Results from a primary care-based autoantibody screening program in Germany lend support to the idea of broad population screening for type 1 diabetes.
Findings from the 4-year program were published online January 28 in JAMA by Anette-Gabriele Ziegler, MD, and colleagues.
This is the first attempt to introduce preschool screenings for type 1 diabetes in a general population, and the success shows large-scale screenings are possible and there are clear benefits to early diagnosis of type 1 diabetes, say Ziegler, of the Institute of Diabetes Research, Helmholtz Zentrum München, Neuherberg, Germany, and coauthors.
Among more than 90,000 children screened who were aged 2-5 years in Bavaria, Germany, 0.31% were identified as high risk for developing type 1 diabetes through the presence of two or more islet autoantibodies. Of those 280 children, 24.9% subsequently developed the condition.
There are currently no approved interventions that would prevent or delay the onset of type 1 diabetes among those found to be at high risk.
However, "game-changer" results from the type 1 diabetes prevention study consortium TrialNet reported last summer for the first time showed that such a therapeutic approach is possible using teplizumab, an investigational anti-CD3 monoclonal antibody (Provention Bio).
Moreover, many experts argue that another potential clinical benefit of identifying presymptomatic type 1 diabetes is that it offers the opportunity to prevent diabetic ketoacidosis (DKA) and its sequelae by educating parents to be on the lookout for early signs and symptoms.
Population Screening for Type 1 Diabetes Justifiable Now
Asked to comment, TrialNet chair Carla Greenbaum, MD, told Medscape Medical News, "As demonstrated by this study in Germany, population-based screening combined with education and monitoring of antibody-positive individuals is clearly an effective way to identify people destined to develop clinical type 1 diabetes."
"Whether through population-based screening programs such as this one, or through screening of relatives as done by TrialNet, identifying individuals before the clinical diagnosis decreases the morbidity frequently associated with [type 1] diabetes onset," added Greenbaum, who is director of the diabetes program and clinical research center at Benaroya Research Institute, Seattle, Washington.
And although the cost of screening and follow-up is certainly a consideration until teplizumab or another such intervention is available, she still believes that population screening is justifiable now.
"To truly reap the dollar benefit of universal screening, intervention to alter the course of disease is needed. Due to the high cost of annual diabetes care, in addition to the burden to the patient and family, delaying the onset of disease would have a much greater financial impact than screening alone," she observed.
But, she stressed, "Population screening and prevention studies go hand in hand. Since great strides have been made with therapies that may indeed do that, it is a terrific idea to move ahead to institute universal screening," while at the same time “studying how people in different parts of the world react to screening, understand results, and agree to get involved in clinical trials."
Screening Feasible in Primary Care
The German screening program was a lead-in to the Fr1da Insulin Intervention trial, which is supported by several funders including JDRF, the Leona M. and Harry B. Helmsley Charitable Trust, LifeScience-Stiftung, Bavarian State Ministry of Health and Care, and German Federal Ministry of Education and Research.
Islet autoantibody screening — using two blood samples — was offered to 90,632 children aged 1.75 to 5.99 years between 2015 and 2019 by 682 primary care pediatricians in Bavaria during well-baby visits.
Families of children with at least two islet autoantibodies (presymptomatic type 1 diabetes) were invited to participate in a program of diabetes education, metabolic staging, assessment of psychological stress associated with diagnosis, and prospective follow-up for progression to clinical diabetes until July 31, 2019.
Of the 280 (0.31%) children identified with presymptomatic type 1 diabetes, 120 had two autoantibodies, 91 had three autoantibodies, and 69 had four autoantibodies. Nineteen (0.03%) were diagnosed with clinical (stage 3) type 1 diabetes before the second sample could be collected.
Adjusted relative risks for presymptomatic type 1 diabetes were higher in children who had a first-degree relative with type 1 diabetes (3.69; P < .001), in obese children (1.77; P = .01), in those aged 4-4.99 years(1.50; P = .02), and in those aged 5-5.99 years (1.86; P < .001). There were no differences by gender or region.
Among the 280 with presymptomatic type 1 diabetes, the cumulative risk for developing full-blown clinical type 1 diabetes was 24.9% over 3 years of follow-up, or about 9.0% per year. The risk was higher for those with four versus two autoantibodies (hazard ratio, 1.85; P = .04).
"A crucial finding of the study is that there is a 9% annualized risk for disease progression in children with presymptomatic disease," said Ziegler in a statement issued by JDRF.
"This is remarkably similar to the risk in previously studied genetically susceptible children. Its implication is that multiple antibodies can be used to identify children with presymptomatic type 1 diabetes who could benefit from intervention.”
Sixty-two children with presymptomatic type 1 diabetes progressed to clinical type 1 diabetes, of whom two (3.2%) had a laboratory diagnosis of mild (pH 7.28) or moderate (pH 7.14) asymptomatic diabetic ketoacidosis (DKA); 60 of the 62 children (96.8%) did not have DKA. The two children with DKA were hospitalized but did not require intensive care treatment.
"In this study, the prevalence of DKA was less than 5%. The previously reported prevalence in unscreened children is more than 20% in Germany and 40% in the United States," Ziegler and colleagues point out.
"If we identify children at high risk of developing type 1 diabetes, we can monitor their disease progression to prevent DKA, a life-threatening condition that often goes undiagnosed, as well as potentially enroll them in clinical trials aimed at halting or delaying the progression toward type 1," said Sanjoy Dutta, PhD, vice president of research at JDRF, in the statement.
"JDRF has proudly supported this study since it officially launched in 2015, and we congratulate Dr Ziegler and her team for this critical work that has become a model for other initiatives around the world aimed at improving health outcomes for people with type 1 diabetes," said Dutta.
Psychological stress scores were significantly greater among mothers — but not fathers — of children with presymptomatic type 1 diabetes compared to mothers of children without islet autoantibodies, but those scores declined after 12 months of follow-up.
Meanwhile, There's TrialNet in North America, Europe, and Australia
This initial research is now progressing in several ways.
The study will continue under the name Fr1da-plus, adding 9- and 10-year-old children in addition to 2- to 5-year-olds. The researchers will also perform a cost-benefit analysis of screening, as part of the evidence to move screening to the public health sector as a standard of care.
Greenbaum told Medscape Medical News that individuals with a first- or second-degree family member with type 1 diabetes are at 15-fold higher risk of developing the condition than the general population.
"Clinicians should inform their patients of this fact and let them know that they can be screened at no cost through TrialNet. They should direct family members to TrialNet.org and learn how to get tested at multiple locations in North America, Europe, and Australia," she explained.
"Indeed, in the United States, the sign-up process is online and testing can be done conveniently — at home, at multiple local laboratories, or at a TrialNet site," she said.
In addition to the teplizumab trial, TrialNet has three other trials underway and several more in the pipeline using multiple therapies with the aim of delaying disease onset.
"With screening as part of clinical care, more trials testing different therapies may be able to happen sooner," she said.
In addition, although TrialNet doesn't screen people without first-degree relatives with type 1 diabetes, if someone without a family member has been found to have multiple antibodies, they may still be eligible for a TrialNet clinical trial, Greenbaum said.
More information is available at www.trialnet.org.
Ziegler has reported no relevant financial relationships. Greenbaum has reported research support from Janssen and Bristol-Meyers Squibb.
JAMA. 2020;323:339-351. Abstract
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Cite this: Screening Kids for Type 1 Diabetes in Primary Care Is Feasible - Medscape - Feb 06, 2020.