Hydrolyzed infant formula and early β-cell autoimmunity: a randomized clinical trial.

Importance The disease process leading to clinical type 1 diabetes often starts during the first years of life. Early exposure to complex dietary proteins may increase the risk of β-cell autoimmunity in children at genetic risk for type 1 diabetes. Extensively hydrolyzed formulas do not contain intact proteins. Objective To test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of diabetes-associated autoantibodies in young children. Design, Setting, and Participants A double-blind randomized clinical trial of 2159 infants with HLA-conferred disease susceptibility and a first-degree relative with type 1 diabetes recruited from May 2002 to January 2007 in 78 study centers in 15 countries; 1078 were randomized to be weaned to the extensively hydrolyzed casein formula and 1081 were randomized to be weaned to a conventional cows’ milk–based formula. The participants were observed to April 16, 2013. Interventions The participants received either a casein hydrolysate or a conventional cows’ milk formula supplemented with 20% of the casein hydrolysate. Main Outcomes and Measures Primary outcome was positivity for at least 2 diabetes-associated autoantibodies out of 4 analyzed. Autoantibodies to insulin, glutamic acid decarboxylase, and the insulinoma-associated–2 (IA-2) molecule were analyzed using radiobinding assays and islet cell antibodies with immunofluorescence during a median observation period of 7.0 years (mean, 6.3 years). Results The absolute risk of positivity for 2 or more islet autoantibodies was 13.4% among those randomized to the casein hydrolysate formula (n = 139) vs 11.4% among those randomized to the conventional formula (n = 117). The unadjusted hazard ratio for positivity for 2 or more autoantibodies among those randomized to be weaned to the casein hydrolysate was 1.21 (95% CI, 0.94-1.54), compared with those randomized to the conventional formula, while the hazard ratio adjusted for HLA risk, duration of breastfeeding, vitamin D use, study formula duration and consumption, and region was 1.23 (95% CI, 0.96-1.58). There were no clinically significant differences in the rate of reported adverse events between the 2 groups. Conclusions and Relevance Among infants at risk for type 1 diabetes, the use of a hydrolyzed formula, when compared with a conventional formula, did not reduce the incidence of diabetes-associated autoantibodies after 7 years. These findings do not support a benefit from hydrolyzed formula. Trial Registration clinicaltrials.gov Identifier: NCT00179777 Type 1 diabetes is characterized by selective loss of insulin-producing β cells in the pancreatic islets in genetically susceptible individuals. Overt clinical disease is preceded by an asymptomatic period of highly variable duration1 during which diabetes-associated autoantibodies appear in the peripheral circulation as markers of emerging β-cell autoimmunity. Several disease-related autoantibodies predict clinical type 1 diabetes including classical islet cell antibodies (ICA), insulin autoantibodies, autoantibodies to glutamic acid decarboxylase (GAD), and the tyrosine phosphatase-related insulinoma-associated 2 molecule (IA-2).2 In natural history studies from infancy, positivity for at least 2 autoantibodies signals a risk of approximately 60% for the development of clinical diabetes over 10 years, whereas the 10-year risk among those with a single autoantibody is about 15% and among those with no detectable autoantibodies less than 1%.3 Accumulating evidence suggests that β-cell autoimmunity emerges early in life.4,5 The incidence of type 1 diabetes is increasing among children in Europe and North America,6,7 although some studies suggest it may be stabilizing.8 This scenario implies that any measure aimed at primary prevention of type 1 diabetes, ie, prevention of the initiation of the diabetic disease process, has to be started in infancy. Early feeding may modify the risk of type 1 diabetes later in life. Some epidemiological and immunological studies suggest that exposure to complex foreign proteins in early infancy may increase the risk of β-cell autoimmunity and type 1 diabetes in genetically susceptible individuals,9- 11 although others do not.12,13 A pilot study suggested that weaning to an extensively hydrolyzed casein formula (99.7% of the generated peptides having a molecular weight of less than 2000 Da) decreased the cumulative incidence of diabetes-associated autoantibodies in children with an affected first-degree relative and a risk-associated HLA genotype.14,15 This led to TRIGR (Trial to Reduce IDDM in the Genetically at Risk), with the study powered to assess the effect of the intervention on the development of type 1 diabetes by age 10 years. A prior prespecified end point, early humoral β-cell autoimmunity, is reported herein.