Lipids made simple

2,031 views

Published on

Published in: Sports, Automotive

Lipids made simple

  1. 1. LIPIDS in primary care
  2. 2. • • • • • • Lipoprotein metabolism LDL TGL HDL Current guidelines Case discussion
  3. 3. Lipoprotein metabolism
  4. 4.  What are the important components (two) of lipids in the plasma ? 1. Ester. Cholesterol (EC) 2. Triglycerides (TG)  What are the other two components in lipids in their outer layer ? 1. Free Cholesterol (FC) 2. Phospholipids (PL)  What are Apoproteins ? Why are they needed in the lipid molecules ? 1. The outer protein coat is made of Apoproteins 2. To make lipids soluble and thus help transport 
  5. 5. TG EC Apoprotein boat 1. 2. 3. 4. Make the lipids soluble and transportable Structural Integrity of the lipoprotein Act as ligands for cell receptors Activate enzymes such as LPL, LCAT as cofactors
  6. 6. Cholesterol biosynthesis
  7. 7. Structure of lipoprotein INTEGRAL APOPROTEINS CHOLESTEROL ESTERS MONOLAYER OF PHOSPHOLIPID AND CHOLESTERLOL CORE TRIGLYCERIDES PERIPHERAL APOPROTEINS
  8. 8. The Lipoprotein Particles
  9. 9. Lipemic Turbid Serum
  10. 10. The Atherogenic Particles Measurements Chylo M VLDL VLDLR TG-rich lipoproteins Apolipoprotein B Non-HDL-C IDL LDL Lp(a) SLDL The smaller the particle The greater is the danger
  11. 11. Fat apo B-48 CCK Bile salts Duodenum Chylomicron Micelles ACAT Enterocytes apo-C apo-E Lacteal Thoracic duct Systemic circulation
  12. 12. LDL-R Chylomicron remnant receptor apo-B-48 VLDL apo-E apo-C Liver apoE Chylomicron Adipocyte Chylomicron remnant When TGs < 20% remaining, they loose apoC
  13. 13. apo-B-100 Liver VLDL apo-B-100 TGs <50% Remains attached to LPL LPL VLDL Remnant TGs <30% Cell wall Aldosterone Cortisol Sex hormones Adipocyte & Myocyte VLDL LDL-R IDL TGs < 10% Loses apoE & apoC LDL apoB-100
  14. 14. Chylomicrons and VLDL
  15. 15. • • • • • • Lipoprotein metabolism LDL TGL HDL Current guidelines Case discussion
  16. 16. Havoc by LDL at Endothelium Vessel Lumen Monocyte LDL Adhesion Molecules Cytokines Macrophage 21 Ross R. N Engl J Med 1999;340:115-126. MCP-1 LDL Modified LDL Foam Cell Endothelium Intima Growth Factors Metalloproteinases Cell Proliferation Matrix Degradation
  17. 17. Statin Evolution PROVE IT 22 CARDSTIME AZZ SEARC ALLHAT LIPID – H AFCAPS/TexCA REVERSAL IDEA Post CABG PS MIRACL PROSPE R ASCOT TNT L CARE FLORIDA 4S HP MARS WOSCOPS S 1991 1993 1994 1995 Pravastati n NCEP Approved (ATP II) Simvastati n Approved 1997 Atorvastatin Approved Cervastatin Approved 1999 2001 20032004 Ezetimibe Approved NCEP (ATP III) Cervastatin Withdrawn Rosuvastati n Approved
  18. 18. Relation Between CHD Events and LDL-C in Recent Statin Trials 30 4S-PI 2° Prevention 25 4S-Rx 20 % with LIPID-Rx 15 CHD event CARE-Rx 10 LIPID-PI CARE-PI 1° Prevention WOSCOPS-PI AFCAPS/TexCAPS-PI 5 AFCAPS/TexCAPS-Rx 0 90 110 130 150 WOSCOPS-Rx 170 190 Mean LDL-C level at follow-up (mg/dL) PI=placebo; Rx=treatment Shepherd J et al. N Engl J Med. 1995;333:1301-1307. 4S Study Group. Lancet. 1995;345:1274-1275. Sacks FM et al. N Engl J Med. 1996;335:1001-1009. Downs JR et al. JAMA. 1998;279:1615-1622. Tonkin A. Presented at AHA Scientific Sessions, 1997. 210
  19. 19. Summary of Effects of Lipid Lowering on Lipids and Clinical Events in Recent Statin Trials %+ Nonfatal 8 10 CHD All-cause 5 5 MI/CHD 5 death mortality LDL-C TC death 0 HDL-C -5 -10 -9 -15 -20 -20 -20 -20 -22 -25 -24 -25 -26 -30 -28 -30 -31 -35 -33 -34 -35 -40 -42 -45 WOSCOPS (N=6,595) 4S (N=4,444) CARE (N=4,159) 1o prevention N=number enrolled. 2o prevention 2o prevention
