Safety Evaluation of Adverse Reactions in Diabetes

Study Overview
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Brief Summary
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The purpose of this study is to assess the effects of incretin-based antidiabetic therapies (DPP-4 inhibitors and GLP-1 agonists) on cardiovascular, gastrointestinal and renal system and to detail the mechanisms underlying their action in these systems.

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Exenatide
* Drug: Linagliptin
* Drug: Gliclazide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2 diabetes mellitus Metformin monotherapy - stable dose during last 3 months HbA1C 48-75 mmol/mol (IFCC) BMI 25-40 kg/m2 Age 35-70 years (women postmenopausal) Use of ACE inhibitors or ATII receptor blockers for at least 3 months before enrollment Exclusion Criteria: eGFR<30 ml/min/1.73m2 (MDRD) Treatment with incretin mimetics during 3 months before enrollment Chronic insulin therapy Chronic use of loop diuretics, glucocorticoids, NSAID, immune suppressants, antimicrobial agents, chemotherapeutics, bile acid sequestrants (colestyramin, colesevelam) History of pancreatic disease or impaired pancreatic function (defined as the need to use pancreatic enzymes) Active liver disease or a 3-fold elevation of liver transaminases (ALT, AST) Active malignancy History of severe cardiovascular disease including acute coronary syndrome, stroke or transient ischemic neurologic disorder during previous 6 months, atrial fibrillation or other arrhythmia requiring chronic antiarrhythmic medication, chronic heart failure (New York Heart Association grade III/IV) History of alcohol abuse, defined as >4 units of alcohol/day (32 g or 40 ml of 100% alcohol) History of allergy for GLP-1 receptor agonists or DPP-4 inhibitors Any disease that could interfere with study procedures (e.g. decreased mobility, mental incapacity) Inability to give informed consent

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 70 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: GLP-1 agonist<br>Exenatide 5 ug s.c. bid for the 1st month, 10 ug s.c. bid for the next 2 months | Drug: Exenatide<br> <br> |
| Active Comparator: DPP-4 inhibitor<br>Linagliptin 5 mg tbl qd for 3 months | Drug: Linagliptin<br> <br> |
| Active Comparator: Sulfonylurea derivate<br>Gliclazid 30 mg tbl qd for 3 months | Drug: Gliclazide<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Heart rate |  | 90 days after treatment initiation | 
| Gastric evacuation velocity |  | 90 days after treatment initiation | 
| Blood pressure |  | 90 days after treatment initiation | 
| Left ventricular ejection fraction |  | 90 days after treatment initiation | 
| Intimomedial thickness |  | