The International Society for Pediatric and Adolescent Diabetes (ISPAD) guidelines represent a rich repository that serves as the only comprehensive set of clinical recommendations for children, adolescents, and young adults living with diabetes worldwide.

This guideline serves as an update to the 2022 ISPAD consensus guideline on staging for type 1 diabetes (T1D).

Key additions include an evidence-based summary of recommendations for screening for risk of T1D and monitoring those with early-stage T1D. In addition, a review of clinical trials designed to delay progression to Stage 3 T1D and efforts seeking to preserve beta-cell function in those with Stage 3 T1D are included.

Lastly, opportunities and challenges associated with the recent US Food and Drug Administration (FDA) approval of teplizumab as an immunotherapy to delay progression are discussed.

What Is New

Stages 1, 2a, 2b, 3a, 3b, and 4 type 1 diabetes (T1D) are being used in clinical, research, and regulatory settings.
General population screening programs for T1D are expanding in both research and clinical settings.
Effective screening and monitoring programs include individualized education, psychological support, and metabolic surveillance for those identified with islet autoantibodies.
The anti-CD3 monoclonal antibody (teplizumab) has been approved by the US Food and Drug Administration (FDA) to delay progression from Stage 2 to Stage 3 T1D
These insights emphasize that trials and effective screening and treatments in early-stage T1D need to be inclusive for all children and young people irrespective of geographic location and health systems.

Stage 2 includes multiple islet AABs confirmed on at least 2 samples with elevated fasting glucose or impaired glucose tolerance (IGT) documented by oral glucose tolerance test (OGTT), glycosylated hemoglobin (HbA1c) 5.7–6.5% (39–48 mmol/mol), or ≥10% change in HbA1c. Additional sub-classifications or stages are likely to be adopted as clinicians and researchers seek to describe specific subpopulations.

Stage 2a encompasses those with marginally elevated glucose levels.

Stage 2b includes those with glucose levels nearing Stage 3 thresholds (see section on OGTT for glycemic thresholds defining stage). While Stages 2a and 2b are formally defined in prior literature, we propose this nomenclature to provide clinicians and researchers with additional descriptive terms for these people.

Stage 3 includes hyperglycemia, meeting American Diabetes Association (ADA) glycemic and clinical diagnostic criteria. People may be symptomatic or asymptomatic. Additional sub-classifications or stages are likely to be adopted as clinicians and researchers seek to describe specific subpopulations.

Stage 3a describes those who are asymptomatic but who meet glycemic diagnostic criteria.

Stage 3b describes those with classic onset with overt hyperglycemia and symptoms (e.g., polyuria, polydipsia, and unexplained weight loss) and an immediate need for insulin initiation.

Stage 4 includes long-standing T1D. The stages of T1D inform the progression of the condition. Children with a single islet AAB do not have T1D but are considered “at risk” since they carry an approximately 15% risk of developing Stage 3 T1D within 15 years [1]. In contrast, children with 2 confirmed AABs have early-stage T1D. Among children living with Stage 1 (normoglycemia), 44% will progress to Stage 3 T1D in 5 years, and 80 to >90% will progress within 15 years. In children living with Stage 2 T1D (dysglycemia), 75% will progress to Stage 3 T1D in 5 years and nearly 100% during their lifetime [1‒4].

Development and Progression of T1D

People with a first-degree relative with T1D have up to a 15-fold increased risk of developing T1D compared to persons without a known family history of T1D [A].
People with two or more islet AABs have early-stage T1D and should no longer be referred to as being “at risk for T1D” [A].
The vast majority (90%) of young people with multiple islet AABs progress to Stage 3 within 15 years, compared to only 15% who have a single islet AAB [A].
Progression rates to Stage 3 T1D among those with two or more islet AABs are similar in people with a family history of T1D and those from the general population [A].

