By Magdi El-Shalakany

1. Lipinorm a t o r v a s t a t i n c a l c i u m By Magdi El-Shalakany Hydroxy-methyl-glutaryl CoA reductase - inhibitor =STATINS

2. Lipinorm a t o r v a s t a t i n c a l c i u m For : 1. The treatment of Dyslipidemia And 2. Prevention of Coronary Heart Disease

3. Prevalence of CHD The Problem • More than 8million people die from CHD, every year worldwide, more than cancer, infectious diseases or any other causes. • In the U.S. alone, the prevalence of CHD is around 15 millions (5%) 650’000 die annually of CHD. • In Egypt, the WHO estimate for CHD is 3.5 Million. it is estimated that around 150’000 die from CHD in Egypt annually. • More than 8million people die from CHD, every year worldwide, more than cancer, infectious diseases or any other causes. • In the U.S. alone, the prevalence of CHD is around 15 millions (5%) 650’000 die annually of CHD. • In Egypt, the WHO estimate for CHD is 3.5 Million. it is estimated that around 150’000 die from CHD in Egypt annually.

5. Myocardial infarction recent hemorrhage Coronary artery Coronary artery thrombosis atheromatous plaque

6. Conventional Risk Factors for CHD • Positive family history of premature vascular ds. • Advancing age • Male Gender or post-menopause in females • Dyslipidemia (LDL-C or  HDL-C) • DM II • Smoking • Hypertension • Obesity • Sedentary life

7. Emmerging Risk Factors for CHD • Homocysteinemia. • Hypertriglyceridemia •  lipoprotein (a) Lpa. • Small dense LDL phenotype. • Insulin Resistance & hyperinsulinism. • Underlying inflammation & infection. •  WBC. • Oxidative stress & iron Overload. •  fibrinogen.

8. Conventional Risk Factors for CHD • Positive family history of premature vascular ds. • Advancing age • Male Gender or post-menopause in females • Dyslipidemia (LDL-C or  HDL-C) • DM II • Smoking • Hypertension • Obesity • Sedentary life • Positive family history of premature vascular ds. • Advancing age • Male Gender or post-menopause in females • Dyslipidemia (LDL-C or  HDL-C) • DM II • Smoking • Hypertension • Obesity • Sedentary life

9. Relation Between CHD & DM • DM II predisposes to both premature onset & severity of atherosclerosis in coronary arteries CHD. • CHD is the commonest cause of morbidity & mortality in DM II.

10. Five of the treatable and preventable risk factors for CHD are obesity, sedentary life, hypertension, smoking & dyslipidemia.

11. Management of dyslipidemia is primarily carried out through lifestyle modifications then drug therapy. • In recent years, more emphasis has been focused on the management of cholesterol. cholesterol.

12. HO H O 2 O Cholesterol Cholesterol ester

13. Cholesterol A Very Rigid Molecule

14. FUNCTIONS OF CHOLESTEROL • Structure of cell membrane • Precursor of Steroid Hormones • Precursor of Bile Acids

15. Cholesterol & Lipoproteins. Free Cholesterol Apoproteins Phospholipids Triglycerides Cholesterol Esters

16. LIPOPROTEINS Diameter (nm) Density (g/ml) Protein (%) Total lipid (%) % of Lipid Fraction LP TG PL FC CE 90 - 1000 < 0.95 1 - 2 98 - 99 88 8 1 3 CM 30 - 90 0.95 - 1.006 7 - 10 90 - 93 56 20 8 15 VLDL 25 - 30 1.006 - 1.019 11 89 29 26 9 34 IDL 20 - 25 1.019 - 1.063 21 79 13 28 10 48 LDL 10 - 20 1.063 - 1.125 33 - 57 67 - 43 16 43 10 31 HDL • Lipoproteins have different sizes, different densities, different content, different apoproteins, different receptor sites, different pathways & different effects.

17. Cholesterol Metabolism & Homeostasis

18. Cholesterol Biosynthesis Dietary Fat & Cholesterol To endocrine glands for steroid hormones' synthesis Bile Salts Cholesterol LDL Apo B100, E, CII HDL Apo B100 Apo AI Apo E, B48 Lymph LP/Hepatic Lipase B/E ( ) LDL VLDL receptor Apo B48, E, CII Go lgi CM CII Remnant cholesterol Apo LP Lipase IDL CM Apo E, B100 Peripheral t. LP Lipase capillaries capillaries β-oxidation Hydrolysis of TG ENERGY Lipoprotein Lipase Transported by serum albumin Glucose synthesis in the liver Glycerol free fatty a = Chylomicron CM Cholesterol ester Triacylglycerol TG Fig 1-A Hydrophilic layer: phospholipids, FC, Apoproteins

19. Types & Classification of Dyslipidemia

20. There are two major ways in which dyslipidemias are classified: 1.Etiological i.e. the cause of the condition genetic (familial), or secondary (non familial). 2.Phenotype i.e. the presentation in the body (the specific type of lipid increased). This classification can be problematic, because most conditions involve the intersection of genetics and lifestyle issues. This classification points to the problem, the type of lipoprotein & the specific blood lipid increased as well as the treatment of choice for that specific error. Fredrickson Classification: Phenotype I IIa IIb III IV V Type of Lipoprotein Elevated (VLDL) Triglycerides LDL LDL & VLDL IDL Chylomicrons VLDL & chylomicrons Both Cholesterol Triglycerides

