Question Does weaning to an
extensively hydrolyzed formula decrease the cumulative incidence of
type 1 diabetes in children at risk?
Findings In this randomized clinical
trial that included 2159 children with human leukocyte
antigen-conferred susceptibility to type 1 diabetes and at least 1
affected family member, weaning to a hydrolyzed formula compared
with a conventional formula did not significantly decrease the
cumulative incidence of type 1 diabetes after a median of 11.5
years (8.4% vs 7.6%).
Meaning Weaning to a hydrolyzed
formula did not reduce the risk of type 1 diabetes in children with
an increased disease risk.
The long-awaited results from the first large international
trial to try to prevent type 1 diabetes shows that modified baby
formula in which cow's milk proteins have been split does not
prevent type 1 diabetes in children with genetic risk factors for
the condition, according to researchers at Children's Hospital of
Pittsburgh of UPMC, the coordinating center for the U.S. arm of the
study. The findings were published in the
Journal of the American Medical Association.
Previous studies have reported that early exposure to complex
foreign proteins, such as cow's milk proteins, may
increase the risk of type 1 diabetes in young children
with genetic risk for type 1 diabetes.
In 2002, the research team for TRIGR (Trial to Reduce IDDM in
the Genetically at Risk), led in the U.S. by principal investigator
Dorothy Becker, M.D., professor of pediatrics at Children's
Hospital and the University of Pittsburgh School of Medicine,
embarked on a large-scale study of 2,159 infants with a family
member affected by type 1 diabetes and with genetic risk for type 1
diabetes to find out whether delaying the exposure to complex
foreign proteins such as cow's milk proteins would decrease the
risk of diabetes.
After breastfeeding, infants were either weaned to a special
formula (extensively hydrolyzed casein formula), with the cow's
milk proteins split into small peptides (small pieces of the
protein), or a regular cow's milk-based formula with intact cow's
Infants were fed the study formula for at least two months until
the age of 6 to 8 months and at the same time were given no cow's
milk proteins from any other food sources. The children were
followed for at least 10 years to determine which children
At 11.5 years of follow up, weaning to an extensively hydrolyzed
casein formula during infancy did not result in a reduction in the
incidence of type 1 diabetes compared to regular, intact
"After more than 15 years of effort, this study puts to rest the
controversy regarding the potential role of cow's milk formula in
the development of type 1 diabetes," said Becker. "This once more
shows us that there is no easy way to prevent type 1 diabetes.
Accordingly, there is no evidence to revise the current dietary
recommendations for infants at high risk for type 1 diabetes. We
need to chip away at our research efforts around the world to find
interventions that may change the pre-diabetes course. Ongoing work
of our study is doing just that."
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).