Screening for Early-Stage T1D

General population screening programs using AAB testing alone or combinations of genetic and AAB testing can identify children and young adults with, or at risk of T1D [A].
Screening and follow-up should be completed to identify people with Stages 1, 2, and 3a T1D, reduce the incidence of diabetic ketoacidosis (DKA) and hospitalization, and to direct individuals toward interventions or studies seeking to delay or prevent ongoing beta-cell loss [A].
Screening for islet AABs repeated twice during childhood may provide the most cost-effective means of identifying those who will develop T1D. Optimal ages for screening may depend on background population risk [B].
Screening should be coupled with education and metabolic surveillance programs for those identified with islet AABs [E].
As screening programs expand, individuals with Stages 1, 2a, 2b, and 3a T1D will be more commonly identified. Additional sub-classifications or stages are likely to be adopted as clinicians and researchers seek to describe specific subpopulations [E].
Consider offering access to information regarding available prevention studies to people who screen positive for genetic or immunological markers of T1D [E].
Optimal screening T1D risk programs will depend largely on resources available in individual countries and healthcare systems [E].

Goals of Screening

The long-term vision for T1D screening programs is to identify people at risk of or with early-stage T1D and offer them preventive approaches capable of delaying or preventing the condition entirely. Currently, achievable benefits driving recommendations for screening include the following:

1. Prevention of DKA and its associated short- and long-term morbidity and mortality. Rates of DKA at diagnosis of Stage 3 T1D are 15–80% worldwide in the general population [39‒44], whereas screening programs combined with long-term follow-up reduce DKA rates to less than 5% [7, 39, 40, 45, 46]. DKA prevention at diagnosis has potential lifelong benefits, including avoidance of acute morbidity (cerebral edema, shock), neurocognitive impairment, and mortality [47, 48]. There are also non-causal associations between DKA at onset and risk of future DKA episodes [42, 49], severe hypoglycemia [49], and suboptimal long-term glycemic outcomes identified in some [50‒53], but not all studies [54], which, may in turn, increase the risk of future diabetes-related complications [55].

2. Improving short-term outcomes (symptoms, weight loss, DKA, prolonged hospitalization) [40‒44].

3. Improving quality of life and reducing psychological burden at the time of T1D diagnosis. Caregiver anxiety and depressive symptoms increase in response to their child’s multiple islet AAB positive test results. Preparation for insulin therapy, education, and psychological support may help reduce caregiver anxiety and smooth the transition to Stage 3 T1D and insulin therapy [7, 47], but more research is needed in these areas.

4. Providing opportunities for people to participate in research studies. Despite the benefits associated with screening for T1D, potential harms must also be considered. For some people and families, screening leads to increased anxiety and depressive symptoms [48‒50] and many diagnosed with Stages 1, 2a, or 2b T1D have a limited understanding of its progression [50].

Glycemic Surveillance in Children and Young Adults with Islet Autoimmunity

International Society for Pediatric and Adolescent Diabetes (ISPAD) endorses the published 2024 Consensus Guidance for monitoring of children, adolescents and young adults with single and multiple islet AABs [E].
OGTT is recommended to stage T1D in people with 2 or more islet AABs and counsel them on T1D progression, and it is also recommended to be completed prior to recruitment into prevention trials [E].
Self-monitoring of fingerstick blood glucose, urinary glucose, HbA1c, and continuous glucose monitoring (CGM) are simple measures that can inform T1D progression and may be considered where OGTT is impractical or not available [E].
Surveillance frequency should depend on the risk of progression, with more frequent monitoring offered to children at higher risk of progression [E].
All families need to be counseled about the expected progression to Stage 3 T1D, how to cope with the often-unexpected diagnosis of early-stage T1D, options for glycemic monitoring, and how to identify signs and symptoms of hyperglycemia, and have a team to contact [E].
Partnerships between primary care providers and endocrinologists/diabetologists may be required to follow people with early-stage T1D [E].
Evaluation of all people with Stage 2 T1D by a pediatric endocrinologist/diabetologist is recommended [E].

Cost-Effectiveness

Screening for T1D risk may be cost-effective if the long-term glycemic benefits of early diagnosis and intervention are realized [B].
The potential cost-effectiveness of immune interventions is unknown at this time [E].

Conclusions

Screening for early-stage T1D is an important tool for both researchers and clinicians.

As evidenced by the success of both family history targeted and general population programs, screening and staging provide important opportunities to reduce DKA, begin education before insulin is required, offer condition-modifying immunotherapies, and encourage participation in studies seeking to delay progression to Stage 3 T1D.

In the coming years, general population screening programs will expand and a growing cohort of people with Stage 1 and Stage 2 T1D will be identified.

As detailed throughout this guideline, children and young people with early-stage T1D should receive personalized diabetes education, scheduled metabolic assessments, and appropriate psychological support.

