Understanding Specific DyslipidemiasA Focus on Hypertriglyceridemia Presentation Objectives

Understanding Specific Dyslipidemias—A Focus on Hypertriglyceridemia

Presentation Objectives • This presentation will review the following: • Lipid and lipoprotein metabolism in patients with normal TG levels and hypertriglyceridemia • Changes in lipid and lipoprotein metabolism that occur when hypertriglyceridemia is corrected • Epidemiology of hypertriglyceridemia • Clinical relevance of non–HDL-C • Treatment goals for TG and non–HDL-C levels HDL-C=high-density lipoprotein cholesterol; TG=triglyceride.

Overview of Lipid and Lipoprotein Metabolism

Triglyceride Overview Glycerol TG = H 2 C OH 3 Fatty Acids + R 1 R 2 R 3 Saturated fat (eg, palmitic acid; 16: 0) Monounsaturated fat (eg, oleic acid; 18: 1 ω9) Polyunsaturated fat (eg, linoleic acid; 18: 2 ω-6) Katan MB, et al. Am J Clin Nutr. 1994; 606(suppl): 1017 S-1022 S. Khan-Merchant N, et al. J Nutr. 2002; 132: 3256 -3262. Choi BG, et al. In: Davidson MH, Toth PP, Maki KC, eds. Therapeutic Lipidology; 2007: 1 -22.

Lipoprotein Overview TG Cholesterol HDL LDL IDL VLDL APO AI, IV, V APO CI, CIII APO E APO B APO CI, III APO E Chylomicron APO AI, IV APO B 48 APO CI, III APO E APO=apolipoprotein; IDL=intermediate-density lipoprotein; LDL=low-density lipoprotein; VLDL=very–low-density lipoprotein. Ginsberg HN, et al. Arch Med Res. 2005; 36: 232 -240.

Normal Lipid and Lipoprotein Metabolism Cholesteryl ester Glycerol Apo B DGAT 2 Triglyceride VLDL (Very–low-density lipoprotein) TG: Cholesterol=5: 1 ratio Fatty acids Liver

Normal Lipid and Lipoprotein Metabolism Muscle and adipose tissue Fatty acids Lipoprotein lipase Lipase Bloodstream LDL IDL LDL receptor VLDL Liver Hepatocyte

Lipid and Lipoprotein Metabolism in Hypertriglyceridemia Increased triglyceride secretion Cholesteryl ester VLDL Triglycerides TG: Cholesterol 5: 1 Liver

Lipid and Lipoprotein Metabolism in Hypertriglyceridemia Muscle and adipose tissue Lipoprotein lipase Lipase Bloodstream LDL Decreased conversion to LDL VLDL Liver

Lipid and Lipoprotein Metabolism in Hypertriglyceridemia Lipase Bloodstream CETP Increased VLDL ↑ Small, dense LDL CE TP Rapid degradation Small, dense HDL ↑ Free fatty acids ↑ Triglycerides ↑ Apo-B Lipase Liver ↓ HDL

The Friedewald Formula and Hypertriglyceridemia LDL-C = TC – HDL-C – VLDL-C = TC – HDL-C – (TG/5) • The Friedewald formula tends to become less reliable for estimating LDL-C when plasma TG levels increase • Error in estimated LDL-C increases as TG levels increase • Although inaccuracies in calculated LDL-C vary at higher TG levels, the formula tends to underestimate LDL-C levels. However, some studies have shown both positive and negative errors in LDL-C at high TG levels • Friedewald formula is not recommended to calculate LDL-C in patients with TG >400 mg/d. L TC=total cholesterol. Rifai N, et al. Clin Chem. 1992; 38: 150 -160.

Friedewald Formula Hypothetical Examples • Example 1 • Total cholesterol = 190 mg/d. L, HDL-C = 44 mg/d. L, and TG = 140 mg/d. L • Calculated LDL-C = 190 – (44 + 140/5) = 118 mg/d. L • Example 2 • Total cholesterol = 220 mg/d. L, HDL-C = 34 mg/d. L, and TG = 600 mg/d. L • Calculated LDL-C = 220 – (34 + 600/5) = 66 mg/d. L • Likely to be an inaccurate estimate of actual LDL-C level

Normalizing Lipid and Lipoprotein Metabolism Muscle and adipose tissue Lipoprotein lipase Lipase Bloodstream Proper conversion to LDL VLDL Liver LDL

