Outsmarting the inevitability of type 1

For patients who have either Stage 1 or Stage 2 type 1 diabetes, the lifetime risk of developing Stage 3 approaches 100%, according to two decades of TrialNet research involving more than 160,000 relatives of people with type 1 diabetes² (for a definition of each stage, see Figure 1). While this inevitable progression cannot be completely thwarted, it can be delayed thanks to the approval of teplizumab.

“Identification of the presymptomatic stages of type 1 diabetes can be compared to identification of high blood pressure as a predictor of heart attack and stroke,” TrialNet Chair Carla Greenbaum, MD, said in a TrialNet blog post. “Before treatment for high blood pressure became commonplace, we were missing a key tool to prevent heart disease. Today, people [with early-stage type 1 diabetes] can receive intervention long before they experience symptoms or significant complications.”²

Three reasons to screen children and adolescents

Screening for early-stage type 1 diabetes is important for several reasons, says Anastasia Albanese-O’Neill, PhD, APRN, Director of Community Screening & Clinical Trial Education at JDRF (Juvenile Diabetes Research Foundation), including:

1. Timely referral to an endocrinology specialist. “It’s impossible to know if a patient is at risk for type 1 diabetes unless you screen them,” says Albanese-O’Neill—but once you know, you can promptly refer patients to an endocrinologist for further assessment and monitoring.
2. Delay the burden of insulin therapy. Certain patients with Stage 2 type 1 diabetes may be eligible to start therapy to delay Stage 3 (clinical) type 1, notes Albanese-O’Neill. This is particularly meaningful for pediatric patients and their parents, as it allows them to continue their usual routines and gives them time to prepare, says Dr. Pessah-Pollack. “Type 1 diabetes requires significant lifestyle changes. The difference between monitoring glucose levels, starting on an insulin pump and managing diabetes at age 8 years old versus 10 or at age 10 versus 13 can be significant in a child’s life and development.” 
3. Avoid diabetic ketoacidosis (DKA). Albanese-O’Neill explains, “It’s been demonstrated across multiple research studies over 40 years that type 1 diabetes risk screening and follow-up monitoring can significantly reduce the risk of DKA at diagnosis from 30% to less than 4%. Given the additional health risks and complications associated with DKA at diagnosis, this health benefit alone is an important reason to screen.”

In addition, Albanese-O’Neill notes that screening identifies individuals in early Stages 1 and 2—before insulin is required—who may be eligible for other research studies aimed at delaying the onset of type 1 diabetes. “With the approval of a disease-modifying therapy, and with further research, we may be able to delay onset even longer and eventually prevent the progression to type 1 diabetes altogether. The only way to know someone is at risk and eligible for these studies is to screen them,” she says. 

General pediatric population screening is the goal

First-degree relatives of a person with type 1 diabetes, such as siblings and parents, have up to 15 times higher risk for type 1 diabetes than those without the disease, Albanese-O’Neill says. That makes them good candidates for screening, but it is important to remember that about 85% to 90% of people have no family history of type 1 diabetes at diagnosis.

“This demonstrates the need for general population screening. Momentum is growing for this approach. In fact, general population screening was just approved by the Italian legislature, and a pilot project to implement this legislation will begin in 2024,” says Albanese-O’Neill. “Good candidates for general population screening are children ages 1 to 17.”

The screening process

The American Diabetes Association updated their 2023 guidelines to include a recommendation to screen people who have relatives with type 1 diabetes.³ Some insurance companies will cover the cost of screening for type 1 autoantibodies, but there are also free screening programs for eligible patients (see box).

Albanese-O’Neill says screening for first-degree relatives can take place at a doctor’s office. The following autoantibody tests should be ordered: 

• GAD (glutamic acid decarboxylase)
• IA-2A (islet antigen 2) 
• IAA (insulin antibody) 
• ZnT8A (zinc transporter 8) 

For family members, the practitioner can code these laboratory orders to the ICD-10 code Z83.3 (family history of diabetes). The tests are easy to order, Dr. Pessah-Pollack says.

