Will Obesity Increase the Proportion of Children and Adolescents Recommended for a Statin?
2013; Lippincott Williams & Wilkins; Volume: 128; Issue: 19 Linguagem: Inglês
10.1161/circulationaha.113.002411
ISSN1524-4539
AutoresBrian W. McCrindle, Pascal N. Tyrrell, Rae-Ellen W. Kavey,
Tópico(s)Lipoproteins and Cardiovascular Health
ResumoHomeCirculationVol. 128, No. 19Will Obesity Increase the Proportion of Children and Adolescents Recommended for a Statin? Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBWill Obesity Increase the Proportion of Children and Adolescents Recommended for a Statin? Brian W. McCrindle, MD, MPH, Pascal N. Tyrrell, PhD and Rae-Ellen W. Kavey, MD, MPH Brian W. McCrindleBrian W. McCrindle From the Department of Pediatrics, University of Toronto, Labatt Family Heart Centre, The Hospital for Sick Children, Toronto, Ontario, Canada (B.W.M., P.N.T.); and the Department of Pediatrics, University of Rochester Medical Center, Rochester, NY (R.-E.W.K.). , Pascal N. TyrrellPascal N. Tyrrell From the Department of Pediatrics, University of Toronto, Labatt Family Heart Centre, The Hospital for Sick Children, Toronto, Ontario, Canada (B.W.M., P.N.T.); and the Department of Pediatrics, University of Rochester Medical Center, Rochester, NY (R.-E.W.K.). and Rae-Ellen W. KaveyRae-Ellen W. Kavey From the Department of Pediatrics, University of Toronto, Labatt Family Heart Centre, The Hospital for Sick Children, Toronto, Ontario, Canada (B.W.M., P.N.T.); and the Department of Pediatrics, University of Rochester Medical Center, Rochester, NY (R.-E.W.K.). Originally published5 Nov 2013https://doi.org/10.1161/CIRCULATIONAHA.113.002411Circulation. 2013;128:2162–2165IntroductionNew Expert Panel Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents commissioned by the National Heart, Lung and Blood Institute (NHLBI) recommend universal lipid screening at 9 to 11 years of age and provide a comprehensive algorithm for evaluation and management of identified dyslipidemia.1 The universal screening can be performed with the child either nonfasting (measure total cholesterol and high-density lipoprotein cholesterol [HDL-C] levels, and calculate non-HDL cholesterol level) or fasting (full lipid profile with low-density lipoprotein cholesterol [LDL-C] and triglycerides). Targeted screening with a fasting lipid profile is recommended outside of universal screening for those children and adolescents with a positive family history of premature cardiovascular disease or events, or hyperlipidemia. Further evaluation and confirmation with fasting lipid profiles leads to initial management aimed at achieving optimal lifestyle behaviors, primarily a fat- and cholesterol-restricted diet. For those with persistent and significant lipid abnormalities, moderate- and high-level risk factors and risk conditions, including obesity, contribute to decision-making regarding initiation of lipid-lowering drug therapy at defined LDL-cholesterol cut points (Tables 1 and 2). Recent (2009–2010) National Health and Nutrition Examination Survey (NHANES) data indicate that 16.9% of American children ages 2 through 19 years are obese.2 Will the new guidelines result in an increased proportion of children and adolescents recommended for a statin, particularly among those who are obese?Table 1. Risk Factor Definitions for the Expert Panel Guidelines Dyslipidemia AlgorithmPositive family history of premature cardiovascular disease: myocardial infarction, angina, coronary artery bypass graft/stent/angioplasty, sudden cardiac death; before age 55 years in a parent, grandparent, aunt, or uncle; males aged <55 years, females aged <65 years*High-level risk factors:• Hypertension requiring drug therapy (systolic or diastolic blood pressure ≥ 99th percentile (%ile) + 5 mm Hg)• Current cigarette smoker• Body mass index ≥ 97th percentile• Presence of high-risk conditions*(Diabetes mellitus is also a high-level risk factor, but it is classified here as a high-risk condition to correspond with Adult Treatment Panel III recommendations for adults that diabetes mellitus be considered a cardiovascular disease equivalent.)Moderate-level risk factors:• Hypertension not requiring drug therapy• Body mass index ≥ 95th percentile, < 97th percentile• High density lipoprotein cholesterol (HDL-C) < 40 milligrams per decilitre• Presence of moderate-risk conditions*Adapted from Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: Summary Report. Pediatrics. 2011;128:S213–S256. Authorization for this adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation. HDL-C indicates high-density lipoprotein choleterol.