Beta-Cell Function of Insulin Glargine Compared to Neutral Protamine Hagedorn (NPH) Insuline and to Insulin Detemir in Combination With Metformin

Study Overview
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Brief Summary
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The aim of the study is to show that treatment with Glargine will lead to an improvement in beta cell function especially within times of maximal beta cell stress occurring after a meal. For this reason three different standardized test meals (breakfast, lunch, dinner) will be performed and the postprandial secretion of intact proinsulin levels will be measured. These measurements will be performed with patients treated in combination with metformin and insulin glargine versus metformin plus NPH insulin (within the core study) and if significant difference is observed, with a third treatment arm with metformin plus insulin detemir. Hypothesis is that the area under the curve (AUC) intact proinsulin levels within 2 hours after test meal dinner of metformin plus insulin glargin differs from AUC intact proinsulin levels of metformin plus NPH insulin.

Official Title
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Impact of Insulin (I.)Glargine Compared to NPH I. and to I. Detemir in Combination With Metformin on Prandial ß-cell Function and Overall Metabolic Control in Type 2 Diabetic Patients With Insufficient Metabolic Control During OAD Treatment

Conditions
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Type 2 Diabetic Patients, Insufficient Metabolic Control, OAD Treatment

Intervention / Treatment
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* Drug: Insulin Glargin
* Drug: NPH insulin
* Drug: Insulin detemir
* Drug: metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 Diabetes mellitus according to the ADA criteria HbA1c between 6.5% and 8.5% Individually optimized combination therapy with metformin in combination with sulfonylurea in a stable dosage within the last 3 months Age between 40 and 75 years Fasting intact proinsulin level > 7 pmol/Land < 20 pmol/Lat screening Exclusion Criteria: Type 1 Diabetes mellitus Pre-Treatment with insulin within the last 3 months prior to screening Pre-Treatment with PPARy-agonists (glitazones) within the last 3 months prior to screening Major micro- or macrovascular complications as judged by the investigator BMI > 40 kg/m² Hypokalemia (K < 3.5 mmol /L) History of drug or alcohol abuse Anamnestic history of hypersensitivity to the study drugs or to drugs with similar chemical structures History of severe or multiple allergies Treatment with any other investigational drug within 3 months prior to screening Progressive fatal disease History of significant cardiovascular, respiratory, gastrointestinal, hepatic (ALAT and/or ASAT > 3 times the normal reference range), renal (creatinine > 1.3 mg/dL in women and > 1.7 mg/dL in men), neurological, psychiatric and/or haematological disease as judged by the investigator Pregnancy or breast feeding Sexually active women of childbearing potential not actively and consistently practicing birth control by using a medically accepted device or therapy

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Insulin glargine<br>Insulin glargine, dose individually adapted to reach treatment goal (FBG < 100 mg/dL) | Drug: Insulin Glargin<br> <br> Drug: metformin<br>* metformin (2000 mg/day)<br>|
| Active Comparator: NPH Insulin<br>NPH Insulin, dose individually adapted to reach treatment goal (FBG < 100 mg/dL) | Drug: NPH insulin<br> <br> Drug: metformin<br>* metformin (2000 mg/day)<br>|
| Active Comparator: Insulin detemir<br>Insulin detemir, dose individually adapted to reach treatment goal (FBG < 100 mg/dL) | Drug: Insulin detemir<br> <br> Drug: metformin<br>* metformin (2000 mg/day)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| postprandial dynamics of intact proinsulin secretion after standardized test meals (AUC for two hours after dinner) |  | 12 +/- 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC for intact proinsulin levels for two hours after a standardized test meal (breakfast and lunch) |  | 12 +/- 2 weeks | 
| increase of intact proinsulin after breakfast (BF), lunch (LU) and dinner (DI) |  | 12 +/- 2 weeks | 
| Ratio of exogenous insulin vs. endogenous insulin (measurements of glargine, NPH Insulin, detemir and human insulin levels) |  | 12 +/- 2 weeks | 
| Postprandial endothelial function measured as postischaemic response in LDF measurements (after BF, LU, DI) |  | 12 +/- 2 weeks | 
| Postprandial change in and AUC for hs CRP (after BF, LU, DI) |  | 12 +/- 2 weeks | 
| Postprandial change in and AUC for ADMA (after BF, LU, DI) |  | 12 +/- 2 weeks | 
| Postprandial increase in and AUC for glucose levels (after BF, LU, DI) |  | 12 +/- 2 weeks | 
| Changes in FBG |  | 12 +/- 2 weeks | 
| Changes in 8-point BG profiles |  | 12 +/- 2 weeks | 
| Percentage of patients reaching the treatment goal |  | 12 +/- 2 weeks | 
| Insulin dosage per kg body weight to reach treatment goal |  | 12 +/- 2 weeks |