A Patient with Coronary Artery Disease and Low

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A Patient with Coronary Artery Disease and Low High-Density Lipoprotein: 10 year story Tara

A Patient with Coronary Artery Disease and Low High-Density Lipoprotein: 10 year story Tara Dall, MD

History of Present Illness: A 63 -year old man who has had coronary artery

History of Present Illness: A 63 -year old man who has had coronary artery bypass grafting (CABG) surgery after presentation for atypical chest pain and abnormal catherization showing diffuse disease in LAD.

History (Continued) n Social History: nonsmoker; minimal alcohol intake n Family History: – Mother

History (Continued) n Social History: nonsmoker; minimal alcohol intake n Family History: – Mother died of a myocardial infarction (MI) at 78 years of age – Father died of an MI at 51 years of age – Brother died of a cerebrovascular accident at 43 years of age – A son has high cholesterol and diabetes n Past Medical History: – Gastroesophageal reflux disease – Coronary artery disease – Hypertension n Medications: – Over-the-counter flush free niacin at a dose of 500 mg 3 x/day – Aspirin at a dose of 81 mg daily

Initial Physical Exam n Blood Pressure = 118/76 mm Hg n Height = 5’

Initial Physical Exam n Blood Pressure = 118/76 mm Hg n Height = 5’ 8” n Weight = 168. 2 lbs n Waist Circumference = 40 in n Body Mass Index = 25. 6 kg/m 2

Initial Laboratory Test Results n Lipid Panel: – Total cholesterol = 158 mg/d. L

Initial Laboratory Test Results n Lipid Panel: – Total cholesterol = 158 mg/d. L – Low-density lipoprotein (LDL) cholesterol = 107 mg/d. L – High-density lipoprotein cholesterol = 23 mg/d. L – Non–high-density lipoprotein cholesterol = 135 mg/d. L – Triglycerides = 138 mg/d. L – LDL particle number = 1, 515 – LDL size = 19. 6 nm (small pattern B) n Lipoprotein (a) = 161 mg/d. L (ULN 30 mg/d. L) n Homocysteine = 6. 9 µmol/L n High-sensitivity C-Reactive Protein = 1. 9 mg/L n Glucose = 97 mg/d. L ULN = upper limits of normal

What is most likely causing the patient’s high-density lipoprotein cholesterol to be low? A.

What is most likely causing the patient’s high-density lipoprotein cholesterol to be low? A. Smoking B. Metabolic syndrome C. Familial hypoalphalipoproteinemia D. Diabetes E. Obesity F. Very-low-fat diet

HDL-C Is a Modifier of Risk at All Levels of LDL-C: the Framingham Study*

HDL-C Is a Modifier of Risk at All Levels of LDL-C: the Framingham Study* Patient 1 LDL-C 100 mg/d. L HDL-C 65 mg/d. L Risk level 0. 4 LDL-C 100 mg/d. L HDL-C 45 mg/d. L Risk level 0. 6 Patient 3 LDL-C 100 mg/d. L HDL-C 25 mg/d. L Risk of CHD Patient 2 Risk level 1. 2 Equivalent Risk 3 4 2 1 Patient 4 HDL-C, mg/d. L LDL-C 220 mg/d. L HDL-C 45 mg/d. L Risk level 1. 2 *Men 50 to 70 years of age LDL-C, mg/d. L Castelli WP. Can J Cardiol. 1988; 4(suppl A): 5 A-10 A.

