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  1. 1. Hypertriglyceridemia Why don’t we address it at the next visit? Jenny Gordon March 26, 2004
  2. 3. Overview <ul><li>Case Presentations </li></ul><ul><li>Pathophysiology- review the lipids </li></ul><ul><li>Triglyceride Disorders </li></ul><ul><li>Secondary causes of Hypertriglyceridemia </li></ul><ul><li>Cardiac Risk factor </li></ul><ul><li>Current guidelines </li></ul><ul><li>Treatment options </li></ul>
  3. 4. Patient M.B. <ul><li>40 y/o male comes in to establish care, CPE, wants to make some healthy changes. H/O ETOH abuse, quit 6 months ago. Quit smoking 6 days ago. Concerned about cholesterol, heart disease , etc. </li></ul><ul><li>FH-neg for CAD, HTN, DM , CA </li></ul><ul><li>PMH- ETOH x 25 yrs, Smoking-25pack years </li></ul><ul><li>Meds-Nicotine Patch, MVI </li></ul>
  4. 5. Patient M.B. <ul><li>PE- </li></ul><ul><ul><li>BP 153/85, P 84, Wt 181 lb </li></ul></ul><ul><ul><li>Physical exam unremarkable except for partial dentures and mild abdominal obesity </li></ul></ul><ul><li>Labs- </li></ul><ul><ul><li>CBC, Chem 7, LFT’s wnl </li></ul></ul><ul><ul><li>Tchol 275, HDL 31, LDL 176, TG 34 </li></ul></ul><ul><li>Plan- Diet and Exercise, nutrition visit, recheck chol 3 months </li></ul>
  5. 6. Patient M.B. <ul><li>Returns 2 months later- he has started smoking, wants to quit again. Has seen nutrition and made some diet changes-eating oatmeal and fruit for breakfast-getting dental surgery, so needs to eat soft foods. </li></ul><ul><ul><li>Plan Zyban, Patch , SFGH smoking cessation class </li></ul></ul><ul><li>Returns 1 month later-not smoking ,eating oatmeal and bran, wants to focus on diet changes after smoking cessation </li></ul>
  6. 7. Patient M.B. <ul><li>Returns 2 mo later- still not smoking or drinking </li></ul><ul><li>BP130/86 </li></ul><ul><ul><li>T Chol 258, HDL 49, LDL 129, TG 398 </li></ul></ul><ul><ul><li>Not ready to take medication, really wants to try diet change wholeheartedly now. Pt wants to try a vegetarian diet for 3 months and see if he can decrease his TG. Discussed starting lipid lowering meds if still high at that point. </li></ul></ul>
  7. 8. Patient R.P. <ul><li>57 y/o female seen very briefly in ACC for URI </li></ul><ul><ul><li>Review of labs shows TG 620, TSH 15.2, HgA1c 13.9 </li></ul></ul><ul><ul><li>What is causing her high TG’s? </li></ul></ul>
  8. 9. Questions I Had <ul><li>Were they REALLY fasting or not? </li></ul><ul><li>Is it a risk factor for heart disease or not? What do triglycerides do in the body? </li></ul><ul><li>Do I need any other labs? To rule out any other things? </li></ul><ul><li>Should I treat with meds? Which ones? </li></ul><ul><li>Why is it so hard to spell Hypertriglyceridemia? </li></ul><ul><li>Maybe we should address this at the next visit… </li></ul><ul><li>??? </li></ul>
  9. 10. Review the Lipids (briefly!) <ul><li>Lipids (cholesterol and triglycerides) </li></ul><ul><ul><li>insoluble in plasma </li></ul></ul><ul><ul><li>circulating lipid is bound to lipoprotein </li></ul></ul><ul><li>lipoprotein </li></ul><ul><ul><li>esterified and unesterified cholesterol </li></ul></ul><ul><ul><li>triglycerides </li></ul></ul><ul><ul><li>phospholipids </li></ul></ul><ul><ul><li>Protein -known as apolipoproteins or apoproteins. </li></ul></ul><ul><ul><ul><li>serve as cofactors for enzymes and ligands for receptors. </li></ul></ul></ul>
