Management of Lipid Disorders in Children and Adolescents

Management of Lipid Disorders in Children and Adolescents Britni Delva, MPAS, PA-C, CLS Disclosures Disclosures Consultant/speaker Research funding Stock ownership/corporate boards-employment Off label uses No disclosures No disclosures No disclosures Fenofibrates, gemfibrozil, ezetimibe 1

Objectives Describe pathophysiology and prevalence of dyslipidemias in pediatric patients Understand screening guidelines for dyslipidemia Understand the management of dyslipidemias WHY DO LIPID ABNORMALITIES MATTER IN CHILDREN? 2

Atherosclerosis. The process starts now. Daniels DR, Benuck I, Christakis DA, Gidding SS, et al. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents full report. National Heart Lung and Blood Institute, 2012. NIH Publication No. 12-7486 Bogalusa Heart Study Long term epidemiologic study of risk factors for cardiovascular disease Results: Link antemortem risk factors to the development of atherosclerotic lesions Aorta fatty streaks strongly related to antemortem levels of total cholesterol, LDL-C, and obesity Coronary fatty streaks associated with increased TG, VLDL, systolic and diastolic blood pressure, and obesity As the number of cardiovascular risk factors increase the severity of coronary and aortic atherosclerosis increases. 3

Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Multi-institutional autopsy study conducted in US medical centers Measured extent, prevalence and topography of atherosclerotic lesions Results: Atherosclerosis begins in youth and clinically significant raised lesions increase rapidly in prevalence and extent during the 15 to 34 year age span. Smoking, hypertension, obesity, and impaired glucose tolerance have effects on atherosclerosis Development of Current Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents In 2006 director of the National Heart, Lung, and Blood Institute (NHLBI) appointed an expert panel to develop cardiovascular guidelines The recommendations address two goals: Primordial prevention: prevention of risk factor development Primary prevention: prevention of future cardiovascular disease by management of identified risk factors. Guidelines published in 2011 4

Evidence Grading System WHO SHOULD BE SCREENED? 5

EVERYONE! Universal screening between 9-11 years and 17-21 Lipid profile If non fasting calculate non-hdl-c Non-HDL-C = total cholesterol - HDL-C Lipid Screening Birth to 24 months no lipid screening (Grade C) 2-8 years (Grade B) No routine screening Measure fasting lipid profile (FLP) x 2 if: Family History Parent with total cholesterol 240 mg/dl or known dyslipidemia Child has diabetes, hypertension, BMI 95 th percentile, smokes cigarettes Other moderate to high risk condition FLP should be at least 2 weeks apart, but done within 3 months 6

Lipid Screening 9-11 years (Grade B) Universal screening FLP or if non-flp (calculate non-hdl-c) Non-HDL-C=TC HDL-C If Non-HDL 145 mg/dl or HDL < 40 mg/dl obtain FLP x 2 Screening FLP LDL-C 130 mg/dl, non-hdl-c 145 mg/dl, HDL-C <40 mg/dl TG 100 mg/dl if <10 years or 130 mg/dl if > 10 years Repeat FLP at least 2 weeks apart, but with in three months 12-16 years (Grade B) No routine screening FLP x 2 if: Family history, Parents with TC 240 mg/dl or dyslipidemia, patient has diabetes, hypertension, BMI 85 th percentile, smokes cigarettes, or has a moderate to high risk medical condition Lipid Screening 17-21 years (Grade B) Universal screening with FLP or non-hdl-c 17-19 years Non-HDL-C 145 mg/dl, HDL-C < 40 mg/dl do FLP x 2 If FLP LDL-C 130 mg/dl, non-hdl 145 mg/dl, HDL-C <40 mg/dl, TG 130 mg/dl repeat FLP (between 2 weeks and 3 months after initial FLP) 20-21 years Non-HDL-C 190 mg/dl, HDL-C < 40 mg/dl do FLP x 2 If FLP LDL-C 160 mg/dl, non-hdl 190 mg/dl, HDL-C <40 mg/dl, TG 150 mg/dl repeat FLP (between 2 weeks and 3 months after initial FLP) If elevated follow ATP-III guidelines 7

