Advances In The Treatment of Hyperlipidemia

1. Advances In The Treatment of Hyperlipidemia Hallie Lee PharmD Candidate 2013 Mercer University COPHS December 2012

2. Objectives Background: Lipoproteins & lipid metabolism Etiologies of lipid disorders NCEP ATP III Guidelines NCEP ATP III 2004 update Treatment Options NCEP ATP IV New Potential Goal Modifiers

3. Plasma Lipids • Lipids are transported in the plasma as lipoproteins • The major lipid classes present in lipoproteins • Triacylglycerols(16%) • Phospholipids (30%) • Cholesterol (14%) • Cholesterol esters (36%) • Free fatty acids (4%)

4. Lipoproteins A core of nonpolar cholesteryl esters and triglycerides covered by a polar surface monolayer made up of phospholipids, free cholesterol, and apolipoproteins

5. Lipoprotein components • Cholesterol-structural component of all cell membranes and a precursor for steroid biosynthesis and bile acids • Present in tissues and in plasma either as free cholesterol or combined with a long-chain fatty acid as cholesteryl ester, the storage form • A little more than half comes from the body itself synthesized from acetyl-CoA, the rest comes from the diet • Triglyceride-fatty acids used for energy by the liver and peripheral tissues i.e. muscle • Phospholipid-component of cell membranes Lipids are water insoluble and require lipoprotein transporters to reach body tissues from the bloodstream

6. Lipoprotein Classes VLDL-very low density lipoprotein IDL-intermediate density lipoprotein LDL-low density lipoprotein HDL-high density lipoprotein Apolipoproteins make up the rest

7. Apoplipoproteins • Apolipoproteins carry out several roles: • They form part of the structure of the lipoprotein • They are enzymes, cofactors, or inhibitors • They act as ligands for interaction with lipoprotein receptors in tissues • “Nametags” attached as identifiers

9. Lipid Metabolism Exogenous Endogenous Reverse Transport

10. Lipid Metabolism Exogenous pathway = transport of dietary lipids Lipids from diet absorbed into intestinal villa as fatty acids and cholesterol Re-esterification of fatty acids  TG & cholesterol  cholesteryl ester occurs in mucosal cells TG and cholsteryl ester combined with Apo B-48 and Apo A-I within intestinal wall to form immature chylomicron particles Chylomircons enter the systemic circulation via the lymphatic system Apo C-II and Apo E transferred to chylomicrons from HDL particles in the bloodstream Apo C-II enhances interactions of chylomicron and lipoprotein lipase on the capillary endothelial cell surfaces in tissues, TG hydrolyzed into free fatty acids for storage or energy use by muscle Remnants are cleared by receptors on surface of liver cells that recognize Apo E

11. Exogenous Pathway

12. Lipid Metabolism Endogenous pathway = transport of lipids produced by the body VLDL assembled and secreted by hepatocytes: TG and cholesterol are packaged with Apo B-100 and phospholipids, Apo C-II and Apo E added after VLDL enters the plasma TG core hydrolyzed by lipoprotein lipase in capillary beds releasing fatty acids into tissues Remaining VLDL is now IDL, most surface apos (minus Apo B-100) are transferred to HDL, mediated by cholesteryl ester transfer protein (CETP) IDL removed from liver by Apo E binding to LDL receptor, remaining IDL is converted to LDL via hepatic lipase

13. Endogenous Pathway

15. Lipid Metabolism Reverse cholesterol transport Apo A-I is produced in the liver and intestine, acts as the building block for nascent(immature) HDL Nascent HDL particles act as initial acceptors of free cholesterol from peripheral cells through the receptor ATP binding cassette AI Lecithin cholesterol acetyl transferase (LCAT) converts free cholesterol to cholesteryl ester to form the core of HDL3, LCAT is activated by Apo A-I Enrichment of HDL3 with cholesteryl ester results in formation of HDL2 Cholesteryl ester may be transferred from HDL to VLDL, IDL, or LDL (Apo B lipoproteins)in exchange for triglyceride molecules by cholesterol ester transfer protein (CEPT) Cholesteryl ester may be delivered directly to the liver by HDL itself

