13995448, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pedi.13410 by Consorci De Serveis Universitaris De Catalunya, Wiley Online Library on [04/12/2022].

See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Received: 26 August 2022 Accepted: 29 August 2022
DOI: 10.1111/pedi.13410

ISPAD GUIDELINES

ISPAD clinical practice consensus guidelines 2022: Stages

of type 1 diabetes in children and adolescents

Rachel E. J. Besser1 | Kirstine J. Bell2 | Jenny J. Couper3,4 | Anette-G. Ziegler5 |

6 7 8 9,10
Diane K. Wherrett | Mikael Knip | Cate Speake | Kristina Casteels |
Kimberly A. Driscoll11 | Laura Jacobsen12 | Maria E. Craig13 |
Michael J. Haller12
1
Wellcome Centre for Human Genetics, NIHR Biomedical Research Centre, University of Oxford, Oxford, UK
2
Charles Perkins Centre and Faculty Medicine and Health, University of Sydney, Sydney, Australia
3
Department of Pediatrics, University of Adelaide, South Australia, Australia
4
Robinson Research Institute, University of Adelaide, Adelaide, Australia
5
Institute of Diabetes Research, Helmholtz Zentrum München, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München,
Munich, Germany
6
Division of Endocrinology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada
7
Children's Hospital, University of Helsinki, Helsinki, Finland
8
Center for Interventional Immunology, Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA
9
Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium
10
Department of Development and Regeneration, KU Leuven, Leuven, Belgium
11
Department of Clinical and Health Psychology, University of Florida, Gainesville, Florida, USA
12
Division of Endocrinology, Department of Pediatrics, University of Florida, Gainesville, Florida, USA
13
Department of Pediatrics, The Children's Hospital at Westmead, University of Sydney, Sydney, Australia

Correspondence
Michael J. Haller, Pediatric Endocrinology, Department of Pediatrics, University of Florida Diabetes Institute, PO Box 100296, Gainesville, FL 32610, USA.
Email: [email protected]

1 | I N T RO DU CT I O N differ in low-income countries that may not be able to offer

screening.
This guideline serves as an update to and replacement of the 2018
ISPAD consensus guideline on stages of type 1 diabetes (T1D).
Herein, we provide an evidence-based summary of recommenda- 2 | W H A T I S N E W OR D I F F E R E N T
tions for screening children for T1D risk and discuss potential oppor-
tunities for clinical trials designed to delay progression to Stage • Stages 1, 2, 3, and 4 T1D are being used in clinical, research, and
3 T1D and preserve beta cell function in those with Stage 3 disease. regulatory settings.
We again use the American Diabetes Association's metrics for grad- • General population screening programs to determine T1D risk are
ing evidence from A through E. We acknowledge that priorities may expanding.
• Collaborative T1D networks testing interventions seeking to delay
the disease process at all stages of disease are growing.
• Tools to predict T1D and response to interventions are
The stages of type 1 diabetes (T1D) provide common ground for global efforts to prevent improving.
DKA and delay progression to disease in children and adolescents: An ISPAD consensus
• Anti-CD3 monoclonal antibody (teplizumab) is being evaluated by
guideline.
the U.S. Food and Drug Administration (FDA) for use to delay pro-
Rachel E. J. Besser and Kirstine J. Bell contributed equally to these guidelines as co-first
authors. gression from Stage 2 to Stage 3 T1D.

Pediatr Diabetes. 2022;1–13. wileyonlinelibrary.com/journal/pedi © 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. 1
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2 BESSER ET AL.