If results are negative and the patient is under the age of 18, future rescreening should occur. ADA guidelines recommend that children who do not test positive for diabetes-related autoantibodies continue to get rescreened every year until age 18.³

If results are positive, Albanese-O’Neill says, “it’s important for the patient to follow up immediately with an endocrinologist for confirmatory testing, to get a monitoring plan in place, and to discuss treatment options. Current clinical guidelines recommend anyone with positive antibodies follow up with a specialist (pediatric or adult endocrinologist).”

—by David Levine

The recent FDA approval of a disease-modifying agent marked a major milestone in the treatment of type 1 diabetes. “This really was a landmark breakthrough,” says pediatric endocrinologist Mary Pat Gallagher, MD, of the Pediatric Diabetes Center at Hassenfeld Children’s Hospital at NYU Langone Health. This agent, a novel monoclonal antibody, is the first major development in the management of type 1 diabetes since Charles Banting discovered insulin in 1921, notes Dr. Gallagher. In the ensuing years, she says, “we hadn’t made any progress in preventing or delaying the onset of type 1 diabetes, and we hadn’t made much progress in preserving insulin production for people who were already diagnosed.”

That all changed in November 2022 with the approval of a CD3-directed monoclonal antibody, the first disease-modifying therapy for type 1 diabetes. Specifically, the agent is indicated for delaying the onset of Stage 3 (clinical) type 1 diabetes in adults and pediatric patients 8 years of age and older with Stage 2 (preclinical) type 1 diabetes, which is defined as having:

• ≥2 diabetes-related autoantibodies
• No symptoms
• Dysglycemia (fasting glucose 100-125 mg/dL, 2-hour postprandial glucose 140-199 mg/dL and A1C 5.7-6.4%)

As a result of this approval, the American Diabetes Association updated its 2023 guidelines to include a recommendation to screen at-risk individuals, in particular siblings of patients with type 1 diabetes, and consider therapy for those with Stage 2 (preclinical) type 1 based on the criteria above.¹

A single 2-week course that retrains the immune system

Type 1 diabetes is an autoimmune disease that occurs when immune cells lead to the destruction of insulin-producing beta cells in the pancreas, resulting in a reliance on exogenous insulin injections for survival.² The recently approved disease-modifying therapy works by binding to CD3, a cell surface marker on T cells.³ While the agent's precise mechanism of action is not known, it appears to “retrain the arm of the immune system that has erroneously identified the islets in the pancreas as foreign,” says Dr. Gallagher. “We’re trying to stop that and induce tolerance.” The agent is administered in a single course that requires 30-minute daily infusions for 14 consecutive days.

The study-proven result: a roughly 2-year delay in onset 

The FDA approved this novel disease-modifying therapy on the basis of a phase 2 double-blind trial in which 44 participants were randomly chosen to receive the investigational drug while 32 received the placebo.⁴ Participants were relatives of patients with type 1 diabetes who were at least 8 years of age and had Stage 2 type 1 diabetes. Following active treatment, participants were monitored with oral glucose tolerance tests at 3 and 6 months, then every 6 months, to identify those who progressed to Stage 3 type 1 diabetes.

The study, published in the New England Journal of Medicine, found that those in the active-treatment group significantly delayed the onset of Stage 3 type 1 diabetes. Among participants given the drug, the median time of progression to clinical disease was 48.4 months compared with 24.4 months in the placebo group. Over the course of the study, 19 participants (43%) on active treatment progressed to clinical type 1 diabetes compared with 23 (72%) in the placebo arm.

Dr. Gallagher believes that the roughly 2-year delay in the onset of Stage 3 type 1 diabetes shown in this study “makes it absolutely worth” considering the treatment for appropriately chosen patients. She is quick to add that 2 years was only the median delay, and that some patients may respond better than others with a longer duration of time before development of Stage 3 type 1 diabetes. Moreover, until people with Stage 2 type 1 diabetes who received the agent are followed long term, the potential benefit will remain unknown—and that it’s conceivable that some patients will never progress to clinical type 1 diabetes, says Dr. Gallagher.

In the study, the most common adverse effects were skin rash and transient lymphopenia. However, infection rates were similar in the two treatment groups.

