Type 1 diabetes screening reaches ‘potentially pivotal moment’ with new treatment option
Click Here to Manage Email Alerts
The benefits of type 1 diabetes screening have long been up for debate, but FDA approval of the first therapy to delay the disease’s onset may be changing the conversation.
In November, the FDA approved teplizumab-mzwv (Tzield, Provention Bio) to delay the onset of type 1 diabetes for both adults and children aged 8 years and older with stage 2 type 1 diabetes. Previously, physicians could identify people at high risk for the disease but were unable to provide a treatment to those who have not yet progressed to full-blown diabetes.
Photo courtesy of Richard Oram, MD, PhD. Printed with permission.
“The FDA approval of teplizumab will change the playing field for screening because, suddenly, screening has a purpose not just for preventing diabetic ketoacidosis, but also for offering new therapies that might delay type 1 diabetes onset,” Richard Oram, MD, PhD, associate professor and Diabetes UK Harry Keen Fellow at the University of Exeter Medical School in the United Kingdom, said in an interview.
However, many questions remain about how screening for type 1 diabetes should work as well as how to follow those people who are at high risk, especially because many may never develop the disease.
“It has the potential to dramatically impact the workload of endocrinologists, so thinking about the pros and cons of screening, how it’s integrated into health care, what to do with people who are at high risk and whether physicians will be willing to give them this approved therapy are worth thinking about,” Oram said.
A complex disease
Interest in the genetics of type 1 diabetes has existed for decades. Data from the past 40 years identified certain human leukocyte antigen (HLA) alleles as having the greatest impact on risk for the disease. Approximately 100 other genetic variants scattered across the genome also contribute to risk but to a lesser extent, according to Oram.
“There isn’t a single change in a gene that accounts for type 1 diabetes, and actually, there’s a contribution from many genes that leads to the heritable component of type 1 diabetes,” Oram said.
Many people with a genetic risk for type 1 diabetes, including those with the riskiest combination of HLA alleles, will not develop the disease, Oram noted.
Research evaluating the link between family history and type 1 diabetes risk also illustrates the uncertain association between genetics and actual development of the disease. For example, studies of identical twins have shown that if one twin has type 1 diabetes, the other twin has a 50% to 80% chance of also developing the disease. In comparison, a sibling of a person with type 1 diabetes has a significantly lower risk — approximately 5% to 10% — for developing the disease. This aproximately 15-fold elevated risk compared to the background population is significant, but it is worth remembering that only 15% of people with type 1 diabetes have a relative affected. Therefore, while having a first degree relative affected is a risk factor, it cannot be used to identify all individuals at risk of future type 1 diabetes, according to Oram.
“The biggest challenge is that we do not fully understand the mechanisms that are making those associations between these HLA types and type 1 diabetes risk,” Carla J. Greenbaum, MD, director of the Center for Interventional Immunology and Diabetes Program at the Benaroya Research Institute in Seattle, told Endocrine Today.
Genetics may not predict who will actually develop the disease, but they probably play a role in determining who will develop autoantibodies, which is important when assessing risk for type 1 diabetes.
“The punchline here is: Genes matter. We do not fully understand why they matter, but we can use them to identify people who should be screened for antibodies,” Greenbaum said.
Layering testing to improve accuracy
During the past several decades, researchers pinpointed several antibodies that are associated with type 1 diabetes, including islet cell autoantibodies, glutamic acid decarboxylase autoantibodies, insulinoma-associated-2 autoantibodies, insulin autoantibodies and zinc transporter 8 autoantibodies.
Testing for these antibodies in the blood forms the basis for most of the current type 1 diabetes screening, Laura Jacobsen, MD, pediatric endocrinologist and assistant professor at the University of Florida in Gainesville, told Endocrine Today.
“Several studies in the United States and Europe have shown that if a person has two or more of these autoantibodies, then they have a relatively high lifetime risk for developing type 1 diabetes,” Jacobsen said.
One study published in JAMA in 2013 showed that the majority of children at risk for type 1 diabetes who had multiple antibodies progressed to diabetes during the next 15 years. These results, Oram said, steered the field toward using a staged model of type 1 diabetes. Specifically, stage 1 type 1 diabetes is defined as the development of at least two antibodies, and stage 2 type 1 diabetes is defined as the presence of at least two antibodies in addition to slightly abnormal glucose levels.
“This reflects the fact that people develop autoimmunity but have a latent phase where they are progressing toward clinical type 1 diabetes but don’t yet meet the criteria for a diagnosis of clinical type 1 diabetes,” Oram said.