3 | E X E C U T I V E SU M M A R Y : 3.1 | Stages of T1D

R E C O M M E N D A T I O N S A N D P R I N C I P LE S
T1D is characterized by four stages as shown in Figure 1.
• Individuals with a first-degree relative with T1D have 15-fold Stage 1 Multiple islet autoantibodies, normal blood glucose, pre-
increased relative risk of developing T1D (A). symptomatic.
• Individuals with two or more islet autoantibodies and normoglyce- Stage 2 Multiple islet autoantibodies, abnormal glucose tolerance,
mia have stage 1 T1D (A). usually pre-symptomatic.
• The vast majority (80 - 90%) of children with multiple islet auto- Stage 3 Blood glucose above ADA diagnostic thresholds.
antibodies progress to Stage 3 within 15 years, compared with Stage 4 Established T1D.
15% who have a single islet autoantibody. Nearly 100% of chil- A proportion of individuals who have increased genetic risk of
dren with multiple autoantibodies will ultimately progress to T1D progress at variable rates to immune activation and the develop-
Stage 3 T1D (A). ment of islet autoimmunity. The development of 2 or more islet auto-
• Progression rates are similar between individuals with a family his- antibodies (Stage 1), is typically followed by a period of pre-clinical
tory of T1D and those from the general population (A). dysglycemia (Stage 2), though this stage may not be detected in all
• Targeted screening and monitoring identifies individuals with individuals if progression is rapid. Individuals who develop Stage
Stage 1, Stage 2, and pre-symptomatic Stage 3 diabetes, reduces 3 T1D may be asymptomatic or symptomatic. Established T1D is
the incidence of diabetic ketoacidosis (DKA), reduces rates of described as Stage 4 T1D.
hospitalization, and directs individuals toward studies seeking to
delay or prevent ongoing beta cell loss (A).
• General population screening programs using combinations of 3.2 | Risk of T1D
genetic and autoantibody testing can identify high-risk children (A).
• Both general population and targeted screening should be coupled Individuals with a first degree relative with T1D have an 15-fold
with education and monitoring programs for those identified with increased relative lifetime risk of T1D compared to the general popu-
autoantibodies (B). lation and the prevalence of T1D by age 20 years is 5% compared
• Autoantibody screening at ages 2 and 6 years may provide for to 0.3%, respectively.1–3 However 85% of individuals with a new
optimal sensitivity and positive predictive value in public health diagnosis do not have a family history of T1D.4,5
settings (B). The various stages inform the risk of progression; children with a
• When immunotherapies capable of delaying progression are single islet autoantibody have a  15% risk of reaching Stage 3 T1D
approved by regulatory bodies and economic issues related to within 10 years.6 In contrast, children at Stage 1 have a 44% 5-year
screening are optimized, general pediatric population screening for risk and 80≥90% 15-year risk of developing Stage 3 T1D, and children
islet autoantibodies is expected to be implemented in many regions at Stage 2 have a 75% 5-year risk and a 100% lifetime risk of develop-
(E). ing Stage 3 T1D.6–9
• Individuals who screen positive for genetic or immunological
markers of T1D, whether identified through research or
community-based screening programs, should have access to 3.2.1 | Genetic risk
information regarding available prevention studies (E).
• An oral glucose tolerance test (OGTT) is recommended to stage More than 70 genetic T1D variants have been identified through
disease in individuals with two or more islet autoantibodies prior genome-wide association studies.10 HLA DR and HLA DQ loci confer
to recruitment into prevention trials, and can be used to counsel approximately half of the genetic risk for T1D.11–13 The highest-risk
individuals on risk of progression (E). HLA haplotypes are DRB1*03:01-DQA1*05:01-DQB1*02:01 (also
• Self-monitoring of blood glucose (SMBG), HbA1c, and continuous expressed as DR3-DQ2) and DRB1*04-DQA1*03:01-DQB1*03:02
glucose monitoring (CGM) can be utilized to inform disease pro- (also expressed as DR4-DQ8). In the general population, children
gression and may be considered where OGTT is impractical or not with the HLA DR3-DQ2/DR4-DQ8 genotype have 5% risk for islet
available (E). autoimmunity and T1D.14–16 First-degree relatives carrying HLA
• SMBG and CGM are simple measures that can be taught and pro- DR3-DQ2/DR4-DQ8 have a further increase in risk that reaches
vided to families allowing real-time information to prevent 20%.15,17 Additional risk provided by non-HLA risk genes is roughly
DKA (E). equivalent to that provided by HLA DR-DQ alone.16 The highest non-
• As screening programs expand, individuals with early and late HLA genetic contribution arises from the INS and PTPN22 genes.18
Stage 2 and asymptomatic or symptomatic Stage 3 diabetes will be These, and other risk regions, are included in polygenic risk scores that
more commonly identified and additional sub-classifications or combine HLA and non-HLA genes to substantially improve risk esti-
stages are likely to be adopted (e.g., Stage 3a [asymptomatic] or mates for islet autoimmunity and T1D, particularly in the general pop-
Stage 3b [symptomatic]) (E). ulation.16,19,20 Notably, the risk of developing islet autoimmunity
 13995448, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pedi.13410 by Consorci De Serveis Universitaris De Catalunya, Wiley Online Library on [04/12/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
BESSER ET AL. 3

FIGURE 1 The stages of T1D (DiabetesTrialNet.org)

declines exponentially with age as does the influence of genetic fac- acceptability.29 In time, screening is likely to be embedded in local,
21–23
tors, although there is a paucity of data in adults. Furthermore, regional, and national health systems as the standard of care. That
once a child develops multiple islet autoantibodies, HLA and polygenic said, optimal models for screening and staging for T1D remain unclear
risk scores have only limited further predictive value for stratifying and will ultimately depend on several factors, including the screening
3,24–26
the rate of progression to diabetes. objective, the structure of the local health care system, and available
resources.

