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UPDATE ON MANAGEMENT OF ATHEROGENIC DYSLIPIDEMIA OF INSULIN RESISTANCE, OBESITY, AND TYPE 2 DIABETES: BEYOND LDL CHOLESTER...
Atherogenic Dyslipidemia in Obesity, Insulin Resistance, and Metabolic Syndrome <ul><li>High triglyceride (TG) levels </li...
Metabolic Basis for Atherogenic Dyslipidemia: Concordant Increase in VLDL and Small LDL and Reduction of HDL Smaller LDL H...
Residual Cardiovascular Risk in Major Statin Trials <ul><li>Reprinted from J Am Coll Cardiol, Vol 46, Libby P . The forgot...
Triglyceride Level is an Independent Cardiovascular Disease (CVD) Risk Factor – Meta-Analysis of 17 Studies <ul><li>Adapte...
Triglyceride Level Remains a Cardiovascular Disease (CVD) Risk Factor in Patients Treated With Statins - CARE and LIPID <u...
Coronary Heart Disease (CHD) Risk: HDL Cholesterol vs. LDL Cholesterol as Predictor* <ul><li>Adapted from Castelli WP Can ...
Statin Therapy Does Not Eliminate Cardiovascular Disease (CVD) Risk Associated With Low HDL Cholesterol <ul><li>Adapted fr...
Relative Risk of Myocardial Infarction (MI) According to Triglycerides (TG) and HDL Cholesterol: Case-Control Study in CAD...
LDL Cholesterol Underestimates the Number of LDL Particles When Levels of Small LDL Are Increased Apo B Similar LDL choles...
Favourable Shift in LDL Particle Size is Strongly Associated With End-of-Treatment Triglyceride (TG) Values  <ul><li>Adapt...
Pharmacologic Options for Management of  Atherogenic Dyslipidemia <ul><li>LDL lowering: statin, ezetimibe, resin </li></ul...
Coronary Drug Project: Niacin Effects on 6-Year Cardiovascular Disease (CVD) and 15-Year Mortality <ul><li>Reprinted from ...
Coronary Drug Project: Niacin Effects on 6-Year Nonfatal Myocardial Infarction by Fasting Plasma Glucose  <ul><li>Reprinte...
ADVENT: Safety of Niacin for Dyslipidemia Associated With Type 2 Diabetes  <ul><li>Reprinted from Arch Intern Med, Vol 162...
Primary Prevention With Gemfibrozil  The Helsinki Heart Study <ul><li>Adapted from Manninen V et al. Circulation 1992; 85:...
VA-HIT: Gemfibrozil Effect on Primary Endpoint - Lipids <ul><li>Adapted from Rubins HB et al. N Engl J Med 1999; 341: 410-...
VA-HIT: LDL and HDL Particle Subclasses Are Favourably Affected by Fibrate Treatment <ul><li>Adapted from Otvos JD et al. ...
VA-HIT: LDL and HDL Particle Numbers Are Significant, Independent Predictors of New Coronary Heart Disease Events <ul><li>...
VA-HIT: Cardiovascular Disease Risk Reduction in Nondiabetic Patients <ul><li>Adapted from Rubins HB et al. Arch Intern Me...
Myocardial Infarction Prevention With Bezafibrate in Metabolic Syndrome  <ul><li>Reprinted from Arch Intern Med, Vol 165, ...
Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) <ul><li>Subjects: 9,795 (37% female) patients with type 2 ...
FIELD: End of Study Lipid Results <ul><li>Adapted from Keech A et al. Lancet 2005; 366: 1849-61  </li></ul>Placebo (P) Fen...
FIELD: Primary Endpoint of Coronary Heart Disease (CHD) Events* <ul><li>Adapted from Keech A et al. Lancet 2005; 366: 1849...
FIELD: Primary Endpoint of Coronary Heart Disease (CHD) Events* <ul><li>Adapted from Keech A et al. Lancet 2005; 366: 1849...