  10. 11. Review the Lipids (briefly!) <ul><li>Chylomicrons - Chol and TG </li></ul><ul><ul><li>A-I, A-II, A-IV, B-48, C-I,C-II, C-III, and E. </li></ul></ul><ul><li>VLDL- TG and less chol </li></ul><ul><ul><li>B-100, C-I, C-II, C-III, and E. </li></ul></ul><ul><li>IDL- Chol esters and TG. </li></ul><ul><ul><li>B-100, C-III, and E. </li></ul></ul><ul><li>LDL- chol esters </li></ul><ul><ul><li>B-100. </li></ul></ul><ul><li>HDL- Chol esters. </li></ul><ul><ul><li>A-I, A-II, C-I, C-II, C-III, D, and E. </li></ul></ul>
  11. 12. Atherogenic lipids <ul><li>VLDL </li></ul><ul><li>IDL </li></ul><ul><li>LDL especially small dense LDL </li></ul>
  12. 13. Elevated Triglycerides <ul><li>Normal <150 mg/dL </li></ul><ul><li>Borderline high 150–199 mg/dL </li></ul><ul><li>High 200–499 mg/dL </li></ul><ul><li>Very high >500 mg/dL </li></ul>
  13. 14. Fredrickson Classification
  14. 15. Disorders of TG Metabolism
  15. 16. Borderline High Triglycerides (150–199 mg/dL) <ul><li>Acquired causes </li></ul><ul><li>– Overweight and obesity </li></ul><ul><li>– Physical inactivity </li></ul><ul><li>– Cigarette smoking </li></ul><ul><li>– Excess alcohol intake </li></ul><ul><li>– High carbohydrate intake </li></ul><ul><ul><ul><li>(>60% of total energy) </li></ul></ul></ul><ul><li>Secondary causes </li></ul><ul><li>Genetic causes </li></ul><ul><li>– Various genetic polymorphisms </li></ul>
  16. 17. High Triglycerides (200–499 mg/dL) <ul><li>Acquired causes </li></ul><ul><ul><li>– Same as for borderline high triglycerides (usually combined with foregoing causes) </li></ul></ul><ul><li>Secondary causes </li></ul><ul><li>Genetic patterns </li></ul><ul><ul><li>– Familial combined hyperlipidemia </li></ul></ul><ul><ul><li>– Familial hypertriglyceridemia </li></ul></ul><ul><ul><li>– Polygenic hypertriglyceridemia </li></ul></ul><ul><ul><li>– Familial dysbetalipoproteinemia </li></ul></ul>
  17. 18. Very High Triglycerides (>500 mg/dL) <ul><li>Usually combined causes </li></ul><ul><ul><ul><li>– Same as for high triglycerides </li></ul></ul></ul><ul><li>Familial lipoprotein lipase deficiency </li></ul><ul><li>Familial apolipoprotein C-II deficiency </li></ul>
  18. 19. Secondary causes of Hypertriglyceridemia <ul><li>  Type 2 diabetes mellitus </li></ul><ul><li>   Cholestatic liver diseases </li></ul><ul><li>   Nephrotic syndrome </li></ul><ul><li>  Chronic renal failure </li></ul><ul><li>Hypothyroidism </li></ul><ul><li>Cigarette smoking </li></ul><ul><li>Obesity </li></ul><ul><li>    Drugs (Tamoxifene, glucocorticoids, cyclosporine, Estrogen, Protease inhibitors) </li></ul>
  19. 20. Additional Labs to order <ul><li>Thyroid function tests </li></ul><ul><li>Creatinine </li></ul><ul><li>Fasting glucose </li></ul>
  20. 21. Chylomicronemia syndrome triglycerides >2000 mg/dL) <ul><li>– Eruptive skin xanthomas </li></ul><ul><li>– Hepatic steatosis </li></ul><ul><li>– Lipemia retinalis </li></ul><ul><li>– Mental changes </li></ul><ul><li>– High risk for pancreatitis </li></ul>
  21. 22. Eruptive Xanthoma
  22. 23. Palmare Striatum
  23. 24. A Risk Factor for Heart Disease? <ul><li>Hokanson and Austins meta-analysis of prospective population-based studies </li></ul><ul><ul><li>association between the serum triglyceride concentration and cardiovascular disease </li></ul></ul><ul><ul><li>pooled analysis of 46,413 men enrolled in 16 studies </li></ul></ul><ul><ul><li>univariate risk ratio (RR) for triglyceride of 1.32 (95 percent CI 1.26 to 1.39) for men </li></ul></ul><ul><ul><li>five studies of nearly 10,800 women were associated with a univariate RR of 1.76 (95 percent CI 1.50 to 2.07). </li></ul></ul><ul><ul><li>With adjustment for HDL and other risk factors, correlation was still significant </li></ul></ul>
