Effect of Linagliptin in Comparison With Glimepiride as Add on to Metformin on Postprandial Beta Cell Function, Postprandial Metabolism and Oxidative Stress in Patients With Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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The goal of this mechanistic study is to investigate the effect of Linagliptin in comparison to Glimepiride as add on therapy on several parameters characterizing postprandial metabolism and oxidative stress in type 2 diabetic patients on stable control with metformin.

Detailed Description
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The goal of this mechanistic study is to investigate the effect of Linagliptin in comparison to Glimepiride as add on therapy on several parameters characterizing postprandial metabolism and oxidative stress in type 2 diabetic patients on stable control with metformin. This mechanistic phase IV study has a prospective, comparative, open, randomized, two arm and exploratory design. Overall 40 Patients will be randomized to two treatment arms both receiving Metformin at a maximally tolerated dose. In addition to that both treatment groups will receive either an individually titrated dose of Glimepiride or 5mg once daily of Linagliptin. Subsequent to a standardized meal, several parameters reflecting beta cell function, metabolism and oxidative stress will be evaluated.

Official Title
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Effect of Linagliptin in Comparison With Glimepiride as Add on to Metformin on Postprandial Beta Cell Function, Postprandial Metabolism and Oxidative Stress in Patients With Type 2 Diabetes Mellitus

Conditions
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Diabetes Mellitus Type 2

Intervention / Treatment
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* Drug: Linagliptin
* Drug: Glimepiride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diabetes mellitus type 2 HbA1c > 6.5% - ≤ 8.5% HbA1c > 7.0% - ≤ 8.5% for those patients with a significant cardiovascular history Treatment with metformin at a maximum tolerated dose Age 45 - 75 years (inclusively) Patient consents that his/her family physician/diabetologist will be informed of trial participation. Exclusion Criteria: Pretreatment with PPAR gamma agonists within the last three months History of type 1 diabetes Uncontrolled hypertension (systolic blood pressure >160 mmHg and/or diastolic blood pressure >90 mmHg) Acute infections Medical 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 before trial entry. Progressive fatal disease History of drug or alcohol abuse in the past 2 years State after kidney transplantation Serum potassium > 5.5 mmol/L Pregnancy or breast feeding Sexually active woman of childbearing age not practicing a highly effective method of birth control as defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, hormonal IUDs, sexual abstinence or vasectomized partner. Acute myocardial infarction, open heart surgery or cerebral event (stroke/TIA) within the previous 30 days Any elective surgery during study participation Have had more than one unexplained episode of severe hypoglycemia (defined as requiring assistance of another person due to disabling hypoglycemia) within 6 months prior to screening visit History of pancreatitis History of dehydration, pre-coma diabeticum or diabetic ketoacidosis Acute or scheduled investigation with iodine containing radiopaque material Uncontrolled unstable angina pectoris History of pericarditis, myocarditis, endocarditis Recent pulmonary embolism Hemodynamic relevant aortic stenosis Aortic aneurysm Regular use of NSAID's (no acute use of NSAID within 48 hours before V2,V4,V5) Lack of compliance or other similar reason that, according to investigator, precludes satisfactory participation in the study History of 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 hematological disease as judged by the investigator Lactose intolerance Intake of Coumarin or coumarin derived compounds such as phenprocoumon (Marcumar) or warfarin (Coumadin, Warfant)

Ages Eligible for Study
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Minimum Age: 45 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Glimepiride-ratiopharm<br>Glimepiride (1-4mg) as add on therapy | Drug: Glimepiride<br>* Glimepiride 1-4mg (individually dosed) as add on therapy to an existing metformin therapy<br>* Other names: Glimepirid-ratiopharm;|
| Experimental: Trajenta<br>Linagliptin 5 mg as add on therapy | Drug: Linagliptin<br>* Linagliptin dosed 5 mg as add on therapy to an existing metformin therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Postprandial increase in intact Proinsulin levels (Peak, AUC) |  | 30, 60, 90, 120, 150, 180, 210, 240, 270 300 mins post test meal procedure, 3 times within 12 weeks treatment | 
| Postprandial Proinsulin/Insulin Ratio |  | after 12 weeks treatment | 
| Fasting intact Proinsulin levels |  | after 12 weeks treatment | 
| Fasting Proinsulin/Insulin Ratio |  | after 12 weeks treatment | 
| Fasting Blood Glucose |  | after 12 weeks treatment | 
| Postprandial Blood Glucose Excursions (Peak; AUC) |  | 30, 60, 90, 120, 150, 180, 210, 240, 270 300 mins post test meal procedure, 3 times within 12 weeks treatment | 
| Fasting Lipids |  | after 12 weeks treatment | 
| Postprandial Lipids |  | after 12 weeks treatment | 
| Fasting Erythrocyte Flexibility |  | after 12 weeks treatment | 
| Postprandial Erythrocyte Flexibility |  | after 12 weeks treatment | 
| Fasting GLP-1 levels |  | after 12 weeks treatment | 
| Postprandial GLP-1 levels |  | after 12 weeks treatment | 
| Fasting cGMP |  | after 12 weeks treatment | 
| Postprandial cGMP |  | after 12 weeks treatment | 
| Fasting Calcitonin |  | after 12 weeks treatment | 
| Fasting PAI-1 levels |  | after 12 weeks treatment | 
| Postprandial PAI-1 levels |  | after 12 weeks treatment | 
| Fasting ADMA levels |  | after 12 weeks treatment | 
| Postprandial ADMA levels |  | after 12 weeks treatment | 
| Fasting Malonyldialdehyd |  | after 12 weeks treatment | 
| fasting oxidatively modified nucleosides 8-oxodG and 8-oxoGuo |  | after 12 weeks treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hypoglycemic events |  | after 12 weeks treatment | 
| Body Weight |  | after 12 weeks treatment |