Trial to Assess the Influence of 4 Weeks' Treatment With Linagliptin as Compared to Glimepiride and Placebo on Endothelial Function in Patients With Type 2 Diabetes Using FMD (Flow-Mediated Vasodilation)

Study Overview
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Brief Summary
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The general aim of the present study is to investigate the impact of 4 weeks treatment with linagliptin (5 mg) on endothelial function in patients with type 2 diabetes mellitus. In the current trial this effect of linagliptin treatment on endothelial function will be compared against both the sulfonylurea glimepiride and against placebo, which has not been tested in a trial before; as also is the case for other DPP-4 inhibitors. Besides placebo, glimepiride was chosen as a comparator, as it is one compound of the second most used oral antidiabetic drug class.

Official Title
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Randomized, Three Period Cross Over, Double Blind, Double Dummy Study in Type 2 Diabetic Patients to Assess the Endothelial Effects of Linagliptin, Glimepiride and Placebo Therapy for 28 Days ('ENDOTHELINA')

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Placebo
* Drug: Linagliptin
* Drug: Placebo
* Drug: Placebo
* Drug: Placebo
* Drug: Glimepiride


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Type 2 diabetic male and female patients according to the following criteria: Based upon a complete medical history and clinical laboratory tests Age >= 18 and Age <= 65 years Body mass index >= 25 <= 35 kg/m2 HbA1c <= 7.5% Treatment with metformin (=1500 mg daily) for <= 3 months Signed and dated written informed consent prior to admission to the study in accordance with GCP and the local legislation. For female patients of childbearing potential: Use of acceptable method of contraception (Pearl-Index <1). Exclusion criteria: Treatment with any glucose-lowering drug except for metformin within prior 3 months. Any finding of the medical examination (including blood pressure, pulse rate and electrocardiogram) deviating from normal and of clinical relevance. Any evidence of a clinically relevant acute concomitant disease History of cardiovascular disease (e.g. coronary artery disease history of acute myocard infarction or stroke, peripheral vascular disease). History of major diabetic complications (e.g. nephropathy, retinopathy) Gastrointestinal, hepatic, renal, respiratory, cardiovascular, immunological or hormonal disorders (except: hypertension treated with angiotensin receptor blocker or angiotensin-converting-enzyme inhibitors, hyperlipidemia with statin therapy, thyroid hormone replacement therapy, all stable for at least three months prior to screening). Surgery of the gastrointestinal tract (except appendectomy). Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders. History of relevant orthostatic hypotension, fainting spells or blackouts. Chronic or relevant acute infections. History of relevant allergy/hypersensitivity (including allergy to drug or its excipients). Intake of drugs with a long half-life (> 24 hours) within at least one month or less than 10 half-lives of the respective drug prior to administration or during the trial. Participation in another trial with an investigational drug within one month prior to administration or during the trial. Smoker (>= 1 cigarettes or >= 1 cigars or >= 1 pipes/day). Alcohol abuse (more than 60 g/day). Drug abuse. Blood donation (more than 100 mL within four weeks prior to administration or during the trial). Excessive physical activities (within one week prior to administration or during the trial). Any laboratory value outside the reference range that is of clinical relevance.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Linagliptin 5mg<br>given once daily over 28 days | Drug: Placebo<br>* Placebo matching Glimepiride<br>Drug: Linagliptin<br>* given once daily for 28 days<br>|
| Active Comparator: Glimepiride<br>given once daily in 1mg dosis over 7 days, following a titration step to 2mg and application for 21 days | Drug: Placebo<br>* Placebo matching Linagliptin<br>Drug: Glimepiride<br>* 1 mg for 7 days followed by uptitration to 2 mg (given for following 21 days)<br>|
| Placebo Comparator: Placebo<br>given once daily over 28 days | Drug: Placebo<br>* Placebo matching Linagliptin<br>Drug: Placebo<br>* Placebo matching Glimepiride<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Flow Mediated Vasodilation (FMD) Under Fasted Condition on Day 28 | Endothelial function under fasted condition was measured with flow mediated vasodilation (FMD). The change from baseline was calculated as the value on Day 28 divided by the respective value at baseline. | baseline and day 28 for each treatment arm | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Flow Mediated Vasodilation (FMD) 2 h Post Meal on Day 28 | Endothelial function 2 hours post meal was measured with flow mediated vasodilation (FMD). The change from baseline was calculated as the value on Day 28 divided by the respective value at baseline. | baseline and day 28 for each treatment arm | 
| Change From Baseline in 2 Hours Post Meal Endothelial Independent Vasodilation (EIDV) on Day 28 | Endothelial function 2h post-meal was measured by endothelial independent vasodilation (EIDV). The change from baseline was calculated as the value on Day 28 divided by the respective value at baseline. | baseline and day 28 for each treatment arm | 
| Number of Patients With Adverse Events | Number of patients with any adverse events | up to 20 weeks |