Addressing challenges to treatment

While the therapy is groundbreaking, putting it into practice can be problematic. The main barrier is lack of screening and referral. The pivotal New England Journal of Medicine study recruited relatives of people known to have type 1 diabetes for a good reason: They are 15 times more likely than others to develop the disease themselves.⁵

What’s more, people with undiagnosed Stage 2 type 1 diabetes are asymptomatic. “So they’re just walking around with positive autoantibodies and mildly elevated blood sugar levels,” often unaware that they are at risk for clinical type 1 diabetes, says Dr. Gallagher. Because there are currently no universal screening programs for type 1 diabetes, the disease is usually diagnosed only after a patient has transitioned to Stage 3 and has symptoms.

“Screening the general population will be necessary to identify most of the people who can benefit from this therapy,” says Dr. Gallagher, who notes that Stage 2 type 1 diabetes can occur in people of all ages, yet two-thirds of cases are in children, adolescents and young adults. Organizations such as JDRF are leading a drive to institute universal screening for type 1 diabetes. Until then, family members of people with type 1 diabetes are obvious candidates for screening, and Dr. Gallagher adds that any patient who has previously tested positive for autoantibodies, such as for celiac disease, should also be considered for screening. (For insight on when and how to screen, see Screening for early-stage diabetes).

—by Tim Gower

Starting treatment:
What pediatricians and PCPs should know

1. Be sure vaccinations are up to date. Ensure that a patient has received all age-appropriate vaccinations prior to starting a course of teplizumab, as the treatment may interfere with immune response and decrease vaccine efficacy.
2. Monitor their follow-up schedule. After completion of therapy, the endocrinology specialist will determine a schedule for monitoring the patient’s response to therapy. Dr. Gallagher recommends follow-up at 1 week, then 1 month, then every 3 months.

While much is known about the health obstacles facing patients with early- to late-stage type 1 diabetes, it’s only been in recent years that one specific—and major—hurdle has been rightfully put in the spotlight: the stigma attached to the disease. These patients and their families fear becoming the target of shaming, judgment, discrimination and stereotyping. Surprisingly, a survey of people with any type of diabetes found that those with type 1 reported more stigma—including adult patients and parents of children with type 1—versus those with type 2 diabetes: 72% versus 52%, respectively.¹

The survey, which was supported by the diaTribe Foundation and included more than 5,000 participants, reported that among those with type 1 diabetes, parents of children with the disease were significantly more likely to perceive diabetes stigma than adults with type 1 diabetes (83% versus 74%, respectively). As some parents noted, the general perception is that “the parent or child caused it” and “people think my daughter could eat less and exercise more and not have diabetes.”²

What’s worse, the implications extend well beyond the psychological burden. Consider that the stigma can also hinder self-management—for example, some patients may avoid testing their glucose levels or taking insulin when they can’t do it privately, disregard their nutrition plan when eating in company and lose their overall motivation to adhere to their treatment plan. Hence, identifying and addressing such worries is a crucial element in any care provider’s strategy. Below, how to help patients and their families overcome common hurdles associated with type 1 diabetes stigma.

“I’m so afraid of how an early-stage type 1 diagnosis would change my child’s life that I’d rather not deal with it.”
In some cases, parents can be so anxious about a possible diagnosis that they put off screening and follow-up appointments for their child. For those diagnosed with Stage 1 or Stage 2 type 1 diabetes, the anxiety of becoming insulin dependent can feel even more daunting.

The way to overcome this: Help patients and families to see the information as empowering, as it provides an opportunity to take charge of their lives, says Gary Scheiner, MS, CDCES, of Integrated Diabetes Services in Wynnewood, PA. Scheiner knows their struggle firsthand: He has had type 1 diabetes for nearly 50 years and has dedicated his practice to improving the lives of patients with insulin-dependent diabetes. Scheiner reminds patients and their families that catching the condition early is key. When they are conflicted about screening for Stage 1 or Stage 2 type 1 diabetes, Scheiner tells them, “That old saying—ignorance is bliss—just throw it out the window. This is sort of like changing your oil before your car blows up. This is a case where people need to do a little routine maintenance, and that routine maintenance is screening and follow up.”
Also important: Advise screening for relatives of any family member who has been diagnosed with any stage of type 1 diabetes (Stage 1, 2 or 3).

