2. Classification and Diagnosis of Diabetes: Standards of ... · 2.1 To avoid misdiagnosis or...

2. Classification and Diagnosis ofDiabetes: Standards of MedicalCare in Diabetesd2021Diabetes Care 2021;44(Suppl. 1):S15–S33 | https://doi.org/10.2337/dc21-S002

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes”includes the ADA’s current clinical practice recommendations and is intended toprovide the components of diabetes care, general treatment goals and guidelines,and tools to evaluate quality of care. Members of the ADA Professional PracticeCommittee, a multidisciplinary expert committee (https://doi.org/10.2337/dc21-SPPC), are responsible for updating the Standards of Care annually, or morefrequently as warranted. For a detailed description of ADA standards, statements,and reports, as well as the evidence-grading system for ADA’s clinical practicerecommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc21-SINT). Readers who wish to comment on the Standards of Careare invited to do so at professional.diabetes.org/SOC.

CLASSIFICATION

Diabetes can be classified into the following general categories:

1. Type1diabetes (due toautoimmuneb-cell destruction, usually leading toabsoluteinsulin deficiency, including latent autoimmune diabetes of adulthood)

2. Type 2 diabetes (due to a progressive loss of adequate b-cell insulin secretionfrequently on the background of insulin resistance)

3. Specific typesofdiabetesdue toother causes, e.g.,monogenicdiabetes syndromes(such as neonatal diabetes andmaturity-onset diabetes of the young), diseases ofthe exocrine pancreas (such as cystic fibrosis and pancreatitis), and drug- orchemical-induced diabetes (such as with glucocorticoid use, in the treatment ofHIV/AIDS, or after organ transplantation)

4. Gestational diabetesmellitus (diabetes diagnosed in the second or third trimesterof pregnancy that was not clearly overt diabetes prior to gestation)

This section reviews most common forms of diabetes but is not comprehensive. Foradditional information, see the American Diabetes Association (ADA) positionstatement “Diagnosis and Classification of Diabetes Mellitus” (1).

Type 1 diabetes and type 2 diabetes are heterogeneous diseases in which clinicalpresentation and disease progression may vary considerably. Classification isimportant for determining therapy, but some individuals cannot be clearly classifiedas having type 1 or type 2 diabetes at the time of diagnosis. The traditional paradigmsof type 2 diabetes occurring only in adults and type 1 diabetes only in children are nolonger accurate, as both diseases occur in both age-groups. Children with type 1diabetes typically present with the hallmark symptoms of polyuria/polydipsia, andapproximately one-third present with diabetic ketoacidosis (DKA) (2). The onset of

Suggested citation: American Diabetes Associa-tion. 2. Classification and diagnosis of diabetes:Standards of Medical Care in Diabetesd2021.Diabetes Care 2021;44(Suppl. 1):S152S33

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American Diabetes Association

Diabetes Care Volume 44, Supplement 1, January 2021 S15

2.CLA

SSIFICATIO

NANDDIAGNOSIS

OFDIABETES

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type 1 diabetes may be more variable inadults; they may not present with theclassic symptoms seen in children andmay experience temporary remissionfrom the need for insulin (3–5). Occa-sionally, patients with type 2 diabetesmay present with DKA (6), particularlyethnic and racial minorities (7). It isimportant for the provider to realizethat classification of diabetes type is notalways straightforward at presentationand that misdiagnosis is common (e.g.,adults with type 1 diabetes misdiag-nosed as having type 2 diabetes; indi-viduals with maturity-onset diabetes ofthe young [MODY] misdiagnosed ashaving type 1 diabetes, etc.). Althoughdifficulties in distinguishing diabetestype may occur in all age-groups atonset, the diagnosis becomes more ob-vious over time in people with b-celldeficiency.In both type 1 and type 2 diabetes,

various genetic and environmental fac-tors can result in the progressive loss ofb-cell mass and/or function that mani-fests clinically as hyperglycemia. Oncehyperglycemia occurs, patients with allforms of diabetes are at risk for devel-oping the same chronic complications,although rates of progression may dif-fer. The identification of individualizedtherapies for diabetes in the future willrequire better characterization of themany paths to b-cell demise or dys-function (8). Across the globe manygroups are working on combining clin-ical, pathophysiological, and geneticcharacteristics to more precisely de-fine the subsets of diabetes currentlyclustered into the type 1 diabetes ver-sus type 2 diabetes nomenclature withthe goal of optimizing treatment ap-proaches. Many of these studies showgreat promise and may soon be incor-porated into the diabetes classificationsystem (9).Characterization of the underlying

pathophysiology is more precisely de-veloped in type 1 diabetes than in type 2diabetes. It is now clear from studies offirst-degree relatives of patients withtype 1 diabetes that the persistent pres-enceof twoormore islet autoantibodiesis a near certain predictor of clinicalhyperglycemia and diabetes. The rate ofprogression is dependent on the age atfirst detection of autoantibody, numberof autoantibodies, autoantibody speci-ficity, and autoantibody titer. Glucose

and A1C levels rise well before the clin-ical onset of diabetes, making diagnosisfeasible well before the onset of DKA.Three distinct stages of type 1 diabetescan be identified (Table 2.1) and serveas a framework for future research andregulatory decision-making (8,10). Thereis debate as to whether slowly progres-sive autoimmune diabetes with an adultonset should be termed latent autoim-mune diabetes in adults (LADA) or type 1diabetes. The clinical priority is aware-ness that slow autoimmune b-cell de-struction can occur in adults leading to along duration of marginal insulin secre-tory capacity. For the purpose of thisclassification, all forms of diabetes me-diated by autoimmuneb-cell destructionare included under the rubric of type 1diabetes. Use of the term LADA is com-mon and acceptable in clinical practiceand has the practical impact of height-eningawarenessof apopulationof adultslikely to develop overt autoimmuneb-cell destruction (11), thus acceleratinginsulin initiation prior to deterioration ofglucose control or development of DKA(4,12).

The paths to b-cell demise and dys-function are less well defined in type 2diabetes, but deficient b-cell insulin se-cretion, frequently in the setting of in-sulin resistance, appears to be thecommon denominator. Type 2 diabetesis associated with insulin secretorydefects related to inflammation andmetabolic stress among other contrib-utors, including genetic factors. Futureclassification schemes for diabetes willlikely focus on the pathophysiologyof the underlying b-cell dysfunction(8,9,13–15).

DIAGNOSTIC TESTS FOR DIABETES

Diabetes may be diagnosed based onplasma glucose criteria, either the fast-ing plasma glucose (FPG) value or the2-h plasma glucose (2-h PG) valueduring a 75-g oral glucose tolerancetest (OGTT), or A1C criteria (16) (Table2.2).

Generally, FPG, 2-h PG during 75-gOGTT, and A1C are equally appropriatefor diagnostic screening. It should benoted that the tests do not necessarilydetect diabetes in the same individuals.The efficacy of interventions for primaryprevention of type 2 diabetes (17,18)has mainly been demonstrated amongindividuals who have impaired glucose

tolerance (IGT) with or without elevatedfasting glucose, not for individuals withisolated impaired fasting glucose (IFG)or for those with prediabetes defined byA1C criteria.

The same tests may be used to screenfor and diagnose diabetes and to detectindividuals with prediabetes (Table 2.2and Table 2.5) (19). Diabetes may beidentified anywhere along the spectrumof clinical scenariosdin seemingly low-risk individuals who happen to have glu-cose testing, in individuals tested basedon diabetes risk assessment, and insymptomatic patients.

Fasting and 2-Hour Plasma GlucoseThe FPG and 2-h PG may be used todiagnose diabetes (Table 2.2). The con-cordance between the FPG and 2-h PGtests is imperfect, as is the concordancebetween A1C and either glucose-basedtest. Compared with FPG and A1C cutpoints, the 2-h PG value diagnoses morepeople with prediabetes and diabetes(20). In people in whom there is discor-dance between A1C values and glucosevalues, FPG and 2-h PG are more accu-rate (21).

A1C

Recommendations

2.1 To avoid misdiagnosis or misseddiagnosis, the A1C test should beperformed using amethod that iscertified by the NGSP and stan-dardized to the Diabetes Controland Complications Trial (DCCT)assay. B

2.2 Marked discordance betweenmeasured A1C and plasma glu-cose levels should raise the pos-sibility of A1C assay interferenceand consideration of using anassay without interference orplasma blood glucose criteriato diagnose diabetes. B

2.3 In conditions associated with analtered relationshipbetweenA1Cand glycemia, such as hemoglo-binopathies including sickle celldisease, pregnancy (second andthird trimesters and the postpar-tum period), glucose-6-phosphatedehydrogenase deficiency, HIV,hemodialysis, recent blood lossor transfusion, or erythropoie-tin therapy, only plasma bloodglucose criteria should be used

S16 Classification and Diagnosis of Diabetes Diabetes Care Volume 44, Supplement 1, January 2021

to diagnose diabetes. (See OTHERCONDITIONS ALTERING THE RELATION-

SHIP OF A1C AND GLYCEMIA belowfor more information.) B

The A1C test should be performed usinga method that is certified by the NGSP(www.ngsp.org) and standardized or trace-able to the Diabetes Control and Com-plications Trial (DCCT) reference assay.Although point-of-care A1C assays maybe NGSP certified and cleared by the U.S.Food and Drug Administration (FDA) foruse in monitoring glycemic control inpeople with diabetes in both ClinicalLaboratory Improvement Amendments(CLIA)-regulated and CLIA-waived set-tings, only those point-of-care A1Cassays that are also cleared by theFDA for use in the diagnosis of diabe-tes should be used for this purpose,and only in the clinical settings forwhich they are cleared. As discussed inSection 6 “Glycemic Targets” (https://doi.org/10.2337/dc21-S006), point-of-care A1C assays may be more generallyapplied for assessment of glycemic con-trol in the clinic.A1C has several advantages compared

with FPG and OGTT, including greaterconvenience (fastingnot required), greaterpreanalytical stability, and less day-to-dayperturbations during stress, changes indiet, or illness. However, these advan-tages may be offset by the lower sensi-tivity of A1C at the designated cut point,greater cost, limited availability of A1Ctesting in certain regions of the devel-oping world, and the imperfect correla-tion between A1C and average glucose incertain individuals. The A1C test, with adiagnostic thresholdof$6.5%(48mmol/mol), diagnoses only 30% of the diabetescases identified collectively using A1C,FPG, or 2-h PG, according to National

Health andNutrition Examination Survey(NHANES) data (22).

