For almost 100 years, insulin remains the mainstay of treatment of individuals with type 1 diabetes (T1D). While insulin delivery and glucose monitoring continually improve, all of these efforts aim to control the symptoms of disease – hyperglycemia - and not the underlying disease itself. The unrelenting burden of disease negatively impacts children and their families through all dimensions of their life.

The aim of disease modifying therapy is to change this picture. With the knowledge that type 1 diabetes is an immune mediated disease, clinical trials of immunotherapy began in the 1980s with the aim of halting or suppressing disease progression prior to or soon after clinical diagnosis. We now know that immunotherapy “works” in T1D; there are at least four therapies with a reasonable safety profile that have slowed beta cell loss after clinical diagnosis. Indeed the difference between treatment and control groups in trials of disease modifying therapy in T1D is very similar to that seen in immunotherapy for other immune mediated diseases. Yet, none of these therapies has move into clinical practice. This fact emphasizes that more work is needed to demonstrate the clinical impact of immunotherapy through trials in those after clinical diagnosis aiming to extend the duration of the effects of therapies and increase the number of individuals who respond.

The most compelling case for clinical benefit of disease modifying therapy will likely come from therapies that slow or stop disease progression prior to clinical onset. It has long been known that autoantibodies and reduced insulin secretion is present before clinical diagnosis. The remarkable consistency in data obtained from studies over 35 years in Europe, Australia, and North America has led to new terminology in describing the natural history of disease. As illustrated in the figure, individuals with two or more antibodies and normal glucose tolerance are at stage 1 T1D, stage 2 T1D are those who show abnormal glucose tolerance, and stage 3 T1D is clinical onset. Trials are underway at each stage of disease incorporating evolving information about mechanisms of disease and newer observations about the natural history.

Curing or preventing T1D remains elusive, yet progress has been made and each clinical trial builds on previous results. A key part of bringing disease modifying therapy to clinical use however is not just demonstrating the effectiveness of therapy. Endocrinologists who are so comfortable with glucose monitoring and insulin therapy must learn more about immunology in preparation for using immunotherapeutics in their clinical practice someday.

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2. Battaglia M, Anderson MS, Buckner JH, Geyer SM, Gottlieb PA, Kay TWH, Lernmark A, Muller S, Pugliese A, Roep BO, Greenbaum CJ, Peakman M: Understanding and preventing type 1 diabetes through the unique working model of TrialNet. Diabetologia 2017;60:2139-2147.[Pubmed]

3. Greenbaum C, Lord S, VanBuecken D: Emerging Concepts on Disease-Modifying Therapies in Type 1 Diabetes. Curr Diab Rep 2017;17:119.[Pubmed]