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Treatment of Lipid Disorders

Treatment of Lipid Disorders. Ulrich K. Schubart AECOM/JMC. Prevention, slowed progression, or regression of. atherosclerotic lesions. Stabilization of atherosclerotic lesions. - Especially non-obstructive , vulnerable plaques.

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Treatment of Lipid Disorders

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  1. Treatment of Lipid Disorders Ulrich K. Schubart AECOM/JMC

  2. Prevention, slowed progression, or regression of atherosclerotic lesions • Stabilization of atherosclerotic lesions - Especially non-obstructive , vulnerable plaques • Reduction in inflammatory stimuli - Lipoproteins and modified lipoproteins Proposed Mechanisms of Event Reduction by Lipid Lowering Therapy • Improved endothelium dependent vasodilation • Reduced thrombotic and increased fibrinolytic potential adapted from Libby P. Circulation1995; 91:2844-2850

  3. % Reductions in CV Events depends upon: • Percent cholesterol (and LDL) lowering • Absolute Level of Baseline cholesterol • Duration of cholesterol lowering • Presence of other lipid abnormalities

  4. Dietary Therapy for Elevated Blood Cholesterol Nutrient* Recommended intake Step I Diet Step II Diet <10% oftotal calories < 300 mg/day < 7% oftotal calories < 200 mg/day Total fat Saturated fatty acids Carbohydrates Protein Cholesterol Total calories £ 30% of total calories ³ 55% of total calories ~ 15% of total calories To achieve and maintaindesirable weight * Calories from alcohol not included. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 1993;269:3015-3023.

  5. Drugs to lower LDL Cholesterol % LDL Reduction • Statins (HMG-CoA Reductase Inhibitors) 25-55% • Bile Acid Resins 15-30% • Cholesterol Absorption Inhibitors 15-20% • Niacin 15-25% • Combinations>60% • Estrogen 10-15%

  6. Synergistic effects of diet and drug therapy • Dietary therapy reduces LDL cholesterol • by 7-10% • This is the equivalent of doubling the • daily dose of a statin • Therefore, successful dietary therapy • reduces drug therapy by over 50%

  7. Common Final Mechanism of Statin/BAR/CAI reduction in LDL-C apo B-100 apo E VLDL VLDL PRODUCTION LIPOLYSIS apo C SHUNT PATHWAY CE Liver VLDL Remnant + LDL CLEARANCE CONVERSION Other sites LDL

  8. Generic Trade Dose % LDL Cost Atorvastatin Lipitor 10-80 mg 37-55 Simvastatin Zocor 5-80 mg 24-51% Formulary Lovastatin Mevacor 10-80 mg 19-40% Dependent Pravastatin Pravachol 10-40 mg 20-30% Fluvastatin Lescol 20-80 mg 15-25% Currently Available HMG CoA Reductase Inhibitors Resuvastatin Crestor 10-40 mg 46-55%

  9. Side Effects of HMG CoA Reductase Inhibitors • Myopathy (0.1%) • Abnormal Liver Function Tests (1-2%) • Gastrointestinal Distress and Diarrhea • CNS – Insomnia • Diabetes

  10. Precipitating Factors: • Liver Disease • Multisystem Disease • Drugs: • - Cyclosporin; tacrolimus • - Fibrates • - Erythromycin • - Itraconazole, ketoconazole • - Mibefradil (Posicor) • - ? Protease inhibitors Statins and Myopathy

  11. Statins and Myopathy Check CK prior to initiating statin therapy

  12. Significant Inhibitors of CYP3A4:Potential for interaction with statins clarithromycin* erythromycin* metronidazole Antibiotics ketoconazole* itraconazole** miconazole Antifungals indinivir ritonavir nelfinivir Protease Inhibitors mibefradil** CCB’s cyclosporin A* Immunosuppressant cimetidine H2 Blockers fluoxetine fluvoxamine Antidepressants grapefruit grapefruit juice Food

  13. HypertriglyceridemiaTreatment • Hypocaloric, low fat (10-20%), alcohol restricted diet. Avoid saturates, simple Carbs. Exercise and weight loss. • In DM: Optimize glycemic control • Consider metformin or thiazolidenedione for IGT/insulin resistance • Assess meds: oral estrogens/OCPs, steroids, Retin A, thiazides or B blockers • Drugs: 1 : Fibrates or Niacin (unless DM) 2 : High dose statins, Fish Oils