Increasing Levels of Triglycerides Are Associated With Increasing LDL Subclass Pattern B Cumulative percent 100 Pattern A 80 60 Pattern B 40 Smaller, dense LDL may be more atherogenic than larger, more buoyant particles 20 0 40 80 120 160 200 TG levels (mg/d. L) Austin MA, et al. Circulation. 1990; 82: 495 -506. Krauss RM. Am J Cardiol. 1998; 81(4 A): 13 B-17 B. 240 280

Reduction of Triglycerides Shifts the Atherogenic Lipid Profile TG TG Reproduced, with permission, from: Bays HE, et al. Expert Rev Cardiovasc Ther. 2008; 6: 391 -409.

Overview of Lipid and Lipoprotein Metabolism: Summary £ During normal lipid and lipoprotein metabolism, there is balanced secretion, conversion, and clearance of lipoproteins £ Hypertriglyceridemia adversely affects the balance of secretion, conversion, and clearance £ Reduction of TG levels shifts the atherogenic profile

Epidemiology of Hypertriglyceridemia

Prevalence of Abnormal Triglycerides Has Increased 1 15 Abnormal TG (%)* TG Adults aged 20 -74 years† Adults aged 60 -74 years‡ 5 x 10 2 x 5 0 8. 7 5. 5 2. 4 1. 8 2. 3 3. 5 43. 2 42. 3 50 Abnormal LDL-C (%)* LDL-C 47. 7 45 40 0 43. 5 NHANES II (1976 -1980) NHANES III (1988 -1994) 40. 1 40. 6 NHANES (1999 -2006) ~1. 7% of adults ≥ 20 years old have TG ≥ 500 mg/d. L 2, 3, which corresponds with ~3. 4 million 3 *Percentages represent only those patients having abnormal TG or LDL levels as a single abnormality. †Adults 20 -74 who took the lipid examination from NHANES: II (N=4719), III (N=6119), and 1999 -2006 (N=7670). ‡Older adults 60 -74 were also examined in NHANES: II (N=1785), III (N=1462), and 1999 -2006 (N=1817). NHANES=National Health and Nutrition Examination Survey. 1. Cohen J, et al. Poster presented at: American Heart Association Scientific Session; November 8 -12, 2008; New Orleans, LA. ; 2. Ford ES, et al. Arch Intern Med. 2009; 169: 572 -578; 3. Christian JB, et al. Am J Cardiol. 2011. In press.

Prevalence of Triglyceride Categories by Age and Sex NHANES 1999 -2004 Triglyceride Concentration, mg/d. L # of Participants <150 to <200 to <500 ≥ 500 5610 66. 9 (0. 8) 15. 2 (0. 6) 16. 1 (0. 5) 1. 7 (0. 2) 20 -39 1778 76. 0 (1. 2) 11. 4 (0. 9) 1. 2 (0. 3) 40 -59 1770 62. 6 (1. 3) 17. 0 (0. 9) 17. 4 (1. 1) 2. 9 (0. 4) ≥ 60 2062 58. 5 (1. 4) 18. 7 (0. 9) 22. 2 (1. 2) 0. 6 (0. 2) Men 2837 63. 3 (1. 4) 15. 2 (0. 7) 18. 7 (1. 0) 2. 8 (0. 4) Women 2773 70. 4 (1. 0) 15. 2 (0. 8) 13. 6 (0. 7) 0. 8 (0. 2) Variable Total Age, years Sex Ford E, et al. Arch Intern Med. 2009; 169: 572 -578.

Factors Contributing to Severe Hypertriglyceridemia (≥ 500 mg/d. L) • TG levels ≥ 500 mg/d. L may be the combined result of multiple factors: • Genetics (eg, familial lipoprotein lipase deficiency; familial apolipoprotein CII deficiency) • Obesity and overweight • Physical inactivity • Excess alcohol intake • High-carbohydrate diets (>60% of energy intake) • Comorbidities (hypothyroidism, type 2 diabetes, chronic renal failure, nephrotic syndrome) • Medications (beta-blockers, protease inhibitors, corticosteroids, oral estrogens, retinoids, etc. ) NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Final Report. 2002; NIH Publication No. 02 -5215.

