Oralt insulin fördröjde insjuknandet hos vissa barn med förhöjd risk för typ 1-diabetes

 

 

Nu har forskarna fått svaret på frågan om oralt insulin kan förhindra tidiga tecken på typ 1-diabetes eller klinisk diagnos hos små barn med förhöjd risk att utveckla sjukdomen. Även om behandlingen inte kunde förhindra utvecklingen av diabetesrelaterade autoantikroppar fördröjde oralt insulin sjukdomshastigheten hos barn som utvecklade sådana autoantikroppar. Omkring 170 svenska barn har deltagit i den internationella studien POInT, som publicerar sina resultat i den vetenskapliga tidskriften The Lancet.

 

 

Kortfakta om studien:

Typ 1-diabetes //

Klinisk forskning //

Peer review-granskad publikation //

Forskarinitierad studie //

Randomiserad intervention //

Två grupper barn med hög genetisk risk för typ 1-diabetes //

Multicenter

studie, fas II, dubbelblind prövning

 

Studien POInT har undersökt om förebyggande behandling med oralt insulin kan förhindra utvecklingen av diabetesrelaterade autoantikroppar och typ 1-diabetes hos barn med förhöjd genetisk risk att utveckla sjukdomen. Sådana autoantikroppar används som biomarkör för typ 1-diabetes och förekomsten av två eller flera autoantikroppar ses som ett förstadium till sjukdom.

Den internationella studien omfattar 1050 barn från Sverige, Tyskland, Polen, Belgien och Storbritannien. Hälften av barnen fick daglig behandling med oralt insulin medan den andra hälften fick placebo under sina tre första levnadsår. Vid typ 1-diabetes reagerar immunsystemet felaktigt på de insulinproducerande betacellerna i bukspottkörteln och förstör dem.

 

– Alla barn som har deltagit i studien har gjort en enorm insats tillsammans med sina föräldrar. Oralt insulin tas upp av munhålan och tarmkanalen och vi har undersökt om det kan leda till större tolerans för kroppens eget insulin hos små barn med förhöjd risk för sjukdomen, säger Helena Elding Larsson, vetenskapligt ansvarig för den svenska delen av studien POInT och medförfattare till studien i The Lancet.

 

 

• Fördröjde sjukdomshastigheten

Trots att barnen fick en hög dos av oralt insulin kunde behandlingen inte förhindra utvecklingen av diabetesrelaterade autoantikroppar. Däremot fördröjde oralt insulin sjukdomshastigheten hos barn som fick diabetesrelaterade autoantikroppar. När forskarna jämförde sjukdomshastigheten hos gruppen som fick oralt insulin med kontrollgruppen kunde de se att behandlingen ledde till att sjukdomshastigheten minskade med nästan 50 procent, från upptäckten av två eller flera diabetesrelaterade autoantikroppar till klinisk diabetes.

 

– Naturligtvis är det tråkigt att oralt insulin inte kunde förhindra utvecklingen av typ 1-diabetes. Det är däremot positivt att oralt insulin tycks fördröja sjukdomshastigheten hos barn med diabetesrelaterade autoantikroppar och vi behöver nu bekräfta dessa resultat i nya studier. Typ 1-diabetes är en besvärlig sjukdom att ha och det kan betyda en hel del om det går att fördröja sjukdomen med några år. Det innebär färre år med insulinbehandling och minskad risk för att drabbas av komplikationer, säger Helena Elding Larsson, professor i autoimmuna sjukdomar vid Lunds universitets diabetescentrum och barnläkare vid Skånes universitetssjukhus.

 

Barnens genetiska risk för att utveckla typ 1-diabetes har kartlagts och med hjälp av denna information har forskarna lyckats identifiera en grupp barn som tycks ha särskild nytta av behandlingen. Oralt insulin var förknippat med betydelsefullt skydd mot diabetes hos deltagare med en viss genuppsättning som fanns hos över hälften av alla deltagare och som återfinns hos omkring 60 procent av alla som har typ 1-diabetes.