3.2.2 | Environmental exposures

3.3.1 | Goals of screening
The increasing incidence of T1D globally coupled with a reduction in
the proportion of individuals with the highest risk HLA haplotypes The long-term vision for T1D screening programs is to identify indi-
developing T1D, highlights the significant contribution environmen- viduals at risk of, or with early-stage, T1D to offer them interventions
27
tal exposures play in the pathogenesis of T1D. Different environ- to delay and, ultimately, prevent the condition. However, there are
mental exposures likely interact with multiple risk genes to drive the other important and currently achievable clinical benefits that drive
development of islet autoimmunity and the progression to Stage current recommendations for screening, including to:
3 T1D. Putative exposures are likely to vary across individuals and in
combination with different gene—environment and environment— 1. Prevent DKA and its associated short- and long-term morbidity
environment interactions. The impact of nutrition, growth, and infec- and mortality.
tions and their interactions with the “omic” biological systems have 2. Prepare children and families for a smoother transition to insulin
been investigated in epidemiological studies and in at-risk cohorts, therapy.
28
from birth, and more recently, from pregnancy. The onset of islet 3. Advance preventative therapies through clinical trial recruitment.
autoimmunity from infancy implicates very early life exposures in
some children.28 Screening programs significantly reduce DKA rates, usually to
less than 5%, and reduce hospitalization when coupled with long-
term monitoring.3,30–33 The rates of DKA at diagnosis range from
3.3 | Screening for pre-symptomatic T1D 15% to 70% in Europe and North America and as high as 80% in
under-resourced countries.34–39 DKA prevention at diagnosis has
Screening for risk of T1D is gaining international momentum. While potential lifelong benefits, including avoidance of acute morbidity
the majority of screening programs remain within the context of (cerebral oedema, shock), neurocognitive impairment, and mortal-
research trials, implementation science programs in Europe, the ity.40,41 There are also non-causal associations between DKA at
United States, and Australia are actively demonstrating feasibility and onset and future risk of DKA,38,42 severe hypoglycemia42 and long-
 13995448, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pedi.13410 by Consorci De Serveis Universitaris De Catalunya, Wiley Online Library on [04/12/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
4 BESSER ET AL.

term hyperglycemia43–45 which increases the risk of serious future of infants and toddlers who rapidly develop T1D in the first
diabetes-related complications.46 Furthermore, parental anxiety at 2 years of life and who have the highest rates of DKA with
diagnosis is approximately halved for children in screening programs the greatest risk for associated morbidities.36,37,55,56 Additional
3
compared to the general community. The additional time provided studies and analyses are needed to balance sensitivity, specificity,
for counseling, preparation for insulin therapy and education, deliv- public health priorities, cost, and local resources when developing
ered across time in the community or outpatient setting, may help specific screening programs.
reduce parental anxiety and smooth the transition to symptomatic Genetic risk factors can be used to identify the subset of children
T1D and insulin requirement.3,47 with an increased risk of T1D who would benefit most from islet auto-
Screening also identifies children suitable for recruitment into antibody screening. Such an approach57,58 has also been used in
clinical prevention trials, which include screening platforms such as GPPAD to efficiently identify children with the highest risk of devel-
T1D TrialNet, Type1Screen, Autoimmunity Screening for Kids (ASK), oping T1D for prevention trials (e.g., in the Primary Oral Insulin
INNODIA and GPPAD (Global Platform for the Prevention of Trial).59
Diabetes). Genetic risk can be broadly inferred through family history of
T1D, as in T1D TrialNet, or assessed using a polygenic risk score in
the general population. Some international programs, including
3.3.2 | Target population for screening GPPAD, evaluate polygenic risk scores from dried bloodspots col-
lected as part of the existing Newborn Screening Program, thereby
Given the current inability to intervene effectively in the T1D dis- leveraging existing infrastructure and reducing the need for an addi-
ease process, international debate continues about whether screen- tional screening intervention. As polygenic risk scores are a continu-
ing should be population-wide or limited to first-degree family ous scale, the threshold defining “at-risk” can be altered to suit the
members. Notably, current evidence suggests that the rate of dis- screening purpose. For example, lowering the threshold from the top
ease progression, once Stage 1 diabetes is confirmed, is not signifi- 1% to the top 10% of infants by risk, reduces their risk of T1D from
cantly different between individuals with a family member compared 10% to 2.4% but increases the number of future cases captured from
to the general population.6,48 Routine screening for family members 30% to 80%.16,19 A high threshold may be considered more effec-
as part of clinical care has been proposed as an intermediate step tive if the primary goal is to enroll children into prevention trials, while
toward general population screening.49 However, as DKA rates are lower thresholds may be better suited to efforts prioritizing DKA pre-
lower in individuals with a first-degree relative of T1D compared vention, because they capture a greater proportion of future
with those without42,50 and the vast majority of individuals (at least cases.36,38,55 Currently all polygenic risk scores for T1D have been
85%) who develop T1D do not have a family history of the disease, developed using largely Caucasian datasets. While the incidence of
meaningful DKA prevention will ultimately require population-wide T1D is higher in Caucasian individuals, a polygenic risk score that is
1,2,51
screening. either validated in or developed specifically for diverse ethnicities will
be required for population-wide routine screening.60

