1) A 43-year-old male presented with chest pain and was diagnosed with an acute inferior STEMI while in normal sinus rhythm. His medical history included atherosclerosis. 2) Atherosclerosis is caused by plaque buildup in arteries and accounts for over 70% of cardiovascular deaths in the US. Elevated LDL cholesterol increases the risk of atherosclerosis and heart disease. 3) Therapeutic lifestyle changes like diet and exercise can modestly lower LDL cholesterol by about 5% on average but response varies between individuals. High fat, low carb diets may improve glycemic control in diabetes without worsening lipids.

1. Pfizer Talk Family Medicine 13/1/2010 Dr Ihab Suliman

2. 43 years old male with Chest Pain

3. Acute Inferior STEMI in NSR.

4. Atherosclerosis

6. The Impact of Elevated LDL-C and Associated Atherosclerosis Atherosclerosis is caused by a build-up of plaque in arterial walls, obstructing blood flow Atherosclerosis accounts for more than 70% of all deaths from cardiovascular disease in the US Elevated LDL (low-density lipoprotein) cholesterol increases risk of atherosclerosis and coronary heart disease The risk of coronary heart disease increases by about 2% for each 1% elevation in total cholesterol National Center for Health Statistics. Health, United States, 2005.http://www.cdc.gov/nchs/hus.htm. Accessed May 17, 2006 Kwiterovich PO Jr. Am J Cardiol. 1998,82:3U-17U

7. Cholesterol is important in so many metabolic activities , there fore it is more important in adults or infants????

8. What is the normal Cholesterol level in Infancy???.

9. Cholesterol Levels By Species Infant Adult American Hunter-Gatherer Humans: Hazda Inuit IKung Pygmy San Wild Primates: Baboon HowlerMonkey Night Monkey Wild Mammals: Horse Boar Peccary BlackRhinoceros AfricanElephant Modern Human: 50 70 90 110 130 150 170 190 210 Mean Total Cholesterol Level JACC 2004;43:2142-6

10. Discovery of statins Some drugs available but not effective In 1971,Endo and Kuroda (Sankyo Pharmaceuticals in Japan) began search for better drugs Cholesterol pathway known and they wanted to find a HMG-CoA reductase inhibitor – looked for a microorganism – screened over 6000 Two (3rd later) cmpds identified - one was from Penicillium citrinum - named mevastatin In 1976 isolated and crystallized Clinical trials started in 1978 and quickly stopped because of animal tumors

12. Heavy alcohol use

14. Diabetes mellitus

15. Hypercholesterolemia

16. Obesity

17. Insulin resistance?

18. Cardiac diseasesAtrial fibrillation Coronary artery disease CHF

19. Causes of death, 2001: USA 1. Infectious and parasitic diseases: 14.9 million 6. 2. Heart diseases: 11.1 million 1. 3. Cancers: 7.3 million 2. 4. Stroke: 5.5 million 3. 5. Respiratory diseases: 3.6 million 4. 6. Accidents, fires, drowning, etc.: 3.5 million 5. 7. Maternal and perinatal: 3.0 million 8. Violence (war, homicide, suicide): 1.6 million Population: 6,122,210,000 Deaths: 56,554,000 World Health Organization World Health Report 2002

20. Therapeutic lifestyle change is the cornerstone of the management of hyperlipidemia and dyslipidemia?  LDL-C with AHA diet: ~ 5% Response variability: familial/genetic Hypocaloric diets in overweight & obese

21. A high fat, low carb diet does not worsen serum lipids/lipoproteins and improves glycemic control in patients with diabetes LDL-C is unchanged HDL-C is unchanged or slightly higher Triglyceride is lower by~25% Variability in response? HbA1c better than with LFHC diet

22. Dietary Nuances Fish: twice/wk; omega-3 fatty acids, 1000 mg/d Eliminate/reduce trans FA Plant stanols/sterols reduce LDL-C by ~10% Antioxidant vitamins are not cardioprotective and interfere with effects of niacin on HDL-C Homocysteine: folic acid, vitamins B6 and B12not proven to be cardioprotective.

