This article is more than 5 years old. Information may no longer be current.
Screening for type 1 diabetes: not ready for clinical implementation
Screening programs are not standard practice — will screening provide any value in the clinical setting?
Click Here to Manage Email Alerts
If type 1 diabetes could be prevented, millions of people throughout the world could live longer, healthier lives free from the burden and complications of managing the disease.
The past two decades have seen several diabetes breakthroughs — researchers have discovered genetic and immune factors that contribute to risk, for example — but also a growing incidence of disease. About one in every 400 to 600 children in the United States had diabetes in 2005.
Continued research into type 1 diabetes has allowed researchers to identify individuals at risk and design studies and clinical trials to test strategies aimed at preventing or delaying the onset of the disease. A population-wide screening program for type 1 diabetes is not yet standard practice; will it ever become standard to screen for type 1 diabetes?
Several experts Endocrine Today interviewed said screening for type 1 diabetes should, at present, only be used for research purposes.
“Screening should only be a research endeavor,” said Dorothy Becker, MBBCh, director of the Diabetes Program at the Children’s Hospital of Pittsburgh. “There is no evidence that screening, from a clinical point of view, is of any value – particularly as there is no known intervention.” The only clinically important reason to screen would be for a patient at very high risk — for example 80% — and then checking their blood glucose or performing oral glucose tolerance tests with them more often, according to Becker, chief of endocrinology at Children’s Hospital.
 Dorothy Becker |
“At this stage, screening is really more case finding to understand more about the natural history of disease, to understand the mechanisms leading to disease and to enroll patients in intervention studies,” Desmond Schatz, MD, said in an interview.
The World Health Organization recommends clinical screening only for diseases for which there are effective prevention or treatments.
“Once we have a therapy that can delay or prevent the disease, then routine screening would be absolutely justifiable,” said Schatz, medical director of the Diabetes Center at University of Florida.
Joseph Wolfsdorf, MB, MBBCh, had a similar point of view. “We are not at the point where routine screening is warranted,” said the clinical director of the division of endocrinology at the Children’s Hospital in Boston. “Until we have a viable intervention, screening should not be a routine part of medical practice.”
Screening for prevention, intervention
“Although we have made wonderful progress in understanding the natural history of the prediabetic period, we have really learned little about the underlying mechanisms leading to the disease,” Schatz said.
|
Photo by Sarah Kiewel |
“We don’t really understand why this suicide of the pancreas occurs or why the pancreas is in such a difficult position for us to access,” he said.
Some experts believe that the acute onset of diabetes renders screening unnecessary, but studies indicate that the latent autoimmunity in the prediabetic period that typically precedes diagnosis makes screening and prevention through immune modulation a tangible goal.
In most cases, a blood test can identify risk of developing type 1 diabetes, based on measurement of antibodies to biochemically characterized antigens like insulin, glutamic acid decarboxylase (GAD), islet antigen 2 and zinc transporter 8 (ZnT8). Previous studies have indicated that individuals who are positive for two autoantibodies have a 80% cumulative disease risk over the following four years and individuals who are positive for three autoantibodies have an even higher risk. Researchers are also examining genetic predisposition in certain alleles of immune response genes, such as human leukocyte antigen (HLA) genotyping.
Earlier this year, Jay M. Sosenko, MD, and colleagues introduced a risk score for diabetes based on an algorithm factoring in age, BMI, fasting C-peptide and total fasting glucose. The risk score appeared to accurately predict disease in islet cell autoantibody-positive relatives of affected patients enrolled in the Diabetes Prevention Trial-Type 1. A previously published report from the Childhood Diabetes in Finland study demonstrated that age, HLA-defined diabetes predisposition, increasing number of autoantibodies, reduced first-phase insulin response and decreased insulin sensitivity were predictors of progression to diabetes in a subgroup of autoantibody-positive siblings. Young age was a common feature in both studies, which indicates that initiation of the disease process early in life resulted in rapid progression to overt disease, according to Mikael Knip, MD, who wrote a 2008 editorial about this topic in Diabetes Care.