*Data that were not available as part of the NHANES data collection.MethodsWe performed a cross sectional analysis of U.S. children ages 12 to 17 years who had fasting or nonfasting lipid measurement performed through NHANES data from 1999 to 2010.3 The results also provide information on blood pressure, smoking status, and body mass index (BMI). Calculation of the proportion of individuals who would be recommended for drug therapy based on the Expert Panel guidelines1 was performed, with the following modifications based on limitations of the NHANES data: (1) all categorizations regarding need for drug therapy were based on the available single fasting lipid profile measurement (the guideline algorithm is based on the average of 2 measurements); (2) the impact of lifestyle management was unknown (in the guideline recommendations, lipid therapy is only considered after a 6-month trial of lifestyle change); (3) data regarding family history of cardiovascular events/death and all risk conditions specified in guidelines were not available and, hence, not considered in assessment of the algorithm; and (4) current smoking as a risk factor was defined as a serum cotinine level ≥10 ng/mL.4 For comparison, we calculated the proportion recommended for drug therapy based on the previous guidelines from the National Cholesterol Education Program (NCEP) and the American Academy of Pediatrics (AAP).5,6 SAS version 9.3 (SAS Institute, Cary, NC) was used for all analyses using SAS Survey procedures to adjust for the complex sampling design of NHANES.ResultsScreeningThe unweighted response rate for NHANES participation over the surveys included ranged from 76% to 80%. The total population sample for children ages 12 to 17 years was 8861 participants for the 1999 through 2010 surveys. Of these, 692 participants were excluded from analysis by NHANES (nonresponse, ineligible). The primary lipid measure was a nonfasting lipid assessment, with a representative subsample requested for fasting lipid assessment (n=3505). Lipid data or height and weight were not available for 513 participants for the nonfasting group, leaving 4151 participants for analysis of nonfasting lipid values. Based on the screening recommendations from the Expert Panel guidelines to calculate non-HDL-C from non-fasting total cholesterol and HDL-C, 24.6% (95% confidence interval, 22.5–26.8%) of these participants would have been identified as having possible dyslipidemia (non–HDL-C ≥145 mg/dL or HDL-C <40 mg/dL) and required further evaluation with a fasting lipid profile.The Expert Panel guidelines also recommend that screening may be performed with a fasting lipid profile. This analysis used 3315 of the 3505 participants who had fasting lipid assessment, with 190 participants (6%) missing data in order of exclusion regarding height and weight (n=28), cotinine (n=48), blood pressure (n=80), or specific lipid variables (n=34). Based on screening with a fasting sample, 20.3% (95% confidence interval, 18.3–22.3%) of these participants met the non–HDL-C and HDL-C cut points defining dyslipidemia, and 6.5% (95% confidence interval, 5.4–7.6%) met the LDL-C cut point of ≥130 mg/dL, hence meeting criteria for further evaluation.ManagementThe algorithm for lipid management from the Expert Panel guidelines begins when a child or adolescent has an average LDL-C on ≥2 fasting lipid profiles of ≥130 mg/dL (95th percentile from normative data). Using the NHANES fasting subsample to represent this result, the weighted proportion of participants with a single fasting LDL-C ≥130 but <160 mg/dL was 5.2% (95% confidence interval, 4.2–6.1%), ≥160 but <190 mg/dL for 1.0% (0.5–1.4%) and ≥190 mg/dL for 0.4% (0.0–0.8%). For these participants, assuming no changes in the lipid profile on repeat fasting assessment, the algorithm would recommend a 6-month trial of lifestyle therapy using evidence-based recommendation specific to the pattern of dyslipidemia.If fasting LDL-C levels remain ≥130 mg/dL after the trial of lifestyle therapy, identified risk factors and risk conditions (Table 1) are combined with LDL-C results to determine additional therapeutic steps (Table 2). In the NHANES fasting subsample, the weighted proportion of participants with high-level cardiovascular risk factors included 0.2% (95% confidence interval, 0.0–0.3%) with blood pressure level at stage 2 hypertension cut points, 9.6% (8.1–11.2%) with cotinine evidence for current smoking, and 12.1% (10.4–13.9%) with a BMI ≥97th percentile. The proportion with moderate-level risk factors included 2.5% (95% confidence interval, 1.8–3.2%) with blood pressure level at stage 1 hypertension cut points, 13.4% (11.8–15.9%) with HDL-C <40 mg/dL, and 5.1% (4.0–6.1%) with BMI ≥95th but <97th percentile. Information on risk conditions is not available. Combining the LDL-C results with identified risk factors, and assuming that none of these participants with initial high LDL-C responded to lifestyle therapy, 