Management of cholesterol issues in pediatrics: Which kids get Lipitor?

1. Management of cholesterol issues in pediatrics:Which kids get Lipitor? Current Guidelines for Screening and Treatment Mark D. DeBoer Pediatric Endocrinology University of Virginia

2. Disclosures • I have no financial conflicts to disclose. • Most cholesterol treatment in children is not FDA approved, though the AAP and several major organizations endorse treatment in specific circumstances.

3. Cases Case 2 Case 1 16 y.o. boy Type 1 diabetes Sedentary Obese (BMI 28) FH: father w/ angina at 58 y.o. LDL 135 (nl <110) 16 y.o. boy “Healthy” Sedentary Obese (BMI 28) FH: father w/ angina at 48 y.o. LDL 155 (nl <110) Which of these boys qualifies to receive medical therapy for high LDL cholesterol? Based on what clinical information?

4. Outline Cholesterol screening & treatment in children • Role of cholesterol in CVD pathogenesis in adults and children • Pediatric diseases assoc. w/ high LDL • Guidelines for screening & treatment • Tools for treatment

5. Why this is important to pediatrics • Cholesterol: vital compound

6. Why this is important to pediatrics • Cholesterol: vital compound • Complex process for delivery

7. Why this is important to pediatrics • Cholesterol: vital compound • Complex process for delivery • Excess amounts deposited • Fatty streaks Atheroma “Gruel” “blob”

8. Why this is important to pediatrics • Cholesterol: vital compound • Complex process for delivery • Excess amounts deposited • Fatty streaks

9. Why this is important to pediatrics • Cholesterol: vital compound • Complex process for delivery • Excess amounts deposited • Fatty streaks

10. Why this is important to pediatrics • Cholesterol: vital compound • Complex process for delivery • Excess amounts deposited • Fatty streaks

11. Why this is important to pediatrics • Cholesterol: vital compound • Complex process for delivery • Excess amounts deposited • Fatty streaks

12. Why this is important to pediatrics • Cholesterol: vital compound • Complex process for delivery • Excess amounts deposited • Fatty streaks • Increases risk of CVD • Starts in childhood Li JAMA ’03

13. Why this is important to pediatrics • Cholesterol: vital compound • Complex process for delivery • Excess amounts deposited • Fatty streaks • Increases risk of CVD • Starts in childhood • >30% of teens have coronary artery plaques Berenson NEJM ’98

14. Why this is important to pediatrics • Cholesterol: vital compound • Complex process for delivery • Excess amounts deposited • Fatty streaks • Increases risk of CVD • Starts in childhood • >30% of teens have coronary artery plaques • Most severe childhood cases: • Death by MI by 20 y.o.

15. Dose response • Area under the curve: • LDL x time = atherosclerosis LDL level Childhood Time (age)

16. Dose response • Area under the curve: • LDL x time = atherosclerosis LDL level Childhood Time (age)

17. Adult studies LDL cholesterol: the lower the better Adult treatment goal: High risk (current CAD): LDL <100 Grundy Circulation ’04

18. Adult studies LDL cholesterol: the lower the better Adult treatment goal: Moderate risk (2 risk factors): LDL <130 Grundy Circulation ’04

19. Adult studies LDL cholesterol: the lower the better MI, stroke or death from cardiovascular cause. Final LDL 109 mg/dL Cumulative incidence Initial labs 55 mg/dL LDL 108 mg/dL hsCRP 4.2 mg/L Men > 50 y.o., women > 60 y.o. w/o CVD and LDL<130 but CRP>2 Ridker NEJM ’08

20. Summaryso far: • LDL cholesterol: associated with coronary artery plaque formation in childhood. • Time of exposure and absolute levels of LDL are important factors in CVD. • Preview: Intervention is focused on risk of CVD • Known genetic syndromes • Presence of additional risk factors

21. Cholesterol transport Kwiterovich JCEM ’08

22. HMGCoA reductase Bile acid Cholesterol ester Chylomicron remnant Acetyl Co-A Cholesterol LRP ApoE ApoB48 Lipo-protein Lipase Chylomicron

23. FFA ApoB100 Hepatic Lipoprotein Small, lipase lipase dense LDL HMGCoA reductase Bile acid Cholesterol ester Chylomicron Niemann-Pick remnant C1-like protein Acetyl Co-A FFA TG VLDL ApoB Cholesterol Tissue ApoE IDL LDL LRP LDL Oxidation SR-A ApoE ApoB48 LPL Chylomicron ABCG5,8

24. FFA ApoB100 Lipoprotein Hepatic lipase lipase HMGCoA reductase Bile Cholesterol Phospholipid acid transfer protein ester transfer protein Cholesterol Nacent Cholesterol ester HDL ester Chylomicron Niemann-Pick C1-like protein remnant Acetyl Co-A FFA TG VLDL ApoB Cholesterol Tissue ApoE IDL LDL-R LDL LRP Oxidation SR-A ApoE ApoB48 HDL LPL ABCA1 Chylomicron ApoA1

25. FFA ApoB100 Lipoprotein Hepatic lipase lipase HMGCoA reductase Bile Phospholipid acid transfer protein Nacent Cholesterol Cholesterol ester ester HDL Chylomicron Niemann-Pick remnant C1-like protein Acetyl Co-A FFA TG VLDL ApoB Cholesterol Tissue ApoE IDL LDL-R SRB1 LDL LRP Oxidation SR-A ApoE ApoB48 HDL LPL ABCA1 Chylomicron ApoA1