What is the primary target of therapy for a patient with coronary artery disease

What is the primary target of therapy for a patient with coronary artery disease and low HDL-C? A. Raise HDL-C to >40 mg/d. L Lower LDL-C to <70 mg/d. L C. Lower triglycerides to <100 mg/d. L D. Reduce lipoprotein (a) to <30 mg/d. L B. Reduce the LDL particle number to <1000 nmol/L F. Reduce apolipoprotein B to <80 mg/d. L G. Reduce non–HDL-C to <100 mg/d. L E. HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol

LDL-C and Non-HDL-C Goals LDL-C Goal + 30 mg/d. L = Non–HDL-C Goal LDL-C

LDL-C and Non-HDL-C Goals LDL-C Goal + 30 mg/d. L = Non–HDL-C Goal LDL-C Goal (mg/d. L) Non-HDL-C Goal (mg/d. L) No CHD, 0– 1 risk factors <160 <190 No CHD, 2+ risk factors <130 (optional <100) <160 CHD/CHD risk equivalent <100 <130 CVD + DM/MS/Cigs/ACS <70 (optional) <100 (optional) Patient Category ACS = acute coronary syndrome; CHD = coronary heart disease; Cigs = cigarettes; CVD = cardiovascular disease; DM = diabetes mellitus; MS = metabolic syndrome; HDL-C = highdensity lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol Adapted from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001; 285: 2486– 2497. | Grundy SM, et al. Circulation. 2004; 110: 227 -239.

ADA and ACC Consensus Statement on Lipoprotein Management in Patients With Cardiometabolic Risk LDL-C

ADA and ACC Consensus Statement on Lipoprotein Management in Patients With Cardiometabolic Risk LDL-C (mg/d. L) Non-HDL-C (mg/DL) Apo B (mg/d. L) Highest-risk patients, including those with 1) known CVD or 2) diabetes plus one or more additional CVD risk factor <70 <100 <80 High-risk patients, including those with 1) no diabetes or known clinical CVD but 2 or more additional major CVD risk factors or 2) diabetes but no other CVD risk factors <100 <130 <90 TREATMENT GOALS ACC = American College of Cardiology; ADA = American Diabetes Association; Apo B = apolipoprotein B; CVD = cardiovascular disease; LDL-C = low-density lipoprotein cholesterol; HDL-C = high-density lipoprotein cholesterol Brunzell JD, et al. Diabetes Care. 2008; 31: 811– 822.

6 Months After Coronary Artery Bypass Grafting n Current Medications: – 20 -mg esomeprazole

6 Months After Coronary Artery Bypass Grafting n Current Medications: – 20 -mg esomeprazole magnesium – 500 -mg niacin 3 x/day (flush free) n Lipid Profile: – Total cholesterol = 161 mg/d. L – LDL-C = 121 mg/d. L – HDL-C = 24 mg/d. L – Triglycerides = 77 mg/d. L – Non–HDL-C = 137 mg/d. L n Initial Intervention: lovastatin 20 mg (the only generic statin available at the time) HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol

Eight Months After Coronary Artery Bypass Grafting n Current Medications: 20 -mg lovastatin and

Eight Months After Coronary Artery Bypass Grafting n Current Medications: 20 -mg lovastatin and 2, 000 -mg niacin n Physical Exam: – Weight = 165. 1 lbs (↓ 4. 8 lbs) – Blood Pressure = 132/76 mm. Hg n Lipid Profile: – Total cholesterol = 156 mg/d. L – Low-density lipoprotein cholesterol = 105 mg/d. L – High-density lipoprotein cholesterol = 26 mg/d. L – Triglycerides = 130 mg/d. L – Non–high-density lipoprotein cholesterol = 130 mg/d. L – Lipoprotein (a): 164 mg/d. L n Intervention: Increased lovastatin to 40 mg and continued niacin diet supplement, but avoiding flush free niacin which is not effective for cholesterol reduction and avoiding sustained release (Slo. Niacin) which has potential for hepatotoxicity, Advised Immediate release taken 2 -3 times/day or Niaspan prescription

Which therapy will achieve further reductions of non–high-density lipoprotein cholesterol? A. Double the dose

Which therapy will achieve further reductions of non–high-density lipoprotein cholesterol? A. Double the dose of lovastatin B. Switch to a higher efficacy statin C. Add a bile acid sequestrant D. Add omega-3 fatty acids E. Add fenofibrate F. Increase niacin G. All of the above