22. Cholesterol Biosynthesis Dietary Fat & Cholesterol To endocrine glands for steroid hormones' synthesis Bile Salts Cholesterol LDL Apo B100, E, CII HDL Apo B100 Apo AI Apo E, B48 Lymph LP/Hepatic Lipase B/E ( ) LDL VLDL receptor Apo B48, E, CII CM CII Remnant cholesterol LP Lipase IDL CM Apo Apo E, B100 Peripheral t. CII LP Lipase capillaries capillaries β-oxidation Hydrolysis of TG ENERGY Lipoprotein Lipase Transported by serum albumin Glucose synthesis in the liver Glycerol free fatty a = Chylomicron CM Cholesterol ester Triacylglycerol TG Fig 1-A Hydrophilic layer: phospholipids, FC, Apoproteins

24. Statins are indicated for : Indications of Lipinorm 1. Lipinorm is indicated for the treatment of : 4. Familial hypercholesterolemia 5. Combined hyperlipidemia 6. Familial Dysbetalipoproteinemia 1.  LDL-cholesterol 2.  total-cholesterol 3. ApoB lipoproteinemia

25. Indications of Statins (Lipinorm) 1. Lipinorm is indicated for the treatment of : 4. Familial hypercholesterolemia 5. Combined hyperlipidemia 6. Familial Dysbetalipoproteinemia 1.  LDL-cholesterol 2.  total-cholesterol 3. ApoB lipoproteinemia 2. Lipinorm is indicated for the Prevention of : • Coronary Heart Disease in High Risk patients: i.e. with multiple risk factors. • Reduces the risk of angina • Reduces the risk of myocardial infarction • Reduces the risk of stroke

26. Conventional Risk Factors for CHD • Positive family history of premature vascular ds. • Advancing age • Male Gender or post-menopause in females • Dyslipidemia ( LDL-C or  HDL-C) • DM II • Smoking • Hypertension • Obesity • Sedentary life • Positive family history of premature vascular ds. • Advancing age • Male Gender or post-menopause in females • Dyslipidemia (LDL-C or  HDL-C) • DM II • Smoking • Hypertension • Obesity • Sedentary life • Positive family history of premature vascular ds. • Advancing age • Male Gender or post-menopause in females • Dyslipidemia (LDL-C or  HDL-C) • DM II • Smoking • Hypertension • Obesity • Sedentary life  HDL-C Treatment with retinopathy, albuminuria or macroangiopathy. Indications of Statins (Lipinorm): • 1- Prevention of Cardiovascular Disease in  risk adults: • Reduces the risk of angina. • Reduces the risk of myocardial infarction. • Reduces the risk of stroke. • 2- Treatment of Dyslipidemia: •  LDL-cholesterol  total-cholesterol • ApoB lipoproteinemia Familial hypercholesterolemia • Combined hyperlipidemia Familial Dysbetalipoproteinemia

27. NOERMAL HDL-C  40 mg% (35  60) NOERMAL LDL-C  130 mg % NOERMAL Total-C  200 mg% Total/HDL Ratio

28. ATORVASTATIN EFFICACY Comparative Studies

29. 16 weeks comparative study

30. 16 weeks comparative study

31. 16 weeks comparative study

32. Frederickson's phenotypeIIa

33. Frederickson's phenotypeIIb

34. A significant proportion of patients switching from atorvastatin to simvastatin received a low dose in terms of efficacy -lower than that which can achieve the therapeutic goal- which may have an adverse impact on patients' healthcare quality and probability of vascular morbidities and mortality. • Switching from more expensive brand name drugs to generic equivalents may reduce aggregate prescription costs. • Therapeutic benefit may not be compromised if the patient is switched to a generic with an equivalent therapeutic profile. Reference: Gregory Hess, Therapeutic Dose Assessment of Patient Switching from Atorvastatin to Simvastatin (Am J Manag Care. Jun 2007; suppl 3; vol 13:S80-S85)

35. By the end of the first 16-week period, when patients in both groups were on the 10 mg/day dose, 10 of the 15 patients on atorvastatin (66%) presented a LDL-C level <130 mg/dl, while only 4 of the 15 patients on simvastatin (27%) achieved this goal. • Atorvastatin in equipotent doses to simvastatin appeared to be more effective than the latter in reducing triglyceride and plasma fibrinogen in patients with hypercholesterolaemia, and also in those with Frederickson's phenotype IIb. • Regarding HDL-C, it was increased by simvastatin only with the 20mg dose: 7%vs. baseline vs. atorvastatin; 4% at the 10mg dose and 5% at the 20mg dose vs. baseline. Reference: Atorvastatin vs. Simvastatin on Lipid Profile from Clinical Drug Investigation [TM] 2002.

38. ATORVASTATIN SAFETY

39. ATORVASTATIN The Most Extensively Used Statin World-wide No.1 Pharmaceutical Product Sold in the World

40. ATORVASTATIN The Most Effective Statin The Safest Statin With a Reasonable Price