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

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 What type of conditions does one see in a Lipid Clinic? hFH. Autosomal dominant . Effects 1 in 500 persons (one of the most common genetic conditions). Familial combined hyperlipidemia � 1 or 2/100 in the general population.What type of conditions does one see in a Lipid Clinic? hFH. Autosomal dominant . Effects 1 in 500 persons (one of the most common genetic conditions). Familial combined hyperlipidemia � 1 or 2/100 in the general population.

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.

9. Concentrations of Total and LDL Cholesterol Among Children & Adolescentsin the U.S.

10. Cholesterol is a Risk Factor Not a Disease

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

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

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 What causes increased IMT? Not inert pipes. Continually in movement and extremely active metabolically.What causes increased IMT? Not inert pipes. Continually in movement and extremely active metabolically.

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

18. Usefulness of Childhood Lipoprotein Measures in Predicting Adult SubclinicalAtherosclerosis: The Bogalusa Heart Study

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

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

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

22. Original National Cholesterol Education Program (NCEP)-1992 NCEP guidelines Classification Total cholesterol LDL 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

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

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)

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

32. Impact of Statins on Vascular End points

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-?7-reductase Defects in sterol-?7-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.

37. Systematic Review & Meta-analysis of Statins for heFH in Children: Evaluationof Cholesterol Changes and Side Effects

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.

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