TECHNICAL REPORT ManagementofType2DiabetesMellitusinChildrenand Adolescents abstract ·...

TECHNICAL REPORT

Management of Type 2 Diabetes Mellitus in Children andAdolescents

abstractOBJECTIVE: Over the last 3 decades, the prevalence of childhood obe-sity has increased dramatically in North America, ushering in a varietyof health problems, including type 2 diabetes mellitus (T2DM), whichpreviously was not typically seen until much later in life. This technicalreport describes, in detail, the procedures undertaken to develop therecommendations given in the accompanying clinical practice guide-line, “Management of Type 2 Diabetes Mellitus in Children and Ado-lescents,” and provides in-depth information about the rationale forthe recommendations and the studies used to make the clinicalpractice guideline’s recommendations.

METHODS: A primary literature search was conducted relating to thetreatment of T2DM in children and adolescents, and a secondary lit-erature search was conducted relating to the screening and treatmentof T2DM’s comorbidities in children and adolescents. Inclusion criteriawere prospectively and unanimously agreed on by members of thecommittee. An article was eligible for inclusion if it addressed treat-ment (primary search) or 1 of 4 comorbidities (secondary search) ofT2DM, was published in 1990 or later, was written in English, andincluded an abstract. Only primary research inquiries were consid-ered; review articles were considered if they included primary data oropinion. The research population had to constitute children and/oradolescents with an existing diagnosis of T2DM; studies of adultpatients were considered if at least 10% of the study populationwas younger than 35 years. All retrieved titles, abstracts, andarticles were reviewed by the consulting epidemiologist.

RESULTS: Thousands of articles were retrieved and considered in bothsearches on the basis of the aforementioned criteria. From those, inthe primary search, 199 abstracts were identified for possible inclu-sion, 58 of which were retained for systematic review. Five of thesestudies were classified as grade A studies, 1 as grade B, 20 as gradeC, and 32 as grade D. Articles regarding treatment of T2DM selectedfor inclusion were divided into 4 major subcategories on the basis oftype of treatment being discussed: (1) medical treatments (32 stud-ies); (2) nonmedical treatments (9 studies); (3) provider behaviors (8studies); and (4) social issues (9 studies). From the secondary search,an additional 336 abstracts relating to comorbidities were identifiedfor possible inclusion, of which 26 were retained for systematic re-view. These articles included the following: 1 systematic review ofliterature regarding comorbidities of T2DM in adolescents; 5 expert

Shelley C. Springer, MD, MBA, MSc, JD, Janet Silverstein,MD, Kenneth Copeland, MD, Kelly R. Moore, MD, Greg E.Prazar, MD, Terry Raymer, MD, CDE, Richard N. Shiffman,MD, Vidhu V. Thaker, MD, Meaghan Anderson, MS, RD, LD,CDE, Stephen J. Spann, MD, MBA, and Susan K. Flinn, MA

KEY WORDSchildhood, clinical practice guidelines, comanagement, diabetes,management, treatment, type 2 diabetes mellitus, youth

ABBREVIATIONSAAP—American Academy of PediatricsACE—angiotensin-converting enzymeADA—American Diabetes AssociationAHA—American Heart AssociationBG—blood glucoseCAM—complementary and alternative medicineCES-D—Center for Epidemiologic Studies Depression ScaleCVD—cardiovascular diseaseHbA1c—hemoglobin A1cLDL-C—low-density lipoprotein cholesterolPCP—primary care providerQDS—Quality Data SetRCT—randomized controlled trialT1DM—type 1 diabetes mellitusT2DM—type 2 diabetes mellitus

This document is copyrighted and is property of the AmericanAcademy of Pediatrics and its Board of Directors. All authorshave filed conflict of interest statements with the AmericanAcademy of Pediatrics. Any conflicts have been resolved througha process approved by the Board of Directors. The AmericanAcademy of Pediatrics has neither solicited nor accepted anycommercial involvement in the development of the content ofthis publication.

The guidance in this report does not indicate an exclusivecourse of treatment or serve as a standard of medical care.Variations, taking into account individual circumstances, may beappropriate.

All technical reports from the American Academy of Pediatricsautomatically expire 5 years after publication unless reaffirmed,revised, or retired at or before that time.

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opinions presenting global recommendations not based on evidence; 5 cohort studies reporting natural history of diseaseand comorbidities; 3 with specific attention to comorbidity patterns in specific ethnic groups (case-control, cohort, andclinical report using adult literature); 3 reporting an association between microalbuminuria and retinopathy (2 case-control,1 cohort); 3 reporting the prevalence of nephropathy (cohort); 1 reporting peripheral vascular disease (case series); 2discussing retinopathy (1 case-control, 1 position statement); and 3 addressing hyperlipidemia (American Heart Associationposition statement on cardiovascular risks; American Diabetes Association consensus statement; case series). A breakdownof grade of recommendation shows no grade A studies, 10 grade B studies, 6 grade C studies, and 10 grade D studies. Withregard to screening and treatment recommendations for comorbidities, data in children are scarce, and the availableliterature is conflicting. Therapeutic recommendations for hypertension, dyslipidemia, retinopathy, microalbuminuria, anddepression were summarized from expert guideline documents and are presented in detail in the guideline. The referencesare provided, but the committee did not independently assess the supporting evidence. Screening tools are provided in theSupplemental Information. Pediatrics 2013;131:e648–e664

INTRODUCTION

This technical report details the pro-cedures undertaken to develop therecommendations given in the accom-panying clinical practice guideline,“Management of Type 2 Diabetes Melli-tus in Children and Adolescents.” Whatfollows is a description of the process,including the committee’s objectives;methods of evidence identification, re-trieval, review, and analysis; and sum-maries of the committee’s conclusions.

Statement of the Issue

Over the last 3 decades, type 2 diabetesmellitus (T2DM), a disease previouslyconfined to adult patients, has mark-edly increased in prevalence amongchildren and adolescents. Currently, inthe United States, approximately 1 in 3new cases of diabetes mellitus diag-nosed in patients younger than 18 yearsis T2DM,1,2 with a disproportionate re-presentation in ethnic minorities,3,4

especially among adolescents.5 Thistrend is not limited to the United Statesbut is occurring internationally aswell.6

The rapid emergence of childhood T2DMposes challenges to the physician who isunequipped to treat adult diseases en-countered in children. Most diabetestraining and educational materialsdesigned for pediatric patients addresstype 1 diabetes mellitus (T1DM) and em-phasize insulin treatment and glucose

monitoring, which may or may not beappropriate for children with T2DM.7,8

Most medications used for T2DM havebeen tested for safety and efficacy onlyin individuals older than 18 years, andthere is scant scientific evidence foroptimal management of children withT2DM.9,10 Extrapolation of data fromadult studies to pediatric populationsmay not be valid because the hormonalmilieu of the prepubescent and pubes-cent patient with T2DM can affecttreatment goals and modalities in waysheretofore unencountered in adultpatients.11

The United States has a severe shortageof pediatric endocrinologists, makingaccess to these specialists difficult or, insome cases, impossible.12 Vast geo-graphic areas lack a pediatric endo-crinologist: in 2011, 3 states had nopediatric endocrinologists, and 22 hadfewer than 10, and the situation is un-likely to improve in the near future.13 In2004, the National Association of Child-ren’s Hospitals and Related Institutionsperformed a workforce survey andfound that patients had to wait almost9 weeks for an appointment to see anendocrinologist.14 Because the numberof patients with T1DM and T2DM hasincreased since then, this situation ispresumably worse today. Regardless oftheir age, most patients in the UnitedStates who have T2DM are cared forby primary care providers (PCPs).15

Furthermore, given the expected in-creases in the national and global inci-dence of T2DM and the near impossibilitythat the pediatric endocrine workforcewill increase proportionately, PCPs mustbe prepared for and capable of managingchildren and adolescents who have un-complicated T2DM.

Numerous experts have argued thatthe ideal care of a child with T2DM isprovided through a team approach,with care shared among a pediatricendocrinologist, diabetes nurse edu-cator, nutritionist, and behavioral spe-cialist.16–18 In areas of limited access topediatric endocrinologists, however,contact with the pediatric endocri-nology team might involve contact atdiagnosis for initial diabetes educa-tion and intermittently thereafter;annually, with interval care by a PCPand interval communication with thepediatric endocrinology team; or atevery visit, for those patients whoare either doing poorly or are takinginsulin.