One Year After Coronary Artery Bypass Grafting n Current Medications: 40 -mg lovastatin 2,

One Year After Coronary Artery Bypass Grafting n Current Medications: 40 -mg lovastatin 2, 000 -mg, Immediate release niacin 500 mg four times daily n Lipid Profile: – Total cholesterol = 156 mg/d. L – Low-density lipoprotein cholesterol (LDL) = 121 mg/d. L – Triglycerides = 60 mg/d. L – High-density lipoprotein cholesterol = 26 mg/d. L – Non–high-density lipoprotein cholesterol = 130 mg/d. L – Concentration of LDL particles = 1, 552 – LDL size = 20. 1 nm (small pattern B) n Intervention: Switch to 20 -mg rosuvastatin

Pharmacologic Therapy: Dose Response of Different Statins Response to Minimum/Maximum Statin Dose % Reduction

Pharmacologic Therapy: Dose Response of Different Statins Response to Minimum/Maximum Statin Dose % Reduction in LDL-C Fluvastatin Pravastatin Lovastatin Simvastatin Atorvastatin 10/80 mg 20/80 mg 31 37 40 LDL-C = low-density lipoprotein cholesterol Illingworth DR. Med Clin North Am. 2000; 84: 23– 42. 47 55

Dose Efficacy of Statin-Based Therapies for LDL-C Reduction (%) Dose Efficacy in STELLAR* Single

Dose Efficacy of Statin-Based Therapies for LDL-C Reduction (%) Dose Efficacy in STELLAR* Single Agent 10 mg 20 mg 40 mg 80 mg Rosuvastatin 46 52 55 NA Atorvastatin 37 43 48 51 Pravastatin 20 24 30 NA Simvastatin 28 35 39 46 Fixed-Dose Combination Ezetimibe 10 mg/Simvastatin 10– 80 mg reduces low-density lipoprotein cholesterol by 45% to 60% NA = not applicable Created from Jones PH, et al. Am J Cardiol. 2003; 92: 152– 160.

Thirteen Months After Coronary Artery Bypass Grafting n Current Medications: – 20 -mg rosuvastatin

Thirteen Months After Coronary Artery Bypass Grafting n Current Medications: – 20 -mg rosuvastatin – 81 -mg aspirin – 2, 000 -mg immediate release niacin (immediate release diet supplement taking 500 four times daily) – Multiple supplements (Vitamin E, Vitamin C, multivitamins) n Lipid Profile: – Total cholesterol = 114 mg/d. L – Low-density lipoprotein cholesterol = 74 mg/d. L – High-density lipoprotein cholesterol = 25 mg/d. L – Triglycerides = 75 mg/d. L – Non–high-density lipoprotein cholesterol = 89 mg/d. L

What is the risk for coronary heart disease events during statin therapy when optimal

What is the risk for coronary heart disease events during statin therapy when optimal levels of LDL and non–HDL cholesterols have been achieved?

Low HDL-C Increases CVD Risk Even if LDL-C Levels Are Well-Controlled: Treating to New

Low HDL-C Increases CVD Risk Even if LDL-C Levels Are Well-Controlled: Treating to New Targets Study 5 - Year Risk of Major CVD Events (%) Patients With LDL-C ≤ 70 mg/d. L on a Statin*† HDL-C Quintiles* mg/d. L Hazard Ratio vs. Q 1‡ n = 2, 661 Q 1 <37 Q 2 37 to <42 0. 85 Q 3 42 to <47 0. 57 Q 4 47 to <55 0. 55 Q 5 ≥ 55 0. 61 *On-treatment level (3 months statin therapy); †mean LDL-C = 58 mg/d. L and mean triglycerides = 126 mg/d. L; ‡P = 0. 03 for differences among quartiles of HDL-C CVD = cardiovascular disease; LDL-C = low-density lipoprotein cholesterol; HDL-C = high-density lipoprotein cholesterol Barter P, et al. N Engl J Med. 2007; 357: 1301– 1310.

