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.

Summary

In genetically at-risk infants, daily high-dose oral insulin did not reduce the development of multiple islet autoantibodies or diabetes compared with placebo. A significant interaction with INS genotype suggested potential benefit on dysglycaemia/diabetes in carriers of susceptible alleles and possible harm in non-susceptible genotypes. Safety profiles were similar between groups.

Key Findings

• No overall prevention: primary outcome occurred in 10% (oral insulin) vs 9% (placebo), HR 1.12 (95% CI 0.76–1.67), p=0.57.
• INS genotype interaction: increased primary outcome in non-susceptible genotypes (HR 2.10) and protection from dysglycaemia/diabetes in susceptible genotypes (HR 0.38).
• Safety: hypoglycaemia was rare and comparable; adverse event rates were similar across groups; one death was adjudicated unrelated.

Clinical Implications

Oral insulin should not be used for primary prevention of islet autoimmunity in unselected genetically at-risk infants. Future prevention efforts may consider INS genotype stratification within clinical trials rather than routine practice.

Limitations

• Primary endpoint focused on islet autoimmunity rather than clinical diabetes; genotype subgroup analyses may be underpowered.
• Generalizability beyond studied populations and adherence dynamics were not fully detailed.

Future Directions

Conduct genotype-selected (INS) prevention trials, explore alternative tolerogenic antigens or combinatorial strategies, and extend follow-up to overt diabetes to clarify clinical benefit.