3.3.3 | Screening modalities

3.3.4 | Follow-up in high genetic risk children
There are currently two primary strategies used for T1D screening.
The optimal frequency of islet autoantibody testing in genetically
1. Population-wide islet autoantibody screening. high-risk individuals remains unclear. Clinical trials have utilized vary-
2. Genetic risk-stratified islet autoantibody screening. ing frequencies of antibody screening in high genetic risk children.
Some efforts have screened every 3 months through 2 years of life
Islet autoantibody screening aims to identify individuals in the (TEDDY), while some obtain annual antibodies, and others have pro-
target population with pre-symptomatic, Stage 1 or Stage 2 T1D. posed at least once between 1 and 5 years of age.59,61–63 More fre-
Advancements in islet autoantibody assays are enabling ultra-low quent monitoring may be beneficial in infants and toddlers, given their
blood volumes, including testing using capillary samples and dried rapid progression to Stage 3 T1D and increased risk of severe DKA.
bloodspots, which facilitate minimally invasive collection at Nevertheless, the economic and psychological impacts of repeated
home or in community settings.52,53 Several groups have tried to screening must always be considered.3,6
determine optimal ages for performing autoantibody screening;
modeled data from international cohort studies suggest the
sensitivity of one-off autoantibody screening between the ages of 3.3.5 | Glycemic surveillance in individuals with
3–5 years is 35% and can be improved to 50% with repeated islet autoimmunity
population screening at both 2–3 years and 5–7 years.21,54
Notably, sampling from 2 years of age does not capture all children Once a young person has multiple islet autoantibodies, they should be
who will develop T1D and misses the small, but important, subset offered glycemic staging and ongoing monitoring to identify disease
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BESSER ET AL. 5