In areas where access to subspecialistsis hampered by geographic distancesand/or professional shortages, careprovided by local generalists who areskilled in treating children and youthwith T2DM is likely to improve access tomedical care. Although there are nopediatric studies evaluating this issue,the committee believes that this im-proved access to care might result in:

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� Reduced wait times and increasedtimeliness of care.

� Reduced economic burden to thepatient, including reduced need totravel and reduced time lost fromwork and/or school.

� Potentially improved patient reten-tion. Kawahara et al19 reportedthat 56.9% of patients with T2DMstopped coming to their hospitaldiabetes clinic appointments, mostcommonly because they were “toobusy” to keep their appointments.

Recent advances in medical technol-ogy have the potential to amelioratelimited access to specialists. Reportingon the provision of clinical specialtydiabetes care to remote locations usingtelemedicine, Malasanos et al20 foundthat weekly telemedicine clinics wereable to effectively replace quarterlyface-to-face clinics after an initial face-to-face clinic visit. This more frequentcontact provided by the telemedicineclinics resulted in improved hemoglo-bin A1c (HbA1c) concentrations, betterpatient satisfaction, fewer days missedfrom work or school, more time spentwith the patient during clinic visits,and fewer subsequent hospitalizationsand emergency department visits. Tele-medicine is costly, however, andrequires equipment to be in place atboth the subspecialist’s office and theremote clinic; it is, therefore, not ap-propriate for every practice. It is pos-sible that a similar model of servicecould be provided by a generalistworking locally and in close commu-nication with a specialist.

For family physicians and others whocare for adult patients, managing T2DMin children poses potential challenges.The first is that what works for adultsmay not work for children. Experiencesand results observed in adults do notnecessarily apply to children. Children(and even adolescents) are not smalladults; they have a changing hormonal

environment, have differences in phy-siology, and their growth can haveeffects on medication doses, toxicity,and responses.11 As a result, general-ists who are confident in caring foradults with diabetes may attempt toapply adult practice experiences tochildren, in whom these may not nec-essarily be appropriate. Kaufman citeddata on various drugs’ effects in chil-dren and argued that harm may occurif children with T2DM are treated likeadults with T2DM.11 The author calledfor treatment trials for children withT2DM, to “better define the risk-benefitratio in children and youth, since thismay differ substantially from that inthe adult type 2 diabetic population.” Incontrast, others have noted that mostadolescents with T2DM are similar toadults in terms of size and reproduc-tive maturity and argued that, in theabsence of studies specifically targetedto adolescents, treatment regimenscan be extrapolated from studies ofadults with T2DM; they do agree, how-ever, that more randomized controlledtrials (RCTs) are needed in the pedi-atric population.1

A second challenge is presented by theconflicting evidence regarding out-comes in patients with diabetes whoare managed by generalists versussubspecialists. Some studies in adultpatients indicate that generalists arecapable of achieving outcomes similarto those of subspecialists. Greenfieldet al21 observed that physiologic andfunctional status (ie, physical, psy-chological, social functioning) weresimilar at both 2 and 4 years andmortality was similar at 7 years inadult hypertensive patients with di-abetes treated in multispecialty groupsversus health maintenance organiza-tion general practices. Other studiesindicate that generalists may achieveoutcomes similar to those of diabetesspecialists, as long as they have inputfrom subspecialists.

Indeed, unlike diseases in several otherspecialties, care for children with di-abetes that is conducted by generalistswithout input from specialists may beinferior to that provided by specialists.Ziemer et al22 used an RCT design toexamine the effect of providing 5minutes of direct feedback from anendocrinologist to a PCP every 2weeks. Performance in the feedbackgroup was sustained after 3 years, andperformance decayed in a comparisongroup that received computer-generateddecision support reminders, includinga flow-sheet section showing previousclinical data and a recommendationssection. Specialist feedback contrib-uted independently to intensificationof diabetes management. In addition,“clinical inertia” (defined as failure byproviders to intensify pharmacologictherapy for hyperglycemia) was morelikely in a primary care versus a di-abetes clinic setting (91% vs 52%) andresulted in higher HbA1c concentra-tions among patients.23

How these observations might be ap-plied to the child who has T2DM is notentirely clear, but they suggest thatregular, direct contact between thegeneralist and a specialist can have apositive outcome on these patients. DeBerardis et al24 reported that, com-pared with adult patients with diabetesmellitus who were seen in generalpractice offices, patients cared for indiabetes clinics were more likely toconform with process-of-care mea-sures, including HbA1c concentrations,blood pressure, total cholesterol andlow-density lipoprotein cholesterol(LDL-C) levels, microalbuminuria test-ing, and foot and eye examinations andwere more likely to have adequateconcentrations of total cholesterol. Nodifferences were found in glycemic,blood pressure, or LDL-C control, how-ever. In that same study, all process-of-care measures improved when thepatient was seen by a single physician


as opposed to being seen by severaldifferent physicians. No similar studieshave been performed in children, andit is therefore unknown whether simi-lar outcomes can be achieved in thepediatric population.

A third challenge is presented by thefact that children with T2DM areoverrepresented among racial andethnic minority populations and aremore likely to be living in poverty;therefore, they may face significantchallenges in accessing specialists, evenunder the best situations.25 Recognizingthese barriers to care and patients’real-world needs, it is the committee’sconsensus that it is impractical to ex-pect every patient with T2DM to be ableto access a pediatric endocrinologist ona regular basis. It is also unreasonableto assume that these visits will be fre-quent enough to provide the level ofcare needed to maintain the best pos-sible metabolic control. For this reasonalone, PCPs must have a thoroughknowledge of the management of T2DM,including its unique aspects related tochildhood and adolescence.

The committee also believes it is thePCP’s responsibility to obtain the re-quisite skills for such care and to com-municate and work closely with adiabetes team of subspecialists when-ever possible. For this reason, whentreatment goals are not met, the com-mittee encourages clinicians to consultwith an expert trained in the care ofchildren and adolescents with T2DM.When first-line therapy fails (eg, metfor-min), recommendations for intensifyingtherapy should be generally the samefor pediatric and adult populations. Thepicture is constantly changing, however,as new drugs are being introduced, andsome drugs that initially seemed to besafe exhibit adverse effects with wideruse. Clinicians should, therefore, remainalert to new developments in this area.Seeking the advice of an expert canhelp ensure that the treatment goals are

appropriately set and that cliniciansbenefit from cutting-edge treatment in-formation in this rapidly changing area.

Stated Objective of the AmericanAcademy of Pediatrics

Because the PCP caring for childrenwill likely encounter T2DM, the Amer-ican Academy of Pediatrics (AAP), thePediatric Endocrine Society, theAmerican Academy of Family Physi-cians, the American Diabetes Associ-ation (ADA), and the American DieteticAssociation undertook a cooperativeeffort to develop clinical guidelines forthe treatment of T2DM in children andadolescents, for the benefit of subspe-cialists and generalists alike. Represen-tatives from these groups collaborated ondeveloping an evidence profile thatserved as a major source of informationfor the accompanying clinical practiceguideline recommendations. This re-port, based on a review of the currentmedical literature covering a periodfrom January 1, 1990, to July 1, 2009,provides a set of evidence-based guide-lines for the management and treatmentof T2DM in children and adolescents.

It should be noted that, becausechildhood T2DM is a relatively recentmedical phenomenon, there is a pau-city of evidence for many or most ofthe recommendations provided in theaccompanying guideline. Committeemembers have made every effort todemarcate in the guideline those ref-erences that were not identified in theoriginal literature search and are notincluded in this technical report. Al-though provided for the reader’s in-formation, these references notidentified in the literature search didnot affect or alter the level of evidencefor specific recommendations.

Composition of the Committee

The ad hoc multidisciplinary commit-tee was cochaired by 2 pediatricendocrinologists pre-eminent in their

field and included experts in generalpediatrics, family medicine, nutrition,Native American health, epidemiology,and medical informatics. All panelmembers reviewed the AAP Policy onConflict of Interest and Voluntary Dis-closure and declared all potentialconflicts.

