Beta Cell Relieving and Cardiovascular Protective Effects of LANTUS Treatment in Type 2 Diabetes Patients

Diabetes Mellitus, Type 2 Clinical Trial

Official title:

Beta Cell Relieving and Cardiovascular Protective Effects of LANTUS Treatment in Type 2 Diabetes Patients - Investigation on Postprandial Excursions of Proinsulin and PAI-1 Levels

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01206712
• Other study ID #: SAN-FORST-001
• Status: Completed
• Phase: Phase 4
• First received: September 21, 2010
• Last updated: September 21, 2010
• Start date: November 2009
• Est. completion date: July 2010

Study information

• Verified date: September 2010
• Source: ikfe-CRO GmbH
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• Study type: Observational

Clinical Trial Summary

The purpose of this phase IV clinical trial is to investigate the effect of Insulin glargine + metformin treatment vs. sulfonylurea + metformin treatment vs. DPP-4 + metformin treatment vs. healthy volunteers on ß-cell function after the uptake of a standardized meal.

Description:

Type 2 diabetes mellitus is a progressive disease characterised by a steady loss of beta cell function and an increase in the proinsulin/insulin ratio. During the recent years intact proinsulin has been the topic of interest in numerous preclinical and clinical studies in patients with type 2 diabetes mellitus. Intact proinsulin was confirmed as a marker of functional beta cell failure and as a predictor of increased beta cell loss due to apoptosis and/or diminished neogenesis.

A number of population based studies showed that intact proinsulin is a strong predictor of coronary heart disease in diabetic, and in non-diabetic patients. In a clinical trial investigating human proinsulin as a therapeutic approach for the treatment of diabetes mellitus an eight fold increase in CVD was found during treatment with human proinsulin compared to human regular insulin, indicating a thrombo-embolic potential of intact proinsulin. In a recent investigation an association could be confirmed between increased proinsulin plasma concentrations and the severity of angiographical characterised CHD.

Even the exact mechanism how proinsulin is involved in the pathogenesis of atherosclerosis is not completely recognized, it was already shown that PAI-1 activity increases after proinsulin administration in vitro, and there is increasing evidence that the atherogenic effects of proinsulin might be linked to increasing plasminogen activator inhibitor-1 (PAI-1) levels with subsequent inhibition of fibrinolysis and an augmented thrombogenic potency.

Treatment with sulfonylurea increases intact proinsulin secretion, and in a couple of studies, sulfonylurea treatment was found to be associated with an increased cardiovascular risk. In contrast, several studies have shown that after the introduction of insulin treatment in type 2 diabetic patients intact proinsulin levels and plasma PAI 1 levels decline, indicating not only beta cell protection, but also antiatherogenic properties of insulin. In a recent study, we have shown that treatment with basal insulin in combination with metformin effectively reduces intact proinsulin levels, and that insulin glargine is superior to NPH insulin in controlling postprandial release of intact proinsulin over an entire day.

Recently a new therapeutic concept using DPP IV inhibitors in combination with metformin has been introduced in the treatment of type 2 diabetic patients. There is some evidence that, in the beta cell, DPP IV Inhibitors might improve the conversion of intact Proinsulin into Insulin and C-peptide and thereby reduce circulating intact proinsulin levels. Since the number of type 2 diabetic patients treated with DPP-IV inhibitors is steadily increasing, there is a need to generate more data on the postprandial release of intact proinsulin in patients treated with DPP-IV inhibitors compared to Insulin or sulfonylurea treatment.

The rationale of the study is to investigate the effect of glargine and metformin treatment compared to sulfonylurea and metformin treatment and compared to DPP-4 inhibitor and metformin treatment on postprandial intact proinsulin release and postprandial PAI-1 levels. Accompanying a comparison of postprandial intact proinsulin release and the time course of postprandial PAI-levels in between all three antidiabetic treatment groups and a non-diabetic control group will be performed as well.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 106
• Est. completion date: July 2010
• Est. primary completion date: July 2010
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 40 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Inclusion criteria - applicable for T2DM group only:

