NEW YORK – The landmark approval of a drug to delay the onset of type 1 diabetes has called attention to efforts to identify people who are at risk of developing the disease. But while there are promising screening methods, doctors are waiting on updates from implementation studies and guidelines bodies before incorporating such tests into routine patient care.
Provention Bio's Tzield (teplizumab), which the US Food and Drug Administration greenlighted in November 2022, is a CD3-directed monoclonal antibody injection for patients who are asymptomatic but progressing toward clinical diabetes. It's the first-ever disease-modifying therapy approved for type 1 diabetes.
"Type 1 diabetes knowledge of genetics and risk has been growing," said Stephen Rich, a professor in the University of Virginia School of Medicine's public health sciences department. "It's going to be a remarkably interesting — and hopeful — time over the next five to 10 years, [where] we can really do something to intervene before people develop diabetes."
Rich is a co-chair of the Precision Medicine in Diabetes Initiative (PMDI), a group established by the American Diabetes Association and the European Association for the Study of Diabetes in 2018 to assess ways in which precision medicine may be able to improve diabetes care. The PMDI in October produced an international consensus report based on an evidence review of promising precision medicine interventions in diabetes and their clinical readiness.
"Precision diabetes medicine is currently largely aspirational," Rich and colleagues wrote in the report, which was published in Nature Medicine.
However, they identified genetic risk assessments and islet autoantibody testing to predict development of type 1 diabetes as two of the most promising areas for "immediate clinical implementation."
Improving outcomes for at-risk patients
Before adding a new screening to routine healthcare, it's critical to ensure there are care management steps a patient can take to improve outcomes based on their results. Otherwise, it's just testing for the sake of testing.
"When you think about reasons you would want to do screening, you always want to have something you can do about what you find," said Emily Sims, a pediatric endocrinologist and an associate professor in the pediatrics department at Indiana University School of Medicine, who was also a coauthor on the consensus report.
There are an estimated 8.4 million people worldwide with type 1 diabetes, a chronic autoimmune disease in which the body's immune system attacks insulin-producing beta-cells in the pancreas. It's a life-changing and sometimes costly diagnosis, since to treat the condition, patients must take insulin, monitor blood sugar, and manage lifestyle factors like diet for the rest of their lives. Left untreated, type 1 diabetes can lead to severe health issues, including damage to nerves, kidneys, and eyes and diabetic ketoacidosis, a life-threatening yet common complication that's sometimes even the first sign of the disease in undiagnosed patients.
Tzield, which works by binding to and deactivating certain immune cells, seeks to improve patients' quality of life by delaying the clinical stage of disease and associated complications. It's available to patients who are at least 8 years of age and at stage 2 of type 1 diabetes. Type 1 diabetes is characterized on a scale of stages 0 to 3 based on patients' symptoms, blood sugar levels, and the presence of diabetes-related islet autoantibodies. Stage 3 marks the clinical diagnosis of what's traditionally thought of as type 1 diabetes, while the earlier phases represent progression toward that final stage.
Tzield's approval is a big step toward improving type 1 diabetes care, Sims said, but it's just the start. Development of additional disease-modifying drugs to delay or even prevent disease onset or to reduce risk of complications will be essential.
Even if a patient isn't yet eligible for Tzield, knowing that a child is at high risk of developing type 1 diabetes allows families to get a jump-start on education, according to Sims. Physicians can take this time to make families aware of what symptoms to look out for and what assessments might be needed to keep an eye on disease progression, such as monitoring based on A1C and oral glucose tolerance tests.
When patients are diagnosed with type 1 diabetes, they often need a "crash course" in monitoring blood sugar and carbohydrates, Sims said. It can be "super overwhelming for families and patients," she added. "If you find someone who you know is progressing … you can introduce these different ideas in a graduated way."
Screen time
Two potential screening approaches called out in the consensus report are genetic risk assessments and islet autoantibody testing.
