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Dyslipidemia [Compatibility Mode]

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Dyslipidemia [Compatibility Mode]

  1. 1. DYSLIPIDEMIA Integrated Therapeutics I Seminar Msc, Clinical Pharmacy PG Study School of Pharmacy, JU Moti Deressa hundera Jimma, Oromia, Ethiopia September 2009
  2. 2. OUTLINE Introduction Defn & epidemiology Overview of Lipid transport/ metabolism Classification Causes / risk factors Dx & Screening Management Outcome evaluation
  3. 3. Cholesterol – A Hot Topic CVD & death Prevalence of CVD is worldwide. Major,independent risk factors of ajor,i atherosclerosis Hypertriglyceridemia :acute pancreatitis Robs dollar: 17% of total direct health care costs Huge profit: WOW! PROVE-IT Trial 4
  4. 4. CHD Risk Factors ranking - PROCAM Study Risk factor Relative risk P Value Smoking 2.3 0.001 LDL cholesterol (mg%) > 100 but < 160 1.9 0.01 > 160 4.3 0.001 Hypertension (SBP > 140; DBP > 90) 1.8 0.001 HDL cholesterol (mg%) 40 to 55 1.7 0.01 < 40 2.7 0.001 Triglycerides (mg%) 105- 167 1.6 0.01 >167 2.6 0.001 Fasting blood glucose (mg%) 110 - 126 1.4 0.05 > 126 1.9 0.01 Family history of MI 1.4 4 0.05
  5. 5. 5 Why much concern…? Relative risk of CHD Additive Effect 4.5 3 1.6 Smoking 16 SBP >160 6 5 4 Dyslipidemia With DM all risks are doubled 5
  6. 6. Definition: Hyperlipidemia abnormal levels of lipids in blood TC, LDL-cl, TG, apo-B, or Lp(a) above the 90th percentile ,Or HDL-c or apo A-1 <10th percentile several forms: – Hyperlipoproteinemia: lipoprotein – Hyperlipidemia: TG & cholesterol – Hypertriglyceridemia: TG only – Hypercholesterolemia: cholesterol 6 1
  7. 7. Major Plasma & lipoproteins: Typetypes Source Major lipid Apoproteins ELFO Athero- genicity – Chylomicr Dietary A-I, B-48, no Gut ons TGs C-I, C-III, E mobility (pancreat itis) Endogeno B-100, E, VLDL Liver us C-II, C- Pre-β + TGs III, VLDL Ch esters, B-100, C- Slow IDL + remnant TGs III, E pre- β VLDL, 7 LDL Ch esters B-100 β +++ 7 IDL anti-
  8. 8. Epidemiology Prevalence ??? 2002 audit of GP practices in England >50% US adults > 20 yrs have TC ≥200 mg/dL. Patients with CVD Detected & Controlled > 1/2 of borderline to high risk remain unaware Detected & Uncontrolled <1/2 of highest-risk are on drug therapy only 1/3 are achieving their LDL goal Undetected <20% of CHD patients are at their LDL goal NHANES, : 199-2000 Br J Cardiol 2006;13:145
  9. 9. 9 Intestinal Cholesterol Absorption Intestinal Biliary Dietary epithelial cell cholesterol cholesterol Through lymphatic system to the liver MTP CM Cholesteryl esters Luminal cholesterol ACAT excretion Bile (esterification) acid ABCG5 Micellar ABCG8 cholesterol Free cholesterol uptake Bays H et al. Expert Opin Pharmacother 2003;4:779-790.