Definitions

� Children and adolescents: patients≥10 and ≥18 years of age.

� Childhood T2DM: disease in thechild who typically: is obese (BMI≥85th to 94th percentile and>95th percentile for age and gen-der, respectively); has a strongfamily history of T2DM; has sub-stantial residual insulin secretorycapacity at diagnosis (reflected bynormal or elevated insulin and C-peptide concentrations); has insidi-ous onset of disease; demonstratesinsulin resistance (including clinicalevidence of polycystic ovarian syn-drome or acanthosis nigricans);and lacks evidence of diabetic auto-immunity. These patients are morelikely to have hypertension and dys-lipidemia than those with T1DM.

� Hyperglycemia: definition as ac-cepted by the ADA. Specifically: fast-ing blood glucose (BG) concentration>126 mg/dL, random or 2-hour post-Glucola (Ames Co, Elkhart, IN) BGconcentration >200 mg/dL.

� Clinician: any provider within his orher scope of practice; includes med-ical practitioners (including physi-cians and physician extenders),dietitians, psychologists, and nurses.

� Comorbidities: specifically limited tocardiovascular disease (CVD), hyper-tension, dyslipidemias and hypercholes-terolemias, atherosclerosis, peripheralneuropathy, retinopathy, and nephro-pathy (microvascular and macrovas-cular). Obesity was considered aprediabetic condition and was specif-ically excluded.




� Diabetes: according to the ADA cri-teria, defined as:

1. HbA1c concentration ≥6.5%(test performed in an appropri-ately certified laboratory); or

2. Fasting (defined as no caloricintake for at least 8 hours)plasma glucose concentration≥126 mg/dL (7.0 mmol/L); or

3. Two-hour plasma glucose con-centration ≥200 mg/dL (11.1mmol/L) during an oral glucosetolerance test (test performedas described by the WorldHealth Organization by usinga glucose load containing theequivalent of 75 g of anhydrousglucose dissolved in water); or

4. A random plasma glucose con-centration ≥200 mg/dL (11.1mmol/L) with symptoms of hy-perglycemia.

(In the absence of unequivocal hy-perglycemia, criteria 1–3 should beconfirmed by repeat testing.)

� Diabetic ketoacidosis: the absoluteor relative insulin deficiency result-ing in fat breakdown with resultantformation of β-hydroxybutyrateand accompanying acidosis. Symp-toms include nausea, vomiting,Kussmaul respirations, dehydra-tion, and altered mental status.

� Fasting BG: BG concentration ob-tained before the first meal of theday and after a fast of at least 8hours.

� Glucose toxicity: the effect of highBG causing both insulin resistanceand impaired β-cell production ofinsulin.

� Intensification: increasing frequencyof BG monitoring and adjustment ofthe dose and type of medication todecrease BG concentrations.

� Intercurrent illnesses: febrile ill-nesses or associated symptomssevere enough to cause the patient

to stay home from school and/orseek medical care.

� Microalbuminuria: albumin-to-creatinine ratio ≥30 mg/g creati-nine but <300 mg/g creatinine.

� Moderate hyperglycemia: BG con-centration of 180 to 250 mg/dL.

� Moderate to vigorous exercise: ex-ercise that makes the individualbreathe hard and perspire andwhich raises his or her heart rate.An easy way to define exercise in-tensity for patients is the “talktest”: during moderate physical ac-tivity a person can talk but notsing. During vigorous activity, a per-son cannot talk without pausing tocatch a breath.

� Obese: BMI ≥95th percentile forage and gender.

� Overweight: BMI between 85th and94th percentile for age and gender.

� Prediabetes: Fasting plasma glu-cose concentration ≥100 to 125mg/dL or 2-hour glucose concen-tration during an oral glucose tol-erance test ≥126 mg/dL but <200mg/dL or HbA1c of 5.7% to 6.4%.

� Severe hyperglycemia: BG concen-tration >250 mg/dL.

� Thiazolidinediones: oral hypoglyce-mic agents that exert their effectat least in part by activation of theperoxisome proliferator-activatedreceptor-γ.

� T1DM: diabetes secondary to auto-immune destruction of β-cellsresulting in absolute (complete ornear complete) insulin deficiencyand requiring insulin injectionsfor management.

� T2DM: The investigators’ designa-tion of the diagnosis was usedfor the purposes of the literaturereview. The committee acknowl-edges that the distinction betweenT1DM and T2DM in this populationis not always clear-cut, and clinical

judgment plays an important role.Typically, this diagnosis is madewhen hyperglycemia is secondaryto insulin resistance accompaniedby impaired β-cell function, result-ing in inadequate insulin productionto compensate for the degree of in-sulin resistance.

� Youth: used interchangeably with“adolescent” in this document.

FORMULATION AND ARTICULATIONOF THE QUESTION ADDRESSED BYTHE COMMITTEE

The committee first formulated explicitquestions for which evidence would bequeried by the epidemiologist. Specificclinical questions addressed by thecommittee included: (1) the effective-ness of treatment modalities for T2DMin children and adolescents; (2) theefficacy of pharmaceutical therapiesfor treatment of children and adoles-cents with T2DM; (3) appropriaterecommendations for screening forcomorbidities typically associated withT2DM in children and adolescents; and(4) treatment recommendations forcomorbidities of T2DM in children andadolescents.

These recommendations pertain spe-cifically to patients at least 10 butyounger than 18 years of age withT2DM. Although the distinction be-tween T1DM and T2DM in children maybe difficult,26,27 for purposes of thisreport, the definition of childhood T2DMincludes the child who typically isoverweight or obese (defined as havinga BMI ≥85th to 94th percentile and>95th percentile for age and gender,respectively); has a strong family his-tory of T2DM; has substantial residualinsulin secretory capacity at diagnosis(reflected by normal or elevated insulinand C-peptide concentrations); has in-sidious onset of disease; demonstratesinsulin resistance (including clinicalevidence of polycystic ovarian syndromeor acanthosis nigricans); and lacks


evidence of diabetic autoimmunity (neg-ative for autoantibodies typically associ-ated with T1DM). Patients with T2DM aremore likely to have hypertension anddyslipidemia than are those with T1DM.

Methods

Primary Literature Search: Treatmentof T2DM

The committee unanimously agreed onthe objectives of the guideline andscope of the evidence search. A pri-mary literature search was conductedby the consulting epidemiologist, usingthe strategy as described in the fol-lowing text.

An article was eligible for inclusion if itaddressed treatment of T2DM, waspublished in 1990 or later, was writtenin English, and included an abstract.Only primary research inquiries wereconsidered; review articles were con-sidered if they included primary dataor opinion. Children and/or adolescentswith an existing diagnosis of T2DMwererequired to constitute the researchpopulation; studies of adult patientswere considered if ≥10% of theirpopulation was younger than 35 years.

The electronic databases PubMed, Co-chrane Collaboration, and Embase weresearched using the following MedicalSubject Headings, alone and in variouscombinations: diabetes, mellitus, type 2,type 1, treatment, prevention, insipidus,diet, pediatric, T2DM, T1DM, non–insulindependent diabetes mellitus (NIDDM),metformin, lifestyle, RCT, meta-analysis,child, adolescent, therapeutics, control,adult, obese, gestational, polycysticovary syndrome, metabolic syndrome,cardiovascular, dyslipidemia, men, andwomen. In addition, the Boolean oper-ators NOT, AND, and OR were used withthe aforementioned terms, also in vari-ous combinations. Search limits in-cluded clinical trial, meta-analysis,randomized controlled trial, review,child: 6–12 years, and adolescent: 13–18years.

Reference lists of identified articleswere searched for additional studiesusing the same criteria for inclusionenumerated earlier. Finally, articlespersonally known to members of thecommittee that were not identified byother means were submitted forconsideration and were included ifthey fulfilled the inclusion criteria.

A total of 196 articles were identifiedby using these search criteria. Ofthose, 58 were accepted as evidencefor the guideline, and 138 were re-jected as not meeting all require-ments. A summary evidence table forthe accepted articles can be found inSupplemental Information A.

