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.

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.