16. Reverse Cholesterol Transport

17. Etiology • Primary hyperlipoproteinemia: lipoprotein abnormalities direct result of specific defects in synthesis/degradation of particles 1. Familial hypercholesterolemia • Defective gene for LDL receptor • Characterized by sever elevations of LDL, tendon xanthomas, and premature atherosclerosis 2. Polygenic hypercholesterolemia • variety of genetic defects resulting in less active LDL receptor • Possibly the underlying disorder in as many as 80% of people with hypercholesterolemia • Elevated LDL and premature atherosclerosis 3. Familial combined hyperlipidemia • Associated with overproduction of VLDL due to increased production of Apo B-100 • Elevated LDL and/or TG and premature atherosclerosis

18. Etiology • Secondary hyperlipoproteinemia: elevated lipoprotein levels occur as part of an underlying disorder or drug therapy • Hypercholesterolemia • Hypothyroidism, liver disease, nephrotic syndrome • Meds: progestins, thiazides, glucocorticoids, BB, cyclosporine, mirtazepine • Hypertriglyceridemia • Obesity, DM, Pregnancy, acute hepatitis • Meds: alcohol, estrogens, isotretinoin, BB, glucocorticoids, azole antifungals • Low HDL • Malnutrition, obesity • Meds: anabolic steroids, isotretinoin, progestins

19. Disease Terminology Hyperlipoproteinemia - high lipoproteins Hypercholesterolemia -high TC or LDL Hyperlipidemia -high TC, TG, or LDL Hypertriglyceridemia -high TG Dyslipidemia -high TC, TG, LDL or low HDL TC-total cholesterol TG-triglycerides

20. National Cholesterol Education Program Adult Treatment Panel III“NCEP ATP III Guidelines”

21. Current Treatment Guidelines

22. NCEP ATP III Focus • All adults ≥ 20 years old should have a fasting lipid panel performed every 5 years • A complete lipoprotein profile is preferred • Fasting TC, LDL, HDL, and TG • Secondary option • Non-fasting TC and HDL • Proceed to lipoprotein profile if TC ≥ 200 or HDL < 40 • LDL is the primary target • If TG are > 500mg/dL, TG should be targeted first • Once LDL goal is achieved, attention should be focused on the other parameters (non HDL cholesterol) • Non HDL-C = Total cholesterol - HDL cholesterol

23. 3 Categories of Risk that Modify LDL Goals* Risk Category • CHD and CHD risk equivalents • Multiple (2+) risk factors • Zero to one risk factor *Per the 2001 NCEP ATP III Guidelines LDL Goal (mg/dL) <100 <130 <160

24. Risk Factors • Positive Risk Factors • Age : M ≥ 45 F ≥ 55 • Family history : premature CHD in 1st degree relative M <55 F <65 • Current smoker • HTN >140/90 or on medication • Low HDL <40 • Negative Risk Factors • High HDL ≥ 60

25. Risk Assessment • All patients without CHD or CHD risk equivalents: • Count the number of risk factors • If multiple risk factors ≥ 2 use Framingham scoring to determine 10 year CHD risk • For patient with 0-1 risk factors • 10 year risk assessment not required

26. Managing lipids for risk reduction: Focus on the new National Cholesterol Education Program guidelines. Vascular Biology Working Group. University of Flordia 2001. Available at http://www.vbwg.org/quickorder/resource_slides.cfm?itemID=6&TypeID=4&StartRow=6#mark. Accessed December 9, 2012.

27. Managing lipids for risk reduction: Focus on the new National Cholesterol Education Program guidelines. Vascular Biology Working Group. University of Flordia 2001. Available at http://www.vbwg.org/quickorder/resource_slides.cfm?itemID=6&TypeID=4&StartRow=6#mark. Accessed December 9, 2012.