Secondary Literature Search:Comorbidities of T2DM

After completion of the primary liter-ature review, at the request of thecommittee, a second literature reviewwas conducted to identify evidencerelating to screening, diagnosis, andtreatment of comorbidities of T2DM inchildren and adolescents. Similar toinclusion criteria for the primary re-view, an article relating to comorbid-ities was eligible for inclusion if it waspublished in 1990 or later, was writtenin English, and included an abstract.Again, only primary research inquirieswere considered; review articles wereconsidered if they included primarydata or opinion. Children and/or ado-lescents in whom either T1DM or T2DMwas diagnosed were required to con-stitute the research population; stud-ies of adult patients were considered if≥10% of the population was youngerthan 35 years. The focus of the re-search article must be hyperlipidemia,microalbuminuria, retinopathy, or“comorbidities of diabetes mellitus.”

The electronic databases PubMed,Cochrane Collaboration, and Embasewere searched using the followingMedical Subject Headings, alone andin various combinations: diabetes,

mellitus, type 2, type 1, pediatric, T2DM,T1DM, NIDDM, hyperlipidemia, retino-pathy, microalbuminuria, comorbid-ities, screening, RCT, meta-analysis,child, and adolescent. In addition, theBoolean operators NOT, AND, and ORwere used with the aforementionedterms, also in various combinations.Search limitations included clinicaltrial, meta-analysis, randomized con-trolled trial, review, child: 6–12 years,and adolescent: 13–18 years. Refer-ence lists of identified articles weresearched for additional studies, withthe use of the same criteria for in-clusion enumerated earlier. Finally,articles personally known to mem-bers of the committee that were notidentified by other means were sub-mitted for consideration and wereincluded if they fulfilled the inclusioncriteria.

A total of 75 articles were identified byusing these search criteria. Of those,26 were accepted as evidence for theguideline, and 49 were rejected as notmeeting all requirements. A summaryevidence table for the acceptedcomorbidity articles can be found inSupplemental Information B.

Analysis of Available Evidence

A strict evidence-based approach wasused to extract data used to developthe recommendations presented in theaccompanying clinical practice guide-line. Individual articles meeting theprospective search criteria were crit-ically appraised for strength ofmethodology, and they were assignedan evidence level grade on the basis ofguidelines published by the Universityof Oxford’s Centre for Evidence-basedMedicine, which are synthesized in thenext discussion.28

Levels of Evidence (Based onMethodology)

� Level 1A: Systematic review withhomogeneity of included RCTs.




� Level 1B: Individual RCT with nar-row CI and >80% follow-up.

� Level 2A: Systematic review withhomogeneity of cohort studies.

� Level 2B: Individual cohort study,follow-up of untreated controls inan RCT, or low-quality RCT (ie, lessthan 80% follow-up).

� Level 2C: “Outcomes research.”

� Level 3A: Systematic review with ho-mogeneity of case-control studies.

� Level 3B: Individual case-controlstudies.

� Level 4: Case series; poor-quality co-hort and/or case-control studies.

� Level 5: Expert opinion without ex-plicit critical appraisal or based onphysiology, bench research, or“first principles.”

Grades of Evidence Supporting theRecommendations

The AAP policy statement, “ClassifyingRecommendations for Clinical Prac-tice Guidelines,” was followed in des-ignating grades of recommendation(Fig 1, Table 1), based on the levels ofavailable evidence. AAP policy stip-ulates that the evidence in support ofeach key action statement be pro-spectively identified, appraised, andsummarized and that an explicit linkbetween level of evidence and gradeof recommendation be defined.

Possible grades of recommendationsrange from A to D, with A being thehighest. Some qualification of thegrade is further allowed on the basisof subtle characteristics of the level ofsupporting evidence. The AAP policystatement is consistent with thegrading recommendations advancedby the University of Oxford’s Centre forEvidence-based Medicine. The AAPpolicy statement “Classifying Recom-mendations for Clinical PracticeGuidelines” offers further details.29

� Grade A: Consistent level 1 studies.(Examples include meta-analyses

with appropriate adjustments forheterogeneity, well-designed RCTs,or high-quality diagnostic studieson relevant populations.)

� Grade B: Consistent level 2 or level3 studies or extrapolations fromlevel 1 studies. (Examples includeRCTs or diagnostic studies withmethodologic flaws or performedin less relevant populations; con-sistent and persuasive evidencefrom well-designed observationaltrials.)

� Grade C: Level 4 studies or extrap-olations from level 2 or level 3studies. (Examples include poor-quality observational studies, in-cluding case-control and cohortdesign methodologies, as well ascase series.)

� Grade D: Level 5 evidence, or trou-blingly inconsistent or inconclusivestudies of any level. (Examples in-clude case reports, expert opinion,

reasoning from first principles, ormethodologically troubling studieswith questionable validity.)

� Level X: Not an explicit level of ev-idence as outlined by the Centrefor Evidence-based Medicine. Re-served for interventions that areunethical or impossible to test ina controlled or scientific fashion,in which the preponderance ofbenefit or harm is overwhelming,precluding rigorous investigation.

The relationship between grades ofevidence supporting recommendationsand recommended key action state-ments is depicted in Fig 1. Note that anygiven recommended key action state-ment may only be as strong as itssupporting evidence will allow.

Recommended Key Action Statements

After considering the available levelsof evidence and grades of recom-mendations, the committee formulated

FIGURE 1Evidence quality. Integrating evidence quality appraisal with an assessment of the anticipated balancebetween benefits and harms if a policy is carried out leads to designation of a policy as a strongrecommendation, recommendation, option, or no recommendation.

TABLE 1 Grades of Study According to Subdivision

Evidence Quality Medical Treatment Nonmedical Treatment Provider Behaviors Social Issues

A 4 1 0 0B 0 1 0 0C 4 3 7 6D 24 4 1 3


several recommended key action state-ments, published in the companionclinical practice guideline. As discussedpreviously, recommended key actionstatements vary in strength on the basisof the quality of the supporting evidence.

� Strong recommendation: The high-est level of recommendation, thiscategory is reserved for recom-mendations supported by grade Aor grade B evidence demonstratinga preponderance of benefit orharm. Interventions based on levelX evidence may also be categorizedas strong on the basis of theirrisk/benefit profile. A strong rec-ommendation in favor of a particu-lar action is made when theanticipated benefits of the recom-mended intervention clearly ex-ceed the harms (as a strongrecommendation against an actionis made when the anticipatedharms clearly exceed the benefits)and the quality of the supportingevidence is excellent. In someclearly identified circumstances,strong recommendations may bemade when high-quality evidenceis impossible to obtain and the an-ticipated benefits strongly out-weigh the harms. The implicationfor clinicians is that they shouldfollow a strong recommendationunless a clear and compelling ra-tionale for an alternative approachis present.

� Recommendation: A recommendedkey action statement is made whenthe anticipated benefit exceeds theharms but the evidence is not asmethodologically sound. Recom-mended key action statementsmust be supported by grade B orgrade C evidence; level X evidencemay also result in a recommenda-tion depending on risk/benefit con-siderations. A recommendation infavor of a particular action is madewhen the anticipated benefits exceed

the harms, but the quality of evi-dence is not as strong. Again, insome clearly identified circumstan-ces, recommendations may be madewhen high-quality evidence is impos-sible to obtain but the anticipatedbenefits outweigh the harms. Theimplication for clinicians is that theywould be prudent to follow a recom-mendation but should remain alertto new information and sensitive topatient preferences.

� Option: Option statements are of-fered when the available evidenceis grade D or the anticipated ben-efit is balanced with the potentialharm. Options define courses thatmay be taken when either the qual-ity of evidence is suspect or care-fully performed studies have shownlittle clear advantage to 1 approachover another. The implication forclinicians is that they should con-sider the option in their decision-making, and patient preferencemay have a substantial role.

� No recommendation: When pub-lished evidence is lacking, and/orwhat little evidence is availabledemonstrates an equivocal risk/benefit profile, no recommendedkey action can be offered. No rec-ommendation indicates that thereis a lack of pertinent published ev-idence and that the anticipatedbalance of benefits and harms ispresently unclear. The implicationfor clinicians is that they should bealert to new published evidencethat clarifies the balance of benefitversus harm.