Lipid and Lipoprotein Values in Children in Adolescents Category Acceptable Borderline Low HDL-C > 45 40-45 < 40 ApoA-I >120 115-120 <115 Lipid Disorders in Children and Adolescents Familial Hypercholesterolemia Increased LDL-C Familial defective apolipoprotein B Elevated LDL-C Polygenic hypercholesterolemia Increased LDL-C Familial Combined Hyperlipidemia Type IIa: increased LDL-C Type IV: increased VLDL-C, Increased TG Type IIb: Increased LDL-C, VLDL-C, and TG Types IIb and IV often with decreased HDL-C Familial hypertriglyceridemia Increased VLDL and TG (200-1000 mg/dl) Severe hypertriglyceridemia Increased VLDL, chylomicrons, and TG ( 1000 mg/dl) Familial hypoalphalipoproteinemia Decreased HDL-C Dysbetalipoproteinemia Increased IDL-C and cylomicron remants (TC 250-500 mg/dl; TG 250-600 mg/dl) 8

Heterozygous Familial Hypercholesterolemia Occurs in 1 out of every 250-500 people Suspected in children and young adults (<20) if LDL-C 160 mg/dl or non-hdl- C 190 mg/dl When LDL-C 190 the probability that patient has FH is 80% Screen for family history A brief period ( 3 months) of diet intervention should be trialed, repeat FLP to determine inherited versus acquired dyslipidemia Heterozygous Familial Hypercholesterolemia Treatment: Diet low in saturated fat and cholesterol Regular aerobic exercise Anti-tobacco counseling Statin therapy- begin treatment between 8-10 years of age with LDL >190 or 160 after dietary intervention Goal 50% reduction in LDL-C or LDL-C <130 mg/dl PCSK9 Inhibitors, new promising treatment used in adults 9

Homozygous Familial Hypercholesterolemia Occurs in about 1 out of every 1 million people Total cholesterol levels of 650-1,000 mg/dl Begin therapy at time of diagnosis regardless of age Statins, bile acid sequestrants, cholesterol absorption inhibitors, and other agents may used to help lower LDL Apheresis usually necessary to achieve target LDL-C levels. Important to monitor for the presence and development of CVD Coronary angiography These children usually develop cardiovascular disease by the second decade of life. Combined Dyslipidemia The most common dyslipidemia pattern in childhood Moderate to severe triglyceride elevation (typically 150-400 mg/dl) Non-HDL-C elevation (>145 mg/dl) Mild or no LDL-C elevation Decreased HDL-C (<40 mg/dl) Present in 40% of adolescents with BMI >95 th percentile. NMR Spectroscopy Increased LDL particle number Increase small dense LDL-C Reductions in total HDL-C and large HDL particles 10

Combined dyslipidemia Association with non-alcoholic fatty liver disease Treatment Primary focus is diet, exercise, and weight loss when appropriate Small amount of weight loss will often normalize cholesterol When fail to control with lifestyle modifications, statins are a logical first choice treatment Secondary Causes and Risk Factors for Dyslipidemia Exogenous Alcohol, Drug Therapy (i.e. 2 nd generation anti-psychotics, hydrochlorothiazide) Endocrine/Metabolic Hypothyroidism/hypopituitarism, diabetes, pregnancy, polycystic ovarian syndrome, lipodystrophy, acute intermittent porphyria Renal Chronic renal disease, hemolytic uremic syndrome, nephrotic syndrome Infectious Acute viral or bacterial infection, HIV, hepatitis Hepatic Obstructive liver disease/cholestatic conditions, biliary cirrhosis, Alagille syndrome, NAFLD Inflammatory Disease Systemic lupus erythematosis, juvenile rheumatoid arthritis Storage Disease Glycogen storage disease, Gaucher s disease, Cystine storage disease, Juvenile Tay-Sachs disease, Niemann-Pick disesease Other Kawasaki Disease, anorexia nervosa, post solid organ transplantation, childhood cancer survivor, Progeria, idiopathathic hypercalcemia, Klinefelter syndrome, Werner s Syndrome 11

Risk Factors Family History Myocardial infarction, angina, s/p coronary artery bypass graft/stent/angioplasty, sudden cardiac death Parent, grandparent, aunt, or uncle Male < 55 y, Female <65 y High Level Risk Factors Hypertension requiring drug therapy Cigarette smoker BMI 97 th percentile Presence of high risk conditions Moderate Hypertension- not requiring drug therapy BMI 95 th percentile, 97 th percentile HDL-C <40 Dyslipidemia Treatment Algorithm: Target LDL-C 12

