Diabetes: Putting off until tomorrow what could happen today can be good

Type 1 diabetes (T1DM) is a less common form of diabetes, but it is often the most dramatic. It is characterized by loss of pancreatic beta cells with low or ultimately virtually absent levels of insulin, making patients with T1DM particularly prone to present with or develop ketoacidosis and organ damage. While aggressive exogenous insulin therapy has been shown to reduce the complications of T1DM,¹ prevention of beta-cell loss and preservation of endogenous insulin production have been attractive treatment prerogatives.

Pancreatic islet cell autoantibodies are the laboratory footprint of autoimmune T1DM, which may account for 10% of all patients with diabetes mellitus.² There are multiple implicated antibodies, with anti–glutamic acid decarboxylase (GAD) perhaps the best known, although occasional patients with presumed autoimmune diabetes mellitus have no identifiable antibodies.³ Pancreatic autoantibodies can be detected in patients months to many years before clinical diabetes mellitus is recognized, similar to the observation that patients with systemic lupus or rheumatoid arthritis have circulating antibodies (eg, antinuclear antibody, rheumatoid factor, anti–cyclic citrullinated peptide) for years before the clinical presentation of their systemic autoimmune disease.⁴

The evolution of autoimmune T1DM has been divided into 3 sequential stages^1,5 that may be used to guide the choice of potentially effective immunotherapy as well as traditional diabetes medications. Stage 1 includes patients with identified pancreatic autoantibodies in the absence of evidence of islet dysfunction. Glucose levels are normal, even when stressed by glucose tolerance testing, as is the hemoglobin A1c. But there is approximately a 44% risk of developing clinical T1DM within 5 years (84% in 15 years) due to an extremely variable but seemingly relentless immune destruction of islets when multiple diabetes-associated antibodies are present. Stage 2 is characterized by “dysregulation” of glucose control (slight abnormalities in the A1c and with the oral glucose tolerance test). There is an approximate 60% risk of developing T1DM by 2 years and 75% risk by 5 years. Patients in stage 3 have clinically diagnosed T1DM and will require insulin.

While T1DM is more prevalent in children and adolescents, Lundholm and Zhou⁶ in this issue of the Journal discuss the recognition and management of a subset of autoimmune diabetes mellitus in adults, which has been termed latent autoimmune diabetes in adults (LADA). In an accompanying editorial, Hoogwerf⁷ argues, based in part on the relentless march of these patients with autoimmune T1DM toward true islet failure, that patients with LADA should receive insulin therapy very early following the diagnosis.

Patients with LADA exhibit various rates of progression. There are genetic and undoubtedly environmental factors at play. Many patients with LADA have other autoimmune disorders that may impact their clinical course. If autoantibodies (and likely cell-mediated immunity) are responsible for the islet demise, and autoimmunity can be detected in a preclinical phase, perhaps targeted immunotherapy can slow or reverse the destructive course if introduced early enough. For that hope to be realizable, adult patients at high risk for autoimmune T1DM will need to be routinely screened for the presence of diabetes-associated autoantibodies. Given the relative infrequency of LADA, screening should be targeted to those adult patients at high risk, and I believe that will require an educational campaign directed at nondiabetologists: primary care clinicians and subspecialists. A first step in identification of patients with stage 1 T1DM with islet autoantibodies can be made by screening first-degree relatives of patients with autoimmune T1DM. Recognizing these patients, particularly those with multiple autoantibodies, permits close follow-up for development of clinical diabetes mellitus, avoiding the uncommon but potentially devastating initial presentation of their diabetes mellitus as ketoacidosis.⁸ The real therapeutic opportunity, however, is to have available an immunotherapy that can markedly slow or prevent beta-cell autodestruction.

In 2019 Herold et al⁹ published results of a 76-person randomized, placebo-controlled trial testing whether a T-cell–directed therapy could impact the progression to clinical diabetes in a group of nondiabetic relatives (> 8 years old with ≥ 2 diabetes-associated autoantibodies) of patients with T1DM with stage 2 disease. The results led to US Food and Drug Administration approval for the drug teplizumab.

Teplizumab is an anti-CD3 monoclonal antibody with a modified Fc region that does not bind the Fc receptor, hence minimizing potential complications, including cytokine-release syndrome. In the Herold et al⁹ study, a daily teplizumab infusion for 14 days resulted in 57% of treated individuals, compared with 28% in the placebo group, remaining diabetes-free at study end (median 745 days; the duration of follow-up was more than 3 years in 75% of participants). Sims et al¹⁰ in an extended follow-up (median 923 days) of 76 individuals at high risk for T1DM demonstrated incomplete but ongoing efficacy (Table 1).

The mechanism of action is complex. Teplizumab induces both partial “immune exhaustion” in a population of CD8 cells, resulting in less pancreas cytotoxicity, and an increase in regulatory suppressor T cells. The efficacy seems not to depend on the transiently observed lymphopenia. The side-effect profile is manageable, without evidence for development of frequent or severe bacterial or viral infections, even in those few patients who had detectable Epstein-Barr virus or cytomegalovirus circulating DNA. An extremely detailed practical guide to infusion management has been published by Mehta et al,¹¹ but not emphasized is the estimated list cost of $190,000 for the 14 infusions.

A forward-looking question is whether this specific strategy may be successful in other autoimmune conditions that can be identified before clinical expression of disease. Alternative immunotherapy approaches have been attempted in other systemic autoimmune diseases. A study of blockade of T-cell activation with abatacept delayed but did not fully prevent the clinical onset of rheumatoid arthritis in patients with anti–cyclic citrullinated peptide antibodies who at the time of study entry had polyarthralgias and some magnetic resonance imaging findings of joint inflammation but no joint swelling. Six months of weekly treatment with abatacept (vs placebo) reduced the development of rheumatoid arthritis at 1 year from 35% in placebo-treated patients to 8% in those who received abatacept.¹² Presently, no therapy is currently approved for rheumatoid arthritis prevention.

These studies are not “home runs.” But, they warrant optimism for a successful, new approach to autoimmune T1DM and other immune-mediated diseases.

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