Controversies in Management of Lipids in Children Adolescents

1. Controversies in Management of Lipids in Children & Adolescents Ramin Alemzadeh, MD Professor of Pediatrics Director, CHW Diabetes Center Medical College of Wisconsin

2. Objectives • Cholesterol Metabolism • Factors affecting Cholesterol metabolism • Etiologies & Prevalence of Hypercholesterolemias • Cholesterol as a cardiovascular risk factor • Approaches of Cholesterol Screening • Discuss the use of lipid lowering therapy & recommendations for use of HMG-CoA reductase inhibitors (STATINS) • Conclusions

3. Dietary Cholesterol VLDL cholesterol via liver synthesis Cholesterol synthesis Acetyl CoA viaCirculation LDL cholesterol HMG-CoA HMG-CoA reductase Uptake via LDL receptor Mevalonate Intracellular Fates: esterification by ACAT and storage; steroid hormone/ vitamin D synthesis Cellular Cholesterol Esterification/removal by LCAT/HDL CE in HDL Cholesterol excretion as bile acids Bile Acids (lipid absorption) A X Liver uptake via apo E receptor B X Cholesterol in liver partly metabolized Summary of cholesterol metabolism. A and B represent feedback repression of these enzymes ACAT: acyl CoA:cholesterol acyltransferase; LCAT: lecithin:cholesterol acyltransferase

4. Role of Cholesterol in The Body • Importance of cholesterol synthetic pathway in body • component in cell membranes • cell proliferation • transmembrane signaling and important cellular functions • Importance of cholesterol in the brain • Important component in myelin sheaths • Brain cholesterol accounts for 25% of total body store • Promotes Synaptogenesis & neuronal plasticity • Precursor for steroid hormones such as cortisol, aldosterone, estrogen and testosterone • Precursor for bile salts

5. Etiologies of Hypercholesterolemia • Primary causes (genetic defects) • Heterozygous familial hypercholesterolemia (heFH)-AD • Homozygous familial hypercholesterolemia • Familial combined hyperlipidemia (hyperapobetalipoproteinemia) • Polygenic hypercholesterolemia • Secondary causes • Obesity • Hypothyroidism • Cholestasis • Immunosuppressive Rx in oncology & transplant patients • Antiretroviral therapy in HIV-infected children • Use of steroids • Systemic lupus erythematosus

6. Heterozygous Familial Hypercholesterolemia (heFH) • Autosomal dominant mode of inheritance • Prevalence: 1 in 500 worldwide • Total cholesterol: 270-500 mg/dL • ~50% of men experience a cardiovascular event (CVE) by age 50 years • Only 15% of men reach 65 years without experiencing a CVE

7. Homozygous Familial Hypercholesterolemia • Total Cholesterol > 500 mg/dL • Relatively normal TG • Severe Defect in LDL receptor • Occurs in about 1 in 1 million persons • Tuberous or tendon xanthomas • Symptoms of vascular disease before puberty • Rarely survive beyond 2nd decade of life • Little or no response to drugs • Respond to plasmapheresis and LDL- apheresis

8. Concentrations of Total and LDL Cholesterol Among Children & Adolescentsin the U.S. • NHANES 1999 to 2006 for participants 6 to 17 years of age. • The mean concentration of total cholesterol among participants 6 to 17 years of age was 163.0 mg/dL (n=9868). • The mean concentration for LDL-C for participants 12 to • 17 years of age was 90.2 mg/dL (n=2724). • An elevated concentration of total cholesterol (95th% for age & gender: 191-208 mg/dL) for 9.6% to 10.7%. • An elevated concentration of LDL-C (95th% for age & gender: 133-137 mg/dL) was noted for 5.2% to 6.6% of participants. • Approximately 0.8% (n=26) of adolescents 12 to 17 years of age were potentially eligible for pharmacological treatment for elevated concentrations of LDL-C. Ford ES et al Circulation 2009

9. Concentrations of Total and LDL Cholesterol Among Children & Adolescentsin the U.S. Ford ES et al Circulation 2009

10. Cholesterol is a Risk Factor Not a Disease Belay, et al. Pediatrics 2007;119:370-380

11. The Atherosclerotic Process in Children • Atherosclerotic disease begins in childhood • Autopsies of young Korean and Vietnam veterans • Pathobiological Determinants of atherosclerosis in Youth (PDAY): victims of accidental trauma, suicide, or homicide • Bogalusa Heart Study: victims of accidents or suicide • Lipid levels show strong genetic & environmental components: • Monogenic dyslipidemias • High fat diet, polygenic disorders and environmental causes like obesity are the most common causes of hypercholesterolemia in children

