Protective Effects of Sitagliptin on β Cell Function in Patients With Adult-onset Latent Autoimmune Diabetes (LADA)

Phase 1

Completed

• Conditions: Type 1 Diabetes
• Interventions: Drug: Insulin; Drug: sitagliptin

• Registration Number: NCT01159847
• Lead Sponsor: European Foundation for the Study of Diabetes

Brief Summary

The aim of this study is to investigate the protective effects of sitagliptin on β cell function in patients with adult-onset latent autoimmune diabetes (LADA) and its mechanisms.

Detailed Description

Adult-onset latent autoimmune diabetes (LADA), etiologically belongs to type 1 diabetes (T1D), is characterized by the presence of islet autoantibodies, such as islet cell antibody (ICA) and glutamic acid decarboxylase antibody (GADA), and is prone to develop β-cell failure. The goals of treatment for LADA are suppression of autoimmune β cell destruction, preservation of islet function and prevention of diabetic complications. Recently two classes of compounds have been approved by the FDA as type 2 diabetes (T2D) therapeutics: the glucagon-like peptide-1 (GLP-1) receptor agonist (incretin mimetic) exenatide (Byetta) and the dipeptidyl peptidase IV (DPP-IV) inhibitor sitagliptin (Januvia) and vildagliptin (Galvus). They have been shown to reduce HbA1c, fasting glucose and to improve β cell function in T2D patients, as a mono-therapy or in combination with metformin or thiazolidinediones. Besides, in vitro studies showed incretin-based therapy can stimulate β-cell proliferation and survival, increase β cell insulin content and inhibit apoptosis. Moreover, several short-term pilot studies suggest GLP-1 may also have the potential for treating T1D. Several findings suggest that Ex-4 may also act as a regulator of the immune response in addition to its potential effects on β cell proliferation. Therefore, we hypothesized DPP-IV inhibitors might provide therapeutic advantages in T1D though no study has been reported. Besides the β cell function, another important target is insulin sensitivity. As for DPP-IV inhibitor, clinical trials demonstrated their beneficial effects on insulin sensitivity in subjects with T2D and impaired fasting glucose (IFG) and in diabetic rat model. We'd like to further explore the possible effect of sitagliptin on insulin sensitivity in LADA patients by homeostasis model assessment for insulin resistance (HOMA-IR) index and euglycemic clamp technique. In addition, the systemic inflammation associated with a wide array of plasma proteins and pro-inflammatory cytokines (i.e., C reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-6) play an additional role in the pathogenesis of insulin resistance in diabetes. It will be of interest to investigate the adipokines and proinflammatory cytokines after the sitagliptin therapy in the study. Hence, we aim to explore the effects of sitagliptin plus insulin on β cell function, insulin sensitivity, pro-inflammatory cytokines and immune regulation including Teff and Treg frequency, and function in patients with LADA.

Study Timeline

• Study Start: 2010-01
• Study First Submitted: 2010-05-05
• Study First Submitted QC: 2010-07-09
• Study First Posted: 2010-07-12
• Primary Completion: 2012-07
• Study Completion: 2012-12
• Status Verified: 2018-07
• Last Update Submitted: 2018-07-30
• Last Update Posted: 2018-07-31

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

1. Diabetes diagnosed according to the report of WHO in 1999.
2. Age at onset between 25~70 years.
3. Disease duration of less than 3 year.
4. No ketoacidosis within the first 6 months after diagnosis of diabetes.
5. GADA positive twice within one month.
6. Fasting C-peptide (FCP) level of 0.2 nmol/L or more.

Exclusion Criteria

1. Insulin requirements more than 0.8 units/kg/day.
2. Evidence of chronic infection or acute infection affected blood glucose control within 4 weeks prior to visit 1.
3. History of any malignancy.
4. Pregnancy, breastfeeding or planned pregnancy within two years.
5. Secondary diabetes.
6. Congestive heart failure requiring pharmacologic treatment.
7. Renal disease or renal dysfunction or diabetic nephropathy suggested by serum creatinine levels≥1.5 mg/dL (132μmol/L) for males and ≥1.4mg/dL (123μmol/L) for females or abnormal creatinine clearance at Visit 1.
8. Concurrent medical condition that may interfere with the interpretation of efficacy and safety data during the study.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Insulin	Insulin	Patients will receive insulin therapy without sitagliptin.
Sitagliptin	Insulin	Patients will receive insulin therapy with sitagliptin.
Sitagliptin	sitagliptin	Patients will receive insulin therapy with sitagliptin.

Primary Outcome Measures

Name	Time	Method
The effects of sitagliptin on β cell function and insulin sensitivity of LADA patients	2 years	1. The assessment of the change of β cell function in patients with LADA treated with sitagliptin plus insulin by the standardized mixed meal stimulation test and insulin sensitivity by HOMA-IR.; 2. The assessment of the change of insulin sensitivity in LADA patients by sequential insulin infusion with the euglycemic glucose clamp technique.

Secondary Outcome Measures

Name	Time	Method
The possible immunomodulatory effects of sitagliptin on LADA patients	2 years	The change of the adiponectin, IL-6, IL-17 and CRP etc. before and after the sitagliptin treatment in LADA patients.

Trial Locations

Locations (1)

Diabetes Center, Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University; 🇨🇳 Changsha, Hunan, China