Finally, with the approval of teplizumab in Stage 2 T1D in the USA, a growing list of agents capable of slowing beta-cell decline, and improving tools to screen and stage T1D, clinical and research programs will continue to rapidly evolve.

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En läkare och forskare vid University of Florida Health ledde ett internationellt team av experter på typ 1-diabetes som nyligen utvecklade nya behandlingsriktlinjer som betonar bredare screening för sjukdomen bland barn och ungdomar i den allmänna befolkningen innan symtom uppstår.

Det skulle inkludera screening av unga släktingar till personer med typ 1-diabetes, till exempel syskon, eftersom de har högre genetisk risk att utveckla diabetes.

Insatsen leddes av Michael Haller, M.D., chef för pediatrisk endokrinologi vid UF College of Medicine’s Department of Pediatrics och medlem av UF Diabetes Institute.

Riktlinjerna omfattar screening, stadieindelning och strategier för att bevara betacellernas funktion hos barn och ungdomar med typ 1-diabetes. De publicerades förra månaden i tidskriften Hormone Research in Paediatrics och ges ut under paraplyet av International Society for Pediatric and Adolescent Diabetes, eller ISPAD.

Riktlinjerna täcker cirka 20 olika aspekter av diabetesvården och uppdateras regelbundet av ISPAD. De spelar en viktig roll för att vägleda behandlingen för miljontals människor globalt.

”Typ 1-diabetes drabbar 1 av 300 personer, så det är inte en sällsynt sjukdom”, säger Haller. – Det är förmodligen den näst vanligaste kroniska sjukdomen i barndomen efter astma. Vi har vetat i flera decennier att sjukdomen kan identifieras tidigt. Den stora utmaningen är att vi egentligen inte hade något annat vi kunde göra åt det än att övervaka dessa barn och se dem fortsätta att utvecklas mot typ 1-diabetes.

Så är dock inte längre fallet.

I slutet av 2022 godkände den amerikanska läkemedelsmyndigheten FDA en läkemedelsbehandling som kallas teplizumab och som kan fördröja sjukdomsförloppet med i genomsnitt upp till två år hos vissa högriskpatienter. UF Health deltar i TrialNet, ett internationellt forskningskonsortium för att förebygga typ 1-diabetes, och var en av de större kliniska prövningsplatserna för sitt arbete med teplizumab.

”Teplizumab är en stor förändring för fältet och en som nu motiverar att erbjuda screening till ett mycket större antal människor nu när vi har möjlighet att fördröja sjukdomsprogressionen”, säger Haller.

Michael J. Haller, läkare

Tidig upptäckt av typ 1-diabetes minskar dramatiskt risken för komplikationer vid diagnos, vilket särskilt gäller för underbetjänade populationer som historiskt sett står inför en högre risk för diabetisk ketoacidos vid diagnos, säger Haller.

Diabetisk ketoacidos är en komplikation av diabetes där brist på insulin i slutändan leder till en ökning av livshotande syror, så kallade ketoner, i blodet.

Han noterade också att screening av barn utanför förstagradssläktingar som har typ 1-diabetes kommer att kräva att fler allmänläkare och allmänna barnläkare utbildas om vad de kan göra med data.

”Det kommer bara att understryka bristen på barnendokrinologer”, säger Haller. – Vi är en väldigt liten subspecialitet och det blir allt svårare att rekrytera folk till området. Vi behöver sätta ljuset på behovet av att fler människor kommer in i branschen. Vi måste inspirera nästa generation av framtida läkare att satsa på karriärer inom barnendokrinologi.

Att göra det, tillade han, kan kräva statlig och federal politik för att uppmuntra läkare att komma in på området.

Haller sa att UF Diabetes Institute förmodligen är bland de fem främsta centra globalt som undersöker typ 1-diabetes.

”Vi har ett fantastiskt forskarteam som spänner över hela spektrumet, från mycket grundläggande vetenskap till mycket translationellt arbete”, säger han. ”Vi kommer att fortsätta att göra dessa saker nationellt och internationellt med hopp om att i slutändan utveckla behandlingar som varaktigt kan förebygga sjukdomen och kanske en dag till och med vända den.”

Laura Jacobsen, M.D., biträdande professor vid UF College of Medicine’s Department of Pediatrics och forskare vid UF Diabetes Institute, bidrog också till ISPAD:s riktlinjer.

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