Beta-Cell Preservation in the Wild—Need for Real-World Monitoring, Treatment Protocols, and Efficacy Measures of Potential Disease-Modifying Therapies in Type 1 Diabetes

As screening for type 1 diabetes (T1D) in the asymptomatic state has been moving from the research to the clinical arena, so too has disease-modifying therapy for T1D. The use of the first disease-modifying therapy, teplizumab, in stage 2 T1D (multiple autoantibodies and dysglycemia) has been ramping up since its approval in 2022 by the U.S. Food and Drug Administration (FDA). Urgency is now building, however, as teplizumab for those with new-onset stage 3 T1D has received a National Priority Voucher from the U.S. FDA, which could expedite its approval process. The need for clear, consistent protocols for pre-, peri-, and post-infusion monitoring of this therapy and future therapies to come is of vital importance.

The number of clinicians eligible to prescribe disease-modifying therapies will grow rapidly, even as many have limited or no prior experience. Several clinical and operational barriers to implementation in pediatric and adult endocrinology remain and are discussed below. At the same time, important opportunities exist, including standardized real-world data collection to assess efficacy and therapeutic response across stages of T1D. Electronic health record (EHR) integration and centralized, shared resources will be critical to safe and effective adoption. In this context, the T1D Exchange Quality Improvement (T1DX-QI) Collaborative is uniquely positioned to enable benchmarking and facilitate the dissemination of best practices across centers.^1,2

Translation of clinical trial protocols must be clear and practical. This includes identifying individuals who are best suited for each therapy while not creating inequities in access. Initially, this will be based on the FDA-indicated population, but consideration must be given to concomitant conditions and medications while also using a shared decision-making approach for people with diabetes and their families. Immunomodulatory therapies require people to be low risk for infectious activation pre-infusion and receive counseling on the post-infusion risk of infections. Expectation setting for therapy-specific side effects and access to knowledgeable health care teams during and following infusions is essential. Finally, measuring the efficacy of therapies in trials can be challenging to translate to clinical care, as repeated mixed meal tolerance tests may not be practical, but for those in stage 3, some measure of C-peptide secretion and partial remission is essential.

Our eagerness, however, should not overshadow barriers that may impact the safe and equitable administration of such therapies. These barriers include the cost of and insurance coverage for new therapies and the need for streamlined programs for review and approvals of therapies, which could add to the already insurmountable prior authorization process that U.S.-based health care professionals (HCPs) face. Furthermore, funds for practice reimbursement should be considered, with specific focus on reinvestment of revenue from infusions back to the clinical programs to provide the necessary staff and resources to permit ongoing stability of services rendered.

These therapies require substantial time commitments from people with diabetes, their families, and health care teams, and this must be considered to ensure equitable access for all individuals with T1D. It is well recognized that participants in clinical trials do not reflect the racial and ethnic backgrounds of the broader population living with the condition.³ Moving therapies to clinical approval should lessen that disparity, but only if we take an active role in assuring this.⁴ For example, automated EHR alerts to offer new therapies should be incorporated to reduce provider biases. Importantly, if institutions do not support endocrinology departments/divisions with the staffing and hours of operation needed to perform these infusions, there will not be enough geographic diversity in the centers that care for these individuals. While initially infusions may only be available at centers of excellence with extensive experience through involvement in clinical research trials, the expectation that this will expand over time highlights the need for standardized recommendations to help ensure safety.

From an HCP standpoint, endocrinologists will need to adapt and learn from our rheumatology, gastroenterology, and oncology colleagues to apply new biologic therapies we have not previously encountered. While intravenous administration of immunomodulatory therapies has challenges, the field of endocrinology is not naïve to such protocols given experience with other therapeutics, like bisphosphonate infusions. Similarly, continued iterations of treatment strategies are a hallmark of the management of endocrine conditions, advancing novel, targeted therapies to better support people living with diabetes and endocrine diseases. A specific example includes the use of burosumab in hypophosphatemic rickets where use in clinical centers expanded following trial successes in addition to the development of practice guidelines and reimbursement strategies.⁵

As with access to teplizumab in the real world, research teams that conducted the clinical trials leading to therapy approval are particularly well equipped to support translation into routine clinical care and development of standardized protocols aligned with national and international society guidelines, including guidance on infusion setting (e.g., infusion center vs. home-based care). For pediatric populations, home administration raises important safety considerations, including caregiver preparedness and clear pathways for accessing emergency services.⁶ Since 2022, additional clinical centers with large patient populations, supportive infrastructure and administration, and typically an HCP advocate have established programs to administer teplizumab. However, therapy is not yet universally accessible due to limited availability in rural areas, the need for 14 days of infusion—risking work and school absences, trained staff, and practices to identify autoantibody-positive, presymptomatic individuals.

The recognition of presymptomatic stages of T1D and the use of disease-modifying therapies represents a new paradigm for both pediatric and adult endocrinology. While developing standardized resources and tools is essential, it is equally critical that this evolving framework become integrated into medical, nursing, and advanced practice provider training programs. This is a transformative moment for the field, and sustaining this momentum will help attract and prepare the next generation of clinicians who will be at the forefront of implementing emerging therapies for T1D.

In summary, there remains an important unmet need for high-quality resources developed by trusted health professionals with experience using novel therapies following their regulatory approval, as well as meaningful engagement of people with diabetes and their families as essential stakeholders in this process. Given the multidisciplinary nature of these therapies, strong administrative support will be essential, including reinvestment of generated revenue to ensure the sustainability of the clinical teams delivering care. The T1DX-QI is committed to providing outcome data that can be used to understand the long-term impact of these therapies and identify best practice strategies that can be widely distributed. The framework is built. The time is now to preserve beta cells in the wild.