28. CHD and CHD Risk Equivalents • Established CHD • MI • Myocardial ischemia • Coronary angioplasty/stent placement • CABG • Prior unstable angina • Risk Equivalents • CAD • Stroke • TIA • Carotid stenosis >50% • PAD • Abdominal aortic aneurysm • Diabetes LDL goal is < 100mg/dL for these patients per the 2001 Guidelines

29. Goals • LDL • Optimal < 100 • Near Optimal 100-129 • Borderline 130-159 • High 160-189 • Very high ≥ 190 • Total Cholesterol • Desirable < 200 • Borderline 200-239 • High ≥ 240

30. Goals • Triglycerides • Normal < 150 • Borderline 150-199 • High 200-499 • Very high >500 • HDL • Low < 40 • High > 60

31. Calculating LDL • LDL = TC – HDL – ( TG/5 ) • LDL equals total cholesterol minus HDL minus triglycerides divided by five • TG must be <400 to use • VLDL = TG/5 Example: TC=225 HDL=32 TG=170 LDL = 225-32-(170/5) = 159

32. LDL-Lowering Therapies In Patients With CHD and CHD Risk Equivalents • Baseline LDL cholesterol ≥ 130 mg/dL • Intensive lifestyle therapies • Maximal control of other risk factors • Consider starting LDL-lowering drugs simultaneously with lifestyle therapies • Baseline (or on treatment) LDL 100-129mg/dL • LDL lowering therapy; lifestyle therapy or drugs • Treatment of metabolic syndrome • Weight reduction and increased physical activity • Drug therapy for other lipid risk factors

33. LDL-Lowering Therapies In Patients With CHD and CHD Risk Equivalents • Baseline LDL < 100mg/dL • Further LDL lowering not required • Therapeutic Lifestyle Changes (TLC) recommended • Consider treatment of other lipid risk factors • Ongoing clinical trials are assessing benefit of further LDL lowering

34. LDL-lowering Therapy in Patients With Multiple Risk Factors and 10 Year Risk ≤ 20% • 10 Year Risk 10-20% • LDL-lowering goal <130mg/dL • Aim to reduce short and long term risk • Immediate initiation of TLC if LDL goes >130 • Consider drug therapy if LDL > 130 after 3 months of lifestyle therapies • 10 Year Risk < 10% • LDL goal <130mg/dL • Aim to reduce long term risk • Initiate therapeutic lifestyle changes if LDL > 130 • Consider drug therapy if LDL > 160 after 3 months of lifestyle therapies

35. LDL-Lowering in Patients with 0-1 Risk Factor Aim to reduce long term risk LDL goal <160 Initiate therapeutic lifestyle changes is LDL > 160 If LDL is ≥ 190 after 3 months of lifestyle therapies consider drug therapy If LDL is ≥ 160-189 after 3 months of lifestyle therapies drug therapy is optional

36. Summary Treatment Categories * 100–129 mg/dL = after TLC, consider statin, niacin, or fibrate therapy Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

37. NCEP ATP III 2004Update • For high risk patients: LDL-Lowering Therapies In Patients With CHD and CHD Risk Equivalents LDL goal < 70 in patients with established CHD plus: • Multiple risk factors, esp. diabetes • Severe or poorly controlled risk factors • Metabolic syndrome • Acute coronary syndromes • Consideration of drug treatment in addition to lifestyle therapy for LDL levels ≥100 mg/dLin high-risk patients, and characterizes drug treatment as optional for LDL<100 mg/dL

38. NCEP ATP III 2004Update • For moderately high-risk patients--Individuals who have multiple (2+) CHD risk factors together with a 10-20% risk for a heart attack within 10 years: • The overall goal for moderately high-risk patients is still an LDL < 130 mg/dL • There is a therapeutic option to set the treatment goal at LDL <100 mg/dLand to use drug treatment if LDL is 100-129 mg/dL • For high-risk and moderately high-risk patients: • Advises that the intensity of LDL-lowering drug treatment in high-risk and moderately high-risk patients be sufficient to achieve at least a 30 percent reduction in LDL levels

39. Goals for Therapy: The 2004 Addendum • NCEP ATP III guidelines for LDL Therapy LDL-C <160 for 1 or less risk factors LDL-C <130 for 2+ risk factors < 100 is a therapeutic option LDL-C <100 for CAD and CAD equivalents <70 is option for very high risk patients • CAD + multiple risk factors, especially diabetes • CAD + severe or poorly controlled risk factor(s) • CAD + metabolic syndrome • Acute coronary syndrome • CAD event despite baseline LDL-C < 100

40. LDL Therapy • Lifestyle Changes • Statins • Bile Acid Sequestrants • Ezetimibe • Niacin • Plant Stanols, Sterols, Phytosterols

41. Therapeutic Lifestyle Changes (TLC) • TLC Diet • Reduced intake of cholesterol-raising nutrients • Saturated fats <7% of total calories • Dietary cholesterol <200mg per day • LDL-lowering therapeutic options • Plant stanols/sterols • Soluble fiber 10-25gram per day • Weight reduction • Increased physical activity • Smoking cessation

42. ATP III Guidelines Slide Show. National Heart Lung, and Blood Institute.. Available at http://hp2010.nhlbihin.net/ncep_slds/atpiii/slide31.htm. Accessed December 9, 2012.