When using A1C to diagnose diabetes,it is important to recognize that A1C is anindirect measure of average blood glu-cose levels and to take other factors intoconsideration that may impact hemoglo-bin glycation independently of glycemia,such as hemodialysis, pregnancy, HIVtreatment (23,24), age, race/ethnicity,pregnancy status, genetic background,and anemia/hemoglobinopathies. (SeeOTHER CONDITIONS ALTERING THE RELATIONSHIP

OF A1C AND GLYCEMIA below for moreinformation.)

Age

The epidemiologic studies that formedthe basis for recommending A1C to di-agnose diabetes included only adultpopulations (22). However, recent ADAclinical guidance concluded that A1C,FPG, or 2-h PG can be used to test forprediabetesor type2diabetes in childrenand adolescents (see SCREENING AND TESTINGFOR PREDIABETES AND TYPE 2 DIABETES IN CHILDREN

AND ADOLESCENTS below for additional in-formation) (25).

Race/Ethnicity/Hemoglobinopathies

Hemoglobin variants can interfere withthe measurement of A1C, although mostassays in use in theU.S. are unaffected bythe most common variants. Marked dis-crepancies between measured A1C andplasma glucose levels should promptconsideration that the A1C assay may notbe reliable for that individual. For pa-tients with a hemoglobin variant butnormal red blood cell turnover, such asthose with the sickle cell trait, an A1Cassay without interference from hemo-globin variants should be used. An up-dated list of A1C assays with interferencesis available at www.ngsp.org/interf.asp.

African Americans heterozygous forthe common hemoglobin variant HbSmay have, for any given level of meanglycemia, lower A1C by about 0.3% com-pared with those without the trait (26).Another genetic variant, X-linked glucose-6-phosphate dehydrogenase G202A, car-ried by 11% of African Americans, wasassociated with a decrease in A1C ofabout 0.8% in homozygous men and0.7% in homozygous women comparedwith those without the variant (27).

Table 2.1—Staging of type 1 diabetes (8,10)

Stage 1 Stage 2 Stage 3

Characteristics c Autoimmunity c Autoimmunity c New-onset hyperglycemiac Normoglycemia c Dysglycemia c Symptomaticc Presymptomatic c Presymptomatic

Diagnostic criteria c Multiple autoantibodies c Multiple autoantibodies c Clinical symptomsc No IGT or IFG c Dysglycemia: IFG and/or IGT c Diabetes by standard criteria

c FPG 100–125 mg/dL (5.6–6.9 mmol/L)c 2-h PG 140–199 mg/dL (7.8–11.0 mmol/L)c A1C 5.7–6.4% (39–47 mmol/mol) or $10%increase in A1C

FPG, fasting plasma glucose; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; 2-h PG, 2-h plasma glucose.

Table 2.2—Criteria for the diagnosis of diabetesFPG $126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 h.*

OR

2-h PG$200mg/dL (11.1 mmol/L) during OGTT. The test should be performed as described byWHO,using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.*

OR

A1C$6.5% (48mmol/mol). The test should be performed in a laboratory using amethod that isNGSP certified and standardized to the DCCT assay.*

OR

In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasmaglucose $200 mg/dL (11.1 mmol/L).

DCCT, Diabetes Control and Complications Trial; FPG, fasting plasma glucose; OGTT, oral glucosetolerance test; WHO, World Health Organization; 2-h PG, 2-h plasma glucose. *In the absence ofunequivocal hyperglycemia, diagnosis requires twoabnormal test results from the same sampleorin two separate test samples.

care.diabetesjournals.org Classification and Diagnosis of Diabetes S17

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Even in the absence of hemoglobinvariants, A1C levels may vary with race/ethnicity independently of glycemia (28–30).For example, African Americans mayhavehigher A1C levels than non-HispanicWhites with similar fasting and postglu-cose load glucose levels (31). Thoughconflicting data exists, African Ameri-cans may also have higher levels offructosamine and glycated albuminand lower levels of 1,5-anhydroglucitol,suggesting that their glycemic burden(particularly postprandially) may behigher (32,33). Similarly, A1C levelsmay be higher for a given mean glucoseconcentration when measured withcontinuous glucose monitoring (34).Despite these and other reported dif-ferences, the association of A1C withrisk for complications appears to besimilar in African Americans and non-Hispanic Whites (35,36).

Other Conditions Altering the Relationship

of A1C and Glycemia

In conditions associated with increasedred blood cell turnover, such as sickle celldisease, pregnancy (second and thirdtrimesters), glucose-6-phosphate dehy-drogenase deficiency (37,38), hemodial-ysis, recent blood loss or transfusion, orerythropoietin therapy, only plasmablood glucose criteria should be usedto diagnose diabetes (39). A1C is lessreliable than blood glucose measurementin other conditions such as the postpar-tum state (40–42), HIV treated withcertain protease inhibitors (PIs) and nu-cleoside reverse transcriptase inhibitors(NRTIs) (23), and iron-deficient anemia(43).

Confirming the DiagnosisUnless there is a clear clinical diagnosis(e.g., patient in a hyperglycemic crisis orwith classic symptoms of hyperglycemiaand a random plasma glucose$200 mg/dL [11.1mmol/L]), diagnosis requires twoabnormal test results, either from thesame sample (44) or in two separate testsamples. If using two separate test sam-ples, it is recommended that the secondtest, which may either be a repeat of theinitial test or a different test, be per-formedwithoutdelay. For example, if theA1C is 7.0% (53 mmol/mol) and a repeatresult is 6.8% (51 mmol/mol), the di-agnosis of diabetes is confirmed. If twodifferent tests (such as A1C and FPG) areboth above the diagnostic thresholdwhen analyzed from the same sample

or in two different test samples, this alsoconfirms the diagnosis. On the otherhand, if a patient has discordant resultsfrom two different tests, then the testresult that is above the diagnostic cutpoint should be repeated, with carefulconsideration of the possibility of A1Cassay interference. The diagnosis is madeon the basis of the confirmed test. Forexample, if a patient meets the diabetescriterion of the A1C (two results $6.5%[48 mmol/mol]) but not FPG (,126 mg/dL [7.0 mmol/L]), that person shouldnevertheless be considered to havediabetes.

Each of the tests has preanalytic andanalytic variability, so it is possible thata test yielding an abnormal result (i.e.,above the diagnostic threshold), whenrepeated, will produce a value below thediagnostic cutpoint. This scenario is likelyfor FPG and 2-h PG if the glucose samplesremain at room temperature and are notcentrifuged promptly. Because of thepotential for preanalytic variability, itis critical that samples for plasma glu-cose be spun and separated immedi-ately after they are drawn. If patientshave test results near the margins of thediagnostic threshold, thehealth carepro-fessional should discuss signs and symp-tomswith the patient and repeat the testin 3–6 months.

DiagnosisIn a patient with classic symptoms, mea-surement of plasma glucose is sufficientto diagnose diabetes (symptoms of hy-perglycemia or hyperglycemic crisis plusa random plasma glucose $200 mg/dL[11.1mmol/L]). In thesecases,knowingtheplasma glucose level is critical because, inaddition to confirming that symptoms aredue todiabetes, itwill informmanagementdecisions.Someprovidersmayalsowanttoknow the A1C to determine the chronicityof the hyperglycemia. The criteria to di-agnose diabetes are listed in Table 2.2.

TYPE 1 DIABETES

Recommendations

2.4 Screening for type 1 diabetes riskwith a panel of islet autoanti-bodies is currently recommendedin the setting of a research trial orcan be offered as an option forfirst-degree family members of aproband with type 1 diabetes. B

2.5 Persistence of autoantibodies isa risk factor for clinical diabetes

andmay serveas an indication forintervention in the setting of aclinical trial. B

Immune-Mediated DiabetesThis form, previously called “insulin-dependent diabetes” or “juvenile-onsetdiabetes,” accounts for 5–10%ofdiabetesand is due to cellular-mediated autoim-mune destruction of the pancreaticb-cells.Autoimmunemarkers include isletcell autoantibodies and autoantibodiesto GAD (GAD65), insulin, the tyrosinephosphatases IA-2 and IA-2b, and zinctransporter 8 (ZnT8). Numerous clinicalstudies are being conducted to testvarious methods of preventing type 1diabetes in those with evidence ofislet autoimmunity (www.clinicaltrials.gov and www.trialnet.org/our-research/prevention-studies) (12,45–49). Stage1 of type 1 diabetes is defined by thepresence of two or more of these auto-immune markers. The disease hasstrong HLA associations, with linkageto the DQA and DQB genes. These HLA-DR/DQ alleles can be either predis-posing or protective (Table 2.1). Thereare important genetic considerations,as most of the mutations that causediabetes are dominantly inherited. Theimportance of genetic testing is in thegenetic counseling that follows. Somemutations are associated with other con-ditions, which then may prompt addi-tional screenings.