  20. 20. Lipid Profile Report LIPIDS ESTIMATED TOTAL CHOLESTEROL (TC) HDLc LDLc VLDLc TRIGLYCERIDES (TG) Chylomicrons PP 26 VLDL Fasting
  21. 21. Lipid profile report • TC 200 mg/dl • HDL 40 mg/dl • TGL 150 mg/dl • TC 200 mg/dl • HDL 40 mg/dl • TGL 450 mg/dl • VLDL = 30 (TGL/5) • LDL =130 (TC-HDL-VLDL) • VLDL = 90 (TGL/5) • LDL =70(TC-HDL-VLDL) Non HDL
  22. 22. NON HDL C=Total Cholesterol– HDL cholesterol VLDL IDL VLDL IDL LDL LDL SMALL DENSE NON HDL GOAL: 30mg above LDL goal NON HDL APO B
  23. 23. ATP III • • • • • Obtain a fasting lipid profile CHD risk factor Major risk factors (ABC HF) Target LDL TLC
  24. 24. LDL mass may underestimate atherogenic risk Up to 70% more particles 100 mg/dL 100 mg/dL Cholesterol balance Adapted from Otvos JD, et al. Am J Cardiol 2002; 90 (suppl):22i-29i
  25. 25. Small Dense LDL and CHD: Potential Atherogenic Mechanisms • Increased susceptibility to oxidation • Increased vascular permeability • Decreased affinity for LDL receptor • Association with insulin resistance syndrome • Association with high TG and low HDL Austin MA et al. Curr Opin Lipidol 1996;7:167-171.
  26. 26. Statin Action 36
  27. 27. Time Course of Statin Effects LDL-C lowered* Inflammation reduced Endothelial function restored Days 37 Vulnerable plaques stabilized Ischemic episodes reduced * Time course established Cardiac events reduced* Years
  28. 28. Dual Inhibition LDL apoB100 Liver Statin Duodenum X VLDL apoB100 X Ezetimibe Jejunum Ileum CM Remnant apoB48 38 CM apoB48 Colon
  29. 29. Statin Dose Required to Achieve 45–50% Reduction 10 20 40 Prava Not achieved with maximum licenced dose Fluva 80 mg Not achieved with maximum licenced dose Simva Atorva Rosuva Adapted from Jones P.H. et al. Am J Cardiol 2003;92:152–160
  30. 30. Mean % Change in LDL-C from Untreated Baseline Value 40 10 mg 40 mg Atorvastatin 20 mg Rosuvastatin 30 mg Simvastatin 0% -10% -20% −3 -30% 7 -40% −6 −5 -50% −3 -60% −46† 14% with 3 titrations −6 −3 * * Jones PH, et al. Am J Cardiol. 2003;92:152–160. −2 8 −7 −4 −7 9% with 2 titrations 18% with 3 titrations
  31. 31. Molecular pathway EARLY HIGH DOSE Lipophylic statins better
  32. 32. Rosuvastatin: Additional binding site with HMG-CoA Rosuvastatin Additional sulphone binding site Arg568 Istvan and Deisenhofer Science 2001; 292:1160-1164
  33. 33. Liver effects - Benefit versus Risk ALT >3 × ULN: Frequency by LDL-C reduction Rosuvastatin (10, 20, 40 mg) Occurrence of ALT >3×ULN (%) Atorvastatin (10, 20, 40, 80 mg) 3.0 Simvastatin (40, 80 mg) Lovastatin (20, 40, 80 mg) 2.5 Fluvastatin (20, 40, 80 mg) 2.0 1.5 1.0 0.5 0.0 20 30 40 50 LDL-C reduction (%) Persistent elevation is elevation to >3 x ULN on 2 successive occasions Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K 60 70
  34. 34. Muscle effects - Benefit versus Risk Occurrence of CK >10 × ULN (%) CK >10 x ULN: Frequency by LDL-C Reduction Rosuvastatin (10, 20, 40 mg) Atorvastatin (10, 20, 40, 80 mg) Simvastatin (40, 80 mg) Pravastatin (20, 40 mg) Cerivastatin (0.2, 0.3, 0.4, 0.8 mg) 3.0 2.5 2.0 1.5 1.0 0.5 0.0 20 30 40 50 LDL-C reduction (%) Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K 60 70
  35. 35. Inadequate Achievement of NCEP ATP III Treatment Goals, Especially among Patients at Highest Risk 100% 80% 70% 60% 40% 40% 39% 18% 20% 0% Low Risk n= High Risk CHD 861 1,924 1,352 All Patients 4,137 Drug therapy included statins (fluvastatin, lovastatin, pravastatin, simvastatin), gemfibrozil, bile acid sequestrants, niacin, psyllium fiber, and combination drug therapy. Adapted from Pearson TA et al. Arch Intern Med 2000;160;459-467.