Clinical Characteristics of Patients With Severe Hypertriglyceridemia (≥ 500 mg/d. L) alysis of 5680 individuals, 20 years of age or older, who participated in NHANES between 2 and 2006, to evaluate the epidemiology of adults with severe hypertriglyceridemia (N=87) Characteristic Frequency Alcohol consumption 71. 5% Beta-blocker 12. 7% 10. 7% HDL-C <40 mg/d. L 70. 4% Carbohydrate intake ≥ 60% total Physical activity <150 min/week 64. 0% Hypothyroidism 10. 2% Cancer 9. 5% BMI ≥ 30 kg/m 2 43. 5% Levothyroxine 5. 4% Current smoker 39. 9% CHD 5. 3% Hypertension 31. 2% Diabetes 14. 6% BMI=body mass index; CHD=coronary heart disease. Christian JB, et al. Am J Cardiol. 2011. In press. doi: 10. 1016/j. amjcard. 2010. 11. 008.

Clinical Characteristics Associated With Severe Hypertriglyceridemia (≥ 500 mg/d. L) alysis of 5680 individuals, 20 years of age or older, who participated in NHANES between 2 006, to evaluate the epidemiology of adults with severe hypertriglyceridemia (N=87) as com to subjects without severe hypertriglyceridemia (<500 mg/d. L) (N=5590) Clinical Characteristics Non–HDL-C ≥ 190 mg/d. L Adjusted OR* (95% CI) Referent Group 24. 99 (3. 90 -160. 31) Non–HDL-C <130 mg/d. L HDL-C <40 mg/d. L 11. 45 (6. 28 -20. 86) HDL-C ≥ 40 mg/d. L Non–HDL-C 160 -189 mg/d. L 9. 74 (1. 68, 56. 40) Chronic renal disease Non–HDL-C <130 mg/d. L 7. 32 (1. 45 -36. 94) Without chronic renal CI=confidence interval; OR=odds ratio. disease *Adjusted for gender, age, ethnicity, TC, HDL-C, non-HDL-C, smoking, alcohol, C-reactive protein quintiles, physical activity, BMI, diagnosed diabetes mellitus, myocardial infarction, heart failure, CHD, hypertension, 3. 04 (1. 45 -6. 37) Without diabetes stroke, Diabetes angina, chronic renal disease, liver disease, hypothyroidism, levothyroxine, estrogens, and betablockers. Christian JB, et al. Am J Cardiol. 2011. In press. doi: 10. 1016/j. amjcard. 2010. 11. 008.

Epidemiology of Severe Hypertriglyceridemia: Summary £ NHANES data have shown that the prevalence of abnormal TG levels has increased 1 £ The cause of TG ≥ 500 mg/d. L can be multifactorial 2 £ Clinical characteristics most strongly associated with severe hypertriglyceridemia (compared with TG <500 mg/d. L) include elevated non–HDL-C, low HDL-C, chronic renal disease, and diabetes 3 1. Cohen JD, et al. Circulation. 2008; 118: S 1081 -82; 2. NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Final Report. 2002; NIH Publication No. 02 -5215; 3. Christian JB, et al. Am J Cardiol. 2011. In press. doi: 10. 1016/j. amjcard. 2010. 11. 008.

Clinical Relevance of Non–HDLC HDL-C=high-density lipoprotein cholesterol.

What Is Non–HDL-C? TG Cholesterol Major atherogenic lipoproteins HDL LDL IDL VLDL APO A-1 APO B Chylomicron APO B 48 non-HDL non–HDL-C= TC − HDL-C Ginsberg HN, et al. Arch Med Res. 2005; 36: 232 -240; NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Final Report. 2002; NIH Publication No. 02 -5215; Bays HE, et al. Expert Rev Cardiovasc Ther. 2008; 6: 391 -409.

Percentage of patients with TG levels of ≥ 200 mg/d. L achieving treatment goals NEPTUNE II: Non–HDL-C Identifies the Largest Treatment Gap Achieved LDL-C Goal Achieved LDL-C and Non–HDL-C Goal 100 80 CHD + CHD RE (n=728) 78% 64% 60 71% 52% 40 27% 50% 44% 33% 25% 17% 20 0 0 -1 Risk Factor (n=163) ≥ 2 Risk Factors (n=340) CHD + CHD RE (n=728) CHD (n=320) Diabetes (no CHD) (n=308) Other CHD RE (no CHD) (n=100) NEPTUNE=National Cholesterol Education Program Evaluation Projec. T Utilizing Novel E-Technology; RE=risk equivalent. Davidson M, et al. Am J Cardiol. 2005; 96: 556 -563.