The rate of b-cell destruction is quitevariable, being rapid in some individuals(mainly infants and children) and slow inothers (mainly adults) (50). Children andadolescentsmay presentwith DKA as thefirst manifestation of the disease. Othershave modest fasting hyperglycemia thatcan rapidly change to severe hypergly-cemia and/or DKAwith infection or otherstress. Adults may retain sufficient b-cellfunction to prevent DKA for many years;such individuals may have remission ordecreased insulin needs for months oryears and eventually become dependenton insulin for survival and are at risk forDKA (3–5,51,52). At this latter stage ofthe disease, there is little or no insulinsecretion, as manifested by low or un-detectable levels of plasma C-peptide.Immune-mediated diabetes is the mostcommon form of diabetes in childhoodand adolescence, but it can occur at anyage, even in the 8th and 9th decades of life.


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Autoimmune destruction of b-cellshas multiple genetic predispositions andis also related to environmental factorsthat are still poorly defined. Althoughpatients are not typically obese whenthey present with type 1 diabetes, obe-sity is increasingly common in thegeneralpopulation, and there is evidence thatit may also be a risk factor for type 1diabetes. As such, obesity should notpreclude the diagnosis. People with type1 diabetes are also prone to other au-toimmune disorders such as Hashimotothyroiditis, Graves disease, celiac dis-ease, Addison disease, vitiligo, autoim-mune hepatitis, myasthenia gravis, andpernicious anemia (see Section 4 “Com-prehensive Medical Evaluation and As-sessment of Comorbidities,” https://doi.org/10.2337/dc21-S004).

Idiopathic Type 1 DiabetesSome forms of type 1 diabetes have noknown etiologies. These patients havepermanent insulinopenia and are proneto DKA but have no evidence of b-cellautoimmunity. However, only a minorityof patients with type 1 diabetes fall intothis category. Individuals with autoanti-body-negative type 1 diabetes of AfricanorAsianancestrymaysuffer fromepisodicDKA and exhibit varying degrees of insulindeficiency between episodes (possiblyketosis-prone diabetes). This form of di-abetes is strongly inherited and is not HLAassociated. An absolute requirement forinsulin replacement therapy in affected pa-tientsmaybeintermittent.Futureresearchisneeded to determine the cause of b-celldestruction in this rare clinical scenario.

Screening for Type 1 Diabetes RiskThe incidence and prevalence of type 1diabetes is increasing (53). Patients withtype 1 diabetes often present with acutesymptoms of diabetes and markedlyelevated blood glucose levels, and ap-proximately one-third are diagnosed withlife-threateningDKA (2).Multiple studiesindicate that measuring islet autoanti-bodies in individuals genetically at riskfor type 1 diabetes (e.g., relatives ofthose with type 1 diabetes or individualsfrom the general population with type 1diabetes–associatedgenetic factors) iden-tifies individuals who may develop type 1diabetes (10). Such testing, coupled witheducation about diabetes symptoms andclose follow-up, may enable earlier iden-tification of type 1 diabetes onset. A

study reported the risk of progression totype 1 diabetes from the time of sero-conversion to autoantibody positivity inthree pediatric cohorts from Finland,Germany,andtheU.S.Ofthe585childrenwho developed more than two autoanti-bodies, nearly 70% developed type 1diabetes within 10 years and 84% within15 years (45). These findings are highlysignificant because while the Germangroup was recruited from offspring ofparents with type 1 diabetes, the Finnishand American groups were recruitedfrom the general population. Remark-ably, the findings in all three groupswerethe same, suggesting that the samesequence of events led to clinical diseasein both “sporadic” and familial cases oftype 1 diabetes. Indeed, the risk of type 1diabetes increases as the number of rel-evant autoantibodies detected increases(48,54,55). In The Environmental Deter-minants of Diabetes in the Young (TEDDY)study, type 1 diabetes developed in 21%of 363 subjects with at least one auto-antibody at 3 years of age (56).

There is currently a lack of acceptedand clinically validated screening pro-grams outside of the research setting;thus, widespread clinical testing of asymp-tomatic low-risk individuals is not currentlyrecommended due to lack of approvedtherapeutic interventions. However, oneshould consider referring relatives ofthose with type 1 diabetes for islet au-toantibody testing for risk assessmentin the setting of a clinical research study(see www.trialnet.org). Individuals whotest positive should be counseled aboutthe risk of developing diabetes, diabetessymptoms, and DKA prevention. Numer-ous clinical studies are being conductedto test various methods of preventingand treating stage 2 type 1 diabetes inthose with evidence of autoimmunity withpromising results (see www.clinicaltrials.gov and www.trialnet.org).

PREDIABETES AND TYPE 2DIABETES

Recommendations

2.6 Screening for prediabetes andtype2diabeteswith an informalassessment of risk factors orvalidated tools should be consid-ered in asymptomatic adults. B

2.7 Testing for prediabetes and/ortype 2 diabetes in asymptomaticpeople should be considered in

adults of any age with over-weight or obesity (BMI $25kg/m2 or $23 kg/m2 in AsianAmericans) and who have oneor more additional risk factorsfor diabetes (Table 2.3). B

2.8 Testing for prediabetes and/ortype 2 diabetes should be con-sidered in women with over-weight or obesity planningpregnancy and/or who haveone or more additional risk fac-tor for diabetes (Table 2.3). C

2.9 For all people, testing shouldbegin at age 45 years. B

2.10 If tests are normal, repeat test-ing carried out at a minimum of3-year intervals is reasonable,sooner with symptoms. C

2.11 To test for prediabetes and type2 diabetes, fasting plasma glu-cose, 2-h plasma glucose dur-ing 75-g oral glucose tolerancetest, and A1C are equally ap-propriate (Table 2.2 and Table2.5). B

2.12 Inpatientswithprediabetes andtype 2 diabetes, identify andtreat other cardiovascular dis-ease risk factors. A

2.13 Risk-based screening for predi-abetes and/or type 2 diabetesshould be considered after theonset of puberty or after 10years of age, whichever occursearlier, in children and adoles-centswithoverweight (BMI$85thpercentile) or obesity (BMI$95thpercentile) and who have one ormore risk factor for diabetes. (SeeTable 2.4 for evidence grading ofrisk factors.) B

2.14 Patients with HIV should bescreened for diabetes and pre-diabetes with a fasting glucosetest before starting antiretrovi-ral therapy, at the timeofswitch-ing antiretroviral therapy, and326 months after starting orswitching antiretroviral therapy.If initial screening results arenormal, fasting glucose shouldbe checked annually. E

Prediabetes“Prediabetes” is the term used for indi-vidualswhose glucose levels do notmeetthe criteria for diabetes but are too hightobeconsiderednormal (35,36). Patients


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with prediabetes are defined by thepresence of IFG and/or IGT and/orA1C 5.7–6.4% (39–47 mmol/mol) (Table2.5). Prediabetes should not be viewedas a clinical entity in its own right butrather as an increased risk for diabetesand cardiovascular disease (CVD). Crite-ria for testing for diabetes or prediabetesin asymptomatic adults is outlined inTable 2.3. Prediabetes is associatedwith obesity (especially abdominal orvisceral obesity), dyslipidemia with hightriglycerides and/or low HDL cholesterol,and hypertension.

Diagnosis

IFG is defined as FPG levels from 100 to125 mg/dL (from 5.6 to 6.9 mmol/L)(57,58) and IGT as 2-h PG during 75-gOGTT levels from 140 to 199mg/dL (from

7.8 to 11.0 mmol/L) (59). It should benoted that the World Health Organiza-tion (WHO) and numerous other diabe-tes organizations define the IFG cutoff at110 mg/dL (6.1 mmol/L).

As with the glucose measures, severalprospective studies that used A1C topredict the progression to diabetes asdefined by A1C criteria demonstrated astrong, continuous association betweenA1C and subsequent diabetes. In a sys-tematic reviewof44,203 individuals from16 cohort studies with a follow-up in-terval averaging 5.6 years (range 2.8–12years), thosewithA1Cbetween5.5%and6.0% (between 37 and 42 mmol/mol)had a substantially increased risk of di-abetes (5-year incidence from 9% to25%). Those with an A1C range of 6.0–6.5% (42–48mmol/mol) had a 5-year risk

of developing diabetes between 25% and50% and a relative risk 20 times highercompared with A1C of 5.0% (31 mmol/mol) (60). In a community-based studyof African American and non-HispanicWhite adults without diabetes, baselineA1C was a stronger predictor of sub-sequent diabetes and cardiovascularevents than fasting glucose (61). Otheranalyses suggest that A1C of 5.7%(39 mmol/mol) or higher is associatedwith a diabetes risk similar to that of thehigh-risk participants in the DiabetesPrevention Program (DPP) (62), andA1C at baseline was a strong predictor ofthe development of glucose-defined di-abetes during the DPP and its follow-up(63). Hence, it is reasonable to consideran A1C range of 5.7–6.4% (39–47 mmol/mol) as identifying individuals with pre-diabetes. Similar to those with IFG and/or IGT, individuals with A1C of 5.7–6.4%(39–47 mmol/mol) should be informedof their increased risk for diabetes andCVD and counseled about effective strat-egies to lower their risks (see Section3 “Prevention or Delay of Type 2 Di-abetes,” https://doi.org/10.2337/dc21-S003). Similar to glucose measurements,the continuum of risk is curvilinear, so asA1C rises, the diabetes risk rises dispro-portionately (60). Aggressive interven-tions and vigilant follow-up should bepursued for those consideredat veryhighrisk (e.g., those with A1C .6.0% [42mmol/mol]).