Although the genetic contribution to type 1 diabetes risk requires further investigation, a genetic screen followed by antibody testing and glucose testing for those found to be at high risk has the potential to better identify those who will develop the disease, according to Sanjoy Dutta, PhD, chief scientific officer at JDRF.
“All of this is done before a person develops an HbA1c of 7% and before they are insulin-dependent,” Dutta told Endocrine Today. “This early risk assessment has lots of benefits, such as preventing DKA at diagnosis and even avoiding the disease if preventive therapies become available.”
With the FDA approval of teplizumab-mzwv, novel treatments for prevention are more within reach, according to Jacobsen, and even though screening for type 1 diabetes has generally been limited to research settings, focus is now shifting onto its potential role in clinical practice.
“This advancement gives us the motivation for screening and hopefully gives lawmakers and insurers a reason to pay for screening now that we have a therapy that can delay the onset of type 1 diabetes,” Jacobsen said.
Universal vs. targeted approaches
As screening moves out of the research realm and into the real world, the optimal approach to integrating testing into clinical care remains up for debate.
Historically, especially in the research setting, the populations who underwent screening were primarily composed of relatives of people with type 1 diabetes. However, not only have data shown that family members have a low risk for actually developing the disease, but 85% of people who do have type 1 diabetes do not have a family history, Dutta noted.
“Therefore, the concept of general population screening, particularly in the form of newborn genetic risk screening, is gaining traction. Many states do a routine panel as soon as a child is born using blood from the heel. They screen for conditions such as Down syndrome and Duchenne muscular dystrophy, so we would like to add a panel for type 1 diabetes,” Dutta said. “That’s where we are trending toward: newborn genetic risk screening followed by autoantibody risk screening dwindling down to the highest-risk population.”
This strategy has definite upside, Oram noted, including that the test is cost-effective and easy to do. Moreover, if physicians identify the 10% of babies at highest risk for type 1 diabetes, they will capture approximately 80% to 90% of very early-life type 1 diabetes and slightly less than 80% of all type 1 diabetes presenting in childhood. Additionally, they can mitigate health care disparities, as almost all newborns will be receiving medical care and undergoing the typical newborn screen. This strategy also allows more targeted antibody testing of the highest-risk individuals later in life, which can considerably cut costs, Oram said.
Oram noted that focusing on genetically high-risk children would mean that the 10% to 15% of future type 1 diabetes that comes from children who do not have high genetic risk would not be identified by a genetic screen.
A cross-sectional approach, which involves performing antibody testing on children who are seeing their pediatrician for a vaccine visit at age 2, 3 or 4 years would be effective, albeit slightly less sensitive, according to Oram.
“There is a growing body of evidence that you could theoretically screen at several time points throughout childhood, with one recent paper suggesting that two or maybe three time points is more sensitive,” Oram said.
There are also programs exploring antibody screening or a combination of genetic screening and antibody screening in the general population, including the Autoimmunity Screening for Kids (ASK) program at the Barbara Davis Center for Diabetes in Colorado and the PLEDGE study at Sanford Health across the Midwest.
Another mass screening program is JDRF’s T1Detect that encourages screening through several research programs, including ASK, PLEDGE and TrialNet; blood draw testing at commercial labs; or an at-home test that screens for antibodies using a finger-stick blood sample. Less data are available on the yield for these types of tests, but when considering the large number of people who develop type 1 diabetes without family history, the ability to catch people who may not know their risk otherwise is valuable, Dutta said.
Unfortunately, because most of the research has been conducted in children, many of these screening approaches have more limited guidance for adults. In some ways, a targeted approach is more appropriate in this population, according to Carol J. Levy, MD, CDCES, an adult endocrinologist and professor of medicine in the department of medicine and the division of endocrinology and the department of obstetrics at Icahn School of Medicine at Mount Sinai.
“Not every single person who shows up requires screening for type 1 diabetes. That said, if an adult with hyperglycemia who does not meet the typical criteria for type 2 diabetes, such as obesity or a certain racial or ethnic background, walks through the door, one always needs to consider screening for type 1 diabetes before starting treatment,” Levy told Endocrine Today. “In terms of testing of adults, especially those over the age of 40 years, for risk factors prior to developing diabetes, further data and guidance is needed.”
Balancing benefits, harms of screening
As researchers seek ways to implement or refine screening, physicians are left to consider its utility in clinical practice. Before approval of teplizumab-mzwv, when there was no treatment to offer these high-risk patients, the benefits of screening for type 1 diabetes were arguably questionable.