FIELD Primary Prevention Population: Effects on Coronary Heart Disease (CHD) Events and Total Cardiovascular Disease (CVD)...
FIELD: Microvascular Disease <ul><li>Adapted from Keech A et al. Lancet 2005; 366: 1849-61  </li></ul>Progression Regressi...
FIELD: Clinically Important Adverse Events ALT: alanine aminotransferase CPK: creatine phosphokinase ULN: upper limit of n...
Pharmacologic Options for Atherogenic Dyslipidemia <ul><li>LDL lowering: statin, ezetimibe, resin </li></ul><ul><li>Trigly...
SAFARI: Combination Therapy in Patients With Combined Hyperlipidemia <ul><li>Reprinted from The American Journal of Cardio...
SAFARI: Effects on LDL Particle Subclasses <ul><li>Adapted from Grundy SM et al. Am J Cardiol 2005; 95: 462-8 </li></ul><u...
Atorvastatin and Fenofibrate Alone or in Combination in Patients With Type 2 Diabetes <ul><li>Adapted from Athyros VG et a...
Statin-Fibrate Combination Therapy: Pharmacokinetic Interactions <ul><li>Adapted from: </li></ul><ul><li>TriCor [package i...
Effects of Lovastatin or Lovastatin and Niaspan on Lipid Parameters <ul><li>Adapted from Hunninghake DB et al. Clin Cardio...
Analysis of the HDL-Atherosclerosis Treatment Study (HATS): Angiographic and Clinical Endpoints After 3 Years – Simvastati...
ARBITER 2: Statin Plus Placebo vs. Statin Plus Extended-Release Niacin (ERN) Values are mean    SD  BL: baseline  Adapted...
ARBITER 2: Statin + Placebo vs. Statin + Extended-Release Niacin 1,000 mg/d  Primary Endpoint – Carotid Intima-Media Thick...
Kaplan-Meir Estimates of Incidence of Coronary Events on Patients Receiving Statin or Statins and Omega-3 Fatty Acid (EPA)...
 
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Update on management of atherogenic dyslipidemia of insulin resistance, obesity, and type 2 diabetes: beyond LDL cholesterol

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By Ronald Krauss, MD
Children's Hospital Oakland Research Institute, Atherosclerosis Research, Oakland, CA, USA

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Update on management of atherogenic dyslipidemia of insulin resistance, obesity, and type 2 diabetes: beyond LDL cholesterol

  1. 1. UPDATE ON MANAGEMENT OF ATHEROGENIC DYSLIPIDEMIA OF INSULIN RESISTANCE, OBESITY, AND TYPE 2 DIABETES: BEYOND LDL CHOLESTEROL <ul><li>Ronald M. Krauss, MD </li></ul><ul><li>Children’s Hospital Oakland Research Institute </li></ul><ul><li>UC Berkeley and UCSF </li></ul>
  2. 2. Atherogenic Dyslipidemia in Obesity, Insulin Resistance, and Metabolic Syndrome <ul><li>High triglyceride (TG) levels </li></ul><ul><ul><li>TG-rich remnant lipoproteins (VLDL) </li></ul></ul><ul><ul><li>Altered metabolism of LDL and HDL particles </li></ul></ul><ul><li>Absolute levels of LDL cholesterol are commonly not significantly increased,  number of LDL particles </li></ul><ul><ul><li>Predominantly small, dense LDL particles </li></ul></ul><ul><li>Low levels of HDL cholesterol (may reduce reverse cholesterol transport) </li></ul>Adapted from Haffner SM Diabetes Care 2003; 26: S83-6 and Garvey WT et al. Diabetes 2003; 52: 453-62