Table 2.5 summarizes the categoriesof prediabetes and Table 2.3 the criteriafor prediabetes testing. The ADA diabe-tes risk test is an additional option forassessment to determine the appropriate-ness of testing for diabetes or prediabe-tes in asymptomatic adults (Fig. 2.1)(diabetes.org/socrisktest). For addi-tional background regarding risk fac-tors and screening for prediabetes, seeSCREENING AND TESTING FOR PREDIABETES AND

TYPE 2 DIABETES IN ASYMPTOMATIC ADULTS andalso SCREENING AND TESTING FOR PREDIABETESAND TYPE 2 DIABETES IN CHILDREN AND ADOLES-

CENTS below.

Type 2 DiabetesType 2 diabetes, previously referred toas “noninsulin-dependent diabetes” or“adult-onset diabetes,” accounts for 90–95% of all diabetes. This form encom-passes individuals who have relative(rather than absolute) insulin deficiencyand have peripheral insulin resistance.

Table 2.3—Criteria for testing for diabetes or prediabetes in asymptomatic adults1. Testing should be considered in adults with overweight or obesity (BMI$25 kg/m2 or$23kg/m2 in Asian Americans) who have one or more of the following risk factors:c First-degree relative with diabetesc High-risk race/ethnicity (e.g., African American, Latino, Native American, Asian American,Pacific Islander)

c History of CVDc Hypertension ($140/90 mmHg or on therapy for hypertension)c HDL cholesterol level ,35 mg/dL (0.90 mmol/L) and/or a triglyceride level .250 mg/dL(2.82 mmol/L)

c Women with polycystic ovary syndromec Physical inactivityc Other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosisnigricans)

2. Patients with prediabetes (A1C$5.7% [39 mmol/mol], IGT, or IFG) should be tested yearly.

3. Women who were diagnosed with GDM should have lifelong testing at least every 3 years.

4. For all other patients, testing should begin at age 45 years.

5. If results are normal, testing should be repeated at a minimum of 3-year intervals, withconsideration of more frequent testing depending on initial results and risk status.

6. HIV

CVD, cardiovascular disease; GDM, gestational diabetes mellitus; IFG, impaired fasting glucose;IGT, impaired glucose tolerance.

Table2.4—Risk-based screening for type2diabetesorprediabetes inasymptomaticchildren and adolescents in a clinical setting (202)Testing should be considered in youth* who have overweight ($85th percentile) or obesity

($95th percentile) A and who have one or more additional risk factors based on thestrength of their association with diabetes:

c Maternal history of diabetes or GDM during the child’s gestation Ac Family history of type 2 diabetes in first- or second-degree relative Ac Race/ethnicity (Native American, African American, Latino, Asian American, PacificIslander) A

c Signs of insulin resistance or conditions associated with insulin resistance (acanthosisnigricans, hypertension, dyslipidemia, polycystic ovary syndrome, or small-for-gestational-age birth weight) B

GDM,gestational diabetesmellitus. *After theonset of puberty or after 10 years of age,whicheveroccurs earlier. If tests are normal, repeat testing at a minimum of 3-year intervals (or morefrequently if BMI is increasing or risk factor profile deteriorating) is recommended. Reports oftype 2 diabetes before age 10 years exist, and this can be considered with numerous risk factors.


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At least initially, and often throughouttheir lifetime, these individuals may notneed insulin treatment to survive.There are various causes of type 2

diabetes. Although the specific etiologiesare not known, autoimmune destructionofb-cells does not occur, and patients donot have any of the other known causesof diabetes. Most, but not all, patientswith type 2 diabetes have overweight orobesity. Excess weight itself causes somedegreeof insulin resistance.Patientswhodo not have obesity or overweight bytraditional weight criteria may have anincreased percentage of body fat distrib-uted predominantly in the abdominalregion.DKA seldom occurs spontaneously in

type 2 diabetes; when seen, it usuallyarises in association with the stress ofanother illness such as infection, myo-cardial infarction, or with the use ofcertain drugs (e.g., corticosteroids, atyp-ical antipsychotics, and sodium–glucosecotransporter 2 inhibitors) (64,65). Type2 diabetes frequently goes undiagnosedfor many years because hyperglycemiadevelops gradually and, at earlier stages,is oftennot severe enough for thepatientto notice the classic diabetes symptomscaused by hyperglycemia. Nevertheless,even undiagnosed patients are at in-creased risk of developingmacrovascularand microvascular complications.Patientswith type2diabetesmayhave

insulin levels that appear normal or el-evated, yet the failure to normalize bloodglucose reflects a relative defect inglucose-stimulated insulin secretion. Thus,insulin secretion is defective in thesepatients and insufficient to compensatefor insulin resistance. Insulin resistancemay improve with weight reduction, ex-ercise, and/or pharmacologic treatmentof hyperglycemia but is seldom restoredto normal. Recent interventions with in-tensive diet and exercise or surgical

weight loss have led to diabetes remis-sion (66–72) (see Section 8 “ObesityManagement for the Treatment of Type2 Diabetes,” https://doi.org/10.2337/dc21-S008).

The risk of developing type 2 diabetesincreases with age, obesity, and lack ofphysical activity. It occurs more fre-quently in women with prior gestationaldiabetes mellitus (GDM), with hyperten-sion or dyslipidemia, with polycysticovary syndrome, and in certain racial/ethnic subgroups (African American,American Indian, Hispanic/Latino, andAsian American). It is often associatedwith a strong genetic predisposition orfamily history in first-degree relatives(more so than type1diabetes). However,the genetics of type 2 diabetes ispoorly understood and under intenseinvestigation in this era of precisionmedicine (13). In adults without tra-ditional risk factors for type 2 diabetesand/or younger age, consider islet auto-antibody testing (e.g., GAD65 autoanti-bodies) to exclude the diagnosis of type 1diabetes.

Screening and Testing for Prediabetesand Type 2 Diabetes in AsymptomaticAdultsScreening for prediabetes and type 2 di-abetesriskthroughaninformalassessmentof risk factors (Table 2.3) or with anassessment tool, such as the ADA risktest (Fig. 2.1) (online at diabetes.org/socrisktest), is recommended to guideproviders on whether performing a di-agnostic test (Table 2.2) is appropriate.Prediabetes and type 2 diabetes meetcriteria for conditions in which earlydetection via screening is appropriate.Both conditions are common and im-pose significant clinical and publichealth burdens. There is often a longpresymptomatic phase before the di-agnosis of type 2 diabetes. Simple tests

to detect preclinical disease are readilyavailable. The duration of glycemic bur-den is a strong predictor of adverseoutcomes. There are effective interven-tions that prevent progression fromprediabetes to diabetes (see Section 3“PreventionorDelay of Type2Diabetes,”https://doi.org/10.2337/dc21-S003) andreduce the risk of diabetes complications(73) (see Section 10 “Cardiovascular Dis-ease and Risk Management,” https://doi.org/10.2337/dc21-S010, and Section 11“Microvascular Complications and FootCare,” https://doi.org/10.2337/dc21-S011).In the most recent National Institutesof Health (NIH) Diabetes PreventionProgram Outcomes Study (DPPOS)report, prevention of progression fromprediabetes to diabetes (74) resulted inlower rates of developing retinopathyand nephropathy (75). Similar impacton diabetes complications was reportedwith screening, diagnosis, andcomprehen-sive risk factor management in the U.K.Clinical Practice Research Datalink data-base (73). In that report, progression fromprediabetes to diabetes augmented riskof complications.

Approximately one-quarter of peoplewith diabetes in the U.S. and nearly halfof Asian and Hispanic Americans withdiabetes are undiagnosed (57,58). Al-though screening of asymptomatic indi-viduals to identify thosewithprediabetesor diabetes might seem reasonable, rig-orous clinical trials to prove the effec-tiveness of such screening have not beenconducted and are unlikely to occur.Basedonapopulation estimate, diabetesin women of childbearing age is under-diagnosed (76). Employing a probabilisticmodel, Peterson et al. (77) demonstratedcost and health benefits of preconcep-tion screening.

A large European randomized con-trolled trial compared the impact ofscreening for diabetes and intensivemultifactorial intervention with that ofscreening and routine care (78). Generalpractice patients between the ages of40 and 69 years were screened for di-abetes and randomly assigned by prac-tice to intensive treatment of multiplerisk factors or routine diabetes care. Af-ter 5.3 years of follow-up, CVD risk factorswere modestly but significantly improvedwith intensive treatment compared withroutine care, but the incidence of first CVDevents or mortality was not significantlydifferent between the groups (59). The

Table 2.5—Criteria defining prediabetes*FPG 100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 mmol/L) (IFG)

OR

2-h PG during 75-g OGTT 140 mg/dL (7.8 mmol/L) to 199 mg/dL (11.0 mmol/L) (IGT)

OR

A1C 5.7–6.4% (39–47 mmol/mol)

FPG, fasting plasma glucose; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; OGTT,oral glucose tolerance test; 2-h PG, 2-h plasma glucose. *For all three tests, risk is continuous,extending below the lower limit of the range and becoming disproportionately greater at thehigher end of the range.