While type 1 diabetes isn't fully caused by genetics, patients who develop the disease do have a genetic predisposition, according to Rich. And although researchers haven't characterized all the genetic variants that are likely to be involved in the disease, they have identified "close to 90 percent," he said, such as certain variants in HLA-DRB1 and other HLA genes related to autoimmunity.
A genetic risk score evaluating those genes could inform a physician's understanding of their patients' baseline predisposition to type 1 diabetes, but testing for specific islet autoantibodies would provide additional information on what stage of disease a patient is at. Autoantibodies to insulin and glutamic acid decarboxylase, for instance, can indicate damage to beta cells and predict risk of developing type 1 diabetes. Testing for their presence can be a useful screening tool, Rich said.
The American Diabetes Association's 2024 clinical practice recommendations, released last month, already say islet autoantibody testing, specifically for autoantibodies to insulin, glutamic acid decarboxylase, islet antigen 2, or zinc transporter, may be done to screen patients for presymptomatic type 1 diabetes and that patients with multiple autoantibodies present in the blood should be referred to a specialized center for evaluation and possible treatment. There are, however, currently no type 1 diabetes screening recommendations based on a genetic risk assessment.
The PMDI's new consensus report does not represent an official position or guidance from the ADA and is only meant to represent expert opinion on precision medicine in diabetes, according to Marlon Pragnell, the organization's VP of research and science. The ADA's professional practice committee (PPC) is the party responsible for evaluating and updating standards of care.
"We anticipate that the PPC will consider the current consensus report and any supporting clinical evidence on [type 1 diabetes] genetic risk classification when it makes its next annual review of the literature," he wrote in an email. He also anticipates they will "thoroughly review" scientific evidence on islet autoantibody screening, which could inform updates to existing recommendations.
Among experts, there are a few schools of thought on who should undergo genetic or islet autoantibody screening, if implemented.
One option could home in on screening only those with family history. That's what makes most sense to Dimpi Desai, an endocrinologist and clinical assistant professor at Stanford University School of Medicine, who was not involved in the report.
"I don't think it is cost-effective to be doing it for all pediatric patients," she said.
Still, significant work remains to be done to get to the point of being able to screen those with family history or other risk factors, such as setting guidelines for how to do the screening, determining what follow-up is needed, and assessing accessibility and cost-effectiveness. Genetic risk and autoantibody screenings of this population "will be very useful, if we get to this point," she said.
However, only a minority of patients who develop type 1 diabetes have a first-degree relative with the disease, said Sims. She instead suggested a population-level screening program might make the most sense.
One way of implementing that could involve adding genetic risk assessment for type 1 diabetes to existing newborn screening programs and using that initial genetic screening to expand the population that receives islet autoantibody screening to include not only those with a family history but also those who appear to have a genetic predisposition. Another way to conduct population screening could only involve islet autoantibody screening, with testing done when pediatric patients are already at the clinic or getting blood drawn as part of other laboratory screenings.
"There's a lot of debate right now about what the best approach is going to be," Sims said. But "if we really want the most people to benefit, it makes sense to target everybody."
The discussion over whether to screen for type 1 diabetes, and if so, how, is the hot topic in the field, said Adriana Carrillo Iregui, a pediatric endocrinologist and medical director of the diabetes program within the pediatric endocrinology division at Miami, Florida-based Nicklaus Children's Hospital. Hospital leadership there has started discussing how population screening might work — at what ages to screen and how to fund it — but it hasn't been implemented.
"All this work is in progress," said Carrillo Iregui, who was not involved in the PMDI's report. Currently, patients at Nicklaus Children's Hospital who are at least 2.5 years of age and who have a close family member with type 1 diabetes are screened through TrialNet, a US-based international research project that offers free risk screening to patients with a family history of type 1 diabetes as part of its effort to understand disease progression.