  10. 10. Transport 10
  11. 11. 11 Hyperlipidemias Primary 5% Familial & genetic Secondary 95%
  12. 12. Pathways of Lipid Transport & Inherited Hyperlipidemias Familial Combined Hypertriglyceridemia – Polygenic. VERY COMMON (ApoB) Remnant Removcal Disease – ApoE deficiency. UNCOMMON Familial HyperTriGlyceridemia – LPL deficiency etc. RARE X X Familial Hyper- Hyper- cholesterolemia – LDL receptor deficiency. COMMON. Heterozygotes ~1:500. X = HMG-coA Reductase step – blocked by Statins X = CETP step – blocked by torcetrapib Familial Hypoalphalipoproteinemia (Tangier’s Disease) – HDL low. RARE From: Knopp R.H. Drug Treatment of Lipid Disorders. N Engl J Med 1999:341:498-510
  13. 13. Fredrickson classification of hyperlipidemias Lipoprot Plasm Plasma Athero- Rel. Phenotype a Treatment ein(s) cholesterol genicity freq. TGs – Chylomicron I Norm. to ↑ ↑↑↑↑ pancreatit <1% Diet control s is Bile acid sequestrants IIa LDL ↑↑ Norm. +++ 10% , statins, niacin LDL and Statins, IIb ↑↑ ↑↑ +++ 40% niacin, VLDL fibrates III IDL ↑↑ ↑↑↑ +++ <1% Fibrates Niacin, IV VLDL Norm. to ↑ ↑↑ + 45% fibrates + Niacin, VLDL and V ↑ to ↑↑ ↑↑↑↑ pancreatit 5% fibrates chylomicrons is
  14. 14. Primary hypercholesterolemias Genetic Inheritan Disorder Clinical features defect ce Familial hyper- premature CAD dominant cholesterolemia ( II a) LDL receptor TC > 13 mM Familial defective premature CAD apo B-100 dominant apo B-100 (IIa) TC: 7-13 mM Polygenic multiple premature CAD hyper(cholesterolemia defects and variable TC: 6.5-9 mM ( IIA) mechanisms
  15. 15. Primary hypertriglyceridemias Disorder Genetic defect Inheritance Clinical features hepatosplenomegaly LPL deficiency abd. cramps, endothelial LPL recessive pancreatitis (iv) TG: > 8.5 mM Apo C-II abd. cramps, deficiency Apo C-II recessive pancreatitis ( I, IV) TG: > 8.5 mM Familial hyper- unknown abd. cramps, triglyceridemia enhanced hepatic dominant pancreatitis 15 TG-production TG: 2.3-6 mM ( IV)
  16. 16. Primary mixed hyperlipidemias Disorder Genetic defect Inheritance Clinical features Familial dysbeta- lipoproteinemia Apo E recessive premature CAD high VLDL, rarely TC: 6.5 -13 mM chylo. dominant TG: 2.8 – 5.6 mM (III) unknown premature CAD Familial combined dominant TC: 6.5 -13 mM high Apo B- ( IIb) 100 TG: 2.8 – 8.5 mM 16
  17. 17. Secondary hyperlipidemias Disorder VLDL LDL HDL Mechanism VLDL production ↑, Diabetes mellitus ↑↑↑ ↑ ↓ LPL ↓, altered LDL Hypothyreodism ↑ ↑↑↑ ↓ LDL-rec.↓, LPL ↓ Obesity ↑↑ ↑ ↓ VLDL production ↑ bile secretion ↓, LDL Anorexia - ↑↑ - catab. ↓ Apo B-100 ↑ LPL ↓ LDL- Nephrotic sy ↑↑ ↑↑↑ ↓ rec. ↓ LPL ↓, HTGL ↓ (inhibitors Uremia, dialysis ↑↑↑ - ↓ ↑) oestrogen ↑ Pregnancy ↑↑ ↑↑ ↑ VLDL production ↑, LPL ↓ Biliary obstruction Lp-X ↑ ↑ 17 - - ↓ PBC no CAD; xanthomas
  18. 18. Risk factors Traditional Emerging Risk • Family history 1. Lipoprotein (a) • obesity 2. Homocysteine • age 3. Prothrombotic factors • Smoking 4. Pro-inflammatory • Physical inactivity factors • Overweight/obesity 5. Metabolic syndrome • Total-C/LDL-C/HDL-C/TG 6. Sub-clinical • BP atherosclerosis • Glucose • CHD equivalents
  19. 19. Progression of Atherosclerosis
  20. 20. Screening Diagnosis: ATP III of NCEP - For all above 20 yrs Symptoms: once in q 5 years – asymptomatic, – xanthomas, enlargement of liver or spleen, pancreaitis, - For those above 45 Atherosclerosis yrs – once in 2 years FMH - For those with PE already known lipid abnormality follow-up q lipid panel 3-6 months LDL = TC– (HDL + TG/5)