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excellent care provided to patients in theroutine care group and the lack of anunscreened control arm limited the au-thors’ ability to determine whetherscreening and early treatment improvedoutcomes compared with no screening

and later treatment after clinical di-agnoses. Computer simulation model-ing studies suggest that major benefitsare likely to accrue from the early di-agnosis and treatment of hyperglyce-mia and cardiovascular risk factors in

type 2 diabetes (79); moreover, screen-ing, beginning at age 30 or 45 years andindependent of risk factors, may becost-effective (,$11,000 per quality-adjusted life year gainedd2010 mod-eling data) (80). Cost-effectiveness of

Figure 2.1—ADA risk test (diabetes.org/socrisktest).


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screening has been reinforced in cohortstudies (81,82).Additional considerations regarding

testing for type 2 diabetes and predia-betes in asymptomatic patients includethe following.

Age

Age is a major risk factor for diabetes.Testing should begin at no later than age45years for all patients. Screening shouldbe considered in adults of any age withoverweight or obesity and one or morerisk factors for diabetes.

BMI and Ethnicity

In general, BMI$25 kg/m2 is a risk factorfor diabetes. However, data suggest thatthe BMI cut point should be lower for theAsian American population (83,84). TheBMI cut points fall consistently between23 and 24 kg/m2 (sensitivity of 80%)for nearly all Asian American subgroups(with levels slightly lower for JapaneseAmericans). This makes a rounded cutpoint of 23 kg/m2 practical. An argumentcan bemade to push the BMI cut point tolower than 23 kg/m2 in favor of increasedsensitivity; however, this would lead toan unacceptably low specificity (13.1%).Data from WHO also suggests that aBMI of $23 kg/m2 should be used todefine increased risk in Asian Americans(85). The finding that one-third to one-half of diabetes in Asian Americans isundiagnosed suggests that testing isnot occurring at lower BMI thresholds(86,87).Evidence also suggests that other pop-

ulations may benefit from lower BMI cutpoints. For example, in a large multieth-nic cohort study, for an equivalent in-cidence rate of diabetes, a BMI of 30 kg/m2 in non-Hispanic Whites was equiva-lent to a BMI of 26 kg/m2 in AfricanAmericans (88).

Medications

Certain medications, such as glucocorti-coids, thiazide diuretics, some HIV med-ications (23), and atypical antipsychotics(66), are known to increase the risk ofdiabetes and should be considered whendeciding whether to screen.

HIV

Individuals with HIV are at higher riskfor developing prediabetes and diabe-tes on antiretroviral (ARV) therapies, soa screening protocol is recommended(89). The A1C test may underestimateglycemia in people with HIV; it is not

recommended for diagnosis and maypresent challenges for monitoring (24).In those with prediabetes, weight lossthrough healthy nutrition and physicalactivity may reduce the progression to-ward diabetes. Among patients with HIVand diabetes, preventive health careusing an approach used in patients with-out HIV is critical to reduce the risks ofmicrovascular and macrovascular com-plications. Diabetes risk is increased withcertain PIs and NRTIs. New-onset diabe-tes is estimated to occur in more than5% of patients infected with HIV on PIs,whereas more than 15% may have pre-diabetes (90). PIs are associated withinsulin resistance and may also lead toapoptosis of pancreatic b-cells. NRTIsalso affect fat distribution (both lip-ohypertrophy and lipoatrophy), whichis associated with insulin resistance. Forpatients with HIV and ARV-associatedhyperglycemia, it may be appropriateto consider discontinuing the problem-atic ARV agents if safe and effectivealternatives are available (91). Beforemaking ARV substitutions, carefully con-sider the possible effect on HIV virolog-ical control and the potential adverseeffects of new ARV agents. In somecases, antihyperglycemic agentsmay stillbe necessary.

Testing Interval

The appropriate interval between screen-ing tests is not known (92). The rationalefor the 3-year interval is that with thisinterval, thenumberof false-positive teststhat require confirmatory testing willbe reduced and individuals with false-negative tests will be retested beforesubstantial time elapses and complica-tions develop (92). In especially high-risk individuals, particularly with weightgain, shorter intervals between screen-ing may be useful.

Community Screening

Ideally, testing should be carried outwithin a health care setting because ofthe need for follow-up and treatment.Community screening outside a healthcare setting is generally not recommen-ded because people with positive testsmay not seek, or have access to, appro-priate follow-up testing and care. How-ever, in specific situations where anadequate referral system is establishedbeforehand for positive tests, commu-nity screening may be considered. Com-munitytestingmayalsobepoorlytargeted;

i.e., it may fail to reach the groups mostat risk and inappropriately test those atvery low risk or even those who havealready been diagnosed (93).

Screening in Dental Practices

Because periodontal disease is associ-ated with diabetes, the utility of screen-ing in a dental setting and referral toprimary care as a means to improve thediagnosis of prediabetes and diabeteshas been explored (94–96), with onestudy estimating that 30% of patients$30 years of age seen in general dentalpractices had dysglycemia (96,97). Asimilar study in 1,150 dental patients.40years old in India reported 20.69% and14.60% meeting criteria for prediabetesand diabetes using random blood glu-cose. Further research is needed to dem-onstrate the feasibility, effectiveness,and cost-effectiveness of screening inthis setting.

Screening and Testing for Prediabetesand Type 2 Diabetes in Children andAdolescentsIn the last decade, the incidence andprevalence of type 2 diabetes in childrenand adolescents has increased dramat-ically, especially in racial and ethnic mi-nority populations (53). See Table 2.4 forrecommendations on risk-based screen-ing for type 2 diabetes or prediabetes inasymptomatic children and adolescentsin a clinical setting (25). See Table 2.2 andTable 2.5 for the criteria for the diagno-sis of diabetes and prediabetes, respec-tively,whichapply tochildren,adolescents,and adults. See Section 13 “Children andAdolescents” (https://doi.org/10.2337/dc21-S013) for additional information ontype 2 diabetes in children and adolescents.

Some studies question the validity ofA1C in the pediatric population, especiallyamong certain ethnicities, and suggestOGTT or FPG as more suitable diagnostictests (98). However, many of these stud-ies do not recognize that diabetes di-agnostic criteria are based on long-termhealth outcomes, and validations are notcurrently available in the pediatric pop-ulation (99). The ADA acknowledgesthe limited data supporting A1C for di-agnosing type 2 diabetes in children andadolescents. Although A1C is not recom-mended for diagnosis of diabetes inchildren with cystic fibrosis or symptomssuggestive of acute onset of type 1 di-abetes and only A1C assays without


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interference are appropriate for chil-dren with hemoglobinopathies, theADA continues to recommend A1Cfor diagnosis of type 2 diabetes inthis cohort to decrease barriers toscreening (100,101).

CYSTIC FIBROSIS–RELATEDDIABETES

Recommendations

2.15 Annual screening for cysticfibrosis–related diabetes (CFRD)with an oral glucose tolerancetest should begin by age 10 yearsin all patients with cystic fibrosisnot previously diagnosed withCFRD. B

2.16 A1C is not recommended as ascreening test for cystic fibrosis–related diabetes. B

2.17 Patients with cystic fibrosis–related diabetes should betreated with insulin to attainindividualized glycemic goals. A

2.18 Beginning 5 years after the di-agnosis of cysticfibrosis–relateddiabetes, annual monitoring forcomplications of diabetes is rec-ommended. E

Cystic fibrosis–related diabetes (CFRD) isthemost common comorbidity in peoplewith cystic fibrosis, occurring in about20%of adolescents and 40–50%of adults(102). Diabetes in this population, com-pared with individuals with type 1 ortype 2 diabetes, is associated with worsenutritional status, more severe inflam-matory lung disease, and greater mor-tality. Insulin insufficiency is the primarydefect in CFRD. Genetically determinedb-cell function and insulin resistanceassociated with infection and inflamma-tion may also contribute to the devel-opment of CFRD.Milder abnormalities ofglucose tolerance are even more com-mon and occur at earlier ages than CFRD.Whether individuals with IGT should betreated with insulin replacement hasnotcurrentlybeendetermined.Althoughscreening for diabetes before the age of10 years can identify risk for progressionto CFRD in those with abnormal glucosetolerance, no benefit has been estab-lished with respect to weight, height,BMI, or lung function. OGTT is the rec-ommended screening test; however, re-cent publications suggest that an A1C cutpoint threshold of 5.5% (5.8% in a second

study) would detect more than 90%of cases and reduce patient screeningburden (103,104). Ongoing studies areunderway to validate this approach. Re-gardless of age, weight loss or failure ofexpected weight gain is a risk for CFRDand should prompt screening (103,104).The Cystic Fibrosis Foundation PatientRegistry (105) evaluated 3,553 cysticfibrosis patients and diagnosed 445(13%) with CFRD. Early diagnosis andtreatment of CFRD was associated withpreservation of lung function. The Eu-ropean Cystic Fibrosis Society PatientRegistry reported an increase in CFRDwith age (increased 10% per decade),genotype, decreased lung function, andfemale sex (106,107). Continuous glu-cose monitoring or HOMA of b-cellfunction (108) may be more sensitivethan OGTT to detect risk for progressiontoCFRD; however, evidence linking theseresults to long-term outcomes is lacking,and these tests arenot recommended forscreening outside of the research setting(109).

