Of the 372 subjects who participated in the original DPT-1 study, 275 were eligible for the follow-up study; 97 developed type 1 diabetes at the end of the study in 2003 (0.02 [Q1–Q3: 0–0.5] median years after treatment to type 1 diabetes diagnosis) (). Through the 2009 follow-up study, 206 (75%) of the eligible subjects were contacted with the median follow-up time of 9.1 years (107 were on oral insulin and 99 were on placebo). A total of 37% (n = 77) had developed type 1 diabetes (median 3.7 [2.0–5.3] years after treatment to type 1 diabetes diagnosis); 71% (n = 92, 49 were on oral insulin and 44 on placebo during trial) of the 129 subjects diabetes-free on contact agreed to a clinic visit to complete an OGTT, HbA1c, and Ab testing and 59% (n = 54) completed a follow-up clinic visit. Of these (28 were on oral insulin and 26 on placebo during the trial), OGTT testing identified 26% (n = 14) with impaired glucose tolerance, 11% (n = 6) with asymptomatic type 1 diabetes, and 7% (n = 4) with symptomatic type 1 diabetes. There were no significant changes between baseline and follow-up measures of HbA1c (P = 0.99), GAD65 positivity (P = 0.11), mIAA positivity (P = 0.99), or ICA512 positivity (P = 0.43) in subjects who completed a follow-up visit. Significant changes were noted for mean C-peptide AUC during OGTT (baseline AUC: 491 [SD 185]; follow-up AUC: 647 [SD 233], P < 0.0001) and ICA positivity (P < 0.0001), where all 54 subjects were ICA positive at baseline and 19 (35%) reverted to being ICA negative at the follow-up visit.
Flow diagram of all subjects recruited into the original DPT-1 study and results of the follow-up study. IVGTT, intravenous glucose tolerance test; T1D, type 1 diabetes.
Over the entire study and follow-up, individuals who did not develop type 1 diabetes (n = 198) had a significantly lower median ICA titer (80 vs. 160 Juvenile Diabetes Foundation Units, P < 0.0001), lower mean IAA titer (309.3 vs. 426.5 nU/mL, P = 0.02), lower proportion with ICA512 (45 vs. 60%, P = 0.004), higher mean first-phase insulin response (173.1 vs. 145.6 µU/mL, P = 0.002), higher mean C-peptide peak (5.7 vs. 5.1 ng/mL, P = 0.003), higher mean C-peptide AUC (530.1 vs. 470.7, P = 0.005) measured by OGTT, were more likely to be black or Hispanic (10.5 vs. 4.5%, P = 0.03), and were older at time of randomization in study (median age 11 vs. 9 years, P < 0.0001) compared with individuals who developed type 1 diabetes (n = 174).
provides the baseline characteristics at the time of randomization into the DPT-1 study of the subjects eligible for the follow-up study by whether or not contact was achieved. Individuals contacted were more likely to be white (P < 0.0001) compared with those unable to be contacted.
Baseline characteristics (at time of randomization) of subjects eligible for follow-up study
shows the Kaplan-Meier curve from the start of the DPT-1 to the end of the follow-up for both the entire oral insulin population (, n = 372) and subjects with a baseline confirmed IAA ≥80 nU/mL (, n = 263). The overall median follow-up was 9.1 (Q1–Q3: 8.7–10.1) years. The annualized rate of type 1 diabetes development for the entire population was 7.4% per year in the oral insulin group and 8.2% in the placebo group (hazard ratio [HR] 1.125, 95% CI 0.837–1.511; P = 0.436). In subjects with a baseline confirmed IAA level ≥80 nU/mL, the annualized rate of type 1 diabetes development was 7.7% per year in the oral insulin group and 10.1% in the placebo group (HR 1.384, 95% CI 0.995–1.925; P = 0.052). Even after discontinuing oral insulin treatment, individuals with a confirmed IAA level ≥80 nU/mL who received oral insulin appeared to benefit overall by significantly delaying type 1 diabetes onset by 2.2 years.
Figure 2 A: Time to type 1 diabetes for the entire DPT-1 population from 1994 to 2009. B: Time to type 1 diabetes for subjects with a baseline IAA level confirmed ≥80 nU/mL from 1994 to 2009. (A high-quality color representation of this figure is available (more ...)
breaks down the patient subgroups with confirmed IAAs ≥80 nU/mL into the following: time on (all subjects treated with oral insulin) and off (only subjects contacted through the follow-up) treatment for the oral insulin group () and time on (monitored on study receiving placebo) and off (only subjects contacted through follow-up and no longer monitored on study) treatment for the placebo group (). There were 130 subjects who received oral insulin during the study, and 97 (75%) of those subjects were contacted in the follow-up; 133 subjects received placebo and 85 (64%) were contacted in the follow-up. The annualized rate of diabetes while on oral insulin was 6.2%; after treatment ended, the rate increased to 9.5%, a rate similar to the placebo group (HR 1.492, 95% CI 0.911–2.444; P = 0.110). clearly shows that the reduced rate of diabetes development depicted in is only apparent during the time the subjects received oral insulin. During the time on oral insulin compared with after oral insulin treatment, type 1 diabetes onset was delayed by 3.9 years. After oral insulin ended, the median estimated survival for subjects treated was similar to placebo during the original trial (6.32 years for placebo vs. 6.94 years for oral insulin after oral insulin treatment ended). shows the proportion of the placebo group without diabetes while on study and off study. The annual type 1 diabetes rate on study was 10.4% and off study was 9.7% (HR 0.826, 95% CI 0.513–1.330; P = 0.431). The hazard rate remained relatively constant for subjects in the placebo group over the study and follow-up periods.
Figure 3 Proportion of subjects with IAA levels confirmed ≥80 nU/mL who are diabetes-free by time of study and after study. A: Oral insulin treatment group (where “on treatment [Trt]” is defined as time receiving oral insulin). B: Placebo (more ...)
shows the proportion of subjects diabetes-free in the subgroup who did not have confirmed IAA ≥80 nU/mL for those who received oral insulin () or placebo (). In , the annualized type 1 diabetes rate for the time on oral insulin was 6.9 and 4.5% during the follow-up time after therapy was withdrawn (HR 0.817, 95% CI 0.330–2.022; P = 0.661). describes the proportion of subjects in the placebo group diabetes-free both during study and after study. The annualized rate was 2.7% during the study and 4.2% after study (HR 1.379, 95% CI 0.444–4.286; P = 0.577).
Figure 4 Proportion of subjects with IAA levels not confirmed ≥80 nU/mL who are diabetes-free by time of study and after study. A: Oral insulin treatment group (where “on treatment [Trt]” is defined as time receiving oral insulin). B: Placebo (more ...)