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)

Takuya Awata; Akira Shimada; Taro Maruyama; Yoichi Oikawa; Nobuyuki Yasukawa; Susumu Kurihara; Yumi Miyashita; Masako Hatano; Yuichi Ikegami; Masafumi Matsuda; Masataka Niwa; Youichiro Kazama; Shoichiro Tanaka; Tetsuro Kobayashi

doi:10.1007/s13300-017-0299-7

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)

Diabetes Ther. 2017 Oct;8(5):1123-1134. doi: 10.1007/s13300-017-0299-7. Epub 2017 Sep 19.

Authors

Affiliations

¹ Department of Diabetes, Endocrinology and Metabolism, International University of Health and Welfare Hospital, Iguchi, Nasushiobara-shi, Tochigi, Japan. [email protected].
² Department of Endocrinology and Diabetes, Faculty of Medicine, Saitama Medical University, Saitama, Japan.
³ Department of Internal Medicine, Saitama Social Insurance Hospital, Saitama, Japan.
⁴ Department of Diabetes, Endocrinology and Metabolism, International University of Health and Welfare Hospital, Iguchi, Nasushiobara-shi, Tochigi, Japan.
⁵ Division of RI Laboratory, Biomedical Research Center, Saitama Medical University, Saitama, Japan.
⁶ Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University, Saitama, Japan.
⁷ Iidabashi Medical Clinic, Tokyo, Japan.
⁸ Kazama Medical Clinic, Yamanashi, Japan.
⁹ Ai Home Clinic Toshima, Tokyo, Japan.
¹⁰ Division of Immunology and Molecular Medicine, Okinaka Memorial Institute for Medical Research, Tokyo, Japan.

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.