  36. 36. Statin Therapy Residual CVD Events CTT Meta-Analysis of 14 Statin Trialsa 40 Major Vascular Event Rateb, % 30 34.9 Control Treatmentc CVD Risk Higher Than Patients With No Diabetes on Placebo 29.6 24.8 19.4 20 Residual Risk 10 Residual Risk 0 a4.3-year bNonfatal cEvent Diabetes No Diabetes mean follow-up of 18 686 Diabetes patients with diabetes; n = 71 370 patients with noNo Diabetes diabetes MI, CHD death, stroke, or coronary revascularization rate per 1 mmol/L (39 mg/dL) reduction in LDL-C CTT Collaborators. Lancet. 2008;371:117-125.
  37. 37. • • • • • • Lipoprotein metabolism LDL TGL HDL Current guidelines Case discussion
  38. 38.     Atherogenic Dyslipidemia Adiposity High carbohydrate diet Insulin resistance Genetic predisposition High TG pool Renal clearance TG HL TG CETP Apo CIII TG CE TG LPL TG TG CE Small dense HDL HL TG TG Apo E CE Apo B TGRL Remnants CE CETP TG TG Small dense LDL HL Bays H. Expert Rev Cardiovasc Ther 2004;2:89-105.
  39. 39. Role of Triglycerides: PROVE IT-TIMI* Trial1 30-Day Risk Death, MI, Or Recurrent ASC(%) • Elevated triglyceride level ≥200 mg/dL increases the risk of death, myocardial infarction or acute coronary syndrome significantly LDL-C <70 mg/dL, on statins On – Treatment (mg/dL) 1. Fruchart JC, Sacks F, Hermans MP, et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Am J Cardiol. 2008;102(10 Suppl):1K-34K.
  40. 40. TGL/HDL RATIO • BELOW 3.8 FOR ASIANS 3.0 • GOOD USEFUL RATIO IN DIABETICS, METABOLIC SYNDROME • ABNORMAL RATIO INDICATES INCREASE IN SMALL DENSE LDL ALTHOUGH BLOOD LEVELS OF LDL IS NORMAL OR LOW JACC 2005
  41. 41. • • • • • • Lipoprotein metabolism LDL TGL HDL Current guidelines Case discussion
  42. 42. LDL-C & HDL-C v/s CAD Risk Coronary Artery Disease (CAD) Relative Risk Framingham Heart Study 3 2 25 1 45 65 0 85 220 160 100 mg/dL LDL Cholesterol (LDL-C) 59 Reprinted from Castelli WP. Can J Cardiol. 1988;4: 5A–10A, with permission from Pulsus Group Inc.
  43. 43. Antiatherogenic Actions of HDL-C Reverse Cholesterol Transport Cellular Cholesterol Efflux Anti-infectious Activity Anti-inflammatory Activity HDL-C Antithrombotic Activity Endothelial Repair Antiapoptotic Activity Antioxidative Activity Vasodilatory Activity Adapted from Chapman MJ et al. Curr Med Res Opin. 2004,20:1253-1268, with permission from LibraPharm, Ltd. Assmann G et al. Annu Rev Med. 2003,54:321-341.
  44. 44. Relationship Between Changes in LDL-C and HDL-C Levels and CHD Risk 1% decrease in LDL-C reduces CHD risk by 1% 1% increase in HDL-C reduces CHD risk by 3% Third Report of the NCEP Expert Panel. NIH Publication No. 01-3670. 2001. http://hin.nhlbi.nih.gov/ncep_slds/menu.htm
  45. 45. Nicotinic Acid – Mechanism of Action Mobilization of FFA Apo B VLDL TG synthesis VLDL VLDL secretion Serum LDL LDL Liver Hepatocyte Serum VLDL results in reduced lipolysis to LDL HDL Circulation Systemic Circulation Decreases hepatic production of VLDL and of apo B
  46. 46. Change from Baseline (%) Lipid Effects of Niacin Extended-Release (ER) 30 20 10 0 -10 -20 -30 -40 -50 HDL-C 30 -22 -21 10 -3 -5 -8 -12 -13 -16 -17 -14 -21 LDL-C Lp(a) -25 -30 -26 -32 -39 500 • 21 16 29 24 Lipid effects – Most potent agent for 1000 1500 mg 2000 2500 -44 TG 3000 HDL: 20%+; nonlinear – Favorable effects on LDL-particle density – LDL (linear), TG, and Lp(a) • Tolerability with concomitant statin therapy – No change in rate of liver adverse effects or myositis versus statin monotherapy Capuzzi DM et al. Am J Cardiol 1998;82:74U-81U.