Which of the following agents have been shown to raise high-density lipoprotein cholesterol? A.

Which of the following agents have been shown to raise high-density lipoprotein cholesterol? A. Niacin B. Alcohol C. Omega-3 fatty acids D. Statins E. Pioglitazone F. Fibrates G. All of the above

Effects of Regular Exercise on HDL-C n Regular exercise increases HDL-C n Kokkinos et

Effects of Regular Exercise on HDL-C n Regular exercise increases HDL-C n Kokkinos et al. reported a clear dose-response relationship between aerobic exercise (running) and HDL-C in healthy men HDL-C (mg/d. L) Nonrunners (n=685) 5 miles/ week (n=335) 9 miles/ week (n=512) 12 miles/ week (n=376) 17 miles/ week (n=602) 31 miles/ week (n=396) 47. 3 48. 7 50. 7* 52. 5*† 53. 0*† 56. 3*‡ *P < 0. 001 vs. nonrunners † P < 0. 01 vs. nonrunners and 5 miles/week ‡ P < 0. 01 vs. all other groups HDL-C=high-density lipoprotein cholesterol Kokkinos PF, et al. Arch Intern Med. 1995; 155: 415– 420.

Increasing High-Density Lipoprotein (HDL): Nonpharmacologic Methods 7 n Exercise may be overrated P=0. 015

Increasing High-Density Lipoprotein (HDL): Nonpharmacologic Methods 7 n Exercise may be overrated P=0. 015 triglycerides are high – HDL only with intense, frequent exercise n Alcohol – Raises triglycerides, which affects cholesteryl ester transfer protein activity – Modest HDL changes Changes in HDL-C Concentration (mg/d. L) – HDL only when Frequent, intense exercise 4 Infrequent exercise 1 0 n Smoking cessation n Weight loss Control Moderate Intense -2 Couillard C, et al. Arterioscler Thromb Vasc Biol. 2001; 21: 1226 -1232. | Kraus WE, et al. N Engl J Med. 2002; 347: 1483 -1492.

Lipid-Modifying Drugs That Affect High. Density Lipoprotein Cholesterol Levels Niacin 15– 35% Fibrates 10–

Lipid-Modifying Drugs That Affect High. Density Lipoprotein Cholesterol Levels Niacin 15– 35% Fibrates 10– 15% Statins 5– 10% Omega-3 Fatty Acids 3– 9% Ezetimibe 1– 3% Belalcazar LM, et al. Progr Cardiovasc Dis. 1998; 41: 151– 174.

ADA/ACC Consensus Statement on Lipoprotein Management in Patients With Cardiometabolic Risk n In patients

ADA/ACC Consensus Statement on Lipoprotein Management in Patients With Cardiometabolic Risk n In patients who are taking statins and continuing to have low HDL-C or elevated non–HDL-C, especially if apo B remains elevated, combination therapy is recommended. n The preferred agent to use in combination with a statin is niacin because there is somewhat better evidence for reduction in cardiovascular disease events with niacin than there is for fibrates ACC = American College of Cardiologists; ADA = American Diabetes Association; apo B = apolipoprotein B; HDL-C = high-density lipoprotein cholesterol Brunzell JD et al. Diabetes Care. 2008; 31: 811 -822.

Statins and Other Lipid-Modifying Therapies: Results from the COMPELL Study Atorvastatin 40/Niacin ER 2000

Statins and Other Lipid-Modifying Therapies: Results from the COMPELL Study Atorvastatin 40/Niacin ER 2000 Simvastatin/Ezetimibe 40/10 mg Rosuvastatin 20/Niacin ER 1000 Rosuvastatin 40 mg Change from Baseline At 12 Weeks High-Density Lipoprotein Cholesterol COMPELL = Comparative Effects on Lipid Levels of Combination Therapy With a Statin and Extended Release Niacin or Ezetimibe Versus a Statin Alone; ER = extended release Created from Mc. Kenney JM, et al. Atherosclerosis. 2007; 19: 432 -437.