“Is there a rationale beyond research studies for screening siblings of affected subjects who have a relative risk of type 1 diabetes at least 10 times higher than that in the general population (with the absolute risk in the range of 6% to 10%)?” Knip wrote. “What would be the optimal screening strategy?”
The search for an intervention
“We do not have a lot [of data] to offer people at the moment,” Janet H. Silverstein, MD, chief, department of pediatrics, division of endocrinology, at the University of Florida, Gainesville, told Endocrine Today.
Several studies to screen newborns from the general population and high-risk individuals are currently underway (see sidebar). These trials are conducted with the goal of identifying genes or triggers of autoimmunity and, ultimately, to test interventions to prevent or delay the disease.
Much of the research is carried out through TrialNet, a network of 18 clinical centers and various screening sites throughout the world. Several research efforts are currently in recruitment, such as the Nutritional Intervention to Prevent Type 1 Diabetes Study, which will examine docosahexaenoic acid (DHA) given to pregnant mothers and infants younger than 5 months. Other studies include the Oral Insulin for Prevention of Type 1 Diabetes Study, and the Natural History Study, in which researchers will investigate the risk for diabetes in close relatives of patients with type 1 diabetes.
|
|
Some primary prevention trials are examining environmental exposures in infants who carry the high-risk genotypes identified by genetic screening. The TEDDY trial will look at environmental triggers, TRIGR will study the elimination of cow’s milk from diets, and the Pre-Point study will examine immunomodulation with human oral insulin. Another, DIPP, or the Diabetes Prediction and Prevention Project, will assess newborns for increased genetic risk. Since the project was launched in 1994, more than 8,500 children at increased genetic risk have participated in the study and more than 110 have progressed to clinical diabetes.
To date, the DTP-1 and ENDIT trials, large-scale randomized controlled trials examining the prevention or delay of type 1 diabetes, have failed to demonstrate a treatment effect. However, these trials have shown that individuals with islet autoantibodies have a variable period of mild hyperglycemia that precedes overt insulin dependence by months, sometimes years.
Published data from DAISY suggested that identification of individuals at increased risk and prospective monitoring resulted in early diagnosis and avoidance of severe metabolic decompensation at diagnosis among patients who progressed to overt diabetes.
It all comes down to the physicians, said Silverstein, an Endocrine Today editorial board member. “There are a limited number of people who are eligible for these trials, so we need to make people aware that they exist and how they can participate,” she said. “We, as physicians, need to enroll patients, take the time to explain why we are drawing blood and explain the potential benefits.”
Ethical considerations
“If you discover someone who is positive, what do you do with the information?” Wolfsdorf said.
Opponents of a population-wide screening program argue that tests raise ethical considerations: induced stress, cost, lifestyle changes and potential effects on insurability.
 Lainie Friedman Ross |
“Even our language of calling a patient ‘high risk’ is confusing,” Lainie Friedman Ross, MD, PhD, told Endocrine Today. “Screening for type 1 diabetes does not tell a patient yes or no that he or she has the disease — it only tells the patient he/she is at increased risk. More than 90% of people who are identified as high risk will never go on to develop the disease,” according to Ross, who holds the Carolyn and Matthew Bucksbaum Chair of Clinical Ethics at the University of Chicago. “That is, for every 100 individuals labeled as high risk, fewer than 10 develop the disease, but all 100 worry for years. It is wrong to impose such stress on an unsuspecting population,” she said.
However, in high-risk families, a negative genetic test means that a particular child is not at increased risk. This can be reassuring to the parents. And, if the child does not have the gene, the parents can be prepared, be vigilant for symptoms, and know what to expect. Thus, predictive testing should be restricted to high-risk families as part of rigorous research protocols.