 

– Det är för tidigt att dra säkra slutsatser eftersom det handlar om en mindre grupp deltagare. Jag tycker att det skulle vara väldigt intressant om vi som har samarbetat inom studien kan göra uppföljande studier där vi testar behandlingen på ett noggrant genetiskt urval av barn. Studien visar att oralt insulin är en säker behandling som inte ger några allvarliga biverkningar, säger Markus Lundgren, forskare i pediatrisk endokrinologi vid Lunds universitets diabetescentrum som har varit med och lett den svenska delen av studien.

 

Skydda insulinproducerande celler

Teplizumab är för närvarande den enda godkända behandlingen som används i vissa länder för att fördröja insjuknandet av typ 1-diabetes hos barn som redan har fått diabetesrelaterade autoantikroppar. Vid Lunds universitets diabetescentrum pågår flera studier som undersöker om det är möjligt att förhindra eller fördröja insjuknandet hos barn med förhöjd risk att utveckla sjukdomen i ett ännu tidigare skede.

 

– Vi är inne i ett spännande skede av diabetesforskningen och en viktig målsättning för oss är att identifiera skonsamma behandlingar som kan sättas in i ett tidigt skede. Resultaten från POInT tyder på att förebyggande behandlingar kan behöva skräddarsys beroende på vilka genetiska varianter barnet har.  Även om vi har bra insulinpumpar och hjälpmedel för personer som drabbas av typ 1-diabetes behöver vi utveckla fler behandlingar som kan skydda de insulinproducerande cellerna i olika skeden av livet, säger Helena Elding Larsson.

Publikation
Efficacy of once-daily, high-dose, oral insulin immunotherapy in children genetically at risk for type 1 diabetes (POInT): a European, randomised, placebo-controlled, primary prevention trial, The Lancet

DOI: 10.1016/S0140-6736(25)01726-X

 

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Artificial Intelligence (AI) is playing an increasingly important role in the prevention, diagnosis, and management of diabetes. Here’s a detailed overview of how AI is transforming diabetes care:

https://www.lu.se/search/AI/all/1/undefined

 

 

Press release Lunds universitet

_______________________________

 

Läs mer hels studien i publikation, pdf, free

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)01726-X/fulltext?rss=yes

 

ABSTRACT

Efficacy of once-daily, high-dose, oral insulin immunotherapy in children genetically at risk for type 1 diabetes (POInT): a European, randomised, placebo-controlled, primary prevention trial

Prof Anette-Gabriele Ziegler, MDa,b,c  ∙ Peter Achenbach, MDa,b,c ∙ Andreas Weiß, MSca,c ∙ Prof Reinhard Berner, MDd ∙ Kristina Casteels, MDe,f ∙ Prof Helena Elding Larsson, MDg,h ∙ et al. Show more

Summary
Background
Type 1 diabetes begins with autoimmunity against pancreatic islet antigens, including insulin. The aim of the Primary Oral Insulin Trial (POInT) was to evaluate the efficacy and safety of daily high-dose oral insulin to prevent the development of islet autoantibodies and diabetes.

Methods
In this randomised, controlled, primary prevention trial, genetic screening in seven obstetric and paediatric clinics in Germany, Poland, Sweden, Belgium, and the UK identified newborns with a greater than 10% risk of developing islet autoimmunity. Eligible infants aged 4–7 months were randomly assigned in a 1:1 ratio to receive insulin manufactured from human zinc–insulin crystals administered orally at a once-daily dose of 7·5 mg for 2 months, increasing to 22·5 mg for 2 months and 67·5 mg until age 3 years, or placebo. Participants were randomly assigned via a web-based application and were stratified by site.

