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

Type 1 Diabetes Clinical Trial

— DPP-?LADA  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01159847
• Other study ID #: EFSD DPP-? LADA
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: January 2010
• Est. completion date: December 2012

Study information

• Verified date: July 2018
• Source: European Foundation for the Study of Diabetes
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: December 2012
• Est. primary completion date: July 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 25 Years to 70 Years

Eligibility

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.

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1
• Type 1 Diabetes

Intervention

Drug:
• sitagliptin
sitagliptin tablet,100 mg p.o. qd,2 year
• Insulin

Locations

Country	Name	City	State
China	Diabetes Center, Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University	Changsha	Hunan

Sponsors (3)

Lead Sponsor	Collaborator
European Foundation for the Study of Diabetes	Chinese Medical Association, Eli Lilly and Company

Country where clinical trial is conducted

China, 

References & Publications (25)

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* Note: There are 25 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The effects of sitagliptin on ß cell function and insulin sensitivity of LADA patients	The assessment of the change of ß cell function in patients with LADA treated with sitagliptin plus insulin by the standardized mixed meal stimulation test and insulin sensitivity by HOMA-IR.; The assessment of the change of insulin sensitivity in LADA patients by sequential insulin infusion with the euglycemic glucose clamp technique.	2 years
Secondary	The possible immunomodulatory effects of sitagliptin on LADA patients	The change of the frequency of pathogenic Teff (CD4+Th1, Th2, Th17 and CD8+) cells and CD4+CD25+Foxp3+Treg cells before and after sitagliptin treatment in LADA patients.	2 years
Secondary	The possible immunomodulatory effects of sitagliptin on LADA patients	Effect of sitagliptin on cytokine production of Teff and Treg cells before and after sitagliptin treatment in LADA patients.	2 years
Secondary	The possible immunomodulatory effects of sitagliptin on LADA patients	Effect of sitagliptin on Foxp3 mRNA expression of Treg cells and ROR?T mRNA expression of Th17 cells before and after sitagliptin treatment in LADA patients.	2 years
Secondary	The possible immunomodulatory effects of sitagliptin on LADA patients	The comparison of glutamic acid decarboxylase 65 (GAD65) reactive interferon-?-Th1, IL-4-Th2, IL-17-Th17 and IL-10-Treg cells detected by enzyme-linked immunospot (ELISPOT) before and after sitagliptin treatment in LADA patients.	2 years
Secondary	The possible immunomodulatory effects of sitagliptin on LADA patients	The change of the adiponectin, IL-6, IL-17 and CRP etc. before and after the sitagliptin treatment in LADA patients.	2 years