CFRD mortality has significantly de-creased over time, and the gap in mor-tality between cystic fibrosis patientswith and without diabetes has consid-erably narrowed (110). There are limitedclinical trial data on therapy for CFRD. Thelargest study compared three regimens:premeal insulin aspart, repaglinide, ororal placebo in cystic fibrosis patientswith diabetes or abnormal glucose tol-erance. Participants all hadweight loss inthe year preceding treatment; however,in the insulin-treated group, this patternwas reversed, and patients gained 0.39(6 0.21) BMI units (P 5 0.02). Therepaglinide-treated group had initialweight gain, but this was not sustainedby 6 months. The placebo group contin-ued to lose weight (110). Insulin remainsthe most widely used therapy for CFRD(111). The primary rationale for the use ofinsulin in patients with CFRD is to inducean anabolic state while promoting mac-ronutrient retention and weight gain.

Additional resources for the clinicalmanagement of CFRDcanbe found in theposition statement “Clinical Care Guide-lines forCysticFibrosis–RelatedDiabetes:A Position Statement of the AmericanDiabetes Association and a Clinical Prac-tice Guideline of the Cystic Fibrosis Foun-dation, Endorsed by the Pediatric EndocrineSociety” (112) and in the InternationalSociety for Pediatric and Adolescent

Diabetes’s 2014 clinical practice consen-sus guidelines (102).

POSTTRANSPLANTATIONDIABETES MELLITUS

Recommendations

2.19 Patients should be screened af-ter organ transplantation forhyperglycemia, with a formaldiagnosis of posttransplanta-tion diabetesmellitus being bestmade once a patient is stable onan immunosuppressive regimenand in the absence of an acuteinfection. B

2.20 The oral glucose tolerance testis the preferred test to make adiagnosis of posttransplanta-tion diabetes mellitus. B

2.21 Immunosuppressive regimensshown to provide the best out-comes for patient and graft sur-vival should be used, irrespectiveof posttransplantation diabetesmellitus risk. E

Several terms areused in the literature todescribe the presence of diabetes fol-lowing organ transplantation (113).“New-onset diabetes after transplanta-tion” (NODAT) is one such designationthat describes individuals who developnew-onsetdiabetes following transplant.NODAT excludes patients with pretrans-plant diabetes that was undiagnosedas well as posttransplant hyperglycemiathat resolves by the time of discharge(114). Another term, “posttransplanta-tion diabetes mellitus” (PTDM) (114,115),describes the presence of diabetes inthe posttransplant setting irrespectiveof the timing of diabetes onset.

Hyperglycemia is very common duringthe early posttransplant period, with;90% of kidney allograft recipients ex-hibiting hyperglycemia in the first fewweeks following transplant (114–117).In most cases, such stress- or steroid-induced hyperglycemia resolves by thetime of discharge (117,118). Althoughthe use of immunosuppressive therapiesis a major contributor to the develop-ment of PTDM, the risks of transplantrejection outweigh the risks of PTDMandthe role of the diabetes care provider isto treat hyperglycemia appropriately re-gardless of the type of immunosuppres-sion (114). Risk factors for PTDM includeboth general diabetes risks (such as age,


family history of diabetes, etc.) as wellas transplant-specific factors, such asuse of immunosuppressant agents (119).Whereas posttransplantation hypergly-cemia is an important risk factor forsubsequent PTDM, a formal diagnosisof PTDM is optimally made once thepatient is stable on maintenance immu-nosuppression and in the absence ofacute infection (117–120). In a recentstudy of 152 heart transplant recipients,38% had PTDM at 1 year. Risk factors forPTDM included elevated BMI, dischargefrom the hospital on insulin, and glucosevalues in the 24 h prior to hospitaldischarge (121). In an Iranian cohort, 19%hadPTDMafterheart and lung transplant(122). The OGTT is considered the goldstandard test for the diagnosis of PTDM(1 year posttransplant) (114,115,123,124).However, screening patients using fast-ing glucose and/or A1C can identify high-risk patients requiring further assessmentand may reduce the number of overallOGTTs required.Few randomized controlled studies

have reported on the short- and long-term use of antihyperglycemic agents inthe setting of PTDM (119,125,126).Moststudies have reported that transplantpatients with hyperglycemia and PTDMafter transplantation have higher ratesof rejection, infection, and rehospitaliza-tion (117,119,127). Insulin therapy is theagent of choice for the management ofhyperglycemia, PTDM, and preexistingdiabetes and diabetes in the hospitalsetting. After discharge, patients withpreexisting diabetes could go back ontheir pretransplant regimen if they werein good control before transplantation.Those with previously poor control orwith persistent hyperglycemia shouldcontinue insulin with frequent homeself-monitoring of blood glucose to de-terminewhen insulindose reductionsmaybe needed and when it may be appropri-ate to switch to noninsulin agents.No studies to date have established

which noninsulin agents are safest ormost efficacious in PTDM. The choiceof agent is usually made based on theside effect profile of the medicationand possible interactions with the pa-tient’s immunosuppression regimen(119). Drug dose adjustments may berequired because of decreases in theglomerular filtration rate, a relativelycommon complication in transplantpatients. A small short-term pilot study

reported that metformin was safe touse in renal transplant recipients (128),but its safety has not been determinedin other types of organ transplant. Thia-zolidinediones have been used success-fully in patients with liver and kidneytransplants, but side effects include fluidretention, heart failure, and osteopenia(129, 130). Dipeptidyl peptidase 4 inhib-itors do not interact with immunosup-pressant drugs and have demonstratedsafety in small clinical trials (131,132).Well-designed intervention trials exam-ining the efficacy and safety of theseand other antihyperglycemic agents inpatients with PTDM are needed.

MONOGENIC DIABETESSYNDROMES

Recommendations

2.22 All children diagnosed with di-abetes in the first 6 months oflife should have immediate ge-netic testing for neonatal dia-betes. A

2.23 Children and those diagnosed inearly adulthood who have di-abetes not characteristic of type1 or type 2 diabetes that occursin successive generations (sug-gestive of an autosomal domi-nantpatternof inheritance) shouldhave genetic testing for maturity-onset diabetes of the young. A

2.24 In both instances, consultationwith a center specializing in di-abetesgenetics is recommendedto understand the significanceof these mutations and howbest to approach further eval-uation, treatment, and geneticcounseling. E

Monogenic defects that cause b-celldysfunction, such as neonatal diabetesand MODY, represent a small fraction ofpatients with diabetes (,5%). Table 2.6describes the most common causes ofmonogenic diabetes. For a comprehen-sive list of causes, see Genetic Diagnosisof Endocrine Disorders (133).

Neonatal DiabetesDiabetes occurring under 6 months ofage is termed “neonatal” or “congenital”diabetes, and about 80–85% of cases canbe found to have an underlying mono-genic cause (134–137). Neonatal diabe-tes occursmuch less often after 6months

of age, whereas autoimmune type 1 di-abetes rarely occurs before 6 monthsof age. Neonatal diabetes can either betransient or permanent. Transient dia-betes is most often due to overexpres-sion of genes on chromosome 6q24, isrecurrent in about half of cases, and maybe treatablewithmedications other thaninsulin. Permanent neonatal diabetes ismost commonly due to autosomal dom-inant mutations in the genes encodingthe Kir6.2 subunit (KCNJ11) and SUR1subunit (ABCC8) of the b-cell KATP chan-nel. A recent report details a de novomutation in EIF2B1 affecting eIF2 signal-ing associated with permanent neonataldiabetes and hepatic dysfunction, similarto Wolcott-Rallison syndrome but withfew severe comorbidities (138). Correctdiagnosis has critical implications be-cause most patients with KATP-relatedneonatal diabetes will exhibit improvedglycemic control when treatedwith high-dose oral sulfonylureas instead of insu-lin. Insulin gene (INS) mutations are thesecond most common cause of perma-nent neonatal diabetes, and, while in-tensive insulin management is currentlythe preferred treatment strategy, thereare important genetic counseling consid-erations, as most of the mutations thatcause diabetes are dominantly inherited.

Maturity-Onset Diabetes of the YoungMODY is frequently characterized byonset of hyperglycemia at an early age(classically before age 25 years, althoughdiagnosismay occur at older ages).MODYis characterized by impaired insulin se-cretion with minimal or no defects ininsulin action (in the absence of coexis-tent obesity). It is inherited in an auto-somal dominant pattern with abnormalitiesin at least 13 genes on different chromo-somes identified to date. The most com-monly reported forms are GCK-MODY(MODY2), HNF1A-MODY (MODY3), andHNF4A-MODY (MODY1).

For individuals with MODY, the treat-ment implications are considerable andwarrant genetic testing (139,140). Clin-ically, patients with GCK-MODY exhibitmild, stable fasting hyperglycemia anddo not require antihyperglycemic ther-apy except sometimes during pregnancy.Patients with HNF1A- or HNF4A-MODYusually respond well to low doses ofsulfonylureas,which are consideredfirst-line therapy. Mutations or deletions inHNF1B are associated with renal cysts


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and uterine malformations (renal cystsand diabetes [RCAD] syndrome). Otherextremely rare formsofMODYhavebeenreported to involve other transcriptionfactor genes including PDX1 (IPF1) andNEUROD1.

