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Pharmacological Effects of Statins

Pharmacological Effects of Statins. Overview. Lipids and Lipoproteins Pharmacology of Statins How Do we Choose a Statin?. Lipids and Lipoproteins. Triglycerides Source: sugars, alcohol Essential energy source Energy storage. Cholesterol Source: fats, dietary cholesterol

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Pharmacological Effects of Statins

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  1. Pharmacological Effectsof Statins

  2. Overview • Lipids and Lipoproteins • Pharmacology of Statins • How Do we Choose a Statin?

  3. Lipids and Lipoproteins

  4. Triglycerides Source: sugars, alcohol Essential energy source Energy storage Cholesterol Source: fats, dietary cholesterol Bile acid formation Hormone synthesis Cell membrane component Lipids

  5. Lipids vs. Lipoproteins • Lipids need to get to site of action for use • Not water soluble  not readily carried by bloodstream • Special transport “vehicle” necessary for delivery of lipids to tissues for use • Lipoprotein = Proteins + TG + Cholesterol + Phospholipids

  6. Structure of Lipoproteins Free cholesterol Phospholipid Triglyceride Cholesteryl ester Apolipoprotein

  7. Apolipoproteins • Protein components of lipoproteins • Several functions • Structural stability • Receptor binding (function as ligands in lipoprotein-receptor interactions) • Regulate enzyme activity • lecithin cholesterol acyltransferase (LCAT) • lipoprotein lipase (LPL) • hepatic triglyceride lipase (HTGL) • Concentrations may related to CHD risk • Possible site of genetic variation

  8. Major Lipoproteins Chylomicrons • Formed in intestines • Metabolized via LPL (lipoprotein lipase; a triglyceride hydrolase) into remnants which are taken-up by liver • Primary function is transport of exogenous fatty acids and cholesterol apoB-48 apoE apoA-I, A-IV apoC-I, C-II, C-III

  9. Major Lipoproteins VLDL • Formed in the liver • Metabolized by LPL into IDL • Primary function is TG and cholesterol transport IDL • Formed via VLDL • Metabolized by LPL into LDL • Primary function is TG and cholesterol transport apoB-100

  10. Major Lipoproteins LDL • Formed via IDL • Metabolized by tissue and hepatic uptake • Function is cholesterol transport HDL • Formed primarily via metabolism of chylomicrons and VLDL • Primary function is reverse cholesterol transport

  11. Lipoprotein(a); Lp(a) LDL apoB-100 apo(a) S S Plasminogen-like domain

  12. Exogenous Pathway Food particles Liver Bile Acids Intestines Chylomicrons Chylomicron Remnants Bloodstream Breakdown of Triglyceride Free Fatty Acids

  13. Endogenous Pathway LDL HDL Liver Body Tissues Bloodstream IDL VLDL Breakdown of Triglyceride Free Fatty Acids

  14. Diseases Diabetes Hypothyroidism Nephrotic Syndrome Obstructive Liver Disease Drugs Progestins Corticosteroids Anabolic steroids -blockers Thiazide diuretics Cyclosporin Sulfonylureas Isotretinoin Alcohol Possible Causes of Secondary Dyslipidemia

  15. Benefit of Lowering Cholesterol Meta-analysis of 38 primary and secondary prevention trials, with more than 98,000 patients in total 0.0 –0.2 Total mortality, p=0.04 –0.4 Mortality (log odds ratio) Mortality in CHD, p=0.012 –0.6 –0.8 –1.0 0 4 8 12 16 20 24 28 32 Cholesterol reduction (%) Adapted from Gould AL et al. Circulation 1998;97:946–952

  16. Relationship Between Changes in LDL-C and HDL-C Levels and CHD Risk 1% increasein HDL-C reduces CHD risk by3% 1% decreasein LDL-C reduces CHD risk by1% Third Report of the NCEP Expert Panel. NIH Publication No. 01-3670 2001. http://hin.nhlbi.nih.gov/ncep_slds/menu.htm