  14. Hypertriglyceridemia Drug Therapy: High Risk Patients R/O Secondary Hyperlipidemia Diet/Lifestyle Modification <800 mg/dl Triglycerides > 1,000 mg/dl Treat to prevent/ reverse ASCVD Treat to prevent pancreatitis

  15. TG £ 200 Useful Combinations: Statins+Resins/Ezitamibe Hypercholesterolemia: Statins/Ezit+Niacin, or Mixed HLD: Statins/Ezit+ Fibrates* HypertriglyceridemiaDrug Therapy - High Risk CAD TG 200-400 TG ³ 400 Statin Statin Combined Drug Therapy Resin Niacin Consider High Niacin Gemfibrozil Dose Statins

  16. HypertriglyceridemiaThe bottom line • Triglycerides 150 -1000. Treat to prevent CAD* • Triglycerides > 1000. Treat to prevent • pancreatitis • * If in doubt measure Apo B 100. • Median 100 mg/dl; > 125 mg/dl likely atherogenic

  17. ATP III: Management ofDiabetic Dyslipidemia • Primary target of therapy: identification of LDL-C; goal for persons with diabetes: <100 mg/dL • Therapeutic options: • LDL-C 100–129 mg/dL: increase intensity of TLC; add drug to modify atherogenic dyslipidemia (fibrate or nicotinic acid); intensify risk factor control • LDL-C 130 mg/dL: simultaneously initiate TLC and LDL-C–lowering drugs • TG 200 mg/dL: non–HDL-C* becomes secondary target Note: Diabetic dyslipidemia is essentially atherogenic dyslipidemia in persons with type 2 diabetes.*Non–HDL-C goal is set at 30 mg/dL higher than LDL-C goal. JAMA. 2001;285:2486-2497.

  18. TG 20-50 % HDL-C 10-15 % LDL-C variable Fibric Acid Derivatives • Gemfibrozil (Lopid) 600-1200 mg/day • Clofibrate (Atromid S) 1000-2000 mg/day • Fenofibrate (Tricor) 54-160 ug/ day • Mechanism: Increases clearance of triglyceride-rich lipoproteins (Chylos, VLDL, remnants) through downregulation of Apo CIII and increased LPL activity • Effects on Lipids:

  19. Fibric Acid Derivatives - Indications • Severe Hypertriglyceridemia (TG > 1000 mg/dl) • ? Combination therapy for mixed hyperlipidemia or moderate hypertriglyceridemia • Reduces risk of CHD in subjects with High TG /Low HDL-C • May raise homocysteine levels

  20. Fibric Acid Derivatives • Side Effects • Myopathy • Hepatitis (increases in transaminases) • Gallstones, Nausea, Diarrhea • Contraindications • Absolute:Relative: • Gallstones Use with statins • Hepatic Insufficiency Inhibitors of CYP 3A4 • Pregnancy

  21. Niacin - Indications • Mixed hyperlipidemia • Hypertriglyceridemia • Low HDL (hypoalphalipoproteinemia) • Combination therapy for hypercholesterolemia, • mixed hyperlipidemia

  22. Niacin - Mechanism of Action • Inhibition of hormone-sensitive lipase in fat cells • Reduction of VLDL production rates from liver • Activation of LPL and accelerated • TG rich lipoprotein clearance. • Increased clearance of remnants and LDL • Mechanism of HDL-C increase unknown, but may • be related to decreased TG- cholesterol exchange

  23. Niacin - Side effects • Flushing, pruritis - almost universal, harmless • Insulin resistance/ worsened glucose tolerance • Hyperuricemia/ gout • Hepatitis (fulminant hepatic failure with SR niacin) • Dyspepsia, Exaccerbation of IBD • Toxic ambliopia (rare)

  24. Niacin - Contraindications • Active liver disease, alcoholism • Hx of neural tube defect or hyperhomocysteinemia • Gout or active hyperuricemia • Active peptic ulcer disease (caution if prior Hx) • Inflammatory bowel disease • Pregnancy • Poorly controlled diabetes

  25. Niacin - Prescribing Hints • Dose 1.5 - 6 gms/ day divided t.i.d. IR niacin • Max dose 2.0 gm/day SR niacin (and give folate) • Titrate dose up slowly • Benefit on HDL seen at < 1.5 gms/day; • TG effect dose dependent. • Take with meals; pretreat ~1 hour earlier with NSAID • Avoid alcohol (flushing, hepatitis) _

  26. Bile Acid Binding Resins Cholestyramine (Questran) Colestipol (Colestid) Colesevelam (Welchol) • Indicated for treatment of hypercholesterolemia • Proven efficacy to prevent CHD • Safest agent for reducing cholesterol • (except bran foods and garlic) • Ideal for the young, healthy patient