12. Atherosclerosis Begins in Childhood Berenson GS et al, N Engl J Med, 1998

13. The Effects of Multiple Risk Factors on the Extent of Atherosclerosis • Vascular endothelial dysfunction initiates atherosclerotic process • Extent of atherosclerotic lesions correlated with elevations in: • Total cholesterol • LDL Cholesterol • Triglycerides • Blood Pressure • BMI Berenson et al, Bogalusa Heart Study. N Engl J Med, 1998

14. The function of the vascular endothelium: Progression to Atherosclerosis • Regulation of vascular tone • Controls vascular cell growth, particularly smooth muscle proliferation • Controls leukocyte and platelet adhesion by secretion of selectins and adhesion molecules • Thrombotic and fibrinolytic properties • Endothelial dysfunction- leads to Increased intima media thickening (IMT) and atherosclerotic plaque

15. B-Mode Measurement of Carotid Intima-Media Thickness (cIMT)

16. Carotid artery IMT as a surrogate for coronary artery disease • The Muscatine study found an association between increased carotid IMT and coronary calcification in young adults. (Circulation 1999;100:838-842). • The Multicenter Anti-Atheroma study showed that IMT of the carotid bulb was associated with coronary stenosis in adults with coronary disease (r=0.68, p=0.01). (Stroke 1997;28:1189-1194). • The Rotterdam Study found that the risk of a first myocardial infarction increased when the baseline mean IMT was 0.822 mm or greater, and the risk of stroke when the mean IMT was 0.75 mm or greater. (Circulation 1997;96:1432-7). • Risk factor profile in 12- to 18-year-old adolescents predicts adult cIMT independently of contemporaneous risk factors (Raitakari et al JAMA 2003; 290: 2227-2283). • Numerous adult studies have shown statin therapy prevents the progression of carotid IMT or reduces carotid IMT.

17. Carotid IMT in Young Patients with heFH • 28 patients (11-27 years of age;12M/16F) with FH vs 28 controls • cIMT (0.710.15 vs 0.490.08 mm;p<0.001) • cIMT correlated with: • Total cholesterol • LDL-cholesterol • Triglycerides • Systolic BP Lavrencic et al; Heart 1996;76:321-325

18. Usefulness of Childhood Lipoprotein Measures in Predicting Adult SubclinicalAtherosclerosis: The Bogalusa Heart Study Mean levels of adult carotid IMT by quartile of childhood lipoprotein measures in the Bogalusa Heart Study cohort. Frontini et al Pediatrics 2008; 121: 924-929

19. Early Surrogate Markers of Atherosclerosis in Children & Adolescents • Mean carotid intima-media thickness (cIMT)1 • Flow-mediated dilatation of the brachial artery (FMD): vascular dilatation and nitric-oxide response to ischemia2 • Electron beam computer tomography (EBCT): coronary calcifications3 • Multimodal magnetic resonance imaging (MRI): plaque burden & composition in common carotid artery and abdominal aorta 1. Weigman et al, JAMA 2004 2. de Jongh et al, J Am Coll of Cardiol 2002 3. Gidding et al, Circulation 1998

20. Coronary Artery Plaque (CAP) Scanning • Approximate amounts of lipid Rich, fibrotic, & calcified plaque: • Lipid Rich-33% • Fibrotic-46% • Fibrotic & calcified-20% • CAP can be visualized by B-mode U/S • Calcified plaque is detectable by electron beam computer tomography (EBCT) • Multi-Slice (64-slice) CT Calcification of left coronary artery (LCA) Mixed plaque with predominant soft tissue, Calcification and remodelling & ? ulceration

21. Usefulness of EBCT in Adolescents & Young Adults with heFH • 29 youths 11 to 23 years old with FH • Significant coronary calcification in 7 out of 29 • Increased BMI was associated with the presence of coronary calcium • No other risk factors (i.e., gender, LDL-C level, family history of CAD, tobacco use, etc) were associated with the presence of coronary calcium Gidding et al, Circulation 1998; 98: 2580-2583