  3. 3. Metabolic Basis for Atherogenic Dyslipidemia: Concordant Increase in VLDL and Small LDL and Reduction of HDL Smaller LDL HL Apo AI Renal clearance LPL Remnants LPL/HL VLDL TG CETP Cholesterol HDL TG LDL TG Smaller HDL Apo AI: apolipoprotein AI CETP: cholesteryl ester transfer protein HL: hepatic lipase LPL: lipoprotein lipase TG: triglycerides
  4. 4. Residual Cardiovascular Risk in Major Statin Trials <ul><li>Reprinted from J Am Coll Cardiol, Vol 46, Libby P . The forgotten majority: Unfinished business in cadiovascular risk reduction, 1225-8, Copyright © 2005, with permission from Elsevier </li></ul> LDL N 4,444 4,159 20,536 6,595 6,605 9,014 -36% -28% -29% -26% -27% -25% Secondary High risk Primary Patients experiencing major coronary events (%)
  5. 5. Triglyceride Level is an Independent Cardiovascular Disease (CVD) Risk Factor – Meta-Analysis of 17 Studies <ul><li>Adapted from Austin MA et al. Am J Cardiol 1998; 81: 7B-12B </li></ul>Relative CVD risk † Men (n=22,293) Women (n=6,345) Men (n=46,413) Women (n=10,864) * * * * † Associated with an 89 mg/dl (1.00 mmol/l) increase in triglycerides *p<0.05
  6. 6. Triglyceride Level Remains a Cardiovascular Disease (CVD) Risk Factor in Patients Treated With Statins - CARE and LIPID <ul><li>Adapted from Sacks FM et al. Circulation 2000; 102: 1893-900 </li></ul>CVD event rate* Placebo Pravastatin Triglyceride levels (mg/dl) Slope=0.018 p=0.02 Slope=0.029 p<0.001 n=13,173 *Coronary heart disease death, nonfatal myocardial infarction, coronary artery bypass graft, percutaneous transluminal coronary angioplasty <98 99-126 127-158 159-207 >207
  7. 7. Coronary Heart Disease (CHD) Risk: HDL Cholesterol vs. LDL Cholesterol as Predictor* <ul><li>Adapted from Castelli WP Can J Cardiol 1988; 4 (Suppl A): 5A-10A </li></ul>* Data represent men aged 50 – 70 from the Framingham Heart Study Relative risk of CHD after 4 years LDL cholesterol (mg/dl) 85 65 45 25 HDL cholesterol (mg/dl)
  8. 8. Statin Therapy Does Not Eliminate Cardiovascular Disease (CVD) Risk Associated With Low HDL Cholesterol <ul><li>Adapted from HPS Collaborative Group Lancet 2002; 360: 7-22 and Sacks FM et al. Circulation 2000; 102: 1893-900 </li></ul>CARE: Cholesterol and Recurrent Events HPS: Heart Protection Study LIPID: Long-Term Intervention with Pravastatin in Ischaemic Disease CVD event rate (%) High HDL cholesterol + statin Low HDL cholesterol + statin
  9. 9. Relative Risk of Myocardial Infarction (MI) According to Triglycerides (TG) and HDL Cholesterol: Case-Control Study in CAD Patients <ul><li>Adapted from Gaziano et al. Circulation 1997; 96: 2520-5 </li></ul>Quartiles of TG Quartiles of TG, adjusted for HDL cholesterol Quartiles of log TG/HDL cholesterol
  10. 10. LDL Cholesterol Underestimates the Number of LDL Particles When Levels of Small LDL Are Increased Apo B Similar LDL cholesterol <ul><li>Slower plasma clearance </li></ul><ul><li>Greater artery uptake & retention </li></ul><ul><li>Faster oxidation </li></ul><ul><li>More particles </li></ul>Cholesteryl ester Larger LDL (phenotype A) More cholesterol/particle Smaller LDL (phenotype B) Less cholesterol/particle