The primary outcome was the development of two or more islet autoantibodies or diabetes assessed throughout follow-up until a maximum age of 6·5 years. A secondary outcome was the development of dysglycaemia or diabetes. Islet autoantibodies were measured in samples collected at baseline and during study visits conducted at outpatient clinics at 2, 4, and 8 months after randomisation, at age 18 months, and every 6 months thereafter.

All participants and their family members, investigators of the study, and laboratory personnel remained masked to treatment allocation during the whole study. All randomly assigned participants who correctly fulfilled eligibility criteria and had not reached the primary outcome at the baseline visit (modified intention-to-treat) were included in the primary analysis. All participants who received at least one dose of study drug were included in the safety analysis. POInT is registered with ClinicalTrials.gov (NCT03364868) and is complete.

 

Findings
Of 241 977 screened newborns, 2750 (1·14%) had an elevated genetic risk of developing islet autoimmunity and 1050 (38·2%) of the eligible infants (531 males [51%], 519 females [49%]), were assigned to oral insulin or placebo between Feb 7, 2018, and March 24, 2021. Two participants in the oral insulin group and none in the placebo group were excluded from the modified intention-to-treat analysis.

The primary outcome developed in 52 (10%) participants in the insulin group and 46 (9%) in the placebo group (hazard ratio 1·12 [95% CI 0·76–1·67], p=0·57).

An interaction between treatment and the INS rs1004446 genotype was observed, with an increase in the primary outcome in participants in the insulin group carrying non-susceptible INS genotypes compared with the placebo group (2·10 [1·08–4·09]) and protection against diabetes or dysglycaemia in participants in the insulin group carrying susceptible INS genotypes compared with the placebo group (0·38 [0·17–0·86]).

Blood glucose values less than 50 mg/dL were observed in two (0·03%) of 7210 measurements in the insulin group and six (0·08%) of 7070 measurements in the placebo group. Of 10 252 reported adverse events, 5076 (49·5%) occurred in 507 (96·0%) of 528 participants in the oral insulin group and 5176 (50·5%) occurred in 500 (95·8%) of 522 participants in the placebo group. One death occurred in the oral insulin group and was unrelated to the study drug following independent review.

 

Interpretation
There was no evidence that high-dose, daily oral insulin prevents the development of islet autoantibodies.

 

Funding
Leona M and Harry B Helmsley Charitable Trust.

 

 

Utdrag ur publikation

Research in context
Evidence before this study
For the background in preparing the protocol (submitted to regulators on July 6, 2017) we searched MEDLINE, PubMed, ClinicalTrials.gov, EudraCT, Embase, the Cochrane Central Register of Clinical Trials, and WHO Clinical Trials Registry Platform from Jan 1, 1990, to March 31, 2017, using the keywords “T1D”, “type 1 diabetes”, “oral insulin”, “oral immunotherapy”, “randomised clinical trials”, AND “islet autoantibodies” without language restrictions. We also hand-searched reviews with these search terms published between Jan 1, 1990, and March 31, 2017. The search revealed one phase 2b, randomised, double-blind, placebo-controlled secondary prevention trial evaluating the efficacy of once-daily 7·5 mg oral insulin to delay the onset of type 1 diabetes in individuals who were islet autoantibody positive. No treatment effect was observed in the trial, although a post-hoc analysis showed a significant delay in type 1 diabetes in a subgroup with high-titre insulin autoantibodies who received oral insulin. A small, dose-finding, double-blind, randomised controlled study in islet autoantibody-negative children with high genetic risk for type 1 diabetes (Pre-POInT) identified an immune response to insulin in participants who received a once-daily dose of 67·5 mg oral insulin. Searches were updated to March 31, 2025, revealing one phase 2a, randomised, double-blind, placebo-controlled trial of oral insulin at the doses used in POInT (Pre-POInT early), which showed no safety concerns down to an age of 6 months and an association of an immune response to insulin with type 1 diabetes-susceptible INSgenotypes, but was not designed to assess efficacy. A second phase 2b, randomised, double-blind, placebo-controlled trial done in individuals after the onset of islet autoantibodies (TN07) reported no overall effect of once-daily 7·5 mg oral insulin to delay the onset of type 1 diabetes, but a treatment effect in prespecified strata and in post-hoc analyses in participants with HLA DR4 alleles and IA-2 autoantibodies. No randomised controlled trial assessing the efficacy of treatment with a type 1 diabetes autoantigen administered before the appearance of islet autoantibodies was found. Additional searches were done using the keywords “autoimmune disease”, “autoantigen”, “oral immunotherapy”, “randomised clinical trials”, AND “autoantibodies”, revealing no additional trials evaluating the efficacy of oral autoantigen immunotherapy for the prevention of autoimmunity before the development of autoantibodies or disease symptoms.