Paula Simonen, PhLic, and colleagues assessed the anxiety, emotions and coping behaviors of parents one week after they received the results of their newborn’s genetic test for type 1 diabetes. More than 90% of parents thought it was good to know about their child’s risk. However, 55% of mothers and 37% of fathers of high-risk infants expressed modest worry and increased anxiety. These parents also had negative thoughts of diabetes risk and expressed avoidance of coping attitudes. The researchers concluded that identifying the few parents with strong anxiety may help focus intensified counseling (see chart).
“We should not introduce risk identification when data show that parents of newborns are already anxious. Newborn screening has been a remarkable success in the history of public health interventions. We should not jeopardize public support of newborn screening programs by piggybacking it with research that merely identifies probabilistic risks,” Ross wrote in an Archives of Pediatric and Adolescent Medicine editorial last year.
Yet, Simonen et al said that increased anxiety after receiving risk information dissipates over time, and there is considerable variation based on race/ethnicity and education level.
Other barriers to screening
One problem with antibody screening is that it can change over time, according to Wolfsdorf. “If [a test] were negative today, you cannot tell a patient that they will never develop diabetes because six months from now or 10 years from now the antibody test could become positive,” he said during an interview.
“It is simply a marker,” he said. “It’s like if you look out the window and see smoke on the horizon. All that tells you is there is a fire somewhere. Antibody tests merely indicate that there is an active immunological process, but they do not provide definitive information about the future, which can only be obtained by careful clinical and biochemical monitoring and follow-up.”
According to recent estimates from the American Diabetes Association, diabetes care costs more than $174 billion annually. A screening program must carry a good cost-benefit ratio before its clinical implementation can be justified. Researchers with the DIPP Study evaluated the costs of two different population-based approaches to predict type 1 diabetes: a targeted DIPP method of genetic screening vs. repeated immunological follow-up of all newborns. During 10 years of follow-up, total direct cost per child was $261 with the targeted DIPP method compared with $680 with the non-targeted method. The researchers concluded that targeted prediction based on genetic screening was a cost-saving method.
Still, the pros of screening for type 1 diabetes outweigh the cons, according to Schatz.
Look outside the box
“We have to apply new technology, we have to continue to think outside the box and explore new therapies,” Schatz said. “The future will be a cocktail approach to changing the natural history of the disease.”
The experts interviewed by Endocrine Today encouraged more participation in intervention studies and a focused effort on learning more about the mechanisms behind type 1 diabetes.
In addition, “we need money because large-scale trials are incredibly expensive; we need commitment from the president, who better stop vetoing type 1 diabetes money. We need type 1 diabetes funds to continue. We need enough people to believe this issue is important, and, aside from researchers, we need physicians and clinical endocrinologists to refer patients,” Becker said. “There is no single important thing. We need all of these things and without them we will never find an intervention to prevent type 1 diabetes.” – by Katie Kalvaitis
Should we be screening for type 1 diabetes?
For more information:
- Barker JM, Goehrig SH, Barriga K, et al. Clinical characteristics of children diagnosed with type 1 diabetes through intensive screening and follow-up. Diabetes Care. 2004;27:1399-1404.
- Diabetes Prevention Trial-Type 1 Diabetes Study Group. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med. 2002;346:1685-1691.
- Hahl J, Simell T, Ilonen J, Simell O. Cost analysis of two approaches of type 1 diabetes prediction. Annu Meet Int Soc Technol Assess Health Care.
- Knip M. Should we screen for risk of type 1 diabetes? Diabetes Care. 2008;31:622-623.
- Ross LF. Against newborn screening for type 1 diabetes. Arch Pediatr Adolesc Med. 2007;161:616-617.
- Simonen P, Korhonen T, Simell T, et al. Parental Reactions to Information About Increased Genetic Risk of Type 1 Diabetes Mellitus in Infants. Arch Pediatr Adolesc Med. 2006;160:1131-1136.
- Sosenko JM, Krischer JP, Palmer JP, et al. A risk score for type 1 diabetes derived from autoantibody-positive participants in the Diabetes Prevention Trial-Type 1. Diabetes Care. 2008;31:528-533.