Four Years After Coronary Artery Bypass Grafting n Patient reports atypical chest pain n

Four Years After Coronary Artery Bypass Grafting n Patient reports atypical chest pain n Second cardiac catheterization performed – Diffuse disease unchanged – No progression from previous catherization – Ejection fraction of 56% – Chest pain diagnosed as noncardiac n Patient tested for diabetes – Impaired fasting glucose = 101 mg/dl – Hemoglobin A 1 C = 5. 6 n Intervention for abnormal glucose level – 15 mg pioglitazone added to cholesterol-lowering regimen

Which therapy may have additional beneficial effects on the patient’s lipid profile and abnormal

Which therapy may have additional beneficial effects on the patient’s lipid profile and abnormal glucose level? A. Thiazolidinediones B. Metformin C. Omega-3 fatty acids D. Bile acid sequestrant (Welchol®) E. A and D F. A, B, and D G. All of the above

Changes in Biochemical Parameters: PERISCOPE Trial High-Density Lipoprotein Low-Density Lipoprotein Glimepiride Pioglitazone 16. 0%

Changes in Biochemical Parameters: PERISCOPE Trial High-Density Lipoprotein Low-Density Lipoprotein Glimepiride Pioglitazone 16. 0% P<0. 001 Pioglitazone 6. 9% 6. 6% P=0. 69 4. 1% High Sensitivity C-Reactive Protein 0. 6% -18. 0% P<0. 001 Glimepiride Pioglitazone Triglycerides − 44. 9% Created from Nissen SE, et al. JAMA. 2008; 299: 1561– 1573. P<0. 001 Glimepiride Pioglitazone − 15. 3%

Percent Change PERISCOPE Trial Primary Endpoint: Change in Percent Atheroma Volume P<0. 001 Glimepiride

Percent Change PERISCOPE Trial Primary Endpoint: Change in Percent Atheroma Volume P<0. 001 Glimepiride (n=181) 0. 73 Pioglitazone (n=179) P=0. 002 − 0. 16 P = 0. 44 Created from Nissen SE, et al. JAMA. 2008; 299: 1561– 1573.

Mean Change in Carotid Intima-Media Thickness of the Posterior Wall (mm) Change in Carotid

Mean Change in Carotid Intima-Media Thickness of the Posterior Wall (mm) Change in Carotid Intima-Media Thickness: CHICAGO Trial 0. 015 Glimepiride (n = 186) Pioglitazone HCl (n = 175) 0. 010 0. 005 0. 000 -0. 005 * *P=0. 017 -0. 010 Baseline Least Squares Mean (Standard Error) Week 24 Glimepiride 0. 779 (0. 008) Week 48 Pioglitazone 0. 771 (0. 008) *95% confidence interval: − 0. 024, − 0. 002. Mazzone T, et al. JAMA. 2006; 296: 2572– 2581. Week 72 Difference Between Treatments at Final Visit − 0. 013*

Effects of Colesevelam on Hemoglobin A 1 C Levels in Add-on Therapy Trials Mean

Effects of Colesevelam on Hemoglobin A 1 C Levels in Add-on Therapy Trials Mean Change in Hemoglobin A 1 C (%) GLOWS Week 12 * * P ≤ 0. 007 Metformin Week 26 Sulfonylurea Week 26 * Colesevelam HCl * Insulin Week 16 * Placebo Zieve FJ, et al. Clin Ther. 2007; 29: 74 -83 | Bays H, et al. Abstracts of the 16 th Annual AACE Meeting and Clinical Congress. Abstract 204: 18 | Fonseca VA, et al. Abstracts of the 16 th Annual AACE Meeting and Clinical Congress. Abstract 409: 10 | Goldberg RB, Truitt K. AHA Scientific Sessions 2006: Poster 1581.