Implementation Strategy

Implementing the guideline’s recom-mendations to improve care pro-cesses involves identifying potentialbarriers to the use of the knowledge,creating strategies to address thosebarriers, and selecting appropriatequality improvement methods (eg,

education, audit and feedback,computer-based decision support).

Computer-mediated decision supportoffers an implementation mode thathas been demonstrated to be effec-tive30 and that is expected to be ofincreasing relevance to pediatricianswith the adoption of electronic healthrecords. To facilitate translation of therecommendations into computablestatements, the guideline recommen-dations were transformed into declar-ative production rule (eg, IF-THEN)statements.31 The Key Action State-ments are displayed as productionrules in Supplemental Information C.The concepts required to describe an-tecedent and consequent clauses inthese rules were translated into thefollowing standardized coding systems:SNOMED-CT,32 RxNorm,33 and LOINC.34

In addition, the concepts described inthe guideline recommendations weretranslated, where possible, into ele-ments of the National Quality Forum’sQuality Data Set (QDS).35 The QDSprovides a framework from whichperformance measurement data canbe derived. The QDS is intended toserve as a standard set of reusabledata elements that can be used topromote quality measurement. EachQDS element includes a name, a qualitydata type that describes part of theclinical care process, quality data typespecific attributes, a standard code setname, and a code listing. The Methodsfor Developing the Guidelines sectiondisplays the relevant decision variablesand actions as well as coding in-formation. A QDS listing of decisionvariables and actions is provided inSupplemental Information D.

RESULTS

Primary Literature Search:Treatment of T2DM

Thousands of articles were retrievedand considered on the basis of theaforementioned criteria. From those,




199 abstracts were identified for pos-sible inclusion, and 58 were retainedfor systematic review. Results of theliterature review are presented in thefollowing text and listed in the evidencetables in the Supplemental Information.

Of the 58 articles retained for sys-tematic review, 5 studies were classi-fied as grade A studies, 1 as grade B,20 as grade C, and 32 as grade D.Articles regarding the treatment ofT2DM selected for inclusion were di-vided into 4 major subcategories on thebasis of type of treatment being dis-cussed: (1) medical treatments (32studies); (2) nonmedical treatments (9studies); (3) provider behaviors (8studies); and (4) social issues (9 stud-ies). Detailed information about thesearticles is presented in SupplementalInformation A. A graphic depiction ofthe grades of study according to sub-division is given in Table 1.

Rejected Articles

Of the 257 articles meeting searchcriteria, 199 were rejected, catego-rized as follows:

� Comorbidities: 69 studies. (Note: thesearticles were rejected within the con-text of the primary search string re-lating to treatment of T2DM. A secondprospective literature search wasconducted solely addressing comor-bidities, the results of which are pre-sented in the next section.)

� Medical treatment: 99 articles.

� Nonmedical treatment: 16 articles.

� Social issues: 12 articles.

� Provider behaviors: 3 articles.

To view the recommendations relatedto management of T2DM, please seethe accompanying clinical practiceguideline.36

Secondary Literature Search:Comorbidities of T2DM

Evidence is sparse in children andadolescents regarding the risks for

developing various comorbidities ofdiabetes that are well recognized inadult patients. Numerous reports havedocumented the occurrence of comor-bidities in adolescents with T2DM, butno randomized clinical trials have ex-amined the progression and treatmentof comorbidities in youth with T2DM.29

The evidence that does exist is con-tradictory with regard to both screen-ing and treatment recommendations.After applying the previously describedsearch criteria and screening to thou-sands of articles, an additional 336abstracts relating to comorbiditieswere identified for possible inclusion,of which 26 were retained for system-atic review. Results of this subsequentliterature review are presented inSupplemental Information E.

Articles discussing comorbidities ranthe gamut of study focus, type, level ofevidence, and grade of recommenda-tion. The 26 articles that met the re-vised objective criteria had thefollowing characteristics:

� Expert opinion global recommen-dations not based on evidence (5articles).

� Cohort studies reporting naturalhistory of disease and comorbid-ities (5 articles).

� Specific attention to comorbiditypatterns in specific ethnic groups(case-control, cohort, and clinicalreport by using adult literature: 3articles).

� Association between microalbu-minuria and retinopathy (2 case-control, 1 cohort: 3 articles).

� Prevalence of nephropathy (co-hort: 3 articles).

� Hyperlipidemia (American HeartAssociation [AHA] position state-ment on cardiovascular risks,ADA consensus statement, case se-ries: 3 articles).

� Retinopathy (1 case-control, 1 posi-tion statement: 2 articles).

� Peripheral vascular disease (caseseries: 1 article).

� Systematic review of literature re-garding comorbidities of T2DM inadolescents (1 article).

A graphic depiction of the grades ofrecommendation is given in Table 2.

Rejected Articles

A total of 310 articles did not meetprimary inclusion criteria and wererejected; details are presented inSupplemental Information F. Profilesof the rejected articles are:

� Articles relating to T1DM (125articles); specifically on the follow-ing topics:

▪ Retinopathy (42 articles).▪ Vascular complications (34articles).

▪ Nephropathy (29 articles).▪ Natural history and epidemiol-ogy of T1DM (8 articles).

▪ Hyperlipidemia (5 articles).▪ Risk factors for comorbidities(ie, ethnicity, puberty: 4 articles).

▪ Neuropathy (3 articles).

� Articles involving adults, practicemanagement issues, and othernonpertinent topics (118 articles).

� Articles about nondiabetic subjects,prediabetic subjects, or adults, in-cluding recommendations for testingfor conditions such as hyperlipide-mias and CVD (36 articles).

� Reviews, published trials, guide-lines, and position statements notmeeting criteria (19 articles).

� Studies addressing methods oftesting for comorbidities (12articles).

The initial search strategy for comor-bidities included patients diagnosedwith T1DM. The committee thus as-sumed that (with the exception of ini-tiating screening) the pattern ofcomorbidities—and the need to screenfor and treat them—would be similarbetween T1DM and T2DM. It was also


assumed that comorbidities would besimilar between pediatric and adultpatients, with length and severity ofdisease the driving factors. Duringthe search, articles addressing thefollowing themes were identified andreviewed:

� The pattern of comorbidities inT1DM versus T2DM and the roleof puberty (9 articles).

� Differences in comorbidity pat-terns in children with T2DM com-pared with adults (8 articles).

Although not included in the final list ofstudies, these articles are included inthe Supplemental Information be-cause they resulted in an alteration tothe original inclusion criteria. Theresults of these articles indicate thatthe pattern of comorbidities in chil-dren and adolescents with T2DM maynot resemble that of either T1DM pa-tients (possibly because of the influ-ence of puberty) or adults, as washypothesized by the committee whenidentifying the primary search para-meters. Accordingly, the search stringwas modified to include only childrenand adolescents with the diagnosis ofT2DM.

Recommendations RegardingComorbidities

Unlike T2DM in adult patients, data arescarce in children and adolescentsregarding the diagnosis, natural history,progression, screening recommenda-tions, and treatment recommendations.Numerous reports have documentedthe occurrence of comorbidities inadolescents with T2DM, but no RCTshave examined the progression andtreatment of comorbidities in youth withT2DM.

The available literature is conflictingregarding whether clinical signs ofpathology in adults are variants of nor-mal for adolescents, the role of pu-berty in diagnosis and progression ofvarious comorbidities, the screeningtests that should be performed andhow they should be interpreted, whenscreenings should be initiated, howoften screening should be performedand by whom, and how abnormalresults should be treated. Medicationscommonly prescribed in adult patientshave not been rigorously tested inchildren or adolescents for safety orefficacy. The peculiarities of the de-veloping adolescent brain, typicallifestyle, and social issues confoundissues of treatment effectiveness.