  27. Ge et al Cell Metab 2008

  28. Other Drugs, etc • Estrogen replacement therapy • oral estrogens vs transdermal • selective estrogen receptor modulators (raloxifene) • - risk of TG’s with oral estrogens • Vitamin E (400 - 800 I.U./ day) • Vitamin C 1-2 gm/day • Folic acid (1-2 mg/day), B 2-5 mg/day • Aspirin • ACE inhibitors • LDL apheresis

  29. Statins in CAD

  30. Statin Tx Metaanalysis Lancet 2005

  31. Statin Tx Metaanalysis Lancet 2005

  32. Statin Tx Metaanalysis Lancet 2005

  33. Statins for Primary Prevention

  34. Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) Randomized, double-blind trial to compare lovastatin with placebo for prevention of first acute major coronary event in men and women without clinically evident atherosclerotic CVD 5,608 men and 997 women with average Total-C and LDL-C and below-average HDL-C Downs JR et al. JAMA 1998;279:1615–1622

  35. Primary EndpointFirst Acute Major Coronary Event 0.07 0.06 37% Risk Reduction (p = 0.00008) 0.05 Placebo Cumulative Incidence 0.04 0.03 Lovastatin 0.02 0.01 0.00 0 1 2 3 4 5 5+ Years Years of Follow-up # At Risk Lovastatin N=3304 N=3270 N=3228 N=3184 N=3134 N=1688 N=3301 N=3251 N=3211 N=3159 N=3092 N=1644 Placebo Downs JR et al. JAMA 1998;279:1615–1622

  36. Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)Event Rates by Baseline HDL-C Tertile -45% risk reduction 16 -44% risk reduction 14 Lovastatin Placebo 12 -15% risk reduction 10 Event rate per 1,000 patient-years at risk 8 6 4 2 0  34 35–39  40 HDL-C (mg/dL) Downs JR et al. JAMA 1998;279:1615–1622

  37. Heart Protection Study • Primary prevention with risk factors (hypertension, diabetes, and CVA) • 2x2 factorial design simvastatin 40 mg/day, antioxidant cocktail (600 mg vitamin E, 250 mg vitamin C, 20 mg beta carotene) • N = 20,000; subgroups include: Women (n ~ 5,000) Elderly (>65, n ~ 10,000) Diabetics (n ~ 6,000) Stroke (n ~ 3,000) Hypertension (n ~ 8,000) Noncoronary vascular disease (n ~ 7,000) Low to average blood cholesterol (n ~ 8,000) • FPI – 1996, fully enrolled, results 2001 Heart Protection Collaborative Group. Lancet 2002;360:7–22. Study

  38. HPS: Primary and Secondary Prevention Implications 4S LIPID CARE HPS WOSCOPS HPS AFCAPS 25 20 15 % with CAD event 10 5 0 50 70 90 110 130 150 170 190 210 LDL-C (mg/dL) Adapted from Illingworth. Med Clin North Am. 2000;84:23. At: http://www.hpsinfo.org.

  39. Simvastatin: Major Vascular Events in Upper and Lower Thirds of Baseline LDL(Heart Protection Study) Statin-allocated Placebo-allocated Upperthird LDL % with Major Vascular Events Lowerthird LDL 60 80 100 120 140 160 Average LDL Cholesterol (mg/dl)

  40. HPS: Statin Benefit is EntirelyIndependent of Baseline LDL Risk ratio and 95% CI Statin better Statin worse 24% SE 3 reduction (2P<0.00001) 0.4 0.6 0.8 1.0 1.2 1.4 www.hpsinfo.org

  41. Simvastatin: Major Vascular Events by Year Placebo People Suffering Events (%) Simvastatin 0 1 2 3 4 5 6 Years of Follow-up 60 (18) 5 (3) 20 (4) 35 (5) 46 (5) 54 (7) Benefit/1000 (SE) Heart Protection Study Collaborative Group. Lancet 2002;360:7–22.

  42. Simvastatin: Cause-Specific Mortality Risk ratio and 95% CI STATIN Better PLACEBOBetter 17% SE 4reduction(2P<0.0001) 5% SE 6reduction (NS) 13% SE 4reduction(2P<0.001) 0.4 0.6 0.8 1.0 1.2 1.4

  43. Taggart Lancet 2009

  44. Statins in Diabetes Metaanalysis Lancet 2008

  45. Statins in Diabetes Metaanalysis Lancet 2008

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