14th March 2020, Dr Chee L Khoo
It’s more than 100 years since insulin was first use for patients with type 1 diabetes (T1D). It’s been many decades now since we discovered that autoantibodies pre-dates the development of hyperglycaemia and theoretically, we should be able stop destruction of the beta cells before the onset of hyperglycaemia and “prevent” T1D. Unfortunately, strategies from preclinical and clinical studies thus fat, have not met their primary end points. The beta cells are still disappearing fast and at the end of the day, insulin therapy is still needed. Where are we at now in our efforts in our strategies in halting the immunological killing of beta cells?
The immunological attack
T1D is an immunological disease caused by the killing of beta cells. The immunological onset can be identified by the presence of autoantibodies. Up to five different autoantibodies are measured in research studies of T1D. The long-term risk of T1D for people with a single auto-antibody is greater than for people without autoantibodies, but fewer than 10% of people with a single autoantibody develop diabetes over 10 years. However, when two or more autoantibodies are found, the individual is said to have stage 1 diabetes. Dysglycaemia only appears in Stage 2 and beyond. By the time the patient is symptomatic, only 10-20% of beta cells are left. See Table 1.
Unlike type 2 diabetes, the risk of T1D amongst first degree family members is largely dictated by the presence of high-risk major histocompatibility genotypes: for first-degree relatives with shared high-risk HLA genotypes, the risk of type 1 diabetes is 5% (1,2). Acquired factors, such as viruses or other features of the microbiome, have also been implicated in the cause of T1D. The long-term risk of T1D for people with a single autoantibody is greater than for people without autoantibodies, but fewer than 10% of people with a single autoantibody will develop diabetes over 10 years. Stage 2 diabetes are estimated to have a 5-year risk of symptomatic disease of around 75%.
Screening for stage 1 or 2 T1D
You would think that screening of the general population looking for subjects in stage 1 and stage 2 would be useful to prevent beta cell death before they occur. The only problem is that a large number of people will need to be screened to find those at risk. You would need to screen at least 200 people in the general population in north America and Europe to find one individual at risk of T1D. On the other hand, screening family with affected individuals will identify a much higher incidence. Unfortunately, 85% of individuals have no affected first-degree family members.
The prevention trials
The Finnish TRIGR pilot showed decreased autoantibody development among infants who had early introduction to hydrolysed formula rather than formula based on cows milk (3,4). Subsequent studies however, showed no difference with intervention in either autoantibody development or progression to T1D.42,55. The FINDIA pilot study showed decreased autoantibody development among infants who received insulin-free bovine milk formula, suggesting dietary interventions could be the key to prevention of type 1 diabetes (5). Unfortunately, the BABYDIET trial did not show any significant differences with modulating gluten exposure (6).
In the DPT-1 trials, patients in stage 2 had parenteral insulin to reduce β-cell stress (7). A total dose of 0.25U/kg/day plus annual 4-day continuous insulin infusion. Unfortunately, there was no difference in the proportion of people in each treatment arm who developed diabetes.
It was thought that oral delivery of insulin would prevent disease onset by inducing immune
tolerance to the antigen when delivered to the gastrointestinal tract. Thus, a second DPT-1 trial used oral insulin instead (8). Unfortunately, onset of T1D was not delayed but individuals with the highest titres of antibodies to insulin appeared to benefit.
TrialNet repeated the effort with 560 at-risk relatives with autoantibodies using oral insulin again vs placebo, the time to diagnosis of T1D was also not different between the groups (9). However, in a sub-group of patients who had reduced insulin response, the time to diagnosis was delayed. Further studies using a higher dose of oral insulin is ongoing. The DIAPREV-IT tried to induce tolerance to another antigen, GAD65 but that too, didn’t delay the onset of T1D either (10). TrialNet is experimenting with other agents (abatacept and hydroxychloroquine) and the results are pending.
In the ENDIT trial, individuals who were at risk to treatment with oral modified-release nicotinamide (1・2 g/m2) or placebo for 5 years (11). This trial also did not find a difference in the development of diabetes between the two treatment arms. Intranasal insulin (tested in the DIPP
study) did not show benefit in preventing progression to type 1 diabetes.
The Monoclonal Antibody Prevention Trial
Studies in the early 1990s first suggested that monoclonal antibodies to CD3 might be effective in preventing, and even reversing, autoimmune diabetes in murine models of type 1 diabetes.63–66. Teplizumab is a humanised, FcR nonbinding monoclonal antibody against the έ chain of the
CD3 molecule on T cells. Earlier clinical studies with two FcR non-binding monoclonal antibodies showed improved C-peptide responses and reduced exogenous insulin use in patients with new-onset type 1 diabetes but subsequent Protégé Phase 3 trial did not reach its primary outcome of insulin use less than 0・5 U/kg per day and HbA1c less than 6・5%.22,23,67,68
The teplizumab prevention trial, done by TrialNet recruited from USA, Canada, Germany, and Australia (Campbelltown was one of the sites) (12). 76 relatives of patients with type 1 diabetes, who were at high risk for type 1 diabetes (multiple autoantibody positive and dysglycaemic— ie, stage 2), were enrolled. These individuals were randomly assigned to receive a single 14-day course of teplizumab or placebo, and were followed up for between 74 and 2683 days (median follow-up was 745 days). The primary endpoint was the time to diagnosis of type 1 diabetes. At the end of the trial, compared to placebo, teplizumab was found to reduce progression to T1D and delay the onset of diabetes from 2 years to 4 years for those that progress to T1D.
Implications of the teplizumab prevention trial
A delay of the onset of T1D of 2 years may not sound too exciting but preserving the little amount of beta cells have huge metabolic consequences. Preserving enough insulin production to avoid progression
to overt diabetes means, by definition, that the individual is not exposed during this time either to hyperglycaemia at a level that contributes to long-term complications or, since insulin treatment is
not needed, to any risk of hypoglycaemia: they are in a state of no metabolic risk. Further, even when they progress to overt T1D, the residual beta cells might persist for 2-5 years making achievement of optimal HbA1c easier and leaving a legacy effect.
Delaying full dependence on insulin therapy also have significant social, emotional and developmental effects on a young T1D. An older T1D can manage the complexity of insulin therapy better. Ongoing monitoring of these early stage T1D also reduce the risk of the acute presentation of diabetic ketoacidosis.
It is now possible to delay the onset of T1D in individuals at risk. Individuals who are affected by β-cell autoimmunity can now be maintained in a state of no diabetes or low metabolic risk for many years, leading to a marked reduction in the short-term and long-term complications of type 1 diabetes, and paving the way ultimately to the eradication of the clinical disease.
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- Knip M, Akerblom HK, Al Taji E, et al. Effect of hydrolyzed infant formula vs conventional formula on risk of type 1 diabetes: the TRIGR randomized clinical trial. JAMA 2018; 319: 38–48.
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- Herold KC, Bundy BN, Long SA, et al. An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes. N Engl J Med 2019; 381: 603–613.
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