Effect of Hydrolyzed Infant Formula vs Conventional Formula on Risk of Type 1 Diabetes: The TRIGR Randomized Clinical Trial

Abstract

Importance: Early exposure to complex dietary proteins may increase the risk of type 1 diabetes in children with genetic disease susceptibility. There are no intact proteins in extensively hydrolyzed formulas.

Objective: To test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of type 1 diabetes in young children.

Design, setting, and participants: An international double-blind randomized clinical trial of 2159 infants with human leukocyte antigen-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; 1081 were randomized to be weaned to the extensively hydrolyzed casein formula and 1078 to a conventional formula. The follow-up of the participants ended on February 28, 2017.

Interventions: The participants received either a casein hydrolysate or a conventional adapted cow's milk formula supplemented with 20% of the casein hydrolysate. The minimum duration of study formula exposure was 60 days by 6 to 8 months of age.

Main outcomes and measures: Primary outcome was type 1 diabetes diagnosed according to World Health Organization criteria. Secondary outcomes included age at diabetes diagnosis and safety (adverse events).

Results: Among 2159 newborn infants (1021 female [47.3%]) who were randomized, 1744 (80.8%) completed the trial. The participants were observed for a median of 11.5 years (quartile [Q] 1-Q3, 10.2-12.8). The absolute risk of type 1 diabetes was 8.4% among those randomized to the casein hydrolysate (n = 91) vs 7.6% among those randomized to the conventional formula (n = 82) (difference, 0.8% [95% CI, -1.6% to 3.2%]). The hazard ratio for type 1 diabetes adjusted for human leukocyte antigen risk group, duration of breastfeeding, duration of study formula consumption, sex, and region while treating study center as a random effect was 1.1 (95% CI, 0.8 to 1.5; P = .46). The median age at diagnosis of type 1 diabetes was similar in the 2 groups (6.0 years [Q1-Q3, 3.1-8.9] vs 5.8 years [Q1-Q3, 2.6-9.1]; difference, 0.2 years [95% CI, -0.9 to 1.2]). Upper respiratory infections were the most common adverse event reported (frequency, 0.48 events/year in the hydrolysate group and 0.50 events/year in the control group).

Conclusions and relevance: Among infants at risk for type 1 diabetes, weaning to a hydrolyzed formula compared with a conventional formula did not reduce the cumulative incidence of type 1 diabetes after median follow-up for 11.5 years. These findings do not support a need to revise the dietary recommendations for infants at risk for type 1 diabetes.

Trial registration: clinicaltrials.gov Identifier: NCT00179777.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Knip reported receiving grants from the National Institutes of Health. Dr Lawson reported receiving a grant from the Canadian Institutes of Health Research. Dr Madacsy reported receiving a grant from Semmelweis University, Budapest. Dr Vaarala is an employee of AstraZeneca. No other disclosures were reported.

Figures

Figure 1.. Screening, Randomization, and Follow-up

HLA indicates human leukocyte antigen. aThe sum of the individual reasons is higher than the total because a participant may have had more than 1 reason. bA total of 134 for gestational age greater than 35 weeks; 30 received formula other than Nutramigen, 6 with no parent or sibling with type 1 diabetes, 24 with no HLA sample drawn before age 8 days, 21 newborns had recognizable severe illness, 16 had no signed consent from parent or guardian, 5 with multiple gestation, 21 older than 8 days at randomization, 6 with families unable to participate, and 3 with possibility of random assignment. Note: the sum of individual reasons is higher than the total because a participant may have had more than 1 reason. cRecognizable severe illness within 7 days of birth. dPer-protocol analysis included participants with exposure to the study formula for 60 days or longer and no exposure to nonallowed foods.

Figure 2.. Cumulative Survival Without Type 1 Diabetes

The median follow-up time was 11.5 years (quartile [Q] 1-Q3, 10.1-12.8 years) in the casein hydrolysate group and 11.4 years (Q1-Q3, 10.2-12.8 years) in the control group.