progression. The intensity of those efforts should depend on the goals • Two-hour glucose 7.8–11.1 mmol/L (140–199 mg/dl) = Stage
of the family or any related research study and will be influenced by 2 (impaired glucose tolerance).
resource availability. Those seeking staging for potential inclusion in a • Two-hour glucose ≥11.1 mmol/L (≥200 mg/dl) = Stage 3 T1D.
prevention trial generally require an OGTT (see next section),
whereas, less intensive methods may be suitable in children who are In the presence of multiple islet autoantibodies, the addition of
identified or monitored outside of a research setting. Here, the goal other metrics such as age, sex, C-peptide, insulinoma-associated-2
should be to counsel families about future risk of Stage 3 T1D and the autoantibody (IA–2A), HbA1c, and BMI allows calculation of scores
options for glycemic monitoring, how to identify signs and symptoms which provide information on the risk of progression to stage 3 T1D.
of hyperglycemia, preparation for a smooth transition to insulin ther- These include the 5-timepoint Diabetes Prevention Trial-Type 1 Risk
apy and preventing DKA. Score (DPTRS),66,67 the two-timepoint DPTRS6068 and Index6069 and
the single timepoint M120.70 These scores have similar levels of per-
formance and are superior to using impaired glucose tolerance (IGT)
3.3.6 | Oral glucose tolerance test alone.68 While the majority of these scores have been developed
using data from first-degree relatives being monitored in longitudinal
In the setting of multiple autoantibodies, the standard 2-h oral glucose natural history studies,66–72 the recently published progression likeli-
tolerance test (OGTT) following 1.75 g/kg (75 g maximum) oral glu- hood score from the Fr1Da program showed a 48% 2 year progres-
cose administration remains the gold standard test for disease stag- sion rate from stage 2 T1D to stage 3 T1D in children identified from
ing58 (see “Stages of diabetes” section above). In addition, glucose the the general population.73
values of ≥11.1 mmol/L (≥200 mg/dl) obtained at 30, 60, and 90 min While the OGTT is recommended as the gold standard for staging
after glucose administration have been used in the research setting to children, especially those seeking entry into intervention trials, it is
inform the risk of progression. Furthermore, mid OGTT glucose values not always feasible or acceptable.74 Alternative approaches are dis-
≥11.1 mmol/L (≥200 mg/dl) can be used to formally diagnose Stage 3 cussed next (Table 1).
64,65
T1D in the setting of an elevated HbA1c or fasting glucose.
Categories for fasting plasma glucose (FPG) are defined as follows:
3.3.7 | Glycosylated hemoglobin (HbA1c)
• FPG <5.6 mmol/L (<100 mg/dl) = Stage 1 (normal fasting glucose)
• FPG 5.6–6.9 mmol/L (100–125 mg/dl) = Stage 2 (impaired fasting HbA1c is a specific but insensitive indicator of early onset diabetes.77
glucose) The risk of progression is increased in the context of: (1) 10% rise in
• FPG ≥7.0 mmol/L (≥126 mg/dl) = Stage 3 T1D HbA1c in the non-diabetic range on two consecutive occasions col-
lected 3–12 months apart (median time to “clinical diagnosis”:
Categories for 2-h plasma glucose following OGTT are defined as 1.1 years, hazard ratio 5.7)75; (2) two HbA1c values >41 mmol/mol
follows: (5.9%) (median time to “clinical diagnosis”: 0.9 year, hazard ratio 11.9);
and (3) HbA1c >39 mmol/mol (5.7%), which is an independent predic-
• Two-hour glucose <7.8 mmol/L (<140 mg/dl) = Stage 1 (normal tor for progression.3 Caution is needed in relying on HbA1c in young
glucose tolerance). children who may progress rapidly, and may be missed before a rise in

TABLE 1 Monitoring tools in children with multiple islet autoantibodies

Metric Pros Cons Information gained

OGTT Gold standard Requires glucose load and 2 to 5 blood draws Glycemic staging
Used to stage disease over 2 h Risk scores for progression
and (DPTRS, DPTRS60, Index60, M120)66–70
predict progression
Random venous glucose One-off sample Requires a blood draw Similar to 2-h OGTT-derived glucose71
Low cost
HbA1c Highly specific Insensitive, often normal in asymptomatic or Risk of progression to “clinical disease”:
Can use capillary recent onset Stage 3 diabetes, may be HbA1c >5.7%, or 10% rise over 3–
sample affected by disease states* 12 months75
CGM Use at home Optimal duration and frequency of CGM wear Risk of progression to “clinical disease”:
not yet determined. 10% > 7.8 mmol/L (>140 mg/dl)76
Cost and access issues. Realtime monitoring over 24 h
Self-monitoring blood Simple use at home Optimal timing and frequency have not been Immediate result
glucose determined, unconfirmed glucose values
a
See glycemic control targets and glucose monitoring chapter for further details.
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6 BESSER ET AL.