  11. 11. Favourable Shift in LDL Particle Size is Strongly Associated With End-of-Treatment Triglyceride (TG) Values <ul><li>Adapted from Davidson MH et al. Clin Cardiol 2006; 29: 268-73 </li></ul>Median increase in LDL particle diameter (nm) TG level † (mg/dl) <200 200-299 ≥ 300 Change from baseline (%) TG * Small LDL cholesterol Large LDL cholesterol LDL particle concentration * * TG † <200 mg/dl TG † ≥200 mg/dl † End-of-treatment TG level *p<0.03 vs. TG level ≥200 mg/dl Triglyceride reduction in metabolic syndrome (TRIMS) Significant inverse relationship p value for trend =0.019
  12. 12. Pharmacologic Options for Management of Atherogenic Dyslipidemia <ul><li>LDL lowering: statin, ezetimibe, resin </li></ul><ul><li>Triglyceride reducing, HDL raising: niacin, fibrates, omega-3 fatty acids </li></ul>
  13. 13. Coronary Drug Project: Niacin Effects on 6-Year Cardiovascular Disease (CVD) and 15-Year Mortality <ul><li>Reprinted from Am J Cardiol, Vol 95, Canner PL et al. Benefits of niacin in patients with versus without the metabolic syndrome and healed myocardial infarction (from the Coronary Drug Project) , 254-7 Copyright © 2005, with permission from Elsevier </li></ul>CHD: coronary heart disease MI: myocardial infarction Hazard ratio 0.83 0.71 0.84 0.86 p<0.005 p<0.005 p<0.005 p<0.05 Niacin Placebo
  14. 14. Coronary Drug Project: Niacin Effects on 6-Year Nonfatal Myocardial Infarction by Fasting Plasma Glucose <ul><li>Reprinted from Am J Cardiol, Vol 95, Canner PL et al. Benefits of niacin in patients with versus without the metabolic syndrome and healed myocardial infarction (from the Coronary Drug Project) , 254-7 Copyright © 2005, with permission from Elsevier </li></ul>Fasting plasma glucose (mg/dl) Hazard ratio 0.70 0.76 0.75 0.43 Niacin Placebo <95 95-104 105-125 ≥ 126
  15. 15. ADVENT: Safety of Niacin for Dyslipidemia Associated With Type 2 Diabetes <ul><li>Reprinted from Arch Intern Med, Vol 162, Grundy SM et al. Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial) , 1568-76 </li></ul><ul><li>Copyright © 2002, with permission from Elsevier </li></ul>* Baseline Week 4 Week 8 Week 12 Week 16 n=148 *p=0.048 vs. placebo
  16. 16. Primary Prevention With Gemfibrozil The Helsinki Heart Study <ul><li>Adapted from Manninen V et al. Circulation 1992; 85: 37-45 </li></ul>Incidence of cardiac events per 1,000 person-years 0 5 10 15 20 HDL cholesterol  42 HDL cholesterol  42 TG  200 TG  200 TG  200 TG  200 mg/dl Gemfibrozil TG: triglycerides Placebo Incidence of coronary heart disease events
  17. 17. VA-HIT: Gemfibrozil Effect on Primary Endpoint - Lipids <ul><li>Adapted from Rubins HB et al. N Engl J Med 1999; 341: 410-8 </li></ul>LDL cholesterol TG HDL cholesterol Primary endpoint occurrence*† Change from baseline (%) % Placebo Gemfibrozil *Nonfatal myocardial infarction or death from coronary causes † 22% relative risk reduction (95% CI: 7%–35%, p=0.006) TG: triglycerides
  18. 18. VA-HIT: LDL and HDL Particle Subclasses Are Favourably Affected by Fibrate Treatment <ul><li>Adapted from Otvos JD et al. Circulation 2006; 113: 1556-63 </li></ul>IDL: intermediate-density lipoprotein B: baseline Placebo Fibrate 5% reduction 1364 1463 1352 1290* LDL particle number (nmol/l) B 7 months B 7 months 20% decrease 36% increase * * HDL particle number (  mol/l) 25.2 25.1 26.6 27.6* Placebo Fibrate B 7 months B 7 months 21% increase * * 10% increase *p≤0.0005 vs. placebo at 7 months IDL Large HDL Large LDL Medium HDL Small LDL Small HDL