  17. Managements of Dyslipidaemia • Therapeutic lifestyle change (TLC) • Lipid-lowing agents

  18. Cholesterol-Lowering Drug Therapy HMG CoA Reductase Inhibitors • Amlodipine/Atorvastatin • Aspirin/Pravastatin • Atorvastatin • Cerivastatin (2001/8 withdrawal from market) • Lovastatin • Niacin/Lovastatin • Pitavastatin • Pravastatin • Rosuvastatin • Simvastatin Fibrates • Gemfibrozil • Micronized Fenofibrate • Clofibrate Bile AcidSequestrants • Cholestyramine • Colestipol • Colesevelam Niacin

  19. HMG Reductase B-100 B-48

  20. Effect of Lipid-Modifying Therapies on Lipids Therapy Bile acid sequestrants Nicotinic acid Fibrates(gemfibrozil) Probucol Statins* TC Down 20% Down 25% Down 15% Down 25% Down 15–30% LDL Down 15–30% Down 25% Down 5–15% Down 10–15% Down 24–50% HDL Up 3–5% Up 15–30% Up 20% Down 20–30% Up 6–12% TG Neutral or up Down 20–50% Down 20–50% Neutral Down 10–29% Patient tolerability Poor Poor to reasonable Good Reasonable Good * Daily dose of 40 mg of each drug (cerivastatin 0.3 mg) TC–total cholesterol LDL–low density lipoprotein HDL–high density lipoprotein TG–triglyceride. (Adapted from Yeshurun 1995, Knopp 1999)

  21. Benefits of Therapy Primary Prevention • Fewer coronary events • Fewer angiographies, PTCAs, and CABGs Secondary Prevention • Less lesion progression, fewer new lesions • Increased lesion regression • Fewer coronary events • Less cardiac-related mortality • Less overall mortality

  22. Pharmacology of Statins

  23. History • Isolated from a mold, Penicillium citrinium, and identified as inhibitors of cholesterol biosynthesis in 1976 by Endo et al. • Brown et al,. (1978) established that statins act by inhibiting HNG-CoA reductase • Yamamoto et al., first statin studied in human (1984)---compactin (mevastatin) • Alberts et al., first statin approved (1987) for use in human---lovastain (isolated from Aspergillus terreus)

  24. Fluvastatin Rosuvastatin Atorvastatin Pravastatin B M Y 2000 1991 1996 2003 1987 1993 1997 Lovastatin Cerivastatin Simvastatin History of Statins 2001/8 withdrawal

  25. Cholesterol Synthesis Pathway acetyl CoA HMG-CoA synthase HMG-CoA X Statins HMG-CoA reductase mevalonic acid mevalonate pyrophosphate 蛋白質合成 isopentenyl pyrophosphate geranyl pyrophosphate 信息傳遞 ubiquinones dolichols farnesyl pyrophosphate 細胞能量代謝 細胞能量代謝 squalene Squalene synthase cholesterol 細胞膜穩定維持

  26. Statin Dose-Response Curve CURVES Study. Am J Cardiol 1998;81:582-7.

  27. How do we Choose a Statin?Differences among the HMG-CoA Reductase Inhibitors • Potency (LDL, HDL, TG) • Clinical efficacy • Hydrophilic vs Lipophilic • Pharmacokinetics • Cost • Drug Interactions • Non-lipid effects

  28. Comparative LDL Effects Pravastatin Lovastatin Rosuvastatin Simvastatin Fluvastatin Atorvastatin 20 10 40 20 10 20 40 40 1 20 80 10 40 5 20 80 80 40 80 20 80 Am J Cardiol 1998;81:582-7. Am J Cardiol 2001;88:504-8. J Int Med Res 2000;28:47-68. Clin Cardiol 2000;23:39-46.

  29. Comparative HDL Effects 10 40 40 20 80 10 20 10 40 10 20 20 40 40 20 20 80 40 Atorva Simva Prava Lova Fluva Rosuva CURVES Study. Am J Cardiol 1998;81:582-7.

  30. Comparative TG Effects Atorvastatin Simvastatin Pravastatin Lovastatin Fluvastatin 10 40 20 40 10 20 40 80 10 20 40 20 20 80 40 CURVES Study. Am J Cardiol 1998;81:582-7.