HbA1c can be observed or in the setting of an undiagnosed hemoglo- 3.4 | Psychological burden
binopathy or other conditions that affect erythrocyte turnover.78
A major concern with screening is engendering anxiety and imposing
disease monitoring burden prior to insulin requirement, especially
3.3.8 | Continuous glucose monitoring given there is currently no approved preventive therapy. The majority
of children screened as being at increased genetic risk will never
Normative data taken from children, adolescents, and adults who develop T1D16,19 and for those with early-stage T1D, the latency
are islet autoantibody-negative demonstrate a narrow variability in period may last years.64 “Positive” genetic and islet autoantibody
79
glucose using continuous glucose monitoring (CGM). CGM provides screening results are associated with increased parental stress,3,47,83,84
real-time data and may be useful in identifying children with increased particularly in mothers3,84; however this declines rapidly within
80
glucose variability in addition to elevated blood glucose levels. In 3–12 months.3,83 Furthermore, research programs that have monitored
the largest pediatric study to date assessing CGM as a tool to predict children both at high genetic risk and those identified through islet
progression, a cut-off of 10% time spent at >7.8 mmol/L (>140 mg/dl) autoantibody surveillance programs3 report reduced stress overall in
had an 80% risk of progression to Stage 3 T1D over 1 year (91% spec- children and their parents at the time when insulin therapy is needed
76
ificity, 97% NPV, 88% sensitivity, 67% PPV). However, further vali- compared to community controls. The Fr1da study showed that initial
dation is needed, especially in very young children, to provide better stress associated with multiple autoantibodies was only 50% of that
evidence of when and how to begin insulin therapy. seen in families where children were diagnosed outside of the screen-
ing program.3 These findings are likely explained by the high rates of
depression and parenting stress when T1D is diagnosed and requires
3.3.9 | Random venous glucose and self-monitoring emergency insulin therapy.85 The psychological burden in children and
fingerstick blood glucose parents who continue to undergo glycemic monitoring without devel-
oping Stage 3 T1D for some years remains uncertain.
In the Finnish DIPP study, the median time to diagnosis after a ran-
dom plasma glucose ≥7.8 mmoL/L (140 mg/dl), was 1.0 year in chil-
dren at Stage 1.71 Random plasma glucose is a simple and low-cost 3.5 | Cost-effectiveness
measurement with comparable predictive characteristics to that of
OGTT-derived 2-h glucose value, but with relatively poor sensitivity A major consideration is the total cost and the incremental cost-
of 21% (95% CI 16%, 27%) and a specificity of 94% (95% CI effectiveness for screening, education, and monitoring programs. Cost-
91%, 96%).71 effectiveness analyses in the United States for islet autoantibody-only
Surprisingly little evidence exists for the accuracy of capillary self- screening suggests that screening can be cost-effective with a 20%
monitoring fingerstick blood glucose (SMBG) in pre-symptomatic T1D reduction in DKA at diagnosis and a 0.1% (1.1 mmol/mol) reduction in
in childhood, but it is a simple method that could be used in isolation HbA1c during a lifetime.86,87 Further economic modeling is required,
or with other metrics. Adult data suggests that capillary glucose is a including assessment of different screening and monitoring models of
reliable comparator to venous glucose concentrations (85≥90% accu- care as well as in individual countries due to differing health systems,
81,82
racy for diabetes or IGT) during the OGTT. burden of T1D, and costs of treatment locally. In the future, approval of
preventive therapies will incur additional treatment costs but also likely
result in substantial healthcare cost-savings and improved health bene-
3.3.10 | Recommendations for staging and fits, further improving the incremental cost-effectiveness ratio.
monitoring In some,88–90 but not all91 lower resource countries, islet autoimmu-
nity and genetic risk may be more heterogeneous, adding further complex-
An OGTT is recommended as the gold standard for staging children ity to screening. Lower-resourced countries often have higher rates of
for recruitment into clinical trials. When OGTT is not feasible, alterna- DKA and DKA associated-mortality, however, the lower T1D incidences
tive approaches might include a 6–12 monthly HbA1c and 2-h post- in most of these countries may make screening efforts less cost-effective.
prandial or random glucose, dependent on risk stratification. More Priorities in such countries continue to be correct etiological diagnosis as
frequent monitoring may be offered to children at high risk of pro- well as access to and improvements in clinical care for Stage 3 T1D.
gression (e.g., those who seroconvert before age 2, with high IA–2A,
or ≥3 islet autoantibodies).3,6 If available, CGM could be added if dys-
glycemia is identified. HbA1c and CGM data can provide information 3.6 | Efforts to slow disease progression
on those progressing to insulin requirement within 12 months, pro-
viding an opportunity to counsel individuals/carers and to commence 3.6.1 | Primary and secondary prevention efforts
education as an outpatient. SMBG measurements can provide families
with real-time data to allow early detection of hyperglycemia and pre- Efforts to prevent the development of autoimmunity have historically
vention of DKA. been referred to as primary prevention, while efforts to delay
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BESSER ET AL. 7

TABLE 2 Primary59,63,95–99 and secondary93,100–113 prevention trials in pre-T1D and intervention94,114–133 trials in new onset T1D