4 Years and 9 Months After Coronary Artery Bypass Grafting n Current Medications: –

4 Years and 9 Months After Coronary Artery Bypass Grafting n Current Medications: – Rosuvastatin: 20 mg QD – Over-the-counter immediate-release niacin: 500 mg 4 x/day – Pioglitazone: 15 mg QD n Physical Exam: – Weight = 177. 2 lbs – Blood pressure = 106/66 mm Hg – Body mass index = 26. 9 kg/m 2

4 Years and 9 Months After Coronary Artery Bypass Grafting (Continued) n Lipid Profile:

4 Years and 9 Months After Coronary Artery Bypass Grafting (Continued) n Lipid Profile: – Total cholesterol = 108 mg/d. L – Low-density lipoprotein (LDL) = 60 mg/d. L – High-density lipoprotein (HDL-C) = 31 mg/d. L – Triglycerides = 87 mg/d. L – At goal: Non-HDL-C = 79 mg/d. L (Optimal <100 mg/d. L) – LDL particles = 1, 041 – Small LDL particles = 815

What is the rationale for measuring the concentrations of apolipoprotein B and low-density lipoprotein

What is the rationale for measuring the concentrations of apolipoprotein B and low-density lipoprotein particles?

LDL Particles LDL Cholesterol HDL Cholesterol (mg/d. L) LDL Particles LDL Cholesterol Triglycerides (mg/d.

LDL Particles LDL Cholesterol HDL Cholesterol (mg/d. L) LDL Particles LDL Cholesterol Triglycerides (mg/d. L) HDL = high-density lipoprotein; LDL = low-density lipoprotein Otvos JD, et al. Am J Cardiol 2002; 90: 22 i-29 i. LDL Cholesterol (mg/d. L) LDL Particles (nmol/L) Relationship Between LDL Particles and LDL Cholesterol to Levels of HDL Cholesterol and Triglycerides: The Framingham Offspring Study

Outcome Associations of NMR LDL Particle * Significant and independent after multivariate modeling (lipids

Outcome Associations of NMR LDL Particle * Significant and independent after multivariate modeling (lipids and established risk factors)

Associations Between CHD Events and LDL Particle Number* Versus LDL Cholesterol *Measured by nuclear

Associations Between CHD Events and LDL Particle Number* Versus LDL Cholesterol *Measured by nuclear magnetic resonance. CHD = coronary heart disease; LDL-C = low-density lipoprotein cholesterol; LDL-P = low-density lipoprotein particles Cromwell WC, et al. J Clin Lipidol. 2007; 1: 583– 592.

Physicians Health Study HDL-C vs apo. B in CV Prediction in Men CHD relative

Physicians Health Study HDL-C vs apo. B in CV Prediction in Men CHD relative risk over 6 years HDL-C is inversely related to apo. B 6. 09 (120) However: apo. B adds predictive value at any level of HD-C Relative Risk 7. 0 5. 52 (112) 6. 0 3. 24 (93) 5. 0 2. 83 (61) 4. 0 3. 43 (59) 2. 0 2. 98 (71) 1. 00 (86) 1. 0 0. 0 2. 19 (65) 2. 23 (73) >101 82 -101 <40 40 -49 C DL > 50 < 82 H Apo. B Tertile (mg/d. L) Adjusted for age, smoking, BMI, premature family history, diabetes, physical activity, hypertension and alcohol intake Pischon T et al. Circulation. 2005; 112: 3375 -3383 tile r Te Numbers indicate relative risks; numbers in parentheses indicate number of subjects.

Physicians Health Study Non HDL-C vs apo. B in CV Prediction in Men Conclusions—Although

Physicians Health Study Non HDL-C vs apo. B in CV Prediction in Men Conclusions—Although non–HDL-C and apo. B were both strong predictors of CHD in this male cohort, more so than LDL-C, the findings support the concept that the plasma concentration of atherogenic lipoprotein particles measured by apo. B is more predictive in development of CHD than the cholesterol carried by these particles, measured by non–HDL-C. Pischon T et al. Circulation. 2005; 112: 3375 -3383

Beyond LDL: Combination Therapy Statin 0 WOSCOPS 4 S vs CARE HPS Statin/Niacin FATS

Beyond LDL: Combination Therapy Statin 0 WOSCOPS 4 S vs CARE HPS Statin/Niacin FATS 10 YR HATS -10 -24 Percent -30 -40 -31 -25 -34 -50 -60 -70 -80 -95 -100 -90 Reduction in CV Events Brown BG, et al. N Engl J Med. 2001; 345: 1583 -1592.

