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

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.

Study Overview

• Status: Unknown
• Conditions: Diabetes Mellitus Type 2
• Intervention / Treatment: Drug: Glimepiride; Drug: Linagliptin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Rhineland-Palatinate
    • Mainz, Rhineland-Palatinate, Germany, 55116
      • Recruiting
      • IKFE GmbH
      • Contact: Thomas Forst, MD, PhD; Phone Number: 16 + 49 6131 57636; Email: ThomasF@ikfe.de
      • Contact: Daniela Sachsenheimer, MD; Phone Number: 46 + 49 6131 57636; Email: DanielaS@ikfe.de
      • Sub-Investigator: Stefan Diessel
      • Sub-Investigator: Michael Mitry, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Marcus Borchert
• Collaborators: Boehringer Ingelheim; ikfe-CRO GmbH
• Investigators: Principal Investigator: Thomas Forst, MD, PhD, IKFE GmbH

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Anticipated): October 1, 2012
• Study Completion (Anticipated): October 1, 2012

Study Registration Dates

• First Submitted: February 21, 2012
• First Submitted That Met QC Criteria: March 2, 2012
• First Posted (Estimate): March 7, 2012

Study Record Updates

• Last Update Posted (Estimate): April 11, 2012
• Last Update Submitted That Met QC Criteria: April 10, 2012
• Last Verified: April 1, 2012

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Linagliptin; Glimepiride
• Other Study ID Numbers: ikfe-Lina-002; 2012-000179-17 (EudraCT Number)