Diagnosis of Monogenic DiabetesA diagnosis of one of the three mostcommon forms of MODY, including GCK-MODY, HNF1A-MODY, and HNF4A-MODY,allows for more cost-effective therapy(no therapy for GCK-MODY; sulfonylur-eas asfirst-line therapy forHNF1A-MODYand HNF4A-MODY). Additionally, diag-nosis can lead to identification of otheraffected family members. Genetic screen-ing is increasingly available and cost-effective (138,140).A diagnosis of MODY should be

considered in individuals who haveatypical diabetes and multiple familymembers with diabetes not characteris-tic of type 1 or type 2 diabetes, althoughadmittedly “atypical diabetes” is becom-ing increasingly difficult to precisely de-fine in the absence of a definitive set oftests for either type of diabetes (135–137,139–145). In most cases, the presence of

autoantibodies for type 1 diabetes pre-cludes further testing for monogenicdiabetes, but the presence of auto-antibodies in patients with mono-genic diabetes has been reported (146).Individuals inwhommonogenic diabetesis suspected should be referred to aspecialist for further evaluation if avail-able, and consultation is available fromseveral centers. Readily available com-mercial genetic testing following thecriteria listed below now enables acost-effective (147), often cost-saving,genetic diagnosis that is increasinglysupported by health insurance. A bio-marker screening pathway such asthe combination of urinary C-peptide/creatinine ratio and antibody screeningmay aid in determining who should getgenetic testing for MODY (148). It iscritical to correctly diagnose one ofthe monogenic forms of diabetes be-cause these patients may be incorrectlydiagnosedwith type 1 or type 2 diabetes,leading to suboptimal, even potentiallyharmful, treatment regimens and delaysin diagnosing other family members(149). The correct diagnosis is espe-cially critical for those with GCK-MODY

mutations where multiple studies haveshown that no complications ensue inthe absence of glucose-lowering therapy(150). Genetic counseling is recommen-ded to ensure that affected individualsunderstand the patterns of inheri-tance and the importance of a correctdiagnosis.

The diagnosis of monogenic diabe-tes should be considered in childrenand adults diagnosed with diabetes inearly adulthood with the followingfindings:

c Diabetes diagnosed within the first 6months of life (with occasional casespresenting later, mostly INS and ABCC8mutations) (134,151)

c Diabetes without typical features oftype 1 or type 2 diabetes (negativediabetes-associated autoantibodies,nonobese, lacking other metabolicfeatures, especially with strong fam-ily history of diabetes)

c Stable, mild fasting hyperglycemia(100–150 mg/dL [5.5–8.5 mmol/L]),stable A1C between 5.6% and 7.6%(between 38 and 60 mmol/mol), es-pecially if nonobese

Table 2.6—Most common causes of monogenic diabetes (133)

Gene Inheritance Clinical features

MODY GCK AD GCK-MODY: stable, nonprogressive elevated fasting blood glucose; typically doesnot require treatment; microvascular complications are rare; small rise in 2-h PGlevel on OGTT (,54 mg/dL [3 mmol/L])

HNF1A AD HNF1A-MODY: progressive insulin secretory defect with presentation inadolescence or early adulthood; lowered renal threshold for glucosuria; large risein 2-h PG level on OGTT (.90 mg/dL [5 mmol/L]); sensitive to sulfonylureas

HNF4A AD HNF4A-MODY: progressive insulin secretory defect with presentation inadolescence or early adulthood; may have large birth weight and transientneonatal hypoglycemia; sensitive to sulfonylureas

HNF1B AD HNF1B-MODY: developmental renal disease (typically cystic); genitourinaryabnormalities; atrophy of the pancreas; hyperuricemia; gout

Neonatal diabetes KCNJ11 AD Permanent or transient: IUGR; possible developmental delay and seizures;responsive to sulfonylureas

INS AD Permanent: IUGR; insulin requiringABCC8 AD Permanent or transient: IUGR; rarely developmental delay; responsive to

sulfonylureas6q24 (PLAGL1,

HYMA1)AD for paternalduplications

Transient: IUGR;macroglossia;umbilicalhernia;mechanisms includeUPD6,paternalduplication or maternal methylation defect; may be treatable with medicationsother than insulin

GATA6 AD Permanent: pancreatic hypoplasia; cardiac malformations; pancreatic exocrineinsufficiency; insulin requiring

EIF2AK3 AR Permanent: Wolcott-Rallison syndrome: epiphyseal dysplasia; pancreatic exocrineinsufficiency; insulin requiring

EIF2B1 AD Permanent diabetes: can be associated with fluctuating liver function (138)FOXP3 X-linked Permanent: immunodysregulation, polyendocrinopathy; enteropathy X-linked

(IPEX) syndrome: autoimmunediabetes, autoimmune thyroid disease, exfoliativedermatitis; insulin requiring

AD, autosomal dominant; AR, autosomal recessive; IUGR, intrauterine growth restriction; OGTT, oral glucose tolerance test; UPD6, uniparental disomyof chromosome 6; 2-h PG, 2-h plasma glucose.


PANCREATIC DIABETES ORDIABETES IN THE CONTEXT OFDISEASE OF THE EXOCRINEPANCREAS

Pancreatic diabetes includes both struc-tural and functional loss of glucose-normalizing insulin secretion in the con-text of exocrine pancreatic dysfunctionand is commonly misdiagnosed as type 2diabetes. Hyperglycemia due to generalpancreatic dysfunction has been called“type 3c diabetes” and, more recently,diabetes in the context of disease of theexocrine pancreas has been termed pan-creoprivic diabetes (1). The diverse setof etiologies includes pancreatitis (acuteand chronic), traumaor pancreatectomy,neoplasia, cystic fibrosis (addressed else-where in this chapter), hemochromato-sis, fibrocalculous pancreatopathy, raregenetic disorders (152), and idiopathicforms (1), which is the preferred termi-nology. A distinguishing feature is con-current pancreatic exocrine insufficiency(according to the monoclonal fecal elas-tase 1 test or direct function tests),pathological pancreatic imaging (endo-scopic ultrasound, MRI, computed to-mography), and absence of type 1diabetes–associated autoimmunity (153–157). There is loss of both insulin andglucagon secretion and often higher-than-expected insulin requirements. Risk formicrovascular complications is similar toother forms of diabetes. In the context ofpancreatectomy, islet autotransplanta-tion can be done to retain insulin secretion(158,159). In some cases, autotransplantcan lead to insulin independence. Inothers, it may decrease insulin require-ments (160).

GESTATIONALDIABETESMELLITUS

Recommendations

2.25 Test for undiagnosed prediabe-tes and diabetes at the firstprenatal visit in those with riskfactors using standard diagnos-tic criteria. B

2.26 Test for gestational diabetesmellitus at 24–28 weeks of ges-tation in pregnant women notpreviously found to have di-abetes. A

2.27 Test women with gestationaldiabetes mellitus for prediabe-tes or diabetes at 4–12 weekspostpartum, using the 75-g oralglucosetolerancetestandclinically

appropriate nonpregnancy diag-nostic criteria. B

2.28 Women with a history of ges-tational diabetes mellitus shouldhave lifelong screening for thedevelopment of diabetesor pre-diabetes at least every 3 years.B

2.29 Women with a history of ges-tational diabetes mellitus foundto have prediabetes should re-ceive intensive lifestyle inter-ventions and/or metformin toprevent diabetes. A

DefinitionFor many years, GDMwas defined as anydegree of glucose intolerance that wasfirst recognized during pregnancy (60),regardless of the degree of hyperglyce-mia. This definition facilitated a uniformstrategy for detection and classificationof GDM, but this definition has seriouslimitations (161). First, the best availableevidence reveals that many, perhapsmost, cases of GDM represent preexist-ing hyperglycemia that is detected byroutine screening in pregnancy, as rou-tine screening is not widely performedin nonpregnant women of reproductiveage. It is the severity of hyperglycemiathat is clinically important with regard toboth short- and long-term maternal andfetal risks. Universal preconception and/or first trimester screening is hamperedby lack of data and consensus regardingappropriate diagnostic thresholds andoutcomes and cost-effectiveness (162,163).A compelling argument for further workin this area is the fact that hyperglyce-mia that would be diagnostic of diabetesoutside of pregnancy and is present atthe time of conception is associated withan increased risk of congenital malfor-mations that is not seen with lowerglucose levels (164,165).

The ongoing epidemic of obesity anddiabetes has led to more type 2 diabetesin women of reproductive age, with anincrease in the number of pregnantwomen with undiagnosed type 2 diabe-tes in early pregnancy (166–169). Be-cause of the number of pregnant womenwith undiagnosed type 2 diabetes, it isreasonable to test women with risk fac-tors for type 2 diabetes (170) (Table 2.3)at their initial prenatal visit, using stan-dard diagnostic criteria (Table 2.2).Women found to have diabetes by thestandard diagnostic criteria used outside

of pregnancy should be classified ashaving diabetes complicating pregnancy(most often type 2 diabetes, rarely type1 diabetes or monogenic diabetes) andmanaged accordingly.Womenwhomeetthe lower glycemic criteria for GDMshould be diagnosed with that conditionandmanaged accordingly. Other womenshould be rescreened for GDM between24and28weeksof gestation (see Section14 “Management of Diabetes in Preg-nancy,” https://doi.org/10.2337/dc21-S014). The International Association ofthe Diabetes and Pregnancy Study Groups(IADPSG) GDM diagnostic criteria for the75-g OGTT as well as the GDM screeninganddiagnostic criteriaused in the two-stepapproach were not derived from data inthe first half of pregnancy, so the diagnosisofGDMinearlypregnancybyeither FPGorOGTT values is not evidence based (171)and further work is needed.

GDM is often indicative of underlyingb-cell dysfunction (172), which confersmarked increased risk for later develop-ment of diabetes, generally but not al-ways type 2 diabetes, in themother afterdelivery (173,174). As effective preven-tion interventions are available (175,176),women diagnosed with GDM should re-ceive lifelong screening for prediabetes toallow interventions to reduce diabetes riskand for type 2 diabetes to allow treatmentat the earliest possible time (177).