Dyslipidemia Algorithm: TARGET TG Diet Recommend referral to dietician (Grade B) 25-30% of calories from fat (Grade A) 7% from saturated fat Approximately 10% from monounsaturated fat <200 mg/day of cholesterol Avoid trans fat LDL-C elevation Plant stanol esters or sterol esters Water soluble fiber psyllium Triglyceride elevation Decrease sugar intake (Grade B) Replace simple carbohydrates with complex carbohydrates No sugar sweetened beverages Increase dietary fish to increase omega-3 fatty acids (Grade D) 13

Lifestyle Modifications Physical activity One hour a day of moderate to vigorous physical activity (Grade A) Age appropriate <2 hours per day of screen time (Grade B) Anti-tobacco counseling (Grade B, C) Weight management Calculate and plot BMI 85-95 th percentile overweight 95 th percentile obese Counsel on appropriate weight maintenance or loss recommendations if applicable Medication 14

When to treat with medication Treat LDL-C to target first LDL-C >190 mg/dl treat with statin therapy LDL-C 160-189 mg/dl treat with statin therapy if there is a positive family history, 1 high level risk factor (RF), or 2 moderate RF statin therapy LDL-C 130-159 mg/dl treat with statin therapy if 2 high level RF or 1 high level RF and 2 moderate level RF or clinic cardiovascular disease Once LDL-C at target then focus on non-hdl-c (>145 mg/dl) and triglycerides Triglycerides 200-400 mg/dl treat with statin therapy Triglycerides > 500 mg/dl treat with fibrate first, may need additional therapies Statin Therapy Primary treatment for heterozygous familial hypercholesterolemia and combined dyslipidemia Mechanism of action: inhibit HMG-CoA reductase, the rate limiting enzyme in cholesterol synthesis. Inhibits cholesterol synthesis in hepatic cells, decreases cholesterol pool, resulting in up regulation of LDL receptors Lowers LDL-C, lowers TG, increases HDL Adverse Reactions: raised liver enzymes, raised creatine kinase, mypoathy, rarely rhabdomyolysis Pravastatin may be used in patients 8 years of age and older. All other statins approved 10 years of age or older 15

Statin: Mechanism of Action HMG-CoA Competitive Inhibition Statins HMG CoA Reductase Inhibitors Mevalonate Cholesterol production Cholesterol Production Statin Therapy Begin at lowest available dose If target LDL-C not achieved in 3 months, then dose may be increased, usually by 10 mg Once maximum dosage achieved, may consider alternative statin therapy or a second agent such as bile acid sequestrant or cholesterol absorption inhibitor This should be done under the direction of a lipid specialist Monitor: Clinical symptoms for muscle toxicity Assess hepatic transaminases and creatine kinase Inform patients: Potential drug medication interactions Metabolized by cytochrome P-450 system Risks associated with pregnancy and appropriate contraception strategies 16

Efficacy and safety of atorvastatin in children and adolescents Multi-center, randomized, placebo-controlled trial Results: Atorvastatin tolerated as well as placebo Conclusion: Atorvastatin was safe and effective when used in pediatric patients with familial hypercholesterolemia or severe hypercholesterolemia for 12 months. Efficacy and Safety of Statin Therapy Meta-analysis of randomized, double blind, placebo controlled trials evaluating statin therapy in children and adolescents (8-18y) Results: Decreased TC (mean 23%), Decreased LDL-C (mean 30%), Decreased ApoB (mean 24%), Increased HDL-C (3.64%), increased ApoA1 2.43% No statistically significant differences between statin and placebo treated children with respect to adverse events Conclusion: Statin treatment is safe in children is efficacious and safe in children with heterozygous familial hypercholesterolemia. Further studies are needed to assess lifelong safety 17

Treatment Goals LDL-C <130 mg/dl or half of highest LDL-C Non-HDL-C <145 mg/dl Triglycerides <150 mg/dl Cholesterol Absorption Inhibitors Ezetimibe Dosing: 10 mg once daily Mechanism of action: inhibits cholesterol absorption at the level of the level of the brush border of the small intestine via the sterol transporter. Leads to decreased delivery of cholesterol to the liver, reduction of hepatic cholesterol stores, and increased clearance of cholesterol from the blood Overall effect is a decrease in TC, LDL-C, triglycerides, Apo-B; Increases HDL-C No studies for use as monotherapy in children, use in addition to statin thearpy and dietary changes. Not currently approved in children. May be considered under the care of a lipid specialist. 18