Despite the limited evidence available,the committee provides information onexpert recommendations for the fol-lowing selected comorbidities: hyper-tension, dyslipidemia, retinopathy,microalbuminuria, and depression.These therapeutic recommendationswere summarized from expert guide-line documents and are presented indetail in the following sections. Thereferences are provided, but thecommittee did not independently as-sess the supporting evidence. Samplescreening tools are provided in theSupplemental Information (see Sup-plemental Information H and I).

Hypertension

Hypertension is a significant comor-bidity associated with endothelial dys-function, vessel stiffness, and increasedrisk of future CVD and chronic kidneydisease for the child with diabetes.37,38

It is present in 36% of youth withT2DM within 1.3 years of diagnosis39

and was present in 65% of youth withT2DM enrolled in the SEARCH for Di-abetes in Youth Study (SEARCH study).40

Because development of CVD is asso-ciated with hypertension, recognitionand treatment of this comorbidity areessential, especially in youth with T2DM.

Unfortunately, health care providersunderdiagnose hypertension in childrenand adolescents (both with and withoutdiabetes), resulting in a lack of appro-priate treatment.41

Screening:

� Blood pressure should be measuredwith an appropriate-sized cuff andreliable equipment, monitored at ev-ery clinic visit, and plotted againstnorms for age, gender, and heightprovided in tables available at thefollowing Web site: http://www.nhlbi.nih.gov/guidelines/hypertension/child_tbl.htm42 or in “The FourthReport on the Diagnosis, Evaluation,and Treatment of High Blood Pres-sure in Children and Adolescents.”43

(See the Supplemental Informationfor the National Institutes of Healthtable.)

Treatment:

� Once a diagnosis of hypertensionis established, the clinician can in-stitute appropriate treatment,which might include lifestyle changeand/or pharmacologic agents. Al-though a complete discussion ofthis topic is beyond the scope ofthese guidelines, rational treatmentguidelines exist.43,44 In adult pa-tients with T2DM, concomitant treat-ment of hypertension has beenshown to improve microvascularand macrovascular outcomes atleast as much as control of BG con-centrations.45,46 Therefore, it is theconsensus of this committee thatsimilar benefits are likely with earlyrecognition and treatment of hyper-tension in the child or adolescentwith increased CVD risk secondaryto T2DM.47,48 The committee recom-mends appropriate surveillanceand therapy as outlined in “TheFourth Report on the Diagnosis,Evaluation, and Treatment of HighBlood Pressure in Children andAdolescents.”43

TABLE 2 Grades of Recommendation

Evidence Quality No. of Studies

A 0B 10C 6D 10




http://www.nhlbi.nih.gov/guidelines/hypertension/child_tbl.htm



� Initial treatment of blood pressureconsistently at, or above, the 95thpercentile on at least 3 occasionsshould consist of efforts at weightloss reduction, limitation of dietarysalt, and increased activity.

� If, after 6 months, blood pressureis still above the 95th percentilefor age, gender, and height, initia-tion of an angiotensin-convertingenzyme (ACE) inhibitor should beconsidered to achieve blood pres-sure values that are less than the90th percentile.

� If ACE inhibitors are not toleratedbecause of adverse effects (mostcommonly cough), an angiotensinreceptor blocker should be used.

� If adequate control of hypertensionis not achieved, referral to a physi-cian specialist trained in the treat-ment of hypertension in youth isrecommended.

Dyslipidemia

Long-term complications of T2DM inchildren and adolescents are not aswell documented as those found inadults. It should be noted that thepediatric experience with niacin andfibrates is limited. In a review, however,Pinhas-Hamiel and Zeitler49 noted thepresence of dyslipidemia in a sub-stantial proportion of young patientswith T2DM in various populationsworldwide. The SEARCH study foundthat 60% to 65% of 2096 youth withT2DM had hypertriglyceridemia, and73% had a low high-density lipopro-tein cholesterol level.50 Thus, althoughvariations exist in the criteria used fordefining hyperlipidemia, there is un-equivocal evidence that screening fordyslipidemia is imperative in pediatricpatients with T2DM.49,51,52 Hyperglyce-mia and insulin resistance may playa direct role in dyslipidemia, andcardiovascular risk is further en-hanced by the presence of other riskfactors, including obesity and a family

history of early CVD.49,53 The AHAclassifies T2DM as a tier 2 condition(moderate risk) in which acceleratedatherosclerosis has been documentedin patients younger than 30 years.51

The presence of 2 other risk factors,including obesity, smoking, familyhistory of CVD, and poor exercisehistory, can accelerate this status totier 1 (high risk), which is relevant tomany young patients with T2DM.

Screening:

� On the basis of current recommen-dations by the ADA and the AHA, atthe initial evaluation, all patientswith T2DM should have baselinelipid screening (after initial glyce-mic control has been established)consisting of a complete fastinglipid profile, with follow-up testingbased on the findings or every 2years thereafter, if initial resultsare normal.51–53 (See the Supple-mental Information for screeningtools.)

Treatment:

The committee suggests following theAHA position statement, “Cardiovas-cular Risk Reduction in High-riskPediatric Patients,” for managementof dyslipidemia.51 This position state-ment recommends:

� Evaluation and dietary educationby a registered dietitian for allpatients, with initiation of intensivetherapy and follow-up for patientswith a BMI >95th percentile.

� Lipid targets:○ LDL-C: Initial concentration ≥130mg/dL: nutritionist training withdiet <30% calories from fat,<7% calories from saturatedfat, cholesterol intake <200 mg/day, and avoidance of trans fats.LDL measurements should be re-peated after 6 months. If concen-trations are still 130 to 160 mg/dL,statin therapy should be initiated,

with a goal of <130 mg/dL andan ideal target of <100 mg/dL.

○ Triglycerides: If initial concentra-tions are between 150 and 600mg/dL, patients should decreaseintake of simple carbohydratesand fat, with weight loss man-agement for those who are over-weight. If levels are >700 to 1000mg/dL at initial or follow-up visit,fibrate or niacin should be con-sidered if the patient is olderthan 10 years because of in-creased risk of pancreatitis atthese concentrations.

� Control of hypertension, per guide-lines referenced previously.

� Intensification of management ofhyperglycemia.

� Assessment of parental smokinghistory and patient smoking his-tory if the patient is older than10 years; active antismoking coun-seling at every visit and referral toa smoking cessation program, ifrequired.

� Assessment of family history ofearly CVD along with current fam-ily lifestyle habits; a positive familyhistory increases the level of risk.

� Promotion of physical exercise andlimitation of sedentary activities.

Retinopathy

The eye has been called a uniquewindow into the neural and vascularhealth in patients with diabetes.54 Ret-inopathy is well documented in adults,both alone and in association withother comorbidities,55 but descriptionsof its frequency and associations withother comorbidities in youth are lim-ited. Some observational and case-control studies show that retinopathyin adolescents with T2DM is presentearlier than in adults, whereas othersindicate that it appears much later.56–60

The review by Pinhas-Hamiel andZeitler49 of complications of T2DM among


adolescents cited studies in which thediagnosis of retinopathy appeared tooccur strikingly early in the diseaseprocess. Two large studies in theJapanese population documented earlydevelopment of retinopathy in youngadults, some even before the diagnosisof diabetes mellitus. In a study of 1065patients diagnosed with T2DM before30 years of age, Okudaira et al57

reported the presence of retinopathyin 99 patients (9.3%) before the firstvisit. One hundred thirty-five patients(12.7%) developed proliferative reti-nopathy before 35 years of age, and 32(23.7%) of these patients were blindby a mean age of 32 years. Bronson-Castain et al54 used sophisticated tech-niques to evaluate the neural and vas-cular health of the retina and reporteda much higher incidence of focal reti-nal neuropathy, retinal thinning, andretinal venular dilation in a cohort of15 adolescent patients with T2DMmatched with 26 controls. Okudairaet al observed the development ofretinopathy in 394 patients diagnosedwith T2DM before 30 years of age. Ofthe 322 patients who were free of ret-inopathy at entry, 88 developed back-ground diabetic retinopathy over 5.7years, an incidence of 57.7 per 1000person-years. Fifty of the 160 patientswith background retinopathy developedproliferative retinopathy over 7.1 years,an incidence of 17.9 per 1000 person-years. Poor glycemic control, durationof disease, and high blood pressureseemed to be the primary risk factors.