Outcome
Trial Route Intervention Population Primary outcome achieved
Primary
prevention
BABYDIET PO Late gluten exposure Genetically at-risk infants Islet autoimmunity Unsuccessful
FINDIA PO Bovine insulin-free Genetically at-risk infants Islet autoimmunity Successful
formula
TRIGR PO Hydrolyzed casein Relatives, genetically at-risk infants Stage 3 Unsuccessful
formula
Pre-POInT PO Insulin Relative, HLA risk, AAb neg, 3–7 y AAb and T cell responses Successful
Pre-POInT- PO Insulin Relative, HLA risk, AAb neg, 6 m–2 y AAb and T cell responses Unsuccessfula
early
POInT PO Insulin Relative, HLA risk, AAb neg, 4–7 m Islet autoimmunity Ongoing
SINT1A PO B. Infantis probiotic Relative, genetic risk, 7 days–6 weeks Islet autoimmunity Ongoing
Secondary
prevention
CORD IV Autologous Cord Relative or Gen Pop, Age < 15, ≥2 Ab Stage 3 Ongoing
Blood
ENDIT PO Nicotinamide Relative, ICA+, normal OGTT Stage 3 Unsuccessful
DPT-1 IV/SC Insulin Relative, ICA+, IAA+, FPIR below Stage 3 Unsuccessful
threshold, 3–45 y
DPT-1 PO Insulin Relative, ICA+, IAA+, FPIR above Stage 3 Unsuccessfula
threshold, 3–45 y
DIPP IN Insulin HLA risk, ≥2 AAb + 1, 1–15 y Stage 3 Unsuccessful
INIT-I IN Insulin Relative, ≥1 Ab, normal FPIR, 4–32 y FPIR change Unsuccessful
INIT-II IN Insulin Relative, Stage 1, FPIR above threshold, Stage 3 Unsuccessful
4-30y
Belgian SC Insulin Relative, IA–2A+, 5–40 y Stage 3 Unsuccessful
registry
EPPSCIT SC Insulin Relative, ≥2 AAb, 7–14 y Stage 3 Unsuccessful
TN-07 PO Insulin Relative, Stage 1 (IAA+ required), 3–45 y Stage 3 Unsuccessfula
Fr1da PO Insulin Stage 1, 2–12 y Immune responders then Ongoing
Stage 2/3
DiAPREV-IT SC GAD Stage 1 (GADA+ required), 4–17 y Stage 3 Unsuccessful
TN-10 IV Teplizumab Stage 2, 8–45 y Stage 3 Successful
TN-18 IV Abatacept Stage 1, 6–45 y Stage 2 Ongoing
TN-22 PO Hydroxy-chloroquine Stage 1, 3–45 y Stage 2 or 3 Ongoing
Intervention
TN-05 IV Rituximab Stage 3, new onset, 8–40 y AUC C-peptide Successful
AbATE IV Teplizumab Stage 3, new onset, 8–30 y AUC C-peptide Successful
Protégé IV Teplizumab Stage 3, new onset, 8–35 y Insulin dose+HbA1c Unsuccessfula
T1DAL IM Alefacept Stage 3, new onset, 12–35 y AUC C-peptide Unsuccessfula
EXTEND IV Tocilizumab Stage 3, new onset, 6–17 y AUC C-peptide Unsuccessful
T-Rex IV Autologous Tregs Stage 3, new onset, 8–17 y AUC C-peptide Unsuccessful
TN-09 IV Abatacept Stage 3, new onset, 6–45 y AUC C-peptide Successful
START IV High-dose ATG Stage 3, new onset, 12–35 y AUC C-peptide Unsuccessfula
TN-19 IV Low-dose ATG Stage 3, new onset, 12–45 y AUC C-peptide Successful
T1GER SC Golimumab Stage 3, new onset, 6–21 y AUC C-peptide Successful
TN-14 SC Canakinumab Stage 3, new onset, 6–36 y AUC C-peptide Unsuccessful
PROTECT IV Teplizumab Stage 3, new onset, 8–17 y AUC C-peptide Ongoing

(Continues)
 13995448, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pedi.13410 by Consorci De Serveis Universitaris De Catalunya, Wiley Online Library on [04/12/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
8 BESSER ET AL.

TABLE 2 (Continued)

Outcome
Trial Route Intervention Population Primary outcome achieved
TN-08 SC GAD Stage 3, new onset, 3–45 y AUC C-peptide Unsuccessful
Diamyd SC GAD Stage 3, new onset, 10–20 y AUC C-peptide Unsuccessful
DIAGNODE-3 IL GAD Stage 3, ≤6 m duration, 12–28 y AUC C-peptide Ongoing
Anti-CD40 SC Iscalimab Stage 3, new onset, 6–21 y AUC C-peptide Ongoing
BANDIT PO Baricitinib Stage 3, new onset, 10–30 y AUC C-peptide Ongoing