  24. 25. A Risk Factor for Heart Disease? <ul><li>Physician's Health Study </li></ul><ul><ul><li>The risk of myocardial infarction (MI) was highest among men with the highest tertile for both triglyceride and the TC/HDL-C ratio </li></ul></ul><ul><li>Helsinki Heart Study </li></ul><ul><ul><li>CHD risk was highest in the cohort with a triglyceride level >201 mg/dL and an LDL-cholesterol/HDL-cholesterol ratio >5.0. A benefit from lipid-lowering from gemfibrozol was confined to this high-risk subgroup </li></ul></ul>
  25. 26. A Risk Factor for Heart Disease? <ul><li>Copenhagen Male Study </li></ul><ul><ul><li>gradient of CHD risk with increasing serum triglycerides </li></ul></ul><ul><ul><ul><li>even after adjustment for other major CHD risk factors, including LDL-cholesterol. </li></ul></ul></ul><ul><ul><ul><li>The protective effect of a high HDL-C concentration above 68 mg/dL was not seen in the highest third of triglyceride levels. </li></ul></ul></ul>
  26. 27. A Risk Factor for Heart Disease? <ul><li>It still remains debated whether treating hypertriglyceridemia really independently lowers CHD risk, however almost everyone can agree that elevated triglycerides are a very important marker for </li></ul><ul><li>1. Metabolic Syndrome </li></ul><ul><li>2. Atherogenic dyslipidemia ( high small dense LDL, low HDL, high atherogenic remnants) </li></ul>
  27. 28. Associated Abnormalities <ul><li>Low levels of HDL-C </li></ul><ul><li>The presence of small, dense LDL particles. </li></ul><ul><li>The presence of atherogenic triglyceride-rich lipoprotein remnants   </li></ul><ul><li>Insulin resistance </li></ul><ul><li> Increases in coagulability and viscosity </li></ul>
  28. 29. TG and Small dense LDL
  29. 30. Why High TG causes Low HDL and High small dense LDL <ul><li>High levels of VLDL </li></ul><ul><ul><li>VLDL exchanges its TG for Chol from HDL </li></ul></ul><ul><ul><ul><li>Chol rich VLDL- very atherogenic! </li></ul></ul></ul><ul><ul><ul><li>Chol depleted HDL-can easily dissociate from apo A-1 and be cleared </li></ul></ul></ul><ul><ul><li>VLDL exchanges its TG for Chol from LDL </li></ul></ul><ul><ul><ul><li>LDL gets denser and smaller-Very atherogenic </li></ul></ul></ul>
  30. 31. Identify Metabolic Syndrome <ul><li>Any three of the following </li></ul><ul><li>- Triglycerides 150 mg/dL </li></ul><ul><ul><li>  HDL cholesterol <40 mg/dL in men and <50 mg/dL in women </li></ul></ul><ul><ul><li>  Blood pressure 130/ 85 mmHg </li></ul></ul><ul><ul><li>  Fasting glucose 110 mg/dL </li></ul></ul><ul><ul><li>waist circumference in men >40 in and in women 35 in </li></ul></ul>
  31. 32. TG and Insulin Resistance
  32. 33. TG and Insulin Resistance
  33. 34. Treat Metabolic Syndrome <ul><li>Treat HTN </li></ul><ul><li>Treat Obesity/Abdominal Obesity </li></ul><ul><ul><li>Weight reduction </li></ul></ul><ul><ul><li>Diet and exercise </li></ul></ul><ul><li>ASA if high CHD risk for prothrombotic state </li></ul><ul><li>Treat lipid abnormalities </li></ul><ul><li>Treat insulin insensitivity (Controversial) </li></ul>
  34. 35. Treating Lipids in Insulin Resistance
  35. 36. Guidelines for treatment <ul><li>ATP-III focuses on non-HDL( Total Chol- HDL) as secondary goal after LDL has been addressed . Why? </li></ul><ul><ul><li>TG is more variable day to day than non-HDL </li></ul></ul><ul><ul><li>Non-HDL may actually turn out to be a more powerful predictor of CHD risk than LDL </li></ul></ul><ul><ul><li>Reflects highly atherogenic VLDL+ LDL </li></ul></ul>