“People will think less of me/blame me if I tell them I have (or my child has) type 1 diabetes.”
Fear of being judged often compels people to keep quiet about the condition. In the diaTribe Foundation survey, the greatest difference between respondents with type 1 diabetes and those with type 2 related to misunderstandings about diabetes, including views that type 1 diabetes is contagious or that all types of diabetes are the same.¹

While patients should not have to tell everyone they have diabetes, being transparent with those they see regularly frees them of the burden of “keeping up appearances.” Endocrinologist Deena Adimoolam, MD, who serves as an Advisory Committee Member for the Endocrine Society, tells her patients that not being open simply adds to their stress. “Rather than feeling those negative vibes, you’re able to have a healthier mindset, which allows you to lead a healthier lifestyle around your disease,” she says.

Another way to help alleviate patients’ fears: Encourage them to seek out others with type 1 diabetes to head off feelings of isolation. Regardless of whether they find their support system online, through local meet-ups or at diabetes conventions, the interaction helps foster a sense of normalcy (for resources, visit diatribe.org and jdrf.org/T1Detect). In a group setting, Scheiner says, “everyone’s checking their blood sugar or continuous glucose monitor and taking their shots or bolusing through their insulin pumps—and suddenly it’s the cool thing to do!”

“I’m embarrassed I’ve brought this on myself (or on my child).”
The survey found that the most common form of stigma in respondents with diabetes was self-blame—that having the disease was a failure of personal responsibility.¹ Yet consider: “Millions of people are out of shape in this country, yet only a select percentage develop diabetes,” notes Scheiner. Helping patients understand that diabetes is a multifactorial disease is the first step in easing feelings of self-blame. Dr. Adimoolam also says the attitude you adopt as healthcare provider can go a long way toward countering patient shame. “I try to be as optimistic as possible to really paint a bright future. With diabetes at least we have a lot of possibilities—there’s just so much research out there. You have to focus on what you can do today.” Scheiner has found this tactic of staying positive successful, as well, casting it as an opportunity to “show ‘em” (so to speak). He tells his patients: “Be proud of the fact that you’ve got this chronic health condition that you didn’t ask for, yet you’re able to succeed in life and take care of yourself at the same time.”

“I don’t want people at school to think I’m sick.”
Thanks to the Americans with Disabilities Act, there are laws in place to protect patients from discrimination. Yet some patients fear that informing a teacher will hold them back. Dr. Adimoolam encourages patients to open up, adding that a doctor’s note provides the medical stamp of approval that can ease any awkwardness. People will be likely to sympathize with patients and understand the child’s needs to take breaks for checking glucose levels, administering insulin and so on.

“I’m worried how this will affect my social life or ability to date.”
While it can be awkward for teenagers and young adults to approach the topic with someone new, experts agree that being up front is the best course of action to prevent the other person from feeling deceived down the road. Scheiner’s personal approach when he was dating was to keep it breezy. “I prefer to be casual about it, and I recommend the same to my patients,” he says. He tells patients to use their maintenance tools in front of the person and mention type 1 diabetes like they might be talking about the weather. The key: To stress that it’s being well-managed. Once it’s clear the patient is comfortable with it—and on top of it—the other person is more likely to relax about it as well.

And there’s another way to frame diabetes when it comes to matters of the heart: It’s a hidden opportunity for showing how much someone cares. For example, Scheiner’s dating strategy was to bring up his type 1 diabetes right away: “The first time I met my wife, I was up front about it. And on our first Valentine’s Day together, she was very sensitive. She gave me this giant heart-shaped box full of popcorn instead of [blood-sugar-spiking] chocolate. And I thought ‘This is a woman who is sensitive to my needs!’ But the fact that she was thinking of me—I thought that was really considerate.”

—by Beth Shapouri

 

Does having diabetes in the United States come with social stigma?²

 

Special thanks to our medical reviewer:

Rachel Pessah-Pollack, MD, FACE, Clinical Associate Professor, Division of Endocrinology, Diabetes & Metabolism, NYU School of Medicine, NYU Langone

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