Note: Stage 1 = multiple AAb-positive with normal glucose tolerance (via OGTT); Stage 2 = multiple AAb-positive with abnormal glucose tolerance; Stage
3 = clinical diagnosis of T1D. Bolded indicates emphasize those studies that have demonstrated capacity to prevent autoimmunity, delay progression of
T1D or preserve beta cell function.
Abbreviations: AAb, autoantibody; FPIR, first-phase insulin response; HLA, human leukocyte antigen; IL, intra-lymphatic; IM, intramuscular; IN, intranasal;
IV, intravenous; m, months; PO, per os (oral); SC, subcutaneous; y, years.
a
Post hoc subpopulation response.

progression from Stage 1 or Stage 2 to Stage 3 diabetes are referred medicine approach using targeted combination therapies and timing
to as secondary prevention (Table 2). While a number of proposed of treatment, driven by the individual patient genetic risk and
therapies have been studied, teplizumab, a monoclonal antibody tar- response biomarkers is likely to be the most effective means of inter-
geting the T cell surface marker CD3, is the only therapy that has, to vening in the disease process.136
date, demonstrated efficacy in delaying progression from Stage 2 to Clinical trials at Stage 3 of disease have historically not been avail-
92,93
Stage 3 T1D. This randomized, double-blind, placebo-controlled able in low-income countries. These trials have also enrolled study
trial demonstrated Stage 3 T1D onset was delayed by a median of populations that were predominantly Caucasian, in part due to study
2 years in first- or second-degree relatives of individuals with T1D, sites primarily located in the United States, Canada, United Kingdom,
aged 8–50 years old, with stage 2 T1D at the time of enrolment.92–94 Europe, and Australia. So far, neither efficacy nor risks have been
Subsequent analysis demonstrated that the median delay might shown to differ by racial/ethnic background in published Stage 3 trials;
actually have been as long as 3 years in subjects treated with however, it is possible such differences could be missed due to the
teplizumab versus placebo.93 Teplizumab is currently being reviewed preponderance of Caucasian participants. Moreover, there is emerging
by the U.S. FDA. If granted approval, teplizumab will become the evidence that GRS does not differ by ethnicity.
first immunotherapeutic with such a designation for individuals at
risk for T1D. Trials with other drugs targeting (1) autoimmune
responses; (2) antigen presentation; (3) glycemic dysregulation; and 4 | C O N C LU S I O N S A N D
(4) beta cell stress/dysfunction are also underway. RECOMMENDATIONS

Rapid expansion of screening and intervention networks, with the

3.6.2 | Stage 3 T1D Interventions overall aim to prevent progression to Stage 3 diabetes and preserve
beta cell function, has occurred in the last 5 years. General population
Stage 3 interventions or “new onset” studies seek to halt the disease, screening for T1D has been propelled by technological advances in
preserve residual β-cell function, and potentially delay or prevent the prediction of genetic risk, low volume autoantibody assays, and
complications of T1D in children and adults with newly diagnosed advancements in trials of interventions to slow the progression of
(6–12 weeks) Stage 3 T1D. Numerous efforts have been made to beta cell dysfunction. Screening to detect at-risk children offers the
intervene at this relatively late stage of the disease due to the ease in prospect of preventing DKA at presentation, and accelerated discov-
identifying individuals who might still receive benefit.134 Ultimately, ery of preventative interventions, through enhanced recruitment
relatively few agents are considered to have demonstrated capacity pools for clinical trials. Screening should therefore be accompanied by
to delay C-peptide decline in Stage 3 disease; namely, cyclosporine, clinical care pathways to first reduce risk of DKA, and second, provide
teplizumab, abatacept, alefacept, rituximab, golimumab, and low dose the young person or adult with age and stage-appropriate options to
anti-thymocyte globulin.94,122,126,127,135,136 However, a growing num- receive proven interventions or enter available intervention trials. If
ber of studies continue to focus on Stage 3. These studies not only effective immunotherapies to delay progression and preserve beta cell
have the prospect of providing direct benefit to newly diagnosed function are approved by regulatory bodies, and the cost/benefit ratio
patients but also provide required safety data, particularly in children, related to screening is optimized, it is expected that screening will
where C-peptide decline is faster than in adults, to support moving increasingly become standard practice within the general population.
therapies into Stage 1 or Stage 2 disease. Ultimately a personalized Primary prevention trials in infants and pre-schoolers are planned or
 13995448, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/pedi.13410 by Consorci De Serveis Universitaris De Catalunya, Wiley Online Library on [04/12/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
BESSER ET AL. 9

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