1.1. Type 2 diabetes mellitus 1.2. Duration of T2DM between 3 and 15 years inclusively 1.3. HbA1c up to 7.5% inclusively 1.4. Treated with LANTUS+MET (Group LANTUS+MET) or SU+MET (Group SU+MET) or DPP-4+MET (Group DPP-4+MET) respectively during the past 6 months before entering the study 1.5. Treated on a stable antidiabetic dosage during the past 3 months before entering the study

2. Inclusion criteria - applicable for healthy subject only:

2.1. Fasting blood glucose £ 100 mg/dl (5.6 mmol/l) 2.2. Oral Glucose Tolerance Test (OGTT) revealed no IGT or DM

Inclusion criteria - applicable for all subjects:

3. Age of 40-75 years inclusively

4. BMI between 20 and 35 kg/m2 inclusively

5. Patient informed consent

Exclusion Criteria:

1. Exclusion criteria - applicable for T2DM group only:

1.1. Type 1 diabetes mellitus 1.2. Treatment with any other insulin than LANTUS during the past 6 months in Group LANTUS+MET or with any kind of insulin during the past 3 months in Group SU+MET or Group DPP-4+MET before entering the study 1.3. Treatment with any kind of OAD except MET during the past 6 months in Group LANTUS+MET or with any kind of OAD except MET+SU during the past 3 months in Group SU+MET or with any kind of OAD except DPP-4+SU during the past 3 months in Group DPP-4+MET before entering the study 1.4. Major micro- or macro vascular complications as judged by the investigator

2. Exclusion criteria - applicable for healthy subject only:

2.1. Type 1 or type 2 diabetes mellitus (checked by oGTT) 2.2. Impaired Glucose Tolerance (IGT, checked by oGTT) 2.3. Impaired Fasting Glucose (IFG, checked by oGTT)

Exclusion criteria - applicable for all subjects:

3. History of drug or alcohol abuse within the last five years prior to screening

4. History of severe or multiple allergies

5. Treatment with any other investigational drug within 3 months prior to screening

6. Progressive fatal disease

7. Known psychiatric illness

8. History of significant cardiovascular, respiratory, gastrointestinal, hepatic (ALAT and/or ASAT > 3 times the normal reference range), renal (creatinine > 1.1 mg/dl in women and > 1.5 mg/dl in men), neurological, psychiatric and/or haematological disease as judged by the investigator

9. Pregnancy or breast feeding

10. Sexually active women of childbearing potential not consistently and correctly practicing birth control by implants, injectables, combined oral contraceptives, hormonal intrauterine devices (IUDs), sexual abstinence or vasectomised partner

11. Lack of compliance or other similar reason, that according to investigator, precludes satisfactory participation in the study

Study Design

Observational Model: Case Control, Time Perspective: Prospective

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2

Locations

Country	Name	City	State
Germany	IKFE Institute for Clinical Research and Development	Mainz

Sponsors (3)

Lead Sponsor	Collaborator
ikfe-CRO GmbH	IKFE Institute for Clinical Research and Development, Sanofi

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Investigation of ß-cell function via comparison of AUC0-300 minutes of intact Proinsulin in T2DM patients treated with LANTUS + Metformin (MET) vs. T2DM patients treated with Sulfonylurea (SU) + Metformin	Comparison of AUC0-300 min [intact Proinsulin] between T2DM patients treated with LANTUS + Metformin and T2DM patients treated with Sulfonylurea + MET after uptake of standardized meal	0-300 minutes after standardized meal	No
Secondary	Investigation of insulin, intact proinsulin, glucose and PAI-1 levels over a 5 h period after uptake of a standardized meal comparing four different population groups	Comparison of the AUC0-300 of intact proinsulin between each of the 4 treatment groups with the exception of T2DM patients treated with LANTUS + MET and T2DM patients treated with SU + MET after uptake of a standardized meal.; Comparison of the AUC0-300 for insulin, the AUC0-300 and the AUC0-180 for blood glucose, the mean maximum levels of intact proinsulin, insulin and BG, and the PAI-1 level excursion at the time points 0, 150 and 300 min between each of the 4 treatment groups.; Comparison of the change in the insulin/intact proinsulin ratio between each of the 4 treatment groups	0-300 minutes after standardized meal	No