  36. 37. Borderline TG (150-199) <ul><li>Primary goal: achieve LDL-C goal </li></ul><ul><li>Life-habit changes: first-line therapy </li></ul><ul><ul><li>Body weight control </li></ul></ul><ul><ul><li>Regular physical activity </li></ul></ul><ul><ul><li>Smoking cessation </li></ul></ul><ul><ul><li>Restriction of alcohol use (when consumed in excess) </li></ul></ul><ul><ul><li>Avoid high carbohydrate intakes </li></ul></ul><ul><li>Drug therapy: Triglycerides in this range not a direct target of drug therapy </li></ul>
  37. 38. High TG (200-499) <ul><li>Primary goal: achieve LDL-C goal </li></ul><ul><li>Secondary goal: achieve non-HDL-C goal: 30 mg/dL higher than LDL-C goal </li></ul><ul><li>First-line therapy for high triglycerides: TLC-emphasize weight reduction and exercise </li></ul><ul><li>Se cond-line therapy: drugs to achieve non-HDL-C goal </li></ul><ul><ul><li>Statins: lowers both LDL-C and VLDL-C </li></ul></ul><ul><ul><li>Fibrates: lowers VLDL-triglycerides and VLDL-C </li></ul></ul><ul><ul><li>Nicotinic acid: lowers VLDL-triglycerides and VLDL-C </li></ul></ul>
  38. 39. High TG (200-499) cont.. <ul><li>Alternate approaches to drug therapy for lowering non-HDL-C </li></ul><ul><ul><li>High doses of statins (lower both LDL-C and VLDL-C) </li></ul></ul><ul><ul><li>Moderate doses of statins and triglyceride-lowering drug (fibrate or nicotinic acid): </li></ul></ul><ul><li>Caution: increased frequency of myopathy with statins + fibrates </li></ul>
  39. 40. Very High TG (>500) <ul><li>Goals of therapy: </li></ul><ul><ul><li>Triglyceride lowering to prevent acute pancreatitis (first priority) </li></ul></ul><ul><ul><li>Prevention of CHD (second priority) </li></ul></ul><ul><li>Triglyceride lowering to prevent pancreatitis: </li></ul><ul><ul><li>Very low-fat diet when TG >1000 mg/dL (<15% of total calories as fat) </li></ul></ul><ul><ul><li>Institute weight reduction/physical activity </li></ul></ul><ul><ul><li>Fish oils </li></ul></ul>
  40. 41. Very High TG (>500) cont… <ul><ul><li>Triglyceride-lowering drugs (fibrate or nicotinic acid): most effective </li></ul></ul><ul><ul><li>Statins: not first-line agent for very high triglycerides (statins not powerful triglyceride-lowering drugs) </li></ul></ul><ul><ul><li>Bile acid sequestrants: contraindicated—tend to raise triglycerides </li></ul></ul>
  41. 42. Summary of Non-Hdl goals
  42. 43. Lipid Lowering Drugs
  43. 45. Main Points <ul><li>Hypertriglyceridemia is a marker for metabolic syndrome, increased CHD, and multiple associated lipid abnormalities that further increase CHD risk </li></ul><ul><li>Treatment involves </li></ul><ul><ul><li>Review meds </li></ul></ul><ul><ul><li>Look for acquired causes and secondary causes (TSH, Cr, Fasting Glucose) </li></ul></ul><ul><ul><li>Therapeutic Lifestyle changes </li></ul></ul><ul><ul><li>Meds- statins, niacin, fibrates, </li></ul></ul>
  44. 46. References <ul><li>ATP-III, Third Report of the National Cholesterol education program expert panel. </li></ul><ul><li>Gotto,A., et al, “ High –Density lipoprotein cholesterol and triglycerides as therapeutic targets..”, Am Heart Journal, December, 2002. </li></ul><ul><li>Watson,K., et al, “Lipid abnormalities in insulin resistance states”, Rev Cardiovasc Med. 2003, Vol 4, No 4 </li></ul>
  45. 47. References cont… <ul><li>Hokansen,J. et al, “Plasma triglyceride level is a risk factor for cardiovascular disease…”, Jou Cardiovascular Risk April 1996 </li></ul><ul><li>Collins, R., et al, “Heart protection study of cholesterol lowering with simvastatin in 5963 people with diabetes.”, Lancet, 2003 Vol 361 p2005-2016. </li></ul><ul><li>Up To Date online-multiple topics </li></ul><ul><li>Broset, Tom, Lipid clinic SFGH Gladstone Cardiovascular Institute </li></ul>