  21. 21. Management: principle Treat according to global risk level, not only cholesterol value Achieve at least a 30% to 40% reduction in LDL-C Initial therapy for any lipoprotein disorder is therapeutic lifestyle changes, TLC TLC in all patients with lifestyle-related risk factors regardless of LDL-C level any potential underlying medical problems Initiation & Selection of Drug therapy Monitor for efficacy and safety
  22. 22. Mgt: Goals for Lipids LDL HDL – < 100 →Optimal – < 40 → Low – 100-129 → Near optimal – 130-159 → Borderline – ≥ 60 → High – 160-189→ High Serum Triglycerides – ≥ 190 → Very High – < 150 → normal Total Cholesterol – 150-199 → – < 200 → Desirable Borderline – 200-239 → Borderline – 200-499 → High – ≥240 → High – ≥ 500 → Very High
  23. 23. 23 Treatment Strategy Lipid Profile, Risk Assessment LDL > 100 Look For Sec. Causes Treat the cause, if found Treatment NO CHD CHD + Primary Prevention Sec. Prevention LDL < 130 2 or more < 2 RF RF High Risk Low Risk LDL > 100 LDL <160
  24. 24. Framingham point scale Estimate of 10-year risk 24 24
  25. 25. Updated NCEP ATP III: Risk Categories, LDL-C Goals, Treatment Cutpoints LDL-C goal Initiate TLC* Consider drug Tx Risk category (mg/dL) (mg/dL) (mg/dL) High risk CHD and CHD <100 ≥100 ≥100 risk equivalents (optional goal: <70) (<100: drug optional) (10-year risk >20%) Moderately high risk ≥2 risk factors <130 ≥130 ≥130 (10-year risk 10%-20%) (optional goal: <100) (100-129: drug optional) Moderate risk ≥2 risk factors ≥130 ≥130 ≥160 (10-year risk <10%) Lower risk 0–1 risk factor† <160 ≥160 ≥190 (160-189: drug optional) *TLC=therapeutic lifestyle changes †Almost all people with a 0–1 risk factor have a 10-year risk 25 <10%; thus, risk calculations are not necessary Grundy SM et al. Circulation. 2004;110:227-239.
  26. 26. Therapeutic Lifestyle Changes ,TLC TLC Nutrient Recommended Intake TLC Diet Saturated fat < 7% of calories PUFA fat Up to 10% of calories MUFA fat Up to 20% of calories Weight Total fat 25–35% of calories reduction Carbohydrate 50–60% of calories Fiber 20–30 grams per day Protein Approx. 15% of calories physical Cholesterol Less than 200 mg/day activity DIETARY THERAPY 26
  27. 27. 27 DRUG THERAPY: The Three Canons DYSLIPIDEMIA ↑ LDL - STATIN
  28. 28. Progression of Drug Therapy for LDL-C Lowering Visit 1 Visit 2 Visit 3 F/U q 6 6 Visits Initiate LDL- LDL- If LDL goal If LDL goal 4–6 Monitor lowering wks not achieved, wks not achieved, mo response & drug intensify LDL- LDL- drug therapy adherence therapy lowering or refer to a to therapy therapy lipid specialist Start statin Consider If LDL goal or bile acid higher dose of has been resin or the statin or achieved, nicotinic add a bile acid treat other acid resin or lipid risk nicotinic acid factors Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
  29. 29. 30 Treatment of ↓ HDLc Low HDLc Therapeutic Lifestyle Change Drug Therapy Therapy of Choice : Niacin Add on drug - Finofibrate
  30. 30. 31 Treatment of ↑ TG High TG Therapeutic Lifestyle Change Drug Therapy Therapy of Choice : Fibrate Add on drug – Statin, Niacin
  31. 31. Treatment of Mixed Hyperlipidemia High LDL-C and TGs LDL- Therapeutic Lifestyle Change Drug Therapy STEP 1 Achieve the LDL-C goal: statins LDL- Therapy of Choice : Statin + Fibrate Achieve the non-HDL-C goal non-HDL- STEP 2 Increase LDL-C lowering or LDL- Add a fibrate, niacin or fish oils Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