  19. 19. VA-HIT: LDL and HDL Particle Numbers Are Significant, Independent Predictors of New Coronary Heart Disease Events <ul><li>Adapted from Otvos JD et al. Circulation 2006; 113: 1556-63 </li></ul>Relative odds ratio † LDL particle number LDL particle size * * Relative odds ratio † HDL particle number HDL particle size * * Baseline 7 months † Calculated for a 1-SD increment of each lipoprotein particle in separate logistic regression models adjusted for treatment group, age, hypertension, smoking, body mass index, and diabetes *p<0.05
  20. 20. VA-HIT: Cardiovascular Disease Risk Reduction in Nondiabetic Patients <ul><li>Adapted from Rubins HB et al. Arch Intern Med 2002; 162: 2597-604 </li></ul>Risk reduction ≤ 23 n=434 24-29 30-38 ≥ 39 n=431 n=426 n=442 Quartiles of fasting plasma insulin ( µU/ml) Favours gemfibrozil Favours placebo p=0.04 vs. placebo
  21. 21. Myocardial Infarction Prevention With Bezafibrate in Metabolic Syndrome <ul><li>Reprinted from Arch Intern Med, Vol 165, Tenenbaum A et al. Bezafibrate for the secondary prevention of myocardial infarction in patients with metabolic syndrome , 1154-60 </li></ul><ul><li>Copyright © 2005, with permission from Elsevier </li></ul>0 Myocardial infarction (%) Cardiac mortality (%) Time (years) Time (years) Log-rank p=0.02 Log-rank p=0.07 5 10 15 20 0 5 10 15 Placebo Bezafibrate 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 0
  22. 22. Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) <ul><li>Subjects: 9,795 (37% female) patients with type 2 diabetes aged 50-75 years with and without coronary heart disease (CHD) </li></ul><ul><li>Entry lipid criteria: cholesterol = 116-251 mg/dl (3.00-6.50 mmol/l), plus either </li></ul><ul><ul><li>Cholesterol/HDL cholesterol ratio >4 </li></ul></ul><ul><ul><li>or </li></ul></ul><ul><ul><li>Triglycerides >89 mg/dl (1.00 mmol/l) </li></ul></ul><ul><li>Treatment: fenofibrate 200 mg once daily or placebo for 5 years </li></ul><ul><li>Primary endpoint: CHD death plus nonfatal myocardial infarction </li></ul>Adapted from Keech AC and the FIELD Study Investigators Cardiovasc Diabetol 2004; 3: 9-24
  23. 23. FIELD: End of Study Lipid Results <ul><li>Adapted from Keech A et al. Lancet 2005; 366: 1849-61 </li></ul>Placebo (P) Fenofibrate (F) 113 LDL cholesterol HDL cholesterol Triglycerides Baseline (mg/dl) 117 43 43 164 167 119 LDL cholesterol HDL cholesterol Triglycerides Baseline (mg/dl) 119 43 43 171 173 128 LDL cholesterol HDL cholesterol Baseline (mg/dl) 125 42 40 184 197 Triglycerides Did not start other lipid-lowering therapy n= 3,124 (P) 3,951 (F) Total population Started other lipid-lowering therapy n= 1,776 (P) 944 (F)
  24. 24. FIELD: Primary Endpoint of Coronary Heart Disease (CHD) Events* <ul><li>Adapted from Keech A et al. Lancet 2005; 366: 1849-61 </li></ul>Event rate (%) 11% reduction p=0.16 *Nonfatal myocardial infarction or CHD death
  25. 25. FIELD: Primary Endpoint of Coronary Heart Disease (CHD) Events* <ul><li>Adapted from Keech A et al. Lancet 2005; 366: 1849-61 </li></ul>24% reduction p=0.01 19% increase p=0.22 Placebo Fenofibrate *Nonfatal myocardial infarction or CHD death