25. ALLIANCE: 111  95 mg/dl

27. ATP III Treatment Priorities Reduce LDL-C to goal (new goals) Correct residual lipid/lipoprotein abnormalities( non-HDL-cholesterol) Address the metabolic syndrome

31. Cholesterol absorption inhibitors

32. Bile acid binding resins

34. Subclinical hypothyroidism

36. Hyperlipidemia in Pregnancy TC & TG levels increase throughout pregnancy average cholesterol increase: 30 to 40 mg/dL around weeks 36 to 39 TGs may increase as much as 150 mg/dL Drug therapy typically not initiated/continued during pregnancy TLC is the mainstay but BARs & absorption inhibitors may be considered in high risk patients ezetimibe: category C Statins: category X 24

37. Statin Therapy Can Reduce the Risk of Coronary Heart Disease (CHD) Friday KE. Exp Biol Med. 2003,228:769-778 Wilt TJ et al. Arch Intern Med. 2004;164:1427-1436

38. Diabetic Dyslipidemia Characterized by hypertriglyceridemia, low HDL, & minimally elevated LDL DM ATP III CHD risk equivalent Small, dense LDL (pattern B) in DM patients is more atherogenic than larger, more buoyant LDL (pattern A) 1˚target: LDL Goal of treatment: LDL-C < 100 mg/dL LDL > 130 mg/dL: TLC + drug therapy often required Statins often considered initial drugs of choice 26 Expert Panel on Detection E, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486–2497.

39. Diabetic Dyslipidemia Collaborative AtorvastatinDiabetes Study (CARDS) LDL lowering for 1˚ CHD prevention in type 2 DM Randomized, double-blinded placebo controlled Atorvastatin 10 mg/day versus placebo (n=2,838) diabetes to reduce first CHD events Baseline LDL: 118 mg/dL; LDL ↓ 46 mg/dL with atorvastatin 27 Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): Multicentre randomised placebo-controlled trial. Lancet 2004;364:685–696.

41. Secondary endpoints: total mortality, any CV endpoint, lipids, and lipoproteinsColhoun HM et al. Lancet 2004;364:685-696.

42. CARDS: Patient Baseline Characteristics Colhoun HM et al. Lancet 2004;364:685-696. Reprinted with permission from Elsevier.

43. CARDS: Patient Baseline Lipids *Median (interquartile range) Colhoun HM et al. Lancet 2004;364:685-696. Reprinted with permission from Elsevier.

44. 0 1 2 3 4 4.5 0 1 2 3 4 4.5 CARDS: Lipid Levels by Treatment Total Cholesterol (mg/dL)Average difference 26%,54 mg/dL; P<0.0001 LDL Cholesterol (mg/dL)Average difference 40%,46 mg/dL; P<0.0001 Placebo Placebo Median LDL-C (mg/dL)* Atorvastatin Median TC (mg/dL)* Atorvastatin Years of Study Years of Study Colhoun HM et al. Lancet 2004;364:685-696. Reprinted with permission from Elsevier.

45. CARDS: Effect of Atorvastatin on the Primary Endpoint: Major CV Events Including Stroke Relative Risk Reduction 37% (95% CI, 17–52)P = 0.001 Placebo127 events Cumulative Hazard, (%) Atorvastatin83 events 0 1 2 3 4 4.75 Years 14101428 13511392 PlaceboAtorvastatin 13061361 10221074 651694 305328 Colhoun HM et al. Lancet 2004;364:685-696. Reprinted with permission from Elsevier.

46. CARDS: Adverse and Serious Adverse Events Colhoun HM et al. Lancet 2004;364:685-696.

47. Diabetic Dyslipidemia CARDS trial: 37% reduction in composite 1˚end point 1˚ endpoint: acute CHD death, nonfatal MI, hospitalized unstable angina, resuscitated cardiac arrest, coronary revascularization, or stroke Suggests diabetics should have target LDL much lower than 100 mg/dL 34 Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): Multicentre randomised placebo-controlled trial. Lancet 2004;364:685–696.

48. Atorvastatin 10 mg Number of events 100 Placebo Number of events 154 4 36% reduction 3 Cumulative Incidence (%) 2 1 HR = 0.64 (0.50-0.83) P = 0.0005 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years ASCOT: Primary Endpoint: Nonfatal MI/Fatal CHD Sever PS et al, for the ASCOT Investigators. Lancet. 2003;361:1149-1158.

49. Comparing 2 statin drugs Atarvastatin – 80 mg. Pravastatin – 40 mg. Equivalent doses Trial was designed to demonstrate non-inferiority of pravastatin. Instead, it showed ataravastatin to be superior. Not only did ataravastatin lower cholesterol more (and faster), but it lowered death rate by 16% Study was stopped “early.”

50. FDA 2007 The FDA approved atorvastatin for reducing the risk for nonfatal MI, reducing the risk for fatal and nonfatal strokes, for use in certain types of heart surgery, for reductions in the risk of hospitalization for heart failure, and to reduce chest pain in patients with heart disease. Atorvastatin is the first cholesterol-lowering drug to be approved for reducing the risk of hospitalization for heart failure.

51. Thank You Very Much