Obvious benefits include the potential for increased monitoring, enrollment in clinical trials of preventive therapies, improved glucose control earlier in the disease course and a lower likelihood of presenting with DKA.
“Depending on the study, anywhere between one-third and one-half of people present with DKA at the time of diagnosis, whereas this proportion is less than 3% among those who have engaged in screening and monitoring,” Greenbaum said.
Additionally, although adults likely would not participate in screening in the same way that children do in a clinical context, the benefits of increased awareness of type 1 diabetes screening and prevention of misdiagnosis have the ability to substantially improve outcomes, according to Levy.
“Misdiagnosing patients with type 2 diabetes who actually have type 1 diabetes presents a safety issue,” Levy said, noting that certain drugs used to treat type 2 diabetes can, for instance, be associated with an increased risk for DKA.
However, screening is not without harms. There are psychosocial ramifications of knowing that a person is at high risk for a disease that cannot be prevented, according to Jacobsen. For example, an analysis of The Environmental Determinants of Diabetes in the Young (TEDDY) study published in Diabetes Care in 2017 showed that infant genetic risk screening increased parental anxiety, with autoantibody positivity heightening this anxiety for longer periods of time.
Other major issues pertain to education, support and monitoring. For instance, there is no consensus or clinical practice guideline outlining recommendations for repeat antibody testing, what glucose measures to use or how often people at high risk should be tested. Most studies have conducted oral glucose tolerance tests every 6 to 12 months for monitoring, but these can be cumbersome, so researchers for TEDDY and TrialNet are also investigating the use of HbA1c levels, continuous glucose monitoring, C-peptide levels or some combination of these measures for monitoring, according to Jacobsen.
Importantly, having this plan for monitoring alongside specialized psychological support and consultants who can advise people how to navigate type 1 diabetes before it develops might mitigate some of the psychosocial stress experienced by those who are at high risk for the disease, Greenbaum noted. However, this setup is lacking at most medical centers.
“We need to have an infrastructure set up so that people who are found to be autoantibody-positive aren’t left in limbo. Unfortunately, clinicians often have to convey bad news to people, but they try to reassure them that they will be with them through this journey. Screening in clinical practice when we don’t have that in place is a problem,” Greenbaum said.
Forging ahead
In looking at the future, experts told Endocrine Today that the FDA approval of teplizumab-mzwv represents a significant stride forward, but more work needs to be done.
“We’re very proud of teplizumab, but it’s not a success if there’s only one option because not every drug works for everybody,” Greenbaum said.
Fortunately, a number of drugs are in the pipeline, including antithymocyte globulin (ATG) and verapamil, according to Oram.
TrialNet, which recently launched a trial evaluating ATG for prevention of type 1 diabetes, is also set to announce results from several trials of preventive therapies in the coming year, according to Greenbaum.
Although these treatments will be new, the data on type 1 diabetes screening are not, Dutta noted. Not all the kinks have been ironed out and issues will continue to arise, but perhaps the promise of preventive therapies and increased research into various testing approaches will nudge the field toward implementation of screening into clinical practice.
“We have 30 years of research data, so there is enough to build on. Let’s not let perfection be the enemy of good,” Dutta said.
Click here to read the Point/Counter to the Cover Story.
- References:
- Bonifacio E, et al. Diabetes Care. 2021;doi:10.2337/dc20-2122.
- FDA. FDA approves first drug that can delay onset of type 1 diabetes. fda.gov/news-events/press-announcements/fda-approves-first-drug-can-delay-onset-type-1-diabetes. Published Nov. 17, 2022. Accessed Nov. 25, 2022.
- Johnson SB, et al. Diabetes Care. 2017;doi:10.2337/dc17-0166.
- Ziegler AG, et al. JAMA. 2020;doi:10.1001/jama.2019.21565.
- Ziegler AG, et al. JAMA. 2013;doi:10.1001/jama.2013.6285.
- For more information:
- Sanjoy Dutta, PhD, can be reached at sdutta@jdrf.org.
- Carla J. Greenbaum, MD, can be reached at cjgreen@benaroyaresearch.org.
- Laura Jacobsen, MD, can be reached at lauraj@ufl.edu; Twitter @JacobsenLM.
- Carol J. Levy, MD, CDCES, can be reached at carol.levy@mssm.edu.
- Richard Oram, MD, PhD, can be reached at r.oram@exeter.ac.uk.
Collapse
Read more about
Click Here to Manage Email Alerts