Dysglycemia and Index60 as Prediagnostic End Points for Type 1 Diabetes Prevention Trials

Abstract

Objective: We assessed dysglycemia and a T1D Diagnostic Index60 (Index60) ≥1.00 (on the basis of fasting C-peptide, 60-min glucose, and 60-min C-peptide levels) as prediagnostic end points for type 1 diabetes among Type 1 Diabetes TrialNet Pathway to Prevention Study participants.

Research design and methods: Two cohorts were analyzed: 1) baseline normoglycemic oral glucose tolerance tests (OGTTs) with an incident dysglycemic OGTT and 2) baseline Index60 <1.00 OGTTs with an incident Index60 ≥1.00 OGTT. Incident dysglycemic OGTTs were divided into those with (DYS/IND+) and without (DYS/IND-) concomitant Index60 ≥1.00. Incident Index60 ≥1.00 OGTTs were divided into those with (IND/DYS+) and without (IND/DYS-) concomitant dysglycemia.

Results: The cumulative incidence for type 1 diabetes was greater after IND/DYS- than after DYS/IND- (P < 0.01). Within the normoglycemic cohort, the cumulative incidence of type 1 diabetes was higher after DYS/IND+ than after DYS/IND- (P < 0.001), whereas within the Index60 <1.00 cohort, the cumulative incidence after IND/DYS+ and after IND/DYS- did not differ significantly. Among nonprogressors, type 1 diabetes risk at the last OGTT was greater for IND/DYS- than for DYS/IND- (P < 0.001). Hazard ratios (HRs) of DYS/IND- with age and 30- to 0-min C-peptide were positive (P < 0.001 for both), whereas HRs of type 1 diabetes with these variables were inverse (P < 0.001 for both). In contrast, HRs of IND/DYS- and type 1 diabetes with age and 30- to 0-min C-peptide were consistent (all inverse [P < 0.01 for all]).

Conclusions: The findings suggest that incident dysglycemia without Index60 ≥1.00 is a suboptimal prediagnostic end point for type 1 diabetes. Measures that include both glucose and C-peptide levels, such as Index60 ≥1.00, appear better suited as prediagnostic end points.

Figure 1

A: Comparisons of cumulative incidence curves for type 1 diabetes (T1D) after incident dysglycemia according to concomitant Index60 ≥1.00. The cumulative incidence for T1D is substantially higher if there is concomitant Index60 ≥1.00. B: Comparisons of cumulative incidence curves for T1D after incident Index60 ≥1.00 according to concomitant dysglycemia. The difference between the cumulative incidence curves is much smaller after incident Index60 ≥1.00 than after incident dysglycemia. *Both indicates incident dysglycemia with concomitant Index60 ≥1.00 (DYS/IND+). **Both indicates incident Index60 ≥1.00 with concomitant dysglycemia (IND/DYS+).

Figure 2

HRs with 95% CIs of DYS/IND− and of type 1 diabetes for associations with baseline variables. The HRs of DYS/IND− are discordant from the HRs of type 1 diabetes. Specifically, for age and each C-peptide variable, the HR and 95% CI (all positive) of DYS/IND− is on the opposite side of the null value (i.e., 1.0) from the HR and 95% CI (all inverse) of type 1 diabetes. The HR of DYS/IND− and autoantibody number is inverse and on the opposite side of the null value from the HR of type 1 diabetes and autoantibody number; however, the 95% CI for the HR of type 1 diabetes overlaps the null value. The two panels are shown with different scales to encompass all the variables. DM, diabetes.

Figure 3

HRs with 95% CIs of IND/DYS− and of type 1 diabetes for associations with baseline variables. The HRs of IND/DYS− are concordant with the HRs of type 1 diabetes. Specifically, for age and each C-peptide variable, the HR and 95% CI of IND/DYS− is on the same side of the null value (i.e., 1.0) as the HR and 95% CI (all inverse) of type 1 diabetes. The HR of IND/DYS− and autoantibody number is also positive and on the same side of the null value as the HR of type 1 diabetes and autoantibody number; however, the 95% CI for the HR of type 1 diabetes overlaps the null value. The two panels are shown with different scales to encompass all the variables. DM, diabetes.