Possible Long-Term Efficacy of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, for Slowly Progressive Type 1 Diabetes (SPIDDM) in the Stage of Non-Insulin-Dependency: An Open-Label Randomized Controlled Pilot Trial (SPAN-S)

Abstract

Introduction: We tested the hypothesis that dipeptidyl peptidase-4 (DPP-4) inhibitors are effective in preserving the β-cell function for long-term periods in patients with slowly progressive type 1 diabetes (SPIDDM) or latent autoimmune diabetes in adults (LADA).

Methods: In the present open-label, randomized, controlled trial, 14 non-insulin-requiring diabetic patients with glutamic acid decarboxylase autoantibodies (GADAb) were randomly assigned to receive either sitagliptin (S group) or pioglitazone (P group). As a historical control, the Tokyo Study, in which non-insulin-dependent patients with SPIDDM were assigned to receive treatment by either insulin or sulfonylurea (SU), was used.

Results: On average, the ∑C-peptide values during the oral glucose tolerance test through the follow-up periods showed a nonsignificant increase in the S group (n = 6, n = 5 at 48 months) compared to the P group (n = 5, n = 2 at 48 months). In comparison to the data in the Tokyo Study, treatment by sitagliptin significantly influenced the longitudinal changes in the ∑C-peptide values with a more increased direction than insulin or SU, especially in patients with 48 months of follow-up (p = 0.014 and p = 0.007, respectively). Although the titers of GADAb were not significantly different between the S and P groups during the study, the change ratio of the GADAb titers from baseline was significantly inversely correlated with the change ratio of the ∑C-peptide values from baseline in the S group (p = 0.003); in particular, when the GADAb titers decreased from baseline, the ∑C-peptide values frequently increased.

Conclusion: The present pilot trial suggests that treatment of SPIDDM/LADA by sitagliptin, a DPP-4 inhibitor, may be more effective in preserving the β-cell function than insulin treatment for at least 4 years, possibly through the immune modulatory effects of DPP-4 inhibitors.

Clinical trial registration: Japanese Clinical Trials Registry UMIN000003693.

Keywords: Dipeptidyl peptidase-4 (DPP-4) inhibitor; Intervention; Latent autoimmune diabetes in adults (LADA); Prevention; Sitagliptin; Slowly progressive type 1 diabetes (SPIDDM); Type 1 diabetes.

Figures

Fig. 1

Trial design and participant flow. a Schematic illustration of the trial design. b Participant flow. Data are presented as n. α-GI alpha-glucosidase inhibitor, Lab laboratory test, M month, OGTT 75-g oral glucose tolerance test

Fig. 2

Longitudinal changes in the C-peptide response to the OGTT for 48 months in the patients with sitagliptin treatment and in the Tokyo study. Patients with 48 months of follow-up are shown. The data are expressed as the mean ± SEM. In both the ∑C-peptide values (a) and change ratios from baseline (b), a repeated-measures ANOVA revealed a significant interaction between time and treatment assignment (sitagliptin or insulin; p = 0.030 and p = 0.014, respectively) as well as between time and treatment assignment (sitagliptin or SU; p = 0.00004 and p = 0.007, respectively) in the longitudinal changes

Fig. 3

The correlation between the change ratios of the GADAb titers and of the ∑C-peptide values from baseline in the S group. Spearman correlation calculations revealed a significant inverse correlation between the change ratios of the GADAb titers and those of the ∑C-peptide values from baseline in the patients with sitagliptin treatment (Spearman’s rank correlation coefficient = -0.600, p = 0.003)