43. ATP III Guidelines At a Glance Quick Desk Reference. National Cholesterol Education Program. National Institutes of Health. Available at http://www.nhlbi.nih.gov/guidelines/cholesterol/atglance.pdf. Accessed on December 9, 2012.

44. NCEP ATP IVWhen will it be available? • Draft Completed: Expert panelists have completed a full draft of the systematic review and recommendations. • Federal Review Completed: Federal agency representatives of the NHLBI's National Program to Reduce Cardiovascular Risk (NPRCR) coordinating committee provide review and comment. • Expert Review Completed: External peer reviewers with expertise in the relevant risk factors provide review and comment. • Advisory Council In Progress: The National Heart, Lung, and Blood Advisory Council provides review and comment and recommends approval. • Public Comment: The draft will eventually be offered publicly for review and comment. • HHS Clearance: The U.S. Department of Health and Human Services provides editorial review, comment, and approval once it is made available.

45. Issues for ATP-IV • Should the goals for LDLin primary prevention be lowered? • Where does CRP fit in– routine use in risk stratification, secondary target? • What about Apo-B? • What about secondary targets? • Non-HDL-C, HDL-C, LDL Particle concentration? • Move from a 10-year to lifetime risk?

46. Potential Goal Modifiers • Lp(a)/Apo A • Apo AI • High sensitivity CRP • Lp-PLA2 • Metabolic Syndrome • Apo B • LDL-P vs. LDL-C • Apo E and lipoprotein Genetics

47. Definitions LDL-C: amount of cholesterol in LDL particles LDL-P: number of LDL particles Non-HDL: amount of cholesterol in atherogenicparticles Apo-B: number of atherogenic particles

48. Lp(a) / Apo a • Physiological function is still unknown • High level in the blood is a risk factor for CHD, CVD, atherosclerosis, thrombosis, and stroke • Most LDL-lowering drugs do not effect the blood levels • Apo(a) contains domains that are very similar to plasminogen (PLG) • Lp(a) accumulates in the vessel wall and inhibits binding of PLG to the cell surface, reducing plasmin generation which increases clotting • Suggests it can cause the generation of clots and atherosclerosis • Lp(a) Levels: Desirable: < 14 mg/dL (< 35 nmol/l) Borderline risk: 14 - 30 mg/dL (35 - 75 nmol/l) High risk: 31 - 50 mg/dL (75 - 125 nmol/l) Very high risk: > 50 mg/dL (> 125 nmol/l)

49. Apo AI • The American Association of Clinical Endocrinologists (AACE) Guidelines for Management of Dyslipidemia and Prevention of Atherosclerosis States: • The assessment of Apo AI may be useful in certain cases • A normal Apo AI level in a patient with low HDL-C suggests the existence of an adequate number of HDL-C particles that contain less cholesterol and may be an indication of less risk • The INTERHEART study found that the Apo B to Apo AI ratio was among the most significant risk factors for MI

50. C-Reactive Protein • Produced by the liver • Level rises when there is inflammation throughout the body • High-sensitivity C-reactive protein (hs-CRP) assay tests are available • Determine a person's risk for heart disease • Many consider a high CRP level to be a risk factor for heart disease • It is not known whether it is merely a sign of cardiovascular disease or if it actually plays a role in causing heart problems • According to the American Heart Association: • You are at low risk of developing cardiovascular disease if your hs-CRP level is < 1.0mg/L • You are at average risk of developing cardiovascular disease if your levels are between 1.0 - 3.0 mg/L • You are at high risk for cardiovascular disease if your hs-CRP level is > 3.0 mg/L • AACE recommends CRP testing to stratify CVD risk in patients with a standard risk assessment that is borderline, or in those with an LDL-C con- centration < 130 mg/dL