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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
© 2020 by the American Diabetes Association.Readersmayuse this
article as longas thework isproperly cited, the use is educational
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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
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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.
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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,
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Volume 44, Supplement 1, January 2021
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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.
S26 Classification and Diagnosis of Diabetes Diabetes Care
Volume 44, Supplement 1, January 2021
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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).
S28 Classification and Diagnosis of Diabetes Diabetes Care
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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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