0.85% (95% confidence interval, 0.4–1.3%) of children ages 12 to 17 years would meet criteria for initiation of a hydroxymethylglutaryl coenzyme A reductase inhibitor, or statin, as specified by the Expert Panel guideline algorithm (Table 2).Table 2. Expert Panel Recommendations for Initiation of Statin Therapy for Treatment of Dyslipidemia in Children and Adolescents, Adapted for the Data Available From NHANESInitiate statin therapy if, after 6 months of lifestyle therapy, the fasting lipid profile and current clinical status show the following:*• LDL-C ≥190 milligrams per deciliter†• LDL-C 160–189 milligrams per deciliter and one or more of the following:‡ - a positive family history of premature cardiovascular disease - at least one high-level risk factor or risk condition§ - two or more moderate-level risk factors/ risk conditions• LDL-C ≥130 to 159 milligrams per deciliter and one or more of the following:‡ - two or more high-level risk factors/ risk conditions - one high-level risk factor or risk condition with at least two moderate-level risk factors/ risk conditions - presence of clinical cardiovascular diseaseAdapted from Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: Summary Report. Pediatrics. 2011;128:S213–S256. Authorization for this adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation. LDL-C indicates low density lipoprotein cholesterol.*For children aged ≥10 years; children aged <10 years may be treated with lipid-lowering medication if they have a severe primary hyperlipidemia or a high-risk condition that is associated with serious medical morbidity.†Based on average of 2 fasting lipid profiles.‡After a trial of more intensive lifestyle therapy.§Information on risk conditions is not available from NHANES. High-level risk conditions are disease settings with clinical cardiac events before 30 years of age (chronic kidney disease, post heart transplantation, diabetes mellitus, Kawasaki disease with persistent coronary artery aneurysms). Moderate risk conditions are disease settings with known pathophysiologic evidence of accelerated atherosclerosis (chronic inflammatory disease [systemic lupus erythmatosus, juvenile inflammatory arthritis], HIV, nephrotic syndrome, Kawasaki disease with resolved coronary artery aneurysms).For comparison, the NCEP 1992 guidelines recommended drug therapy after a trial of lifestyle therapy if the LDL-C remained ≥190 mg/dL, or if the LDL-C remained ≥160 mg/dL with either a positive family history of premature cardiovascular disease or the presence of ≥2 other cardiovascular disease risk factors (cigarette smoking, elevated blood pressure, HDL-C <35 mg/dL, weight for height ≥95th percentile, diabetes mellitus, physical inactivity).5 Applying these criteria to the current NHANES dataset with its limitations, 0.5% (95% confidence interval, 0.1–0.9%) would be recommended for drug therapy. The AAP 2008 guidelines recommended drug therapy after a trial of lifestyle therapy if the LDL-C remained ≥190 mg/dL, or if the LDL-C remained ≥160 mg/dL with either a positive family history of premature cardiovascular disease or the presence of any other cardiovascular disease risk factor (cigarette smoking, hypertension, obesity), or if the LDL-C remained ≥130 mg/dL for those with diabetes mellitus.6 Applying these criteria to the current NHANES dataset, 1.0% (95% confidence interval, 0.4–1.5%) would be recommended for drug therapy.Stratified by BMI percentile category, statin therapy would be recommended for 0.6% (95% confidence interval, 0.1–1.1%) of those with BMI <95th percentile, none with BMI ≥95th but 99th percentile, 65% went on to have an adult BMI>35 kg/m2. In the longitudinal Cardiovascular Risk in Young Finns study, the presence of multiple cardiovascular risk factors in childhood and adolescence has been associated with multiple measures of subclinical atherosclerosis, independent of change in risk factor levels from adolescence to adulthood.15–17 These studies support the assertion that multiple risk factors present during youth greatly accelerate the atherosclerotic process.If the current epidemic of obesity continues, complete implementation of the Expert Panel guidelines will potentially result in a greater number of children with dyslipidemia recommended for medical therapy in the years to come. This increase would not be as a result of higher levels of LDL-C, except in the scenario where obesity-related metabolic changes unmask an underlying genetic dyslipidemia, such as familial combined dyslipidemia. LDL-C levels are minimally affected in obesity, and few obese children will be expected to meet criteria for a statin based on associated increases in LDL-C alone. Rather, the association of obesity with low HDL-C, hypertension, and insulin resistance and type 2 