PracticeUpdate: Conference Series | ADC 2018

Can Oral Insulin Delay Progression to T1D? BY THE PRACTICEUPDATE EDITORIAL TEAM O ral insulin therapy does not delay or prevent progression in people who are autoantibody-positive and have a rel- ative with type 1 diabetes (T1D), according to trial findings

pancreas function, which was defined as a normal first-phase insulin response (FPIR) to intravenous glucose. “The rationale was if you were using immunotherapy you wanted to get in as early as you can in the disease process because if you leave it later … the response is not going to be as effective,” said Dr. Wentworth. DPT-1 results showed that treatment with 7.5 mg oral insulin daily, when compared with placebo, had no significant effect in prevent- ing progression to T1D. However, a post hoc analysis suggested oral insulin treatment did have a significant effect in delaying T1D in participants with high titers of insulin autoantibodies. The TrialNet TN07 study was subsequently performed to confirm this finding. TrialNet TN07 TrialNet TN07 participants had two or more islet autoantibodies, including anti-insulin antibody, and normal glucose tolerance and a first-degree relative with T1D. Participants were divided into four strata according to their diabetes-related autoantibodies and FPIR to intravenous glucose. The primary objective of the trial was to assess the effects of oral insulin versus placebo on progression to T1D within the primary stratum. The secondary objectives were to assess the effects of treatment in each stratum and in the overall trial population. Participants in the primary stratum had ICA confirmed, or, if ICA not confirmed, had persistent glutamic acid decarboxylase (GAD) and insulinoma antigen-2 (IA-2). They also had to have a FPIR above a threshold, indicating high functioning beta cells.

presented at ADC 2018. However, contrary to the overall trial results, oral insulin delayed T1D by an average of 31 months in a pre-specified secondary stratum. The TrialNet TN07 study was a randomized, placebo-controlled trial that aimed to determine whether oral insulin prevented pro- gression from preclinical to clinical T1D. This trial was a follow-up to the Diabetes Prevention Trial–Type 1 (DPT-1). The premise of both these trials was that oral insulin treatment would dampen islet autoimmunity and prevent T1D. “Type 1 diabetes is a highly targeted immune attack and there is strong evidence that insulin is part of the process,” explained Endocrinologist and Clinician Scientist John Wentworth, MBBS, PhD, FRACP, of Royal Melbourne Hospital and the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia. Various research has indicated that insulin is a key autoantigen in T1D. Mouse model studies have also shown that insulin-toler- ization therapies prevent and treat T1D. Diabetes Prevention Trial–Type 1 In light of these data, DPT-1 was conducted in the 1990s–2000s in participants at very high risk of developing T1D. All participants were islet cell antibody (ICA)–positive and had to have good

The secondary stratum 1 had the same autoantibodies as the primary stratum but with FPIR lower than the threshold. Secondary stratum 2 were GAD- or IA-2– positive and had FPIR above the threshold, while secondary stratum 3 was identical to secondary stra- tum 2 but with FPIR below the threshold. The primary stratum showed no significant between- group differences in the primary outcome – that is, the rate of progression to T1D. However, in the secondary stratum 1 (n=55), oral insulin treatment led to an average of a 31-month delay in progression to T1D. It was a finding that was “counterintuitive and very, very interesting,” said Dr. Wentworth. “There was no effect of oral insulin to prevent type 1 diabetes in high-risk children who had strong auto- immunity and normal FPIR, although those who were approaching diagnosis were protected from diabe- tes,” he explained. The observation that oral insulin delayed disease progression in individuals with relatively poor beta- cell function raises the possibility that immune therapies might work best towards the end of the preclinical disease phase. Oral insulin treatment was also shown to be without associated significant adverse events in both the TrialNet TN07 and DPT-1 studies.

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PRACTICEUPDATE CONFERENCE SERIES • ADC 2018