ER Niacin induced alterations in lipoprotein particle numbers may contribute to its antiatherosclerotic effects,

ER Niacin induced alterations in lipoprotein particle numbers may contribute to its antiatherosclerotic effects, and these effects may not be evident from the standard lipid profile J of Clin Lipid. 2009, 3, 45 -50

Niacin: Efficacy n In patients with mixed dyslipidemia, niacin has been shown to: –

Niacin: Efficacy n In patients with mixed dyslipidemia, niacin has been shown to: – Decrease LCL-C levels by 5% to 25% – Increase HDL-C levels by 15% to 35% – Decrease triglyceride levels by 20% to 50% n The effects of niacin on lipids are dose-related – 1, 500 mg/day is typically required for an appreciable beneficial effect HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol Adult Treatment Panel III. Circulation. 2002; 106: 3143– 3421. | Grundy SM, et al. Arch Intern Med. 2002; 162: 1568– 1576.

Niacin: Adverse Effects n Flushing*† n Elevations in uric acid may occur* n Hepatotoxicity

Niacin: Adverse Effects n Flushing*† n Elevations in uric acid may occur* n Hepatotoxicity can occur at higher doses†, more likely to occur with use of sustained release diet supplement niacin† n Diabetic patients should be monitored for a potential increase in blood glucose* n Hypophosphatemia and a reduction in platelets are very rare* *Niaspan [package insert]. Cranbury, NJ: Kos Pharmaceuticals, Inc; 2005. † Mc. Kenney J. Arch Intern Med. 2004; 164: 697 -705.

SEACOAST I Efficacy End Points at 24 Weeks Median % Change from Baseline *

SEACOAST I Efficacy End Points at 24 Weeks Median % Change from Baseline * S 20 N/S 1000/20 * N/S 2000/20 *Superior to S 20; P < 0. 05 versus S 20 * * Non–HDL-C * * LDL-C HDL-C TG * * Lp(a) Apo B = apolipoprotein B; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; Lp(a) = lipoprotein (a); TG = triglycerides Modified from Ballantyne CM et al. Am J Cardiol 2008; 101: 1428– 1436.

6 Years After Coronary Artery Bypass Grafting n Current Medications: – Over-the-counter immediate-release niacin:

6 Years After Coronary Artery Bypass Grafting n Current Medications: – Over-the-counter immediate-release niacin: 500 mg 4 x/day – Rosuvastatin: 40 mg – Omega-3 fatty acids: 1 g/day – Pioglitazone/metformin: 15/500 mg 2 x/day – Aspirin 81 mg/day – Clopidogrel bisulfate (Plavix): 75 mg/day – Atenolol 50 mg/day n Physical Exam: – Weight = 180 lbs – Blood pressure = 120/72 mm Hg – Pulse = 80 bpm – Body mass index = 27. 37 kg/m 2 – Waist circumference = 38 in

6 Years After Coronary Artery Bypass Grafting (Continued) n Lipid Profile: – Low-density lipoprotein

6 Years After Coronary Artery Bypass Grafting (Continued) n Lipid Profile: – Low-density lipoprotein (LDL) particle concentration = 983 – Concentration of small LDL particles = 776 mg/d. L – LDL-C = 46 mg/d. L – High-density lipoprotein cholesterol (HDL-C) = 33 mg/d. L – Triglycerides = 100 mg/d. L – Total Cholesterol = 90 mg/d. L – Apolipoprotein B (Apo B) = 65 mg/d. L* – Lipoprotein (a) = 243 nmol/L† – Lipoprotein PLA 2 = 71 mg/d. L n Hemoglobin A 1 C = 5. 8 *The patient has achieved the target for Apo B (<80 mg/d. L) and for non– HDL-C (<100 mg/d. L) but the count of LDL particles is still >700. †The reference range for lipoprotein (a) is <75 nmol/L; a mg/d. L assay was used to measure lipoprotein (a) at baseline.

