 mg/dl Results: Primary Endpoint Between-group Change in CIMT Niacin was superior to ezetimibe for the primary endpoint of the between group difference in carotid intima-media thickness. P =

24 Results: LDL Change vs. CIMT Change In a post hoc analysis, we explored the bivariate relationships between changes in LDL cholesterol levels and mean carotid intima media thickness. Ezetimibe R = -0.31; P < Niacin R = -0.01; P = 0.92 Posted online at Paradoxical increase in CIMT in patients treated with ezetimibe with greater reductions in LDL cholesterol. This effect was not observed with niacin. Hypothesis generating regarding the net effects of ezetimibe s complex mechanism of action in patients with dyslipidemia. Results: Major CVD Events Major adverse cardiovascular events occurred at a significantly lower incidence in the niacin (2/160 patients [1.2%] vs. the ezetimibe group (9/165 patients [5.5%]) Chi-square p=0.04; Log-rank p =

25 New Non-Statin Therapies for LDL Cholesterol Lowering MTP inhibitors Antisense apolipoprotein B PCSK9 inhibitors Eprotirome Liver-specific thyroid hormone b-receptor agonist HDL: So what do we really know? 25

26 HDL and Atherosclerosis Anti-oxidant Anti-inflammatory Anti-thrombotic prostacyclin Promotes vascular reactivity NOS Decreases myeloproliferative cell development Reverse cholesterol transport ApoF ApoE ApoD ApoL-1 PLTP ApoM ApoA-II CETP Clusterin ApoA-IV The HDL Proteome LCAT ApoH ApoC-I Lipid Metabolism ApoC-II ApoC-III SAA1 PON1 ApoA-I ApoC-IV PON3 SAA4 SAA2 AHSG AGT HRP SERF2 Proteinase Inhibitor SERA1 SERF1 AMP KNG1 Complement Regulation C3 Acute Phase Response C4A C4B ORM2 HPX C9 TTR FGA ITIH4 RBP4 TF VTN Vaisar T et al. J Clin Invest. 117:746,

27 HDL- Paradox CETP deficient Japanese families with HDL levels mg/dl or higher in heterozygotes But, possibly an increase in CHD risk Apo A1 Milano Low HDL octagenarians with low CHD risk Tangier Disease ABCA1 gene deficiency Genetically low HDL: Turkey (HTGL gene mutation) and China When relocated to an urban environment, CHD risk Many patients without low HDL have CHD Pro-inflammatory HDL? Type 1 diabetes Effects of Drugs on HDL-C Levels Niacin 15-35% Fibrates 5-15% Statins 5-10% Resins 5-10% Estrogens p.o % CETP inhibitors 25-60% Torcetrapib - abandoned Dalcetrapib (JTT-705): Phase 3 trials Anacetrapib (MK-0859): Phase 3 trials 27

28 Novel Therapies for Raising HDL Reconstituted HDL Apo A-1 Apo A-1 Milano Apo A-1 peptides PPAR-a/d dual agonists New drug classes For HDL, where s the evidence? 28

29 Coronary Drug Project: 15-Year Mortality Results Niacin n=1,119 Placebo n=2,789 Risk Reduction Total Mortality 52% 58% -11% <0.005 P FBG < 100 mg/dl 48% 53% -9% <0.05 FBG 100 mg/dl 56% 63% -12% <0.005 CHD Mortality 36% 41% -12% <0.01 Canner PL et al, J Am Coll Cardiol. 8:1245, CDP - METABOLIC SYNDROME % of Patients with Non Fatal MI Placebo n = 124 Niacin 69% fl 28% fl Metabolic Syndrome (+) Metabolic Syndrome (-) Canner PL et al, Am J Cardiol :477,

30 CDP - METABOLIC SYNDROME % of Patients (Total Mortality) Placebo n = 368 Niacin 27% fl 17% fl Metabolic Syndrome (+) Metabolic Syndrome (-) Canner PL et al, Am J Cardiol :477, 2006 Niacin and CVD Events in the Metabolic Syndrome: FATS, HATS, AFREGS Zhao XQ et al, Am J Cardiol. 104:1457,

31 Definitive HDL Cholesterol Outcome Studies HPS2-Thrive This study is currently recruiting participants. Verified by University of Oxford, November 2009 First Received: April 17, 2007 Last Updated: November 4, 2009 History of Changes Purpose - The primary aim is to assess the effects of raising HDL cholesterol with extended release niacin/laropiprant vs. matching placebo on the risk of MI or coronary death, stroke, or the need for revascularization in people with a history of circulatory problems. Definitive HDL Cholesterol Outcome Studies Aim High Plaque Inflammation and Dysfunctional HDL Cholesterol in Participants Receiving Niacin and Statins in the AIM-HIGH Study (The HDL Proteomics Study) This study is currently recruiting participants. Verified and funded by National Heart, Lung, and Blood Institute (NHLBI), April 2009 First Received: April 10, 2009 No Changes Posted Purpose: This study will examine the CVD risk reduction and include MRI images and blood samples of participants who are taking niacin plus statins or statins alone to determine the effect of these medications on inflammation in atherosclerotic plaques. 31

32 IMPROVE-IT IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin (Ezetimibe/Simvastatin) vs. Simvastatin (Study P04103AM3) clinicaltrials.gov This study is currently recruiting participants. First Received: September 13, 2005 Last Updated: December 10, 2009 History of Changes Primary Outcome: To measure the effect of treatment with ezetimibe/simvastatin compared with simvastatin monotherapy on death due to any CVD events, nonfatal coronary events (i.e. MI), and non-fatal strokes. Time Frame: Trial will continue until a minimum of 5,250 subjects have a primary endpoint event and each subject is followed for a minimum of 2.5 years. New Non-Statin Therapies for Atherogenic Lipoprotein Lowering MTP inhibitors Antisense apolipoprotein B Thyroid hormone b-receptor agonists Pro-drug targeted to the liver PCKSK9 inhibitors 32

33 Lipoprotein (a): What do We Know? 33

34 Lipoprotein (a) Genotype, Level and CHD Risk Clarke R et al, NEJM 361:2518, 2009 The Lipid Patient: Lipoprotein (a) > 30 mg/dl LDL cholesterol Goal <160, <130, <100, <70 mg/dl NCEP-ATP:III <145, <115, <85, <55 mg/dl Suggested goal for lipoprotein (a) > 30 mg/dl 34

35 So What are the Tough Decisions? LDL-C: How low? <100 or < 70 Statin Intolerance Your choice LDL-C: What drugs? All if needed TG: TG, Non-HDL-C or Apo B? Apo B HDL-C: A target for Rx? Probably, but get the LDL down low 1st Lipoprotein (a)? > 30 mg/dl, Ø LDL-C by 15 mg/dl more 35