Added value of this study
POInT is the first randomised, double-blind, placebo-controlled trial to test the efficacy of autoantigen-based therapy (oral insulin) for preventing islet autoimmunity and the first to examine the effect of high-dose oral insulin on the development of type 1 diabetes. It is also the first trial to use newborn genetic screening to enrol infants from the general population who are at risk for type 1 diabetes. The study showed the feasibility of newborn screening and recruitment into primary prevention trials, randomly assigning 1050 infants in 3·1 years, and confirmation of the predicted risk of greater than 10% for early stage type 1 diabetes in eligible infants. The primary outcome was the development of early stage 1, 2, or 3 type 1 diabetes (two or more islet autoantibodies or diabetes). The study found that daily oral insulin treatment did not reduce the incidence of islet autoantibodies. A prespecified analysis showed that treatment was associated with a slower progression to clinical (stage 3) type 1 diabetes in participants who developed islet autoantibodies, suggesting that high-dose oral insulin therapy commenced before the onset of autoimmunity delays the onset of diabetes. A key susceptibility gene for type 1 diabetes is the INS gene, which encodes the treatment antigen—a major autoantigen target of childhood type 1 diabetes. The study found a pharmacogenetic interaction between the treatment and genotypes of this gene. The treatment protected against developing stage 2 or 3 type 1 diabetes in participants with a susceptible genotype. In contrast, treatment was associated with an increased incidence of islet autoantibodies in participants with a non-susceptible genotype. High-dose oral insulin immunotherapy was safe and well tolerated, suggesting that it is suitable for further trials assessing its therapeutic value in preventing type 1 diabetes.
Implications of all the available evidence

At present, teplizumab is the only drug approved in some countries, including the USA, for delaying the onset of clinical type 1 diabetes in individuals with stage 2 type 1 diabetes. No drug is approved or has shown efficacy in earlier stages or given as a primary prevention treatment. Despite no evidence of an effect on the development of islet autoantibodies, our prespecified analyses suggest that daily oral insulin given as a primary prevention therapy can safely modify disease progression. This provides a premise for suitably powered future trials that test this hypothesis. Furthermore, the novel pharmacogenetic interaction supports the concept of personalised antigen-specific therapy based on a priori genetic selection for susceptibility to insulin autoimmunity (HLA DR4 and susceptible INS genotypes) and is supported by the post-hoc observation of oral insulin treatment efficacy in HLA DR4-positive individuals in the TN07 trial. All available evidence, therefore, indicates that autoantigen-specific therapy should be considered as a worthwhile strategy to prevent or delay clinical type 1 diabetes and that the success of this strategy will likely depend on appropriate genetic selection for treatment and timing of the intervention. Genetic selection for trial participation is feasible and successful through newborn screening. Further trials are required to support our observations and to explore different treatment schedules.

