Preventing type 1 diabetes – where are we at?

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.

The risks

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

Antigen Tolerance

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.

In summary

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.

References:

Barrett JC, Clayton DG, Concannon P, et al. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 2009; 41: 703–07.
Bluestone JA, Herold K, Eisenbarth G. Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature 2010; 464: 1293–300.
Knip M, Virtanen SM, Seppa K, et al. Dietary intervention in infancy and later signs of beta-cell autoimmunity. N Engl J Med 2010; 363: 1900–08.
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.
Vaarala O, Ilonen J, Ruohtula T, et al. Removal of bovine insulin from cow’s milk formula and early initiation of beta-cell autoimmunity in the FINDIA pilot study. Arch Pediatr Adolesc Med 2012; 166: 608–14.
Beyerlein A, Chmiel R, Hummel S, Winkler C, Bonifacio E, Ziegler AG. Timing of gluten introduction and islet autoimmunity in young children: updated results from the BABYDIET study. Diabetes Care 2014; 37: e194–95.
Effects of insulin in relatives of patients with type 1 diabetesmellitus. N Engl J Med 2002; 346: 1685–91.
Skyler JS, Krischer JP, Wolfsdorf J, et al. Effects of oral insulin in relatives of patients with type 1 diabetes: The Diabetes Prevention Trial—Type 1. Diabetes Care 2005; 28: 1068–76.
Krischer JP, Schatz DA, Bundy B, Skyler JS, Greenbaum CJ. Effect of oral insulin on prevention of diabetes in relatives of patients with type 1 diabetes: a randomized clinical trial. JAMA 2017; 318: 1891–902.
Elding Larsson H, Lundgren M, Jonsdottir B, Cuthbertson D, Krischer J. Safety and efficacy of autoantigen-specific therapy with 2 doses of alum-formulated glutamate decarboxylase in children with multiple islet autoantibodies and risk for type 1 diabetes: a randomized clinical trial. Pediatr Diabetes 2018; 19: 410–19.
Gale EA, Bingley PJ, Emmett CL, Collier T. European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomised controlled trial of intervention before the onset of type 1 diabetes. Lancet 2004; 363: 925–31.
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.
Colin M Dayan, Maria Korah, Danijela Tatovic, Brian N Bundy, Kevan C Herold. Changing the landscape for type 1 diabetes: the first step to Prevention. Lancet 2019; 394: 1286–96

PFO Closure

Furlan AJ, Reisman M, Massaro J, et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med 2012; 366: 991–

A multicenter, randomized, open-label trial of closure with a percutaneous device, as compared with medical therapy alone, in patients between 18 and 60 years of age who presented with a cryptogenic stroke or transient ischemic attack (TIA) and had a patent foramen ovale. The primary end point was a composite of stroke or transient ischemic attack during 2 years of follow-up, death from any cause during the first 30 days, or death from neurologic causes between 31 days and 2 years.

Results:

Primary end point was 5.5% in the closure group as compared with 6.8% in the medical-therapy group (adjusted hazard ratio, 0.78; 95% confidence interval, 0.45 to 1.35; P = 0.37)

Conclusion:

“In patients with cryptogenic stroke or TIA who had a patent foramen ovale, closure

with a device did not offer a greater benefit than medical therapy alone for the

prevention of recurrent stroke or TIA”

2 Saver JL, Carroll JD, Thaler DE, et al. Long-term outcomes of patent foramen ovale closure or medical therapy after stroke. N Engl J Med 2017; 377: 1022–

A multicenter, randomised, open-label trial ,randomly assigned patients 18 to 60 years of age who had a patent foramen ovale (PFO) and had had a cryptogenic ischemic stroke to undergo closure of the PFO (PFO closure group) or to receive medical therapy alone (aspirin, warfarin, clopidogrel, or aspirin combined with extended-release dipyridamole; medical-therapy group). The primary efficacy end point was a composite of recurrent nonfatal ischemic stroke, fatal ischemic stroke, or early death after randomisation.

Results:

Recurrent ischemic stroke occurred in 18 patients in the PFO closure group and in 28 patients in the medical-therapy group, resulting in rates of 0.58 events per 100 patient-years and 1.07 events per 100 patient years, respectively (hazard ratio 0.55; 0.31 – 0.999; P = 0.046)

Conclusion:

“Among adults who had had a cryptogenic ischemic stroke, closure of a PFO was associated with a lower rate of recurrent ischemic strokes than medical therapy alone during extended follow-up.”

Meier B, Kalesan B, Mattle HP, et al. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med 2013; 368: 1083–

A prospective, multicenter, randomised, event-driven trial, randomly assigned patients to medical therapy alone (anti-platelet or warfarin therapy) or closure of the patent foramen ovale.

Results:

9 patients in the closure group and 16 in the medical-therapy group had a recurrence of stroke (hazard ratio with closure, 0.49; 0.22 – 1.11; P = 0.08). The primary analysis of the intentionto- treat cohort showed a nominal 51% hazard rate reduction with closure, but the reduction did not reach significance.

Conclusions:

” …there was no significant benefit associated with closure of a patent foramen ovale in adults who had had a cryptogenic ischaemic stroke.”

Sondergaard L, Kasner SE, Rhodes JF, et al. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N Engl J Med 2017; 377: 1033–

Multinational trial involving patients with a PFO who had had a cryptogenic stroke, randomly assigned patients to undergo PFO closure plus antiplatelet therapy or to receive antiplatelet therapy alone.

Results:

During a median follow-up of 3.2 years, clinical ischemic stroke occurred in 6 of 441 patients (1.4%) in the PFO closure group and in 12 of 223 patients (5.4%) in the antiplatelet-only group (hazard ratio, 0.23; 0.09 to 0.62; P=0.002).

Conclusions:

“Among patients with a PFO who had had a cryptogenic stroke, the risk of subsequent ischemic stroke was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone; however, PFO closure was associated with higher rates of device complications and atrial fibrillation.”

Mas JL, Derumeaux G, Guillon B, et al. Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. N Engl J Med 2017; 377: 1011–

In a multicenter, randomised, open-label trial patients 16-60 years of age who had had a recent stroke attributed to PFO, to transcatheter PFO closure plus long-term antiplatelet therapy, antiplatelet therapy alone or oral anticoagulation.

Results:

No stroke occurred among patients in the PFO closure group, whereas stroke occurred in 14 of the 235 patients in the antiplatelet- only group (hazard ratio, 0.03; 0 to 0.26; P<0.001). Large number of patients discontinued anti-coagulation in the anti-coagulant group and statistical significance was not analysed because the study was not adequately powered to compare outcomes.

Conclusion:

“Among patients who had had a recent cryptogenic stroke attributed to PFO with an associated atrial septal aneurysm or large interatrial shunt, the rate of stroke recurrence was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone. PFO closure was associated with an increased risk of atrial fibrillation.”

Lee PH, Song J-K, Kim JS, et al. Cryptogenic stroke and high-risk patent foramen ovale: the DEFENSE-PFO Trial. J Am Coll Cardiol 2018; 71: 2335–

Patients with cryptogenic stroke and high-risk PFO were divided between a transcatheter PFO closure and a medication-only group.

Results:

No events occurred in the PFO closure group. 12.9% of patients in the medication group had an event (p= 0.023).

Conclusion:

“PFO closure in patients with high-risk PFO characteristics resulted in a lower rate of the primary endpoint as well as stroke recurrence”