Why is Lp(a) Atherogenic? n Has all the properties of LDL. n Has structural

Why is Lp(a) Atherogenic? n Has all the properties of LDL. n Has structural homology with plasminogen and inhibits fibrinolysis. n May serve as a sink for oxidized pholipids. n Inhibits tissue factor pathway inhibitor (TFPI) activity.

Lp(a) Proven as Causal Factor for MI Copenhagen Heart Study

Lp(a) Proven as Causal Factor for MI Copenhagen Heart Study

Lp(a) Proven as Causal Factor for MI Copenhagen Heart Study

Lp(a) Proven as Causal Factor for MI Copenhagen Heart Study

European Atherosclerosis Society Recommends Screening for Lp(a) • Patients at moderate or high risk

European Atherosclerosis Society Recommends Screening for Lp(a) • Patients at moderate or high risk for CVD should be screened for Lp(a). • Bringing a Patients Lp(a) < 50 mg/d. L should be a treatment priority. • 1 -3 g niacin is best treatment for Lp(a) but further studies are needed to better define treatment and target level. June 2010 Press Release: European Atherosclerosis Society Consensus panel

Pharmacologic and nonpharmacologic effects on Lp (a) n Clinical benefit of therapeutic reduction of

Pharmacologic and nonpharmacologic effects on Lp (a) n Clinical benefit of therapeutic reduction of lp (a) remains uncertain n Pharmacologic agents – Statins: reduction of Lp (a) seen in FH patients, little/no effect in others – Fibrates: limited data with variable results – Niacin: dose dependent reduction of lp (a), up to 30 -40% – Aspirin: Lp (a) reduction in CVD secondary prevention patients – Estrogen: variable effects with different agents – Ezetamibe: limited data n Non-Pharmacologic methods – Therapeutic lifestyle changes (TLC); limited data indicating benefit – LDL apheresis: significant Lp (a) reduction in FH patients Espeland MA, et al Circulation 1998: 97 Linke A et al Atherosclerosis 2009: 205 Joshi PH, et al Curr Treat Options Cardiovascular Med 2010: 12 Nozue. T et al, J Atherosclerosis Thrombosis 2010: 17

Case Summary – 10 Years Post CABG 1 st Visit Follow Up Goal Medication

Case Summary – 10 Years Post CABG 1 st Visit Follow Up Goal Medication OTC flush free niacin 1500, Aspirin 81 Niacin 2500, Aspirin 81, metformin 1000, Lovaza 4, Welchol 625 mg 6/day, Crestor 40, Vitamin D 3 2000, Effient 10 Total Cholesterol (mg/d. L) 158 109 <200 LDL-C (mg/d. L) 107 55 <100 HDL-C (mg/d. L) 23 28 >40 Non-HDL-C (mg/d. L) 135 81 <130 Triglycerides (mg/d. L) 138 128 <150 LDL-P (nmol/L) 1515 1005 <1000 LDL Size (nm) 19. 6 small pattern B 20. 5 Lipoprotein(a) (mg/d. L) 161 171 <30 Homocysteine (umol/L) 6. 9 14 <10 CRP (mg/L) 1. 9 1. 6 <1. 0

10 yrs after CABG

10 yrs after CABG

10 yrs after CABG

10 yrs after CABG

10 yrs after CABG

10 yrs after CABG

10 yrs after CABG

10 yrs after CABG

10 yrs after CABG

10 yrs after CABG

10 yrs after CABG

10 yrs after CABG

10 yrs after CABG

10 yrs after CABG