diabetes mellitus will qualify dyslipidemic obese children for statin therapy. Even still, the proportion meeting criteria for statin therapy remains very low, both overall and in obese children, and the great majority are recommended based on high LDL-C category without multiple risk factors, and would likely be reflective of an underlying genetic dyslipidemia.Universal screening would allow for earlier diagnosis and intervention for children with dyslipidemia secondary to lifestyle factors or genetics.18 Epidemiologic studies from the evidence review for the Expert Panel guidelines have suggested that low cardiovascular risk factor status entering adult life may be associated with significantly reduced cardiovascular mortality and increased longevity.19 Genetic natural history studies allow estimation of the effect of random allocation of alleles via Mendelian randomization. Since the Expert Panel guideline evidence review, several important studies of this kind have been published. In 2010, Cohen et al reported that for individuals with a PCSK9 nonsense mutation in whom LDL-C levels are a mean of 28% lower than the general population, the risk for coronary heart disease was reduced by >80%; this has been confirmed by others.20,21 In 2012, Ference et al reported a meta-analysis of >300 000 individuals with polymorphisms in 6 genes resulting in lower LDL-C. Naturally random allocation to long-term lower LDL-C exposure was associated with a 54.5% reduction in the risk of coronary heart disease for each mmol/L lower LDL-C.22 This represents a 3-fold greater reduction in the risk of coronary heart disease compared with statin treatment started later in life. These studies support the benefit of a lifetime of low risk related to lower LDL-C levels. It has been suggested that this benefit may also be achieved by the early identification and treatment of elevated LDL-C.23 Evidence to conclusively support this will be difficult to achieve in the absence of a decades-long event-driven clinical trial.Universal lipid screening and treatment of identified children with dyslipidemia using the risk-adjusted Expert Panel guidelines would result in a potentially important improvement in cardiovascular risk and a decrease in subsequent disease with a large cost to the health care system. It remains to be seen whether this would be justified by savings in overall health care costs generated by a population of healthier adults.DisclosuresBrian McCrindle is a consultant for Bristol Myers Squibb, Merck, and Eli Lilly, is on the Data and Safety Monitoring Board of Medpace, and has received research support from Schering Plough and Astra Zeneca. The other authors report no conflicts. All of the authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.FootnotesCorrespondence to Brian W. McCrindle, MD, MPH, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. E-mail [email protected]References1. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: Summary report.Pediatrics. 2011; 128Suppl 5:S213–256.CrossrefMedlineGoogle Scholar2. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity and trends in body mass index among US children and adolescents, 1999-2010.JAMA. 2012; 307:483–490.CrossrefMedlineGoogle Scholar3. Centers for Disease Control and Prevention. National Health and Nutrition Examination Survey.[cited 2012 January 25]; Available from: http://www.cdc.gov/nchs/nhanes/htm.Google Scholar4. Benowitz NL, Kuyt F, Jacob P, Jones RT, Osman AL. 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Universal versus targeted blood cholesterol screening among youth: The CARDIAC project.Pediatrics. 2010; 126:260–265.CrossrefMedlineGoogle Scholar19. Stamler J, Stamler R, Neaton JD, Wentworth D, Daviglus ML, Garside D, Dyer AR, Liu K, Greenland P. Low risk-factor profile and long-term cardiovascular and noncardiovascular mortality and life expectancy: findings for 5 large cohorts of young adult and middle-aged men and women.JAMA. 1999; 282:2012–2018.CrossrefMedlineGoogle Scholar20. Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.N Engl J Med. 2006; 354:1264–1272.CrossrefMedlineGoogle Scholar21. Benn M, Nordestgaard BG, Grande P, Schnohr P, Tybjaerg-Hansen A. PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses.J Am Coll Cardiol. 2010; 55:2833–2842.CrossrefMedlineGoogle Scholar22. 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November 5, 2013Vol 128, Issue 19 Advertisement Article InformationMetrics © 2013 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.113.002411PMID: 24190936 Manuscript receivedMarch 4, 2013Manuscript acceptedAugust 30, 2013Originally publishedNovember 5, 2013 Keywordsobesityhypercholesterolemiastatins, HMG-CoApediatricshypercapniaPDF download Advertisement
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