  26. 26. FIELD Primary Prevention Population: Effects on Coronary Heart Disease (CHD) Events and Total Cardiovascular Disease (CVD) Events <ul><li>Adapted from Keech A et al. Lancet 2005; 366: 1849-61 </li></ul>Risk reduction (%) (n=7,664) (n=7,664) p=0.014 p=0.004 CHD events Total CVD
  27. 27. FIELD: Microvascular Disease <ul><li>Adapted from Keech A et al. Lancet 2005; 366: 1849-61 </li></ul>Progression Regression Patients (%) P F P F 14% reduction p<0.001 30% reduction p=0.0003 Placebo Fenofibrate Patients (%) *Progression of albuminuria was defined as the proportion of patients who progressed either from normoalbuminuria to microalbuminuria or from microalbuminuria to macroalbuminuria. Placebo (P) Fenofibrate (F) Laser treatment for retinopathy Progression and regression of albuminuria*
  28. 28. FIELD: Clinically Important Adverse Events ALT: alanine aminotransferase CPK: creatine phosphokinase ULN: upper limit of normal *Myositis was experienced by 1 placebo and 2 fenofibrate patients † Rhabdomyolysis was experienced by 1 placebo and 3 fenofibrate patients (none were taking a statin) ‡ p=0.022 § p=0.031 Adapted from Keech A et al. Lancet 2005; 366: 1849-61 Adverse Event Placebo, % n=4,900 Fenofibrate, % n=4,895 Newly diagnosed cancer 7.6 8.0 Deep-vein thrombosis 1.0 1.4 Pulmonary embolism 0.7 1.1 ‡ Pancreatitis 0.5 0.8 § Myositis* 0.02 0.04 Rhabdomyolysis † 0.02 0.06 Renal disease requiring dialysis 0.4 0.3 ALT 3-5x ULN 0.5 0.2 >5x ULN 0.2 0.2 CPK 5-10x ULN 0.1 0.2 >10x ULN 0.06 0.08 Creatinine increase >2.26 mg/dl 1.0 1.5
  29. 29. Pharmacologic Options for Atherogenic Dyslipidemia <ul><li>LDL lowering: statin, ezetimibe, resin </li></ul><ul><li>Triglyceride reducing, HDL raising: niacin, fibrates; omega-3 fatty acids </li></ul><ul><li>Combination therapy </li></ul>
  30. 30. SAFARI: Combination Therapy in Patients With Combined Hyperlipidemia <ul><li>Reprinted from The American Journal of Cardiology, Vol 95, Grundy SM et al. Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial), 462-8 Copyright © (2005), with permission from Elsevier </li></ul>* * * * Simvastatin 20 Simvastatin 20 + Fenofibrate 160 n=618 *p<0.001 vs. simvastatin
  31. 31. SAFARI: Effects on LDL Particle Subclasses <ul><li>Adapted from Grundy SM et al. Am J Cardiol 2005; 95: 462-8 </li></ul><ul><li>Reproduced with permission </li></ul>Simvastatin +Fenofibrate Simvastatin Simvastatin Change from baseline in LDL pattern (%) Baseline Week 12* Increased particle size n=618 *Significantly different pattern between the 2 treatment groups (p<0.001) B (Smaller, dense) AB (Intermediate) A (Larger, buoyant) Simvastatin +Fenofibrate
  32. 32. Atorvastatin and Fenofibrate Alone or in Combination in Patients With Type 2 Diabetes <ul><li>Adapted from Athyros VG et al. Diabetes Care 2002; 25: 1198-202 </li></ul>Triglycerides LDL cholesterol HDL cholesterol Change from baseline (%) * * * * ‡ * * * † Atorvastatin 20 mg Fenofibrate 200 mg Combination * † n=120 *p <0.0001 vs. baseline † p <0.05 vs. both monotherapies ‡ p <0.05 vs. atorvastatin