 

 

Introduction
Preventing disease through early intervention is a compelling alternative to chronic disease management. Primary prevention of food allergy can be achieved by oral immunotherapy during infancy.1,2 However, this approach has not been tested for autoimmune diseases.
Type 1 diabetes is an autoimmune disease with an incidence that has increased globally over recent decades.3 Over 9 million people are living with type 1 diabetes, including 2·7 million in Europe and 1·8 million children and adolescents worldwide.4 Insulin is a key early autoantigen in childhood type 1 diabetes. Autoantibodies against insulin often appear in genetically susceptible children in the first years of life.5 This loss of immune tolerance to insulin frequently leads to more generalised islet autoimmunity and clinical diabetes.6 The autoimmunity against insulin is strongly associated with the HLA DRB1*04-DQB1*0302 haplotype and genotypes of the INS gene, which encodes insulin.7,8
Attempts have been made to prevent type 1 diabetes in individuals with established islet autoimmunity by administering the insulin autoantigen orally,9,10 intranasally,11,12 intravenously, or subcutaneously.13 Treatment-associated changes in the immune response to insulin were observed in some of the studies, suggesting that the treatment might be immunomodulatory.12,13 None of these trials achieved their primary outcome of diabetes prevention. However, beneficial treatment effects were observed in subgroup analyses of the oral insulin immunotherapy trials.9,10,14
We reasoned that the efficacy of autoantigen-specific therapy would improve if the autoantigen is administered before the development of autoantibodies. Key challenges included the optimal antigen dose and identification of at-risk infants. We previously showed that daily oral administration of high doses (67·5 mg) of insulin was well tolerated, without inducing hypoglycaemia. Treatment was associated with immune responses to insulin with features of immune regulation, primarily in children with a susceptible INS genotype.15,16 We also established a polygenic risk score for islet autoantibodies and diabetes, and assembled a European network to screen newborns for type 1 diabetes genetic risk.17,18
The Primary Oral Insulin Trial (POInT) was conducted to establish whether daily oral administration of insulin from infancy is safe and reduces the incidence of autoantibodies and diabetes in children with elevated genetic risk for type 1 diabetes.19 This is the first trial to assess the efficacy of active oral exposure to an autoantigen before the onset of autoimmunity.

 

Utdrag ur Discussionm avkortat

 

Discussion
In infants with a high genetic risk for type 1 diabetes, daily administration of oral insulin, initiated between 4 and 7 months of age, failed to reduce the incidence of islet autoantibodies compared with a placebo. However, oral insulin delayed progression from autoantibody development to diabetes. A pharmacogenetic interaction between treatment and the INS type 1 diabetes susceptibility gene was observed.’

This is the first trial to test the efficacy of active exposure to an autoantigen in children before the onset of autoimmunity. It is also the first study to recruit infants without a family history of type 1 diabetes into a type 1 diabetes primary prevention trial. The recruitment was possible due to large-scale genetic screening across Europe using a genetic risk score that identifies newborns with greater than 10% risk for developing two or more islet autoantibodies.18 Consistent with this predicted risk, the 5-year probability of developing the primary outcome was 10·1% in the placebo group. Screening and enrolment of 1050 infants were faster than planned. Consent was obtained for almost 40% of the 2750 eligible infants to enter a trial that required daily treatment for 2·5 years. Consent was highest in families with a family history of type 1 diabetes, but was also close to 30% in the absence of the disease in family members. Furthermore, the dropout rate was less than half of the predicted rate and adherence to the study treatment was high. This suggests high interest and motivation in early intervention to prevent type 1 diabetes among families with young children. Screening for risk in infants can lead to increased anxiety and depression in parents. In the POInT trial, we previously reported that only 5% of parents experienced panic-related anxiety after being informed about their child’s increased risk, a rate similar to that of the general German population.21 Symptoms of depression were present in 19·4% of parents at the visit in which results were communicated and declined over the course of participation in POInT.