22. Original National Cholesterol Education Program (NCEP)-1992 NCEP guidelines ClassificationTotal cholesterolLDL • High > 200  130 • Borderline 170-199 110-129 • Acceptable < 170 < 110

23. National Cholesterol Education Program (NCEP) & AHA Recommendations in Children • >2 years of age with parental CHD or a first degree family history of premature CVD • AHA* Steps I & II Diets: 6-12 months • Dietary supplements: fiber, antioxidants, fish oil (omega-3 fatty acids), etc • Physical activity • Statin therapy in children 10 years and older American Heart Association (AHA) Coronary Heart Disease (CHD) Cardiovascular Disease (CVD)

24. Original NCEP Guidelines-1992 Lipid-lowering Drug Treatment • Child at least 10 years of age • LDL-C > 160 mg/dL c/ family hx of premature CVD or 2 risk factors* • LDL-C > 190 mg/dL c/out family hx or 2 risk factors* • Treatment goal: LDL-C<110 mg/dL *HDL-C<35, smoking, DM, obesity, HTN, lack of exercise

25. Current NCEP Modifications* • Overweight & obese should trigger screening • Screen overweight & obese with lipid abnormality for metabolic syndrome • Statin is first-line Rx for children meeting the criteria for lipid-lowering drugs • Additional risk factors or high-risk conditions may lower cut point for LDL-C level and age (8 years) for initiation of Rx: • Male gender • HDL-C<35,  TG, &  VLDL • Features of metabolic syndrome • Diabetes, HIV infection, SLE, organ transplantation, cancer survivors • Hypertension • Current smoking and passive smoke exposure •  Lipoprotein(a),  homocysteine &  C-reactive protein *McCrindle et al. AHA Scientific Statement. Circulation 2007;115:1948-19657

26. *AAP: American Academy of Pediatrics de Ferranti et al. NEJM 2008; 359:1309-1312

27. Pharmacotherapy • Drugs of choice • Bile acid sequestrants (BAS)- cholestyramine, colestipol • proven efficacy and safety • Alternative therapy • Niacin alone or in combination with BAS • Fibric acid derivatives or fibrates • HMG-CoA reductase inhibitors (statins)

28. Statins Approved for Use in Children Belay et al., Pediatrics 2007: 119: 370-380

29. Hydroxamethylglutaryl-CoA(HMG-CoA) Reductase Inhibitors • Recent studies have focused on statins • 7 Short-term and Long-term Clinical trials • Efficacy similar to adult patients •  LDL-C by 18-35% • pravastatin 5-20 mg/d • lovastatin 10-40 mg/d • simvastatin 10 mg/d • atrovastatin 10-20 mg/d

30. Efficacy of 6-month Statin Therapy in Children with Familial Hypercholesterolemia

31. Does Long-term Statin Therapy Affect Cardiovascular Outcomes in Pediatric FH? • Two-year pravastatin therapy1 • Lowered LDL-C & TC • Lowered carotid IMT • No effect on LFTs or CPK • No effect on growth or other endocrine functions • No effect on pubertal hormones or maturation • Two-year pravastatin therapy:LDLR genotype (defective vs null) influenced clinical response to pravastatin2 • Lowered LDL-C & TC • Lowered carotid IMT 1. Wiegman et al. JAMA 2004; 292: 331-337 2. Koeijvoets et al Circulation 2005; 112: 3168-3173

32. Impact of Statins on Vascular End points Changes from baseline (striped bar) to 28 weeks (while bar) in flow-mediated dilatation (FMD) in Placebo and simvastatin groups with familial Hypercholesterolemia; *p<0.0001vs baseline; †p<0.05 for change in placebo vs change vs simvastatin groups. Mean carotid intima-media thickness (IMT) changes From baseline for the different carotid arterial wall segments in the pravastatin and placebo groups of Children with familial hypercholesterolemia. Jongh et al, J Am Coll Cardiol 2002; 40:2117-2121 Wiegman et al, JAMA 2004;292:331-337

33. Potential Effects of Statin Therapy on Steroid Synthetic Pathway • Inhibition of this steroid pathway by a statin may have pleiotropic effects • Influencing antioxidant activity • Intracellular processes: • signal transduction • cell proliferation • apoptosis • Structural components • Synthesis of Steroid hormones

34. Smith-Lemli-Opitz Syndrome • Autosomal recessive disorder • Caused from mutation in the DHCR7 gene • Located at 11q12-13 • Encodes for sterol-Δ7-reductase • Defects in sterol-Δ7-reductase • Build up of 7-dehydrocholesterol • Deficiency of cholesterol • Common characteristics: • Multiple malformations at birth. • Mental retardation later. • Occurrence: • 1 in 20,000 people of central European decedents. • Rare in Africans and Asians.