26. Monogenic cholesterol disorders Kwiterovich JCEM ’08

27. ApoB100 Lipoprotein Hepatic lipase lipase VLDL Tissue ApoE IDL Heterozygotes 1:500 frequency LDL avg. 262 mg/dL (vs. 97 for controls) HDL reduced 5-10% 50% of untreated males, 25% females: CAD by 50 y.o. Homozygotes: 1/1 million Xanthomas, CAD <20 y.o. LDL-R LDL Oxidation SR-A Familial hypercholesterolemia Kwiterovich JCEM ’08

28. ApoB100 Lipoprotein Hepatic lipase lipase VLDL Tissue ApoE IDL Heterozygotes 1:1000 frequency Clinically similar to FH heterozygotes Not as significant a cause of premature CAD LDL-R LDL Oxidation SR-A Familial defective ApoB Kwiterovich JCEM ’08

29. FFA ApoB100 Hepatic Lipoprotein lipase lipase HMGCoA reductase Bile Cholesterol Lecithin- acid ester transfer cholesterol protein transfer Nacent Cholesterol Cholesterol Phospholipid transfer protein ester ester HDL Niemann-Pick Chylomicron remnant C1-like protein Acetyl Co-A FFA TG VLDL ApoB Cholesterol Tissue PCSK9 ApoE IDL ARH LDL-R Other defects? SRB1 LDL LRP Oxidation SR-A ApoB48 HDL LPL ABCA1 Chylomicron ApoA1 ABCG5,8 Kwiterovich JCEM ’08

30. ApoB100 Lipoprotein Hepatic lipase lipase VLDL Tissue ApoE IDL Chronic renal failure Diabetes Nephrotic syndrome Hepatitis Hypothyroidism Alcohol abuse Hypopituitarism Lupus Steroid treatment Storage diseases Oral contraceptives Anorexia nervosa Preganancy LDL-R LDL Secondary causes of high LDL Oxidation SR-A Kwiterovich JCEM ’08

32. Summary • Some of the known genetic and 2O causes of hypercholesterolemia are relatively common. • These may or may not be associated with known family history of cholesterol problems or heart disease. • Who should we be screening for this?

33. NCEP Statement (1992): Lipid screening for children National Cholesterol Education Program Pediatrics ’92 Daniels Pediatrics ’08 Kwiterovich JCEM ’08

34. NCEP Statement (1992): Lipid screening for children Family history: • Early CAD in parents or GP(male<55y; female<65y) Bypass surg. Peripheral/cerebrovasc disease Angioplasy Sudden death Angina Miocardial infarction • Parents with total cholesterol >240 • Unknown family history “Optional”—other risk factors: (smoking, hypertens, obesity, inactivity) National Cholesterol Education Program Pediatrics ’92 Daniels Pediatrics ’08

35. NCEP Statement (1992): Lipid treatment for children AcceptableBorderlineHigh LDL-cholesterol <110 110-129 >130 mg/dL Diet therapy: Step 1  Step 2 to reach LDL<110 Drug therapy: Children >10 y.o. LDL >190 mg/dL LDL >160 plus +FH or >2 risk fcrs (tob., htn, obesity, inactivity, low HDL) National Cholesterol Education Program Pediatrics ’92 Daniels Pediatrics ’08

36. What to measure • Fasting lipid panel Total chol., HDL & TG’s directly measured LDL = Total cholesterol – (HDL + TG/5)

37. Boys Girls LDL When to screen: Cholesterol levels vary through puberty. Cook JPeds ’08

38. When to screen: Cholesterol levels vary through puberty. Boys Girls LDL HDL Cook JPeds ’08

39. When to screen: Cholesterol levels vary through puberty. Boys Girls LDL TG Cook JPeds ’08

40. Summary: Cholesterol screening, at risk children • Who to screen: +family history, 10 y.o., with risk factors • How to screen: fasting lipoprotein profile • When to treat: diet (Step 1&2): LDL>130 meds: LDL >190 LDL >160 w/ risk factors • Higher risk children (diabetes, end-stage renal disease, Kawasaki’s disease) have lower treatment thresholds: meds: LDL >100 Kavey Circulation ’06

42. Treatment of high cholesterol Kwiterovich JCEM ’08

43. Kwiterovich JCEM ’08

44. Step 1 AHA Diet F/M F/M F/M

45. Step 2 AHA Diet F/M F/M F/M

46. Plant stanol & sterol esters Margarine spreads, chews Prevent cholesterol absorption Can decrease LDL 10-15% Kwiterovich JCEM ’08

47. Niemann-Pick C1-like protein Ezetimibe (Zetia) Blocks cholesterol uptake FDA approved for FH in children Can decrease LDL 18% Kwiterovich JCEM ’08

48. Bile acid Bile acid sequestrants Increases chol. excretion Can decrease LDL 17% Cholestyramine: >80% discontinuation rate Gritty taste Constipation Kwiterovich JCEM ’08

49. Bile acid Bile acid sequestrants Colesevelam (Welchol): Higher affinity,lower dose Tablet form (6/day) Lowers LDL 13% Fewer side effects FDA approved FH >10 y.o. Kwiterovich JCEM ’08

50. FFA ApoB100 FFA TG VLDL Niacin Blocks production of free fatty acids Decreases VLDL production Lowers LDL 5-25% i TG 25-50% Side effect: flushing Not commonly used