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

• Postprandial increase in intact Proinsulin levels (Peak, AUC) [ Time Frame: 30, 60, 90, 120, 150, 180, 210, 240, 270 300 mins post test meal procedure, 3 times within 12 weeks treatment ] [ Designated as safety issue: No ]
• Postprandial Proinsulin/Insulin Ratio [ Time Frame: after 12 weeks treatment ] [ Designated as safety issue: No ]
• Fasting intact Proinsulin levels [ Time Frame: after 12 weeks treatment ] [ Designated as safety issue: No ]
• Fasting Proinsulin/Insulin Ratio [ Time Frame: after 12 weeks treatment ] [ Designated as safety issue: No ]
• Fasting Blood Glucose [ Time Frame: after 12 weeks treatment ] [ Designated as safety issue: No ]
• Postprandial Blood Glucose Excursions (Peak; AUC) [ Time Frame: 30, 60, 90, 120, 150, 180, 210, 240, 270 300 mins post test meal procedure, 3 times within 12 weeks treatment ] [ Designated as safety issue: No ]
• Fasting Lipids [ Time Frame: after 12 weeks treatment ] [ Designated as safety issue: No ]
• Postprandial Lipids [ Time Frame: after 12 weeks treatment ] [ Designated as safety issue: No ]
• Fasting Erythrocyte Flexibility [ Time Frame: after 12 weeks treatment ] [ Designated as safety issue: No ]
• Postprandial Erythrocyte Flexibility [ Time Frame: after 12 weeks treatment ] [ Designated as safety issue: No ]
• Fasting GLP-1 levels [ Time Frame: after 12 weeks treatment ] [ Designated as safety issue: No ]
• Postprandial GLP-1 levels [ Time Frame: after 12 weeks treatment ] [ Designated as safety issue: No ]
• Fasting cGMP [ Time Frame: after 12 weeks treatment ] [ Designated as safety issue: No ]
• Postprandial cGMP [ Time Frame: after 12 weeks treatment ] [ Designated as safety issue: No ]
• Fasting Calcitonin [ Time Frame: after 12 weeks treatment ] [ Designated as safety issue: No ]
• Fasting PAI-1 levels [ Time Frame: after 12 weeks treatment ] [ Designated as safety issue: No ]
• Postprandial PAI-1 levels [ Time Frame: after 12 weeks treatment ] [ Designated as safety issue: No ]
• Fasting ADMA levels [ Time Frame: after 12 weeks treatment ] [ Designated as safety issue: No ]
• Postprandial ADMA levels [ Time Frame: after 12 weeks treatment ] [ Designated as safety issue: No ]
• Fasting Malonyldialdehyd [ Time Frame: after 12 weeks treatment ] [ Designated as safety issue: No ]
• fasting oxidatively modified nucleosides 8-oxodG and 8-oxoGuo [ Time Frame: after 12 weeks treatment ] [ Designated as safety issue: No ]

• Hypoglycemic events [ Time Frame: after 12 weeks treatment ] [ Designated as safety issue: Yes ]
• Body Weight [ Time Frame: after 12 weeks treatment ] [ Designated as safety issue: Yes ]

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.

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.

• Drug: Linagliptin
  Linagliptin dosed 5 mg as add on therapy to an existing metformin therapy
• Drug: Glimepiride
  Glimepiride 1-4mg (individually dosed) as add on therapy to an existing metformin therapy
  Other Name: Glimepirid-ratiopharm

• Active Comparator: Glimepiride-ratiopharm
  Glimepiride (1-4mg) as add on therapy
  Intervention: Drug: Glimepiride
• Experimental: Trajenta
  Linagliptin 5 mg as add on therapy
  Intervention: Drug: Linagliptin

Inclusion Criteria:

1. Diabetes mellitus type 2
2. HbA1c > 6.5% - ≤ 8.5%
3. HbA1c > 7.0% - ≤ 8.5% for those patients with a significant cardiovascular history
4. Treatment with metformin at a maximum tolerated dose
5. Age 45 - 75 years (inclusively)
6. Patient consents that his/her family physician/diabetologist will be informed of trial participation.

Exclusion Criteria:

1. Pretreatment with PPAR gamma agonists within the last three months
2. History of type 1 diabetes
3. Uncontrolled hypertension (systolic blood pressure >160 mmHg and/or diastolic blood pressure >90 mmHg)
4. Acute infections
5. Medical history of hypersensitivity to the study drugs or to drugs with similar chemical structures
6. History of severe or multiple allergies
7. Treatment with any other investigational drug within 3 months before trial entry.
8. Progressive fatal disease
9. History of drug or alcohol abuse in the past 2 years
10. State after kidney transplantation
11. Serum potassium > 5.5 mmol/L
12. Pregnancy or breast feeding
13. 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.
14. Acute myocardial infarction, open heart surgery or cerebral event (stroke/TIA) within the previous 30 days
15. Any elective surgery during study participation
16. 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
17. History of pancreatitis
18. History of dehydration, pre-coma diabeticum or diabetic ketoacidosis
19. Acute or scheduled investigation with iodine containing radiopaque material
20. Uncontrolled unstable angina pectoris
21. History of pericarditis, myocarditis, endocarditis
22. Recent pulmonary embolism
23. Hemodynamic relevant aortic stenosis
24. Aortic aneurysm
25. Regular use of NSAID's (no acute use of NSAID within 48 hours before V2,V4,V5)
26. Lack of compliance or other similar reason that, according to investigator, precludes satisfactory participation in the study
27. 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
28. Lactose intolerance
29. Intake of Coumarin or coumarin derived compounds such as phenprocoumon (Marcumar) or warfarin (Coumadin, Warfant)

• ikfe-CRO GmbH
• Boehringer Ingelheim Pharmaceuticals