Effect of Oral Insulin on Prevention of Diabetes in Relatives of Patients With Type 1 Diabetes: A Randomized Clinical Trial

Abstract

Importance: Type 1 diabetes requires major lifestyle changes and carries increased morbidity and mortality. Prevention or delay of diabetes would have major clinical effect.

Objective: To determine whether oral insulin delays onset of type 1 diabetes in autoantibody-positive relatives of patients with type 1 diabetes.

Design, setting, and participants: Between March 2, 2007, and December 21, 2015, relatives with at least 2 autoantibodies, including insulin autoantibodies and normal glucose tolerance, were enrolled in Canada, the United States, Australia, New Zealand, the United Kingdom, Italy, Sweden, Finland, and Germany. The main study group (n = 389) had first-phase insulin release on an intravenous glucose tolerance test that was higher than the threshold. The 55 patients in the secondary stratum 1 had an identical antibody profile as the main study group except they had first-phase insulin release that was lower than the threshold. Secondary strata 2 (n = 114) and strata 3 (n = 3) had different autoantibody profiles and first-phase insulin release threshold combinations. Follow-up continued through December 31, 2016.

Interventions: Randomization to receive 7.5 mg/d of oral insulin (n = 283) or placebo (n = 277), including participants in the main study group who received oral insulin (n = 203) or placebo (n = 186).

Main outcome and measures: The primary outcome was time to diabetes in the main study group. Significance was based on a 1-sided threshold of .05, and 1-sided 95% CIs are reported.

Results: Of a total of 560 randomized participants (median enrollment age, 8.2 years; interquartile range [IQR], 5.7-12.1 years; 170 boys [60%]; 90.7% white non-Hispanic; 57.6% with a sibling with type 1 diabetes), 550 completed the trial including 389 participants (median age, 8.4 years; 245 boys [63%]), 382 (96%) in the main study group. During a median follow-up of 2.7 years (IQR, 1.5-4.6 years) in the main study group, diabetes was diagnosed in 58 participants (28.5%) in the oral insulin group and 62 (33%) in the placebo group. Time to diabetes was not significantly different between the 2 groups (hazard ratio [HR], 0.87; 95% CI, 0-1.2; P = .21). In secondary stratum 1 (n = 55), diabetes was diagnosed in 13 participants (48.1%) in the oral insulin group and in 19 participants (70.3%) in the placebo group. The time to diabetes was significantly longer with oral insulin (HR, 0.45; 95% CI, 0-0.82; P = .006). The HR for time to diabetes for the between-group comparisons for the 116 participants in the other secondary stratum was 1.03 (95% CI, 0-2.11; P = .53) and for the entire cohort of 560 participants was 0.83 (95% CI, 0-1.07; P = .11), which were not significantly different. The most common adverse event was infection (n = 254), with 134 events in the oral insulin group and 120 events in the placebo group, but no significant study-related adverse events occurred.

Conclusions and relevance: Among autoantibody-positive relatives of patients with type 1 diabetes, oral insulin at a dose of 7.5 mg/d, compared with placebo, did not delay or prevent the development of type 1 diabetes over 2.7 years. These findings do not support oral insulin as used in this study for diabetes prevention.

Trial registration: clinicaltrials.gov Identifier: NCT00419562.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Drs Skyler and Greenbaum reported that they have served as advisors for Eli Lilly. No other disclosures were reported.

Figures

Figure 1.. Participant Flow Through Type 1 Diabetes TrialNet Study

Figure 2.. The Proportion of Study Individuals Who Had Not Developed Type 1 Diabetes as a Function of Follow-up

The plus marks indicate that the participants were censored. A, The quartiles of time to diabetes were 18.4, 31.9, and 55.1 months for oral insulin and 18.9, 32.7, and 54.4 months for placebo. Of those in the oral insulin group, 140 participants did not develop type 1 diabetes and 58 did. Of those in the placebo group, 122 participants did not develop type 1 diabetes and 62 did. The median months of follow-up was 32.0 (1.87-114). B, The quartiles of time to diabetes were 12.9, 19.2, and 52.8 months for oral insulin and 10.5, 18.5, and 39.8 months for placebo. Of those in the oral insulin group, 14 did not develop type 1 diabetes and 13 did. Of those in the placebo group, 8 did not develop type 1 diabetes and 19 did. The median months of follow-up was 18.9 (2.33-77.5). C, The quartiles of time to diabetes were 25.3, 49.2, and 65.8 months for oral insulin and 18.1, 30.2, and 63.3 months for placebo. Of those in the oral insulin group, 40 participants did not develop type 1 diabetes and 11 did. Of those in the placebo group, 53 participants did not develop type 1 diabetes and 10 did. The median months of follow-up was 39.4 (6.21-115). D, The quartiles of time to diabetes were 18.4, 34.9, and 59.7 months for oral insulin and 17.8, 31.2, and 54.0 months for placebo. Of those in the oral insulin group, 194 participants did not develop type 1 diabetes and 82 did. Of those in the placebo group, 183 participants did not develop type 1 diabetes and 91 did. The median months of follow-up was 32.4 (1.87-115).