Bile acid sequestrants Colesevelam is indicated as monotherapy or a with a statin in boys and postmenarchal girls > 10 years of age Forms: Tablet and oral solution; Dosing- 3.75 g once daily or 1.875 g twice daily Drug interactions: glyburide, levothyroxine, oral contraseptives, these should be dosed 4 hours before colevelam Mechanism of action: bind intestinal bile acids interrupting enterohepatic recirculation, more cholesterol converted into bile acids, decreases hepatic cholesterol pool and upregulates LDL receptors Adverse reaction: gas, bloating, constipation, cramps, headache Lowers LDL-C (12-25%), slight increase in HDL (4-5%), raises TG in some patients Fish Oil Commercially available; 1-4 g of EPA and DHA omega-3 fatty acids FDA approved preparation only approved in adults with TG > 500 mg/dl Lovaza Vascepa Mechanism of action: decreases hepatic fatty acid (FA) and triglyceride synthesis, while enhancing FA degradation/oxidation, stimulates VLDL clearance Effect: lowers TG, raises HDL-C, can see increase in LDL-C 19

Fish Oil Other possible effects: antiarrhythmic potential, heart rate lowering, blood pressure lowering, and antithrombotic effect 2 recent studies don t show conclusive benefit. RCT of omega 3 s in adolescents showed a minimal decrease in TG levels and no change in LDL particle number or size suggesting no significant benefit in combined dyslipidemia. Fibrates Fenofibrates, gemfibrozil Mechanism of action: Agonist for peroxisome proliferator-activated alpha nuclear receptors that up-regulate LPL and down regulate apoc-iii- both increasing the degradation of VLDL-C and TG. Hepatic synthesis of VLDL-C may also be decreased. Effect: lowers TG, raises HDL-C Not approved for pediatric patients. Use may be considered under the care of a clinical lipid specialist Adverse effects: Minor increase in liver transaminases, dyspepsia, diarrhea; Can cause myopathy when used alone, but increased incidence when gemfibrozil is combined with a statin Contraindications to use Hepatic or severe renal impairment Pre-existing gallbladder disease 20

Conclusion Atherosclerosis is a progressive disease related to the presence of risk factors therefore prevention and treatment of risk factors are important in decreasing the risk of early cardiovascular disease. Statins are first line therapy in familial hypercholesterolemia When unable to successfully treat with lifestyle modifications, statins are a logical first choice treatment for combined dyslipidemia References Daniels DR, Benuck I, Christakis DA, Gidding SS, et al. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents full report. National Heart Lung and Blood Institute, 2012. NIH Publication No. 12-7486 Kavey RE. Combined dyslipidemia in childhood. Journal of Clinical Lipidology 2015; S41-S56 Daniels DR, Benuck I, Christakis DA, Gidding SS, et al. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: Summary Report. Pediatrics 2011; 128; S213 Originally published online November 14, 2011; DOI: 10.542/peds.2009-2107C Berenson GS, Wattigney WA, Tracy RE, Newman WP, III, Srinivasan SR, Webber LS, Dalferes ER, Jr, Strong JP. Atherosclerosis of the aorta and coronary arteries and cardiovascular risk factors in persons aged 6 to 30 years and studied at necropsy (The Bogalusa Heart Study). Am J Cardiol 1992;70(9):851-858. Berenson GS, Srinivasan SR, Bao W, Newman WP, III, Tracy RE, Wattigney WA. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. N Engl J Med 1998;338(23):1650-1656. McGill HC, Jr., McMahan CA, Zieske AW, Malcom GT, Tracy RE, Strong JP. Effects of nonlipid risk factors on atherosclerosis in youth with a favorable lipoprotein profile. Circulation 2001;103(11): 1546-1550. Strong JP, Malcom GT, McMahan CA, Tracy RE, Newman WP, III, Herderick EE, Cornhill JF. Prevalence and extent of atherosclerosis in adolescents and young adults: implications for prevention from the Pathobiological Determinants of Atherosclerosis in Youth Study. JAMA 1999;281(8):727-735. Goldberg AC, Hopkins PN, Toth PP, Ballantyne CM, et al. Familial Hypercholesterolemia: Screening, diagnosis, and management of pediatric and adult patients. Clinical guidance from the National Lipid Association Expert panel on Familial Hypercholesterolemia. J Clinical Lipidology 2011; 5: 133-140. doi:10.1016/j.jacl.2011.03.001 Kwiterovich PO, Jr. Recognition and Management of dyslipidemia in children and adolescents. J Clin Endocrinol Metab 2008;93(11):4200-4209 McCrindle BW, Ose L, Marais AD. Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, randomized, placebo-controlled trial. J Pediatr 2003;143(1):74-80. 21

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