beginning of the end for insulin? – enter immunotherapy for T1DM

Although we have treated type 1 diabetes (T1DM) with insulin for more than 100 years, it has been apparent since the discovery of insulitis in the 1960s and islet cell antibodies in 1974 that T1DM is fundamentally an autoimmune disease, not a metabolic disease.1 Almost all other autoimmune diseases, from inflammatory bowel disease to rheumatoid arthritis, are treated with immunotherapy but not T1DM. In large part this is because of the discovery of insulin: unlike most other autoimmune diseases, a replacement therapy exists for T1DM. As a result, the discovery of insulin can be viewed as both a blessing and a curse. It is a “curse” because most of the major drug companies have developed their large immunotherapy portfolios of drugs for autoimmune diseases other than T1DM, including some such as psoriasis or alopecia areata that might be considered less life-threatening. And it is likely that diabetes practitioners are also partly to blame since they fear immunotherapy since it is a treatment with which they are not familiar. It is important to remind ourselves of the challenges of insulin therapy. It is not a drug without risk: deaths still occur from underdosage (DKA) and overdosage (hypoglycaemia). According to ONS data, in 2021 in England and Wales, 44 people under the age of 50 died of DKA and 154 died of hypoglycaemia.2 Set against this, even despite the introduction of CGM and insulin pumps, fewer than 30% of adults and children with diabetes achieve a target HbA1c < 7.0%, or 53 mmol/mol which obviates the risks of longterm complications.3 Furthermore, insulin management consumes millions of hours of patients and healthcare professional time in training, adjustments, testing and decision-making. Despite this, 36% of children and families continue to need psychological support more than five years after diagnosis (NPDA national audit 2018-2019,3 and up to 50% of adults with T1DM report significant diabetes-related distress. 4 There is a large and expanding world of highly selective immunotherapies that does not include the classic immunosuppressents (e.g. cyclosporin, tacrolimus) used in transplantation. Rather, it includes many drugs known as “biologics” that have been widely used and have been very well tolerated in other autoimmune diseases for more than 20 years. Many are monoclonal antibodies, but small molecule inhibitors such as JAK kinase inhibitors are being introduced.5 At least seven selective immunotherapies have shown efficacy in Phase 2 studies in preserving beta cell function from diagnosis compared to controls.6,7 These treatments reduce progression of the underlying disease process but do not cause regrowth of beta cells. In current clinical practice, T1DM is diagnosed at the time that insulin replacement is required. This is late in the disease course, when it is estimated that more than 80% of functional beta cells have been lost. When selective immunotherapy is given at this stage, some impact on insulin dose (and in some studies also HbA1c and hypoglycaemia rates) is seen, but it is too late to obviate the need for insulin. Fortunately, it is possible to diagnose T1DM at an earlier stage. Multiple studies of birth cohorts in relatives of those with T1DM and the general population have shown that 80-90% of asymptomatic children who are found to have two or more islet autoantibodies (including anti-GAD, anti-IA-2, anti-ZNT8 or anti-insulin) will go on to develop T1DM (Figure 1). Once dysglycaemia develops (equivalent to impaired glucose tolerance), levels of hyperglycaemia Address for correspondence: Professor Colin M Dayan Professor of Clinical Diabetes and Metabolism, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK E-mail: DayanCM@cardiff.ac.uk