  33. 33. Statin-Fibrate Combination Therapy: Pharmacokinetic Interactions <ul><li>Adapted from: </li></ul><ul><li>TriCor [package insert]. Abbott Laboratories; 2004 </li></ul><ul><li>Kyrklund C et al. Clin Pharmacol Ther 2001; 69: 340-5 </li></ul><ul><li>Pan W J et al. J Clin Pharmacol 2000; 40: 316-23 </li></ul><ul><li>Backman JT et al. Clin Pharmacol Ther 2000; 68: 122-9 </li></ul><ul><li>Backman JT et al. Clin Pharmacol Ther 2002; 72: 685-91 </li></ul><ul><li>Abbott Laboratories. Data on file; 2005 </li></ul><ul><li>Davidson MH Am J Cardiol 2002; 90 (suppl): 50K-60K </li></ul><ul><li>Prueksaritanont T et al. Drug Metab Dispos 2002; 30: 1280-7 </li></ul><ul><li>Martin PD et al. Clin Ther 2003; 25: 459-71 </li></ul><ul><li>Bergman AJ et al. J Clin Pharmacol 2004; 44: 1054-62 </li></ul>Cmax: maximum concentrations Gemfibrozil Fenofibrate Atorvastatin Expected  in C max No effect Simvastatin  C max by 2-fold No effect Pravastatin  C max by 2-fold No effect Rosuvastatin  C max by 2-fold No effect Fluvastatin No effect No effect Lovastatin  C max by 2.8-fold Not available Cerivastatin  C max by 2-3 - fold No effect
  34. 34. Effects of Lovastatin or Lovastatin and Niaspan on Lipid Parameters <ul><li>Adapted from Hunninghake DB et al. Clin Cardiol 2003; 26: 112-8 </li></ul>Change from baseline (%) LDL cholesterol HDL cholesterol Triglycerides Lovastatin 40 mg Lovastatin 20 mg + 1,000 mg niaspan (Advicor)
  35. 35. Analysis of the HDL-Atherosclerosis Treatment Study (HATS): Angiographic and Clinical Endpoints After 3 Years – Simvastatin + Niacin vs. Placebo <ul><li>Adapted from Brown BG et al. N Engl J Med 2001; 345: 1583-92 </li></ul>Placebo Mean change in stenosis (%) *p<0.001 vs. placebo ‡ p=0.04 vs. placebo Coronary death, myocardial infarction, stroke or revascularization Simvastatin + Niacin Composite event rate (%) 3.9 23.7 89% reduction -0.5 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Nine proximal lesions 25 20 15 10 5 0 -0.4 2.6 * ‡
  36. 36. ARBITER 2: Statin Plus Placebo vs. Statin Plus Extended-Release Niacin (ERN) Values are mean  SD BL: baseline Adapted from Taylor AJ et al. Circulation 2004; 110: 3512-7 12 months P value BL vs. 12 months Lipid (mg/dl) Statin + Placebo Statin + ERN P Value Statin + Placebo Statin + ERN n 71 78 LDL cholesterol 86  20 85  25 NS NS NS HDL cholesterol 40  9 47  16 0.003 NS <0.001 Triglycerides 164  83 134  87 0.03 NS 0.009 Non-HDL cholesterol 115  21 107  34 NS 0.03 0.02
  37. 37. ARBITER 2: Statin + Placebo vs. Statin + Extended-Release Niacin 1,000 mg/d Primary Endpoint – Carotid Intima-Media Thickness (CIMT) Change <ul><li>Adapted from Taylor AJ et al. Circulation 2004; 110: 3512-7 </li></ul>Statin + Placebo (n=71) Statin + Extended release niacin (n=78) Baseline CIMT (mm) Change in CIMT (mm) Statin + Extended release niacin (n=78) p=0.23* Statin + Placebo (n=71) p<0.001* *Within-group comparisons Baseline  CIMT after 1 year
  38. 38. Kaplan-Meir Estimates of Incidence of Coronary Events on Patients Receiving Statin or Statins and Omega-3 Fatty Acid (EPA) <ul><li>Reprinted from The Lancet, Vol 369, Yokoyama M et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis, 1090-98 </li></ul><ul><li>Copyright © 2007, with permission from Elsevier </li></ul>All patients Primary prevention Secondary prevention 18,645 Japanese (70% women, 61 years) randomized to statin alone or statin + EPA (1.8 g/d) and followed for 5 years

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