  31. Adverse Effects Therapeutic Effects Risk Benefit Muscle Liver Drug interactions Cardiovascular protection Statins – Therapeutic Ratio

  32. Persistent ALT >3 × ULN: Frequency by LDL-C Reduction Rosuvastatin (10–40 mg) Atorvastatin (10–80 mg) Simvastatin (40–80 mg) 3.0 Lovastatin (20–80 mg) 2.5 Fluvastatin (20–80 mg) 2.0 Persistent ALT >3 × ULN (%) 1.5 1.0 0.5 0.0 20 30 40 50 60 70 LDL-C reduction (%) Statin – Liver Effects Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K

  33. CK >10 x ULN: Frequency by LDL-C Reduction 3.0 Rosuvastatin (10–40 mg) Atorvastatin (10–80 mg) 2.5 Simvastatin (40–80 mg) Pravastatin (40–80 mg) 2.0 CK >10 × ULN (%) Cerivastatin (0.2–0.8 mg) 1.5 1.0 0.5 0.0 20 30 40 50 60 70 LDL-C reduction (%) Statin - Muscle Effects Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K

  34. Drug Interactions • Pharmacodynamic • Risk of hepatotoxicity and/or myalgias or myopathy when combined with fibrates or niacin • Pharmacokinetic •  absorption with bile acid sequestrants • Inhibition or induction of CYP-based metabolism • Inhibition of CYP activity

  35. Statin Metabolism Lovastatin, Simvastatin, Atorvastatin CYP3A Active and inactive metabolites, which are excreted in urine and/or bile CYP2C9 Fluvastatin Rosuvastatin Other enzymes/ renal Pravastatin

  36. Potential Drug Interactions 3A4 2C9 • Simvastatin • Atorvastatin • Lovastatin • Diltiazem • Clopidogrel • Amiodarone • Cimetidine • Ery/clarithromycin • Ketoconazole • Carbamazepine • Grapefruit juice • Fluvastatin • Rosuvastatin • Phenytoin • Fluconazole • Warfarin

  37. CYP3A Interactions • ALL statins (except fluvastatin and rosuvastatin) are metabolized at least in part by CYP3A • CYP3A inhibitors may  statin concentrations • Verapamil, diltiazem, Azole antifungals, erythromycin, nefazodone, fluoxetine, Protease inhibitors • CYP3A inducers may  statin concentrations • Rifampin, phenytoin, phenobarbital, troglitazone • Statins may also interact with other CYP3A substrates (i.e., cyclosporine)

  38. CYP2C9 Interactions • Fluvastatin is metabolized by CYP2C9 and inhibits CYP2C9 activity • CYP2C9 inducers (e.g., rifampin) and inhibitors (e.g., amiodarone) may  or  fluvastatin concentrations, respectively • Fluvastatin can inhibit CYP2C9 activity, increasing the concentration and effect(s) of other CYP2C9 substrates (e.g., S-warfarin)

  39. Pharmacokinetic properties of Statins Thomas N. Riley, PhD & Jack DeRuiter, PhD (2004); 陳昭姿, 當代醫學雜誌 (2005)

  40. Pharmacologicproperties of Statins

  41. Comparative efficacyof Statins Am J Cardiol 2004; 93(15): 809-811

  42. Cost - Effective of Statins 陳昭姿, 當代醫學雜誌 (2005) Brown WV et al., Am Heart J. 2002; 144:1036-43.

  43. Thanks for your attention!

  44. Combination Therapy • Superior LDL-lowering ability • Combinations with a resin may provide benefit with little risk of additive toxicity • Some concern about risk of rhabdomyolysis withstatin-niacin or statin-fibrate combinations • Others have found these combinations to be safe Studied Combinations Statin + Resin Statin + Resin + Niacin Statin + Niacin Statin + Fibrate Niacin + Resin

  45. Possible Non-Lipid-Lowering Effects of the Statins • Statins and Endothelial Function • Statins and Plaque Stability • Statins and Inflammation • Statins and Lipoprotein Oxidation • Statins and Coagulation

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