  32. 32. ATP III: The Metabolic Syndrome Diagnosis is established when ≥3 of these risk factors are present. Risk Factor Defining Level Abdominal obesity (Waist circumference) >102 cm (>40 in) Men >88 cm (>35 in) Women TG ≥150 mg/dL HDL-C Men <40 mg/dL Women <50 mg/dL Blood pressure ≥130/≥85 mm Hg Expert Panel on Detection, Evaluation, and Treatment of High 33 ≥110 Cholesterol in Adults. JAMA 2001;285:2486-2497. mg/dL Blood Fasting glucose
  33. 33. 34 Statins – Mechanism of Action Cholesterol VLDL synthesis LDL receptor–mediated receptor– LDL receptor Apo VLDLR B hepatic uptake of LDL& VLDL HMGCoA (B–E receptor) (B– Apo remnants E Serum LDL-C LDL- Intracellular synthesis Apo Cholesterol LDL Serum VLDL remnants B Serum IDL Hepatocyte Systemic Circulation 1. Reduce hepatic cholesterol synthesis (HMG CoA), CoA), 2. lowering intracellular cholesterol, 3. Upregulation of LDL receptor and 4. ↑ the uptake of non-HDL from circulation. non-
  34. 34. The LDL-C–Lowering Efficacy of the Currently Available Statins Daily Atorv Dose a Fluva Lova Prava Simva 10 mg –39% –22% –30% 20 mg –43% –22% –27% –32% –38% 40 mg –50% –25% –32% –34% –41% 80 mg –60% –36% –42% –47% Physician’s Desk Reference. 55th ed. Montvale, NJ: Medical 35 Economics, 2001.
  35. 35. 36 CHD Risk Reduction – Statin Therapy Relative Risk Reduction (%) Endpoints +20 0 –5 –10–15–20–25–30–35–40–45–50 Major coronary events Coronary deaths Cardiovascular deaths Non_CV events Total mortality Strokes Intermittent claudication Angina La Rosa JC et al. JAMA 1999;282:2340-2346.
  36. 36. Fibrates ⇑ FA oxidation in muscle and liver and lipogenesis in the liver Most effective at reducing VLDL (TG); smaller ↓ in LDL-chol but useful ↑ in HDL-chol α Act as PPARα ligands (cf glitazones) -
  37. 37. Fibric Acid Derivatives Indications: Adjunctive therapy to diet Hypertriglyceridemia (Type IV and V) Combined hyperlipidemia (Type IIb) with low HDL-C who do not respond to nicotinic acid Mechanism of Increase peripheral lipolysis and decrease Action: hepatic TG production Efficacy: Decrease TG 25–50% LDL-C decreases, remains the same, or increases Increase HDL-C 15–25% in hypertriglyceridemia Side Effects: GI upset (8%), cholelithiasis, myositis, abn LFTs Contraindications: Hepatic or renal dysfunction Pre-existing gallbladder disease Intervention Trials: HHS, VA-HIT, BIP, LOCAT, BECAIT, DAIS 38
  38. 38. 39 Bile Acid Resins: Mechanism of Action ↑↑ Cholesterol 7-α 7- Gall Bladder hydroxylase Bile Acid ↑ Conversion of cholesterol to BA Enterohepatic Recirculation ↑ BA Secretion Liver Terminal Ileum ↑ LDL Receptors Reabsorption of bile acids ↑ VLDL and LDL removal ↑ BA Excretion Net Effect - ↓ LDL-C LDL-
  39. 39. 40 Nicotinic Acid – Mechanism of Action Mobilization of FFA Apo B Serum VLDL results in reduced VLDL VLDL lipolysis to LDL TG synthesis VLDL Serum LDL secretion LDL HDL Liver Circulation Hepatocyte Systemic Circulation Decreases hepatic production of VLDL and of apo B
  40. 40. 41 Effect of Niacin on Lipoproteins 35% HDL- HDL-C with crystalline niacin 25% HDL- HDL-C with Niaspan® 12.5% Baseline LDL- LDL-C with Niaspan® -15% LDL- LDL-C with crystalline niacin TG with Niaspan® -30% TG with crystalline niacin 0 1g/d 2g/d 3g/d Adapted from Knopp RH. N Engl J Med 1999;341:498-511..