There are other research programs providing genetic screening with follow-up islet autoantibody testing to those without family history, such as the Newborn Screening for Genetic Susceptibility to Type 1 Diabetes and Celiac Disease and Prospective Follow-up Study (BabyScreen) in Finland and the Global Platform for the Prevention of Autoimmune Diabetes (GPPAD) that has sites in multiple countries across Europe. And programs like Autoimmunity Screening for Kids (ASK), a study at the University of Colorado Anschutz Medical Campus, and the Early Detection of Type 1 Diabetes (Fr1da) in Germany offer islet autoantibody testing as a primary screening for type 1 diabetes.
But as data on genetic risk for type 1 diabetes largely has been based on research on patients of European ancestry, continuing to build evidence on non-European ancestry populations is also important, the authors of the PMDI consensus paper noted.
Getting to clinical implementation
Sanford Health, a rural hospital system headquartered in Sioux Falls, South Dakota, has one of a handful of research programs conducting type 1 diabetes risk screening in the US. In 2020, the hospital system launched general population screening as part of a research program dubbed Population Level Estimate of type 1 Diabetes risk Genes in children, or PLEDGE. Researchers are aiming to enroll 20,000 pediatric patients by 2025 into the study, which is assessing clinical outcomes and costs. More than 7,500 patients have enrolled into the program so far.
To participate in the PLEDGE study, patients undergo a blood-based genetic test to establish a genetic risk score, with screening for islet autoantibodies conducted at routine clinic visits around ages 2, 5, and between 9 and 16 years old, with more frequent testing if an islet autoantibody is detected. Patients with relevant autoantibodies are offered educational resources, metabolic monitoring, and information about clinical trials, and are flagged in the electronic health record (EHR) as presymptomatic type 1 diabetes.
To date, researchers have identified three dozen children with persistent positive antibodies who are being monitored for disease progression, said Kurt Griffin, a pediatric endocrinologist at Sanford Health and principal investigator of the PLEDGE study, who was also a coauthor on the PMDI's consensus report. Three of those patients have progressed to a clinical diagnosis based on high blood sugar, but none have presented with symptoms or diabetic ketoacidosis.
"We're still early," Griffin said, so they can't draw conclusions yet. "But I think from what we've picked up so far, we're on the right track."
A key component of Sanford Health's PLEDGE program has been figuring out how to do this screening at scale. With more than 150 of the hospital system's clinics across North Dakota, South Dakota, and Minnesota enrolling patients, it's not feasible to have a dedicated coordinator at each clinic approaching families in the waiting room. So, researchers used the hospital's EHR to create a process to automatically flag new patients eligible for screening and send messages to parents about the study from within the patient portal.
Part of the PLEDGE study's goal is also to develop findings to encourage inclusion of such screening tests as part of standard pediatric care guidelines. For example, by identifying patients with type 1 diabetes at an earlier stage of the disease, the hospital system may be able to save costs related to treating complications that arise when patients are diagnosed later in life, providing the system a rationale to adopt screening.
"We're trying to learn and figure out, long term, what's going to be the best way to do this," Griffin said. He said that evidence supporting islet autoantibody screening is further along, and while he eventually would like to see population-level genetic risk assessments integrated into standard care, additional validation of genetic screening — through programs such as PLEDGE — is needed first. "We're probably not quite there yet, but that's where we're going to go."
There's also the question of cost and accessibility for countries globally, without which precision medicine may unintentionally lead to widening healthcare disparities. In the US in particular, the ability to test patients will hinge on reimbursement by payors, not only of the tests themselves but also of follow-up care like genetic counseling and ongoing monitoring of at-risk patients.
Down the line, there's hope that identifying biomarkers such as particular islet autoantibodies or genetic markers could help to diagnose diabetes with more specificity and also be able to pinpoint best-fit treatments, Indiana University's Sims added. Researchers will need to set up rigorous clinical trial designs to identify those groups and prove treatments in them.
"That's a really exciting prospect, but we're not there yet," she said.