Conversely, the study by Krakoff et al58

of 178 youth that used the propor-tional hazards model showed a lowerrisk for retinopathy in Pima Indians(compared with the Japanese studycited previously), even after adjustingfor glucose concentrations and bloodpressure. Similar results were reportedby Farah et al59 in 40 African Americanand Hispanic youth and by Karaboutaet al60 in 7 adolescent patients. It is

unclear whether these differences inresults arise from variations in studydesign, population demographic char-acteristics, and/or techniques used indiagnosis. Given the variability in theresults of epidemiologic studies andabsence of long-term data, the com-mittee considers it prudent for pro-viders to follow the ADA “Standards ofMedical Care in Diabetes” for identi-fication and management of retinop-athy in adolescents with T2DM, asfollows61:

Screening:

� Patients with T2DM should have aninitial dilated and comprehensiveeye examination performed by anophthalmologist or optometristshortly after diabetes diagnosis.

� Subsequent examinations by anophthalmologist should be repeatedannually. Less frequent examina-tions may be considered (eg, every2–3 years) after 1 or more normaleye examinations. More frequentexaminations are required if reti-nopathy is progressing.

Treatment:

� Providers should promptly referpatients with any level of macularedema, severe nonproliferative di-abetic retinopathy, or any prolifer-ative diabetic retinopathy to anophthalmologist who is knowledge-able and experienced in the man-agement and treatment of diabeticretinopathy.

� Laser photocoagulation therapy isindicated to reduce the risk of vi-sion loss in patients with high-riskproliferative diabetic retinopathy,clinically significant macular edema,and some cases of severe nonproli-ferative diabetic retinopathy.

Microalbuminuria

Microalbuminuria is a marker ofvascular inflammation and a sign of

early nephropathy; it has been foundto be associated with CVD risk inadults. It may be present at diagnosisin youth with T2DM.49 Higher rates ofmicroalbuminuria have been reportedamong youth with T2DM than in theirpeers with T1DM.39,59 Diabetic ne-phropathy may also be more frequentand severe among youth with T2DM.62,63

According to the ADA statement “Careof Children and Adolescents with Type1 Diabetes,” the definition of micro-albuminuria is either:

� “Albumin-to-creatinine ratio 30–299mg/g in a spot urine sample;slightly higher values can be usedin females because of the differ-ence in creatinine excretion,”7,64 or

� “Timed overnight or 24-hour collec-tions: albumin excretion rate of20–199 mcg/min.”7

According to the ADA, “an abnormalvalue should be repeated as exercise,smoking, and menstruation can affectresults and albumin excretion can varyfrom day to day. The diagnosis of per-sistent abnormal microalbumin excre-tion requires documentation of two ofthree consecutive abnormal valuesobtained on different days.”7,65 In ad-dition, nondiabetes-related causes ofrenal disease should be excluded;consultation with specialists trainedin the care of children with renaldiseases should be considered as re-quired. It should be noted that ortho-static proteinuria is not uncommon inadolescents and usually is consideredbenign. For that reason, all patientswith documented microalbuminuriashould have a first morning void im-mediately on arising to determine ifthis is the case. Orthostatic pro-teinuria does not require treatmentwith medication.

The committee considers it prudent forproviders to follow the ADA “Standardsof Medical Care in Diabetes” for theidentification and management of




microalbuminuria in adolescents withT2DM, as described here. Note thatmonitoring should always be done ona first morning void specimen:

Screening:

� Screening for microalbuminuriashould begin at the time of T2DMdiagnosis and be repeated annu-ally.

� An annual random spot urine sam-ple for microalbumin-to-creatinineratio is recommended.66

Treatment:

� Treatment with an ACE inhibitorshould be initiated in nonpregnantindividuals with confirmed persis-tent microalbuminuria from 2 ad-ditional urine specimens, even ifblood pressure is not elevated.

� If possible, treatment with an ACEinhibitor should be titrated to nor-malization of microalbumin excre-tion. “Microalbumin excretionshould be monitored at three- tosix-month intervals to assess boththe patient’s response to therapyand the disease progression, andtherapy should be titrated toachieve as normal an albumin-to-creatinine ratio as possible.”7

Additional relevant issues noted in theADA statement “Care of Children andAdolescents with Type 1 Diabetes” in-clude7:

� Concomitant hypertension shouldbe addressed. If present, hyperten-sion should be aggressively treatedto achieve normotension for age,sex, and height.

� Patients should be educated aboutthe importance of attention to glyce-mic control and avoidance or cessa-tion of smoking in preventing and/orreversing diabetic nephropathy.

� If medical treatment is unsatisfac-tory, referral to a nephrologistshould be considered.

Depression

Depression is a significant comorbiditythat can complicate the medical man-agement of diabetes and is associatedwith poor adherence. Longitudinalstudies of the association betweenT2DM and depression among youth arenot available. In a longitudinal studyamong youth with T1DM, however,Kovacs et al67 estimated the rate ofpsychiatric disorders to be 3 timeshigher in youth with diabetes than inthose without diabetes, with the in-creased morbidity primarily attribut-able to major depression.7,67,68 Inaddition, cross-sectional data from theSEARCH study have shown the preva-lence of depressed mood to be higheramong males with T2DM than amongmales with T1DM.67 Lawrence et al68

also found higher levels of depressedmood to be associated with poor gly-cemic control and number of emer-gency department visits amongparticipants with both T1DM and T2DM,compared with youth with T1DM andT2DM who had “minimal” levels of de-pressed mood.

Because depression is associated withpoor adherence to diabetic treatmentrecommendations, its identificationand proper management are essentialfor maximizing therapeutic success.Given the serious nature of this comor-bidity and its propensity for poormetabolic control, the committee rec-ommends that clinicians assess youthwith T2DM for depression at diagnosis;perform periodic, routine screeningfor depression on all youth with T2DM,especially those with frequent emer-gency department visits or poor gly-cemic control; and promptly refer youthwho have positive screenings to ap-propriate mental health care providersfor treatment. Addressing a family his-tory of diabetes and its effect on thefamily unit can be a major factor indepression as well as compliance withthe disease management needs.

Screening:

� According to the American Psychi-atric Association, a diagnosis ofmajor depressive disorder requires69:

(a). The presence of 5 or more ofthe following symptoms withinthe same 2-week period andrepresents a change from pre-vious functioning. At least 1 ofthe symptoms is either de-pressed mood or loss of inter-est or pleasure.

� Depressed mood most of the day,nearly every day, as indicated byeither substantive report or obser-vation made by others. (Note thatin children and adolescents, thiscan be irritable mood.)

� Markedly diminished interest orpleasure in all, or nearly all, activitiesmost of the day, nearly every day.

� Significant weight loss when notdieting or weight gain (eg, morethan 5% of body weight in amonth), or increased or decreasedappetite nearly every day. (Notethat in children and adolescents,this should include failure to makeexpected weight gains.)

� Insomnia or hypersomnia nearlyevery day.

� Psychomotor agitation or retarda-tion nearly every day (observableby others, not merely the subject’sfeeling restless or slowed down).

� Fatigue or loss of energy nearlyevery day.

� Feelings of worthlessness or inap-propriate guilt (which may be de-lusional) nearly every day.

� Diminished ability to think or toconcentrate, or indecisiveness, nearlyevery day.

� Recurrent thoughts of death (notjust fear of dying), recurrent sui-cidal ideation without a specificplan, or a suicide attempt, or a spe-cific plan to commit suicide.


(b). The symptoms do not meet thecriteria for a mixed episode(defined as a specific time pe-riod in which the individualexperiences nearly daily fluctu-ations in mood that qualify fordiagnoses of manic episodeand major depressive episode).

(c). The symptoms cause clinicallysignificant distress or impair-ment in social, occupational,or other important areas offunctioning.

(d). The symptoms are not due to thedirect physiologic effects of asubstance (eg, a drug of abuse,medication) or a general medicalcondition (eg, hypothyroidism).

(e). The symptoms are not betteraccounted for by bereavement(ie, after the loss of a lovedone), symptoms persist longerthan 2 months, or symptomsare characterized by markedfunctional impairment, morbidpreoccupation with worthless-ness, suicidal ideation, psychoticsymptoms, or psychomotor re-tardation.