  41. 41. 42 Newer Therapies Ezetimibe Lymph Enterocyte Intestinal Lumen Ezetimibe Cholesterol ACA NPC1 T L1 Cholesteryl Ester ABCG5/ Avasimibe G8
  42. 42. Fish Oils Indication Adjunctive therapy to diet s: Hypertriglyceridemia (Type IV and V) With statins or other LDL-C– lowering drugs in mixed hyperlipidemia Efficacy: Decrease TG 30–40% LDL-C remains the same or increases No change in HDL-C Side GI upset and a “fish burp” Effects: 43 Interventi Lyon Heart Study (dietary), GISSI on Trials: Prevenzione Trial, others
  43. 43. Triple-Drug Regimen Lovastatin Niaspan Colestipol + + 40 mg/d 2 g/d 20 g/d Baseline 8 months (mg/dL) (mg/dL) Change (%) LDL-C 215 85 –60% HDL-C 46 52 13% LDL-C/HDL-C 4.8 1.7 –65% 44 ratio BG et al. Am J Cardiol 1997;80:111-115. Brown
  44. 44. Dyslipidemia and DM Elevated TG Elevated VLDL Type Rx used Effect on lipids Insulin Favourable Reduced HDL-C Metformin Mildly favourable Increase in SD-LDL Sulfonylureas Not favourable Decrease in Apo A I Glitazones Favourable Acarbose No effect Increase in Apo B Apo A I / Apo B < 1 All Diabetics must be given STATIN 45
  45. 45. 46 Hypertension Treatment and Lipids Type Rx used Effect on lipids 1. Diuretics Unfavourable 2. Indapamide Mildly favourable 3. ACEi and ARB Very favourable 4. Betablockers Unfavourable 5. Ca channel blockers No effect
  46. 46. Special consideration Elderly: Women – Start slow & go slow HDL > LDL ? – ↓ absolute risk More responsive than reduction ?? men Children: Pregnancy: Not – < 10 years: No drug recommended therapy! - High risk: BAR, – 10-20: d/t guideline Ezetimibe? – First line: BAR→ statins Menopause?
  47. 47. BOTTOM LINE Hyperlipidemia is a modifiable risk factor for IHD and stroke 1° & 2° prevention of ASCVD are possible! TLC is a must ! Intervention with a statin is highly effective and can reduce risk by ~ 1/3rd Follow up
  48. 48. Where are we heading ? ? 20000 B.C. 2004 Paleolithic sup. age Neolithic age 19th century 21st century Technology has changed a lot in the way we live Processed Hunting-gathering foods subsistence - Animal fats and glucides High level of ¯ Dietary fibre physical activity Sedentary But, we have not altered our life style life Thrifty genotype Susceptibility genotype Journal of internal medicine 2003:254(2):114-25
  49. 49. References Joseph T. DiPiro, Pharmacotherapy,A Pathophysiologic Approach,Seventh Edition, 2008 Harrison's PRINCIPLES OF INTERNAL MEDICINE, Seventeenth Edition, 2008 NCEP, www. www.lipidsonline.org
  50. 50. Thanks for your Attention! Questions are guaranteed in life; Answers aren’t!!

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