Type 1 Diabetes—Reaping the Rewards of a Targeted Research Investment

Judith E. Fradkin; Julie A. Wallace; Beena Akolkar; Griffin P. Rodgers


Diabetes. 2016;65(2):307-313. 

In This Article

Testing Strategies to Prevent and Delay Type 1 Diabetes

Even while awaiting new approaches to type 1 diabetes prevention that are anticipated to emerge from TEDDY, another international consortium is testing strategies for the prevention or delay of type 1 diabetes based on the current understanding of the disease, our ability to define the level of risk for type 1 diabetes in asymptomatic individuals, and the results of previous intervention studies suggesting potential efficacy. Type 1 Diabetes TrialNet (TrialNet) evolved from the Diabetes Prevention Trial–Type 1 (DPT-1), which tested whether two separate interventions involving insulin could prevent the progression from autoimmunity to type 1 diabetes. Although protective effects of insulin were not demonstrated, DPT-1 did show in a large cohort that diabetes risk over 5–10 years could be accurately determined in people with autoimmunity from families with type 1 diabetes.[22,23] Accurate risk assessment is essential for the design of studies to prevent or delay the disease and is particularly important as these studies involve children and interventions with some potential for adverse effects. The DPT-1 Risk Score (DPTRS) has now been studied using TrialNet Natural History Study data and has been found to improve type 1 diabetes risk classification accuracy.[24] Data from DPT-1, TrialNet, and other studies form the basis for a new recommendation from JDRF, the Endocrine Society, and the American Diabetes Association for a type 1 diabetes staging classification in at-risk individuals that provides a framework for the research and development of preventive therapies.[25] TrialNet, also supported by the SDP, has screened over 100,000 relatives of people with type 1 diabetes to identify subjects for trials testing strategies for prevention of progression from autoimmunity to type 1 diabetes.

Three prevention trials are ongoing in TrialNet, oral insulin, anti-CD3 monoclonal antibody (teplizumab), and CTLA-4-Ig (abatacept); one is based on a previous prevention study and two are based on promising results in preserving β-cell function in newly diagnosed type 1 diabetes. In DPT-1, oral insulin caused a significant delay of type 1 diabetes onset in a subgroup of subjects with high titers of insulin autoantibodies;[22] this post hoc observation is being tested by TrialNet. Treatment with teplizumab was previously shown to slow the decline in C-peptide production after 2 years in patients with new-onset diabetes.[26] The TrialNet teplizumab study will test whether progression to type 1 diabetes can be prevented or delayed in subjects with two autoantibodies and impaired glucose tolerance. This is the first example of a trial to test a nonantigen-specific immunomodulatory agent in type 1 diabetes prevention. The TrialNet study of abatacept in newly diagnosed patients found that 2 years of monthly drug treatment delayed C-peptide decline.[27] Moreover, treatment effects persisted for 1 year after the drug was discontinued.[28] Abatacept was approved by the FDA as a therapy for rheumatoid arthritis in 2005, illustrating how research in one autoimmune disease can contribute to progress in others. The teplizumab and abatacept prevention trials represent a paradigm in which the efficacy and safety profile of these agents in new-onset type 1 diabetes trials propel testing them earlier in the disease course. Subsequently, such drugs may be studied in combination. If successful, these high-risk, high-reward studies may inform critical future public health efforts to identify those at risk and to intervene to prevent type 1 diabetes.