� Another potentially valuable screen-ing tool for depression is the Centerfor Epidemiologic Studies Depres-sion Scale (CES-D), a 20-item scaleoriginally developed for use inadults70 but which has been usedsubsequently in studies of youth asyoung as 12 years.71–74 (See Supple-mental Information G for this scale.)

Treatment:

� Recognition of depression shouldtrigger a referral to a mentalhealth care provider skilled inaddressing this condition in chil-dren and adolescents.

Other Comorbidities or AssociatedMedical Conditions

In addition to the comorbidities men-tioned previously, T2DM is associated

with other obesity-related medicalconditions, many of which, when dis-covered, necessitate consultation withspecialists who have specific expertisein the field. These associated con-ditions include:

� Nonalcoholic fatty liver disease:Baseline aspartate aminotransfer-ase and alanine aminotransferaseconcentrations should be obtained,especially if treatment with lipid-lowering drugs is instituted. Re-ferral to a pediatric or internalmedicine gastroenterologist maybe indicated.

� Obstructive sleep apnea: The diag-nosis of obstructive sleep apneacan only be made reliably by usinga sleep study. If the diagnosis ismade, an electrocardiogram andpossibly an echocardiogram shouldbe obtained to rule out right ven-tricular hypertrophy. Referral toa pediatric cardiologist, internalmedicine cardiologist, or sleep spe-cialist may be indicated.

� Orthopedic problems: These comor-bidities (especially slipped capitalfemoral epiphysis and Blount dis-ease) require immediate referralto a specialist in orthopedics andwill limit the physical activity thatcan be prescribed to the individual.

COMPLEMENTARY ANDALTERNATIVE MEDICINE

The clinical practice guidelines do notpresent any evidence-based recom-mendations for the use of comple-mentary and alternative medicine(CAM) to treat T2DM in children andadolescents. Limited data are availableon CAM, and none is specific to this agegroup. However, noting that adultpatients with diabetes are 1.6 timesmore likely to use CAM than areindividuals without diabetes, thecommittee believes it is important forclinicians to encourage their patientsto communicate openly about the use

of CAM (especially because the parentsmay have diabetes themselves) and,when acknowledged, to differentiatebetween coadministration with theprescribed therapy versus replacementof (and, thus, noncompliance with) theprescribed therapy.75

CAM is most likely to be used by WestIndian, African, Indian, Latin American,and Asian subjects.76 CAM is also morecommon in families with higher incomeand education levels and an increasedinterest in self-care. One multicenterstudy conducted in Germany foundthat, among 228 families with a T1DMdiagnosis, 18.4% reported using atleast 1 form of CAM.77 Reported pa-rental motivators for using CAM fortheir children included the hope ofimproving their well-being (92.1%);the desire to try every availabletreatment option (77.8%); and the as-sumption that CAM has fewer adverseeffects than conventional therapy(55.2%). Many forms of CAM are usedbecause of patient-perceived inade-quacies of current treatments.75

A wide variety of CAM dietary supple-ments are targeted at patients withdiabetes and promise to lower BGconcentrations or prevent and/or treatcomplications associated with thedisease. Common supplements usedby individuals with diabetes includealoe, bitter melon, chromium, cinna-mon, fenugreek, ginseng, gymnema,and nopal.78 These products lackproduct standardization and are notregulated by the US Food and DrugAdministration for either safety orpossible complications. Although thesesupplements may or may not haveproven beneficial effects on diabetes,many might have harmful adverseeffects and/or lead to medicationinteractions. Adverse effects from di-etary supplements can include gas-trointestinal discomfort, hypoglycemia,favism, insomnia, and increased bloodpressure.78




In addition to dietary supplements,patients may use forms of CAM thatinclude prayer, acupuncture, massage,hot tub therapy, biofeedback, and yoga.The University of Chicago’s Division ofPediatric Endocrinology interviewed106 families with T1DM and found that33% of children had tried CAM in thepast year; the most common formused was faith-healing or prayer.79

Parents who reported the use of CAMfor their children were also morelikely to report having experiencedstruggles with adherence to conven-tional medicine.

It is the committee’s opinion that pro-viders should question patients ontheir use of CAM and also educatepatients on potential adverse effects,review evidence for efficacy, anddiscourage the use of potentiallydangerous or ineffective products.

SUMMARY

The clinical practice guideline that thistechnical report accompanies providesevidence-based recommendations onthe management of patients between10 and 18 years of age who have beendiagnosed with T2DM. The documentdoes not pertain to patients with im-paired glucose tolerance, isolated in-sulin resistance, or prediabetes, nordoes it pertain to obese but nondiabeticyouth. It emphasizes the use of man-agement modalities that have been

shown to affect clinical outcomes in thispediatric population. The clinical prac-tice guideline addresses situations inwhich either insulin or metformin is thepreferred first-line treatment of chil-dren and adolescents with T2DM. Itsuggests integrating lifestyle mod-ifications (ie, diet and exercise) in con-cert with medication rather than as anisolated initial treatment approach.Guidelines for frequency of monitoringHbA1c and finger-stick BG concen-trations are presented. The clinicalpractice guideline is intended to assistclinician decision-making rather thanreplace clinical judgment and/or es-tablish a protocol for the care of allchildren with this condition. These rec-ommendations may not provide the onlyappropriate approach to the manage-ment of children with T2DM. Providersshould consult experts trained in thecare of children and adolescents withT2DM when treatment goals are not metor when therapy with insulin is initiated.

ACKNOWLEDGMENTSThe committee acknowledges the workof Edwin Lomotan, MD, FAAP, and GeorgeMichel, MS, in creating the reports.

SUBCOMMITTEE ON TYPE 2 DIABETES(OVERSIGHT BY THE STEERINGCOMMITTEE ON QUALITYIMPROVEMENT AND MANAGEMENT,2008–2012)Kenneth Claud Copeland, MD, FAAP: Co-chair—Endocrinology and Pediatric Endocrine

Society Liaison (2009: Novo Nordisk, Genentech,Endo [National Advisory Groups]; 2010: NovoNordisk [National Advisory Group]); publishedresearch related to type 2 diabetesJanet Silverstein, MD, FAAP: Co-chair—En-docrinology and American Diabetes AssociationLiaison (small grants with Pfizer, Novo Nordisk,and Lilly; grant review committee for Gen-entech; was on an advisory committee forSanofi Aventis, and Abbott Laboratories for a 1-time meeting); published research related totype 2 diabetesKelly Roberta Moore, MD, FAAP: General Pe-diatrics, Indian Health, AAP Committee on Na-tive American Child Health Liaison (boardmember of the Merck Company FoundationAlliance to Reduce Disparities in Diabetes.Their national program office is the Universityof Michigan’s Center for Managing ChronicDisease.)Greg Edward Prazar, MD, FAAP: General Pe-diatrics (no conflicts)Terry Raymer, MD, CDE: Family Medicine, In-dian Health Service (no conflicts)Richard N. Shiffman, MD, FAAP: Partnershipfor Policy Implementation Informatician, Gen-eral Pediatrics (no conflicts)Shelley C. Springer, MD, MBA, MSc, JD,FAAP: Epidemiologist, neonatologist (no con-flicts)Meaghan Anderson, MS, RD, LD, CDE: Acad-emy of Nutrition and Dietetics Liaison (formerlya Certified Pump Trainer for Animas)Stephen J. Spann, MD, MBA, FAAFP: Ameri-can Academy of Family Physicians Liaison (noconflicts)Vidhu V. Thaker, MD, FAAP: QuIIN Liaison,General Pediatrics (no conflicts)

CONSULTANTSusan K. Flinn, MA: Medical Writer (no con-flicts)

STAFFCaryn Davidson, MA

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Stephen J. Spann and Susan K. FlinnPrazar, Terry Raymer, Richard N. Shiffman, Vidhu V. Thaker, Meaghan Anderson, Shelley C. Springer, Janet Silverstein, Kenneth Copeland, Kelly R. Moore, Greg E.

Management of Type 2 Diabetes Mellitus in Children and Adolescents

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