35. Statin Toxicities in Adults • Hepatotoxicity:<0.1%: 2:1 female to male> 60 yrs • Myotoxicity: 0.5% lovastatin • Statin use with other CYP3A4 inhibitors also increase risk of myopathy: i.e., cyclosporin, erythromycin, azole antifungals • Rhabdomyolysis: ? depletion of mevalonate, farnesol, geranylgeraniol, and mitochondrial ubiquinone • Peripheral Neuropathy: ? small risk; exacerbated in diabetics • Teratogenicity: CNS and cardiac anomalies due to inhibition of cholesterol synthesis and alteration of sterol-dependent morphogens by the lipophilic statins crossing the placenta • Cognitive effects: ? Not conclusive • Cancer: ? Not conclusive

36. Systematic Review & Meta-analysis of Statins for heFH in Children: Evaluationof Cholesterol Changes and Side Effects • The search yielded 2,174 titles. • Of the 63 studies retrieved and reviewed 56 were excluded. • 7 randomized control trials (RCTs) were included in the systematic review, and 4 were included in the meta-analysis. • Significant heterogeneity was detected due to methodological differences & concerns: • Suboptimal blinding • Absence of intention-to-treat in 6 trials despite stated intention • Suboptimal RCT quality criteria • Gender distribution and duration • The meta-analysis showed significant LDL lowering, HDL elevation, and increases in height and weight with statins. • The meta-analysis could not be performed for many side effects of statins, but individual trials showed no significant side effects. Clodagh S, et al Pediatr Cardiol 2009

37. Systematic Review & Meta-analysis of Statins for heFH in Children: Evaluationof Cholesterol Changes and Side Effects Clodagh S, et al Pediatr Cardiol 2009

38. Systematic Review & Meta-analysis of Statins for heFH in Children: Evaluationof Cholesterol Changes and Side Effects • Many authors or institutions were duplicated or acknowledged in multiple trials. • All 7 trials disclosed funding from pharmaceutical sources, which in each case was the manufacturer of the statin under investigation. • This bias may explain why no negative trials of statins for pediatric heFH have been published. • This also may explain the lack of intention-to-treat analysis in many trials. • External funding is a known cause of positive publication bias. • Meta-analysis showed significant LDL lowering with statin treatment. • Further studies, including epidemiologic and multicenter studies, are required. Clodagh S, et al Pediatr Cardiol 2009

39. Statins: Compliance & Safety in Children • Compliance high but therapy was brief • duration- 24 weeks to 2 year • drop-out rates low • Safety • studies have been underpowered for safety • elevation of liver transaminases in 1% to 5% of children • No myopathy has been reported • effects on growth & development may not be evident for years • Adverse events such as headache and flu-like and GI symptoms and/or sore throat were reported in about 64% and 65% of statin and placebo treated patients, respectively

40. Clinical Effects of Statins in Adults: Relevance to Pediatrics • Distinguish primary vs secondary intervention studies in adults • Statin therapy is aimed at mitigating the thrombogenic potential of existing plaque in adults • Statins have decreased cardiac mortality without showing reduction in total mortality in adults • Aggressive lipid-lowering in children based on studies in adults is not justified • Prevention of atherosclerotic plaque development and maturation in children is the goal of statin therapy

41. Conclusions • Lack of definitive long-term data on the effect of drug therapy on preventing CHD in children & adolescents • Long-term safety of most lipid lowering agents in children is unknown- Bile acid sequestrans are the safest option • Balance unknown risks of treatment against estimated risk of premature CHD • Statin therapy is recommended in adolescents with heFH • ? Primary prevention strategy in high risk asymptomatic children: independent clinical trials are needed • Assess the use of various biomarkers including hs-CRP cutoffs in developing therapeutic strategies in adolescents • Noninvasive imaging of childhood atherosclerosis can spare traditionally at-risk children with heFH from risk of unnecessary pharmacotherapy • ? use of statins versus life-style changes in adolescents with T2DM and MS at higher risk of CVD than those with heFH