DiagnosisGDM carries risks for the mother, fetus,and neonate. The Hyperglycemia andAdverse Pregnancy Outcome (HAPO)study (178), a large-scale multinationalcohort study completed by more than23,000 pregnant women, demonstratedthat risk of adverse maternal, fetal,and neonatal outcomes continuously in-creased as a function of maternal glyce-mia at 24–28 weeks of gestation, evenwithin ranges previously considerednormal for pregnancy. For most compli-cations, there was no threshold forrisk. These results have led to carefulreconsideration of the diagnostic criteriafor GDM.

GDM diagnosis (Table 2.7) can be ac-complishedwith either of two strategies:

1. The “one-step” 75-g OGTT derivedfrom the IADPSG criteria, or

2. The older “two-step” approachwith a50-g (nonfasting) screen followed bya 100-g OGTT for those who screen


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positive, based on the work of Car-penter and Coustan’s interpretationof the older OʼSullivan (179) criteria.

Different diagnostic criteria will iden-tify different degrees of maternal hyper-glycemia andmaternal/fetal risk, leadingsomeexperts to debate, and disagree on,optimal strategies for the diagnosis ofGDM.

One-Step Strategy

The IADPSGdefineddiagnostic cut pointsfor GDM as the average fasting, 1-h, and2-h PG values during a 75-g OGTT inwomen at 24–28weeks of gestation whoparticipated in the HAPO study at whichodds for adverse outcomes reached 1.75times the estimated odds of these out-comes at the mean fasting, 1-h, and 2-hPG levels of the study population. Thisone-step strategy was anticipated to sig-nificantly increase the incidence of GDM(from 5–6% to 15–20%), primarily be-cause only one abnormal value, not two,became sufficient to make the diagno-sis (180). Many regional studies haveinvestigated the impact of adopting theIADPSG criteria on prevalence and haveseen a roughly one- to threefold increase(181). The anticipated increase in theincidence of GDM could have a substan-tial impact on costs and medical infra-structure needs and has the potential to

“medicalize” pregnancies previously cat-egorized as normal. A recent follow-upstudyofwomenparticipating in ablindedstudy of pregnancy OGTTs found that11 years after their pregnancies, womenwho would have been diagnosed withGDM by the one-step approach, ascompared with those without, were at3.4-fold higher risk of developing pre-diabetes and type 2 diabetes and hadchildrenwith a higher risk of obesity andincreased body fat, suggesting that thelarger group ofwomen identified by theone-step approach would benefit fromincreased screening for diabetes andprediabetes that would accompany ahistory of GDM (182,183). The ADA rec-ommends the IADPSG diagnostic crite-riawiththe intentofoptimizinggestationaloutcomes because these criteria arethe only ones based on pregnancy out-comes rather than end points such asprediction of subsequent maternaldiabetes.

The expected benefits of using IADPSGto the offspring are inferred from inter-vention trials that focused on womenwith lower levels of hyperglycemia thanidentified using older GDM diagnosticcriteria. Those trials found modest ben-efits including reduced rates of large-for-gestational-age births and preeclampsia(184,185). It is important tonote that 80–90% of women being treated for mild

GDMin these two randomized controlledtrials could be managed with lifestyletherapy alone. The OGTT glucose cutoffsin these two trials overlapped with thethresholds recommended by the IADPSG,and in one trial (185), the 2-h PG thresh-old (140 mg/dL [7.8 mmol/L]) was lowerthan the cutoff recommended by theIADPSG (153 mg/dL [8.5 mmol/L]). Norandomized controlled trials of treatingversus not treating GDM diagnosed bythe IADPSG criteria but not the Carpenter-Coustan criteria have been publishedto date. Data are also lacking on howthe treatment of lower levels of hyper-glycemiaaffects amother’s future risk forthe development of type 2 diabetes andher offspring’s risk for obesity, diabetes,and other metabolic disorders. Addi-tional well-designed clinical studies areneeded to determine the optimal in-tensity of monitoring and treatment ofwomenwith GDMdiagnosed by the one-step strategy (186,187).

Two-Step Strategy

In 2013, the NIH convened a consensusdevelopment conference to consider di-agnostic criteria for diagnosing GDM(188). The 15-member panel had repre-sentatives from obstetrics and gynecol-ogy, maternal-fetal medicine, pediatrics,diabetes research, biostatistics, and otherrelated fields. The panel recommended atwo-stepapproachtoscreeningthatuseda1-h 50-g glucose load test (GLT) followedby a 3-h 100-g OGTT for those whoscreened positive. The American Collegeof Obstetricians andGynecologists (ACOG)recommends any of the commonly usedthresholds of 130, 135, or 140 mg/dLfor the 1-h 50-g GLT (189). A systematicreview for the U.S. Preventive ServicesTask Force compared GLT cutoffs of 130mg/dL (7.2 mmol/L) and 140 mg/dL (7.8mmol/L) (190). The higher cutoff yieldedsensitivity of 70–88% and specificity of69–89%, while the lower cutoff was 88–99% sensitive and 66–77% specific. Dataregarding a cutoff of 135 mg/dL arelimited. As for other screening tests,choice of a cutoff is based upon thetrade-off between sensitivity and spec-ificity. The use of A1C at 24–28weeks ofgestation as a screening test for GDMdoes not function as well as the GLT(191).

Key factors cited by the NIH panel intheir decision-making process were thelack of clinical trial data demonstrating

Table 2.7—Screening for and diagnosis of GDMOne-step strategy

Perform a 75-g OGTT, with plasma glucose measurement when patient is fasting and at 1 and2 h, at 24–28 weeks of gestation in women not previously diagnosed with diabetes.

The OGTT should be performed in the morning after an overnight fast of at least 8 h.

The diagnosis of GDM is made when any of the following plasma glucose values are met orexceeded:

c Fasting: 92 mg/dL (5.1 mmol/L)c 1 h: 180 mg/dL (10.0 mmol/L)c 2 h: 153 mg/dL (8.5 mmol/L)

Two-step strategy

Step 1: Perform a 50-g GLT (nonfasting), with plasma glucose measurement at 1 h, at24–28 weeks of gestation in women not previously diagnosed with diabetes.

If the plasma glucose level measured 1 h after the load is$130, 135, or 140 mg/dL (7.2, 7.5, or7.8 mmol/L, respectively), proceed to a 100-g OGTT.

Step 2: The 100-g OGTT should be performed when the patient is fasting.

The diagnosis of GDM is made when at least two* of the following four plasma glucose levels(measuredfastingandat1,2, and3hduringOGTT)aremetorexceeded (Carpenter-Coustancriteria [193]):

c Fasting: 95 mg/dL (5.3 mmol/L)c 1 h: 180 mg/dL (10.0 mmol/L)c 2 h: 155 mg/dL (8.6 mmol/L)c 3 h: 140 mg/dL (7.8 mmol/L)

GDM, gestational diabetes mellitus; GLT, glucose load test; OGTT, oral glucose tolerance test.*American College of Obstetricians and Gynecologists notes that one elevated value can be usedfor diagnosis (189).


the benefits of the one-step strategy andthe potential negative consequences ofidentifying a large group of women withGDM, including medicalization of preg-nancy with increased health care utiliza-tion and costs. Moreover, screening witha 50-g GLT does not require fasting and istherefore easier to accomplish for manywomen. Treatment of higher-thresholdmaternal hyperglycemia, as identi-fied by the two-step approach, reducesrates of neonatal macrosomia, large-for-gestational-age births (192), and shoulderdystocia, without increasing small-for-gestational-age births. ACOG currentlysupports the two-step approach butnotes that one elevated value, as op-posed to two, may be used for the di-agnosis of GDM (189). If this approach isimplemented, the incidence of GDM bythe two-step strategy will likely increasemarkedly. ACOG recommends either oftwo sets of diagnostic thresholds for the3-h 100-g OGTTdCarpenter-Coustan orNational Diabetes Data Group (193,194).Each is based on different mathematicalconversions of the original recommen-ded thresholds byO’Sullivan (179),whichused whole blood and nonenzymaticmethods for glucose determination. Asecondary analysis of data from a ran-domized clinical trial of identification andtreatment of mild GDM (195) demon-strated that treatment was similarly ben-eficial in patients meeting only the lowerthresholds per Carpenter-Coustan (193)and in those meeting only the higherthresholds per National Diabetes DataGroup (194). If the two-step approach isused, it would appear advantageous touse the Carpenter-Coustan lower diag-nostic thresholds as shown in step 2 inTable 2.7.

Future Considerations

The conflicting recommendations fromexpert groups underscore the fact thatthere are data to support each strategy. Acost-benefit estimation comparing thetwo strategies concluded that the one-step approach is cost-effective only ifpatients with GDM receive postdeliverycounseling and care to prevent type 2diabetes (196). The decision of whichstrategy to implement must thereforebe made based on the relative valuesplaced on factors that have yet to bemeasured (e.g.,willingness tochangeprac-tice based on correlation studies ratherthan intervention trial results, available

infrastructure, and importance of costconsiderations).

As the IADPSG criteria (“one-stepstrategy”) have been adopted interna-tionally, further evidencehas emerged tosupport improved pregnancy outcomeswith cost savings (197), and IADPSG maybe the preferred approach. Data com-paring population-wide outcomes withone-step versus two-step approacheshave been inconsistent to date (198,199).In addition, pregnancies complicated byGDM per the IADPSG criteria, but notrecognized as such, have outcomes com-parable to pregnancies with diagnosedGDM by the more stringent two-stepcriteria (200,201). There remains strongconsensus that establishing a uniformapproach to diagnosing GDMwill benefitpatients, caregivers, and policy makers.Longer-term outcome studies are cur-rently underway.

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