Despite the lack of protection against islet autoantibodies, the trial provided evidence that the treatment elicited changes in the natural course of the disease. Type 1 diabetes starts with the development of autoimmunity and is followed by a distinct progression phase to clinical diabetes. The rate of progression from the occurrence of two or more islet autoantibodies to clinical diabetes was reduced by almost 50% in oral insulin-treated participants. Treatment was given until age 3 years to cover the period of greatest risk for islet autoimmunity in genetically at-risk children. It is possible that continued treatment might have resulted in greater or extended protection against progression. The mechanism of the slower progression is unclear and could include both immune changes or metabolic effects of the oral insulin if it reached the bloodstream. Other exposures during infancy can modify the rate of progression to disease without an apparent effect on the development of autoantibodies.26 The possibility that oral insulin and such exposures modify the phenotype of the islet autoimmunity requires further investigation. In a post-hoc analysis we were able to find preliminary evidence that autoantibody characteristics such as IgG subclasses of IAA differed in participants who received oral insulin as compared with placebo, with an increase of IgG3 IAA responses in the oral insulin group. No analyses of T-cell responses to insulin have been done.
Additionally, we observed a notable interaction between oral insulin treatment and the type 1 diabetes susceptibility gene INS in prespecified subanalyses of the primary and secondary outcomes. Oral insulin was associated with substantial protection against the development of diabetes or dysglycaemia in participants with the type 1 diabetes-susceptible CC genotype, which was present in over half of the participants, and is found in around 40% of the population and 60% of people with type 1 diabetes.8,27 In contrast, treatment was associated with an increased risk of two or more islet autoantibodies in participants with a non-susceptible CT or TT genotype. This pharmacogenetic interaction, therefore, identifies a subgroup that could benefit from primary oral insulin therapy and a subgroup that does not benefit and in whom exposure might increase autoimmunity. Treatment success and failure with adverse reactions to oral immunotherapy is also observed in food allergy.28 An interaction between active exposure to the autoantigen insulin and its genotypic variation on the development of islet autoimmunity suggests that exposure to insulin might be essential in the disease process and that antigen-specific therapy can modulate islet autoimmunity and type 1 diabetes risk. All trial participants were a priori selected to have HLA DR4-DQ8, which is strongly associated with the development of insulin autoimmunity. Therefore, the interaction was observed within a relatively homogeneous HLA class II susceptibility background. It is not known whether a similar interaction between treatment and the INS genotype occurs in high-risk HLA DR4-DQ8-negative children. The mechanism of the interaction is, however, unclear.

The INS gene is remarkable in the pathogenesis of type 1 diabetes, both encoding a major autoantigen and conferring the highest genetic susceptibility for the disease after HLA. Multiple SNPs within the INS-IGF2 gene region, including rs1004446, are associated with susceptibility to type 1 diabetes.27 The rs1004446 SNP was included in the polygenic risk score used for eligibility selection of infants and was, therefore, preselected for subgroup analyses. The rs1004446 SNP is in the IGF2 portion of the INS-IGF2 gene susceptibility region and is associated with the risk for islet autoantibodies in children with HLA DR4-DQ8 genotypes.29 Substantial rs1004446 genotype-associated DNA methylation differences were observed across the INS-IGF2 gene region, including the INS gene. In addition to epigenetic differences,30 genotypic variation in the INS gene is associated with insulin secretion, early blood glucose concentrations, immune tolerance and immune responsiveness, β-cell stress, and microbiome diversity.16,30–35 The mechanisms by which the INS gene influences susceptibility to or protection against islet autoimmunity and type 1 diabetes likely involve an insufficient pool of insulin-specific regulatory T cells in individuals carrying susceptible genotypes, and enhanced protection against β-cell stress in those with protective genotypes. Further investigations are needed to establish if these factors underlie the potentially opposing effects of oral insulin on efficacy in participants with susceptible and non-susceptible INS genotypes. A possible hypothesis is that insulin exposure increases both the number and stability of insulin-specific regulatory T cells in individuals with susceptible genotypes, whereas in those with protective genotypes it might instead destabilise or exhaust these cells.

 

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