Cholesterol (mg/d. L) Non–HDL-C May Be Used to Determine the Need for Treatment 225 Case 1 Case 2 200 HDL TC VLDL 150 100 VLDL LDL 50 TG TC LDL-C VLDL-C HDL-C Non–HDL-C Non-HDL Cholesterol 120 mg/d. L 209 mg/d. L 145 mg/d. L 24 mg/d. L 40 mg/d. L 169 mg/d. L These are hypothetical cases. 508 mg/d. L 209 mg/d. L 88 mg/d. L 32 mg/d. L Non–HDL-C goal = LDL-C goal + 30 177 mg/d. L

Clinical Relevance of Non–HDL-C: Summary £ Non–HDL-C = TC – HDL-C £ NCEP target level for non–HDL-C is 30 mg/d. L > LDL-C goal NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Final Report. 2002; NIH Publication No. 02 -5215.

Treatment Guidelines for Triglycerides and Non–HDL-C=high-density lipoprotein cholesterol.

NCEP Guidelines: Patient Types Based on Fasting Triglyceride Levels Patient Type (Category) Fasting TG Level (mg/d. L) Very high 500 High 200 -499 Borderline high 150 -199 Normal <150 NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Final Report. 2002; NIH Publication No. 02 -5215.

NCEP Guidelines: Treatment Objectives for Elevated Triglycerides Primary Objective Secondary Objective “Very High” TGs ≥ 500 mg/d. L ↓ TG ↓ LDL-C & non–HDL-C “High” TGs 200 -499 mg/d. L LDL-C goal ↓ non–HDL-C (VLDL-C, * LDL-C) *VLDL-C levels are influenced by TG levels. NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Final Report. 2002; NIH Publication No. 02 -5215.

NCEP Guidelines: Treatment Goals Risk Category LDL-C Goal (mg/d. L) Non–HDL-C Goal (mg/d. L) CHD or CHD risk equivalents (10 -year risk >20%) <100 (<70)* <130 (<100)* 2+ risk factors (10 -year risk 20%) <130 (<100)† <160 (130)† 0 -1 risk factor <160 <190 *Optional goal in very–high-risk patients. †Optional goal in moderately high-risk patients (10 -year risk, 10%-20%). NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Final Report. 2002; NIH Publication No. 02 -5215. Grundy S, et al. Circulation. 2004; 110: 227 -339.

ADA/ACC Consensus Statement: Treatment Goals in Patients With Cardiometabolic Risk and Lipoprotein Abnormalities Non–HDLLDL-C (mg/d. L) Apo B (mg/d. L) Highest-risk patient – Known CVD – Diabetes plus ≥ 1 additional major CVD risk factor* <70 <100 <80 High-risk patients – No diabetes or known CVD but ≥ 2 major CVD <100 <130 risk factors* – Diabetes but no other major CVD risk factors* College of Cardiology; ADA=American Diabetes Association; CVD=cardiovascular disease. ACC=American <90 *Major risk factors beyond dyslipidemia include smoking, hypertension, and family history or premature CHD. Brunzell JD, et al. Diabetes Care. 2008; 31: 811 -822.

Non–HDL-C and Guidelines: Summary £ TG levels ≥ 500 mg/d. L are classified as very high (often referred to as severe hypertriglyceridemia) £ NCEP guidelines recommend treating very high TGs as the primary objective of lipid management, with the treatment of LDL-C and non–HDL-C as secondary objectives NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Final Report. 2002; NIH Publication No. 02 -5215.

Overall Summary • This presentation reviewed: Lipid and lipoprotein metabolism in patients with normal TG levels and hypertriglyceridemia Changes in lipid and lipoprotein metabolism that occur when hypertriglyceridemia is corrected Epidemiology of hypertriglyceridemia Clinical relevance of non–HDL-C Treatment goals for TG and non–HDL-C levels

Questions

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Backup Slides (Static Animations)

Normal Lipid and Lipoprotein Metabolism

Normal Lipid and Lipoprotein Metabolism

Lipid and Lipoprotein Metabolism in Hypertriglyceridemia Hepatic Lipase Bloodstream CETP Increased VLDL Small, dense LDL CE T P Rapid degradation Small, dense HDL Hepatic Lipase Liver Increased Triglycerides