  47. 47. Niacin-Induced Flushing Limits Niacin Utilization 100% Percent Users 80% >1500 mg 1001-1500 mg 751-1000 mg 501-750 mg ≤500 mg 60% 40% 20% 0% 4 wk 8 wk 12 wk 24 wk 1y N=14,386 N=6,349 N=5,277 N=5,402 N=2,104 Average Daily Dose of ER Niacin Prescription Refills at Fixed Time Intervals Niaspan discontinuation rate high, adherence rate low, dose less optimal. Only 47% of all ER niacin users reached recommended maintenance dose of 1000 mg or higher, and only 77% reached the dose of 2000 mg during follow-up. Clinical evidence showed that nonadherence for medication leads to the prevalence of the disease and discontinuation from medication increases patient mortality risk. 1. Retrospective cohort study using administrative claims data from 2000 to 2003 Ingenix Lab/Rx Database™. Kamal-Bahl et al. Abstract presented at AHA 7th Scientific Forum on Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke, Washington D.C., May, 2006. 2. Ho PM, et al. Arch Intern Med. 2006;466:1836–1841. 3. Ho PM et al. Arch Intern Med. 2006;166:1842–1847.
  48. 48. AIM-HIGH Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes 3300 patients 4 year follow-up Primary End Point Key Secondary End Points Composite of CHD death, nonfatal MI, ischemic stroke, or hospitalization for high-risk ACS with objective evidence of ischemia Composite of CHD death, nonfatal MI, or ischemic stroke ClinicalTrials.gov Identifier: NCT00120289
  49. 49. ATHEROGENIC THROMBOGENIC DUAL PATHOGEN RISK: 2-4 FOLD WTH LOW HDL: 8 FOLD WITH HIGH LDL: 12 FOLD ALL THREE: 25 FOLD
  50. 50. RESIDUAL RISK DUE TO • • • • • • LOW HDL HIGH TRIGLYCERIDES SMALL DENSE LDL NON HDL CHOLESTEROL Hs CRP LIPOPROTEIN (a)
  51. 51. Rosuvastatin achieves significantly greater increase in HDL-C Mean change in HDL-C from baseline (%) 12 9.6%* 10 8 * Rosuvastatin 7.7% Pravastatin 6 5.7% 4 5.3% 2 3.2% 6.8% Simvastatin 5.6% Atorvastatin 2.1% 0 10 20 40 80 Dose, mg (log scale) *P<0.002 RSV 20 mg vs ATV 20, 40 & 80 mg; RSV 40 mg vs ATV 40 & 80 mg Jones P.H. et al. Am J Cardiol 2003;92:152–160
  52. 52. RESIDUAL RISK THE ISSUES • Whether treating residual risk is really needed when LDL goal is achieved ? • How to treat it? • Is there evidence that treating residual risk decreases clinical events?
  53. 53. 4 major statin benefit groups were identified for whom the ASCVD risk reduction clearly outweighs the risk of adverse events. 1) with clinical ASCVD, 2) primary elevations of LDL–C >190 mg/dL, 3) diabetes aged 40 to 75 years with LDL– C 70 to189 mg/dL and without clinical ASCVD, or 4) without clinical ASCVD or diabetes with LDL–C 70 to189 mg/dL and estimated 10-year ASCVD risk >7.5%.
  54. 54. • • • • • • Lipoprotein metabolism LDL TGL HDL Current guidelines Case discussion
  55. 55. Major recommendations for statin therapy for ASCVD prevention
  56. 56. Major recommendations for statin therapy for ASCVD prevention (Conti.... from prev. page)
  57. 57. Initiating statin therapy in individuals with clinical ASCVD
  58. 58. Initiating statin therapy in individuals without clinical ASCVD
  59. 59. Initiating statin therapy in individuals without clinical ASCVD (Conti.... from prev. page)
  60. 60. Statin Therapy: Monitoring therapeutic response and adherence
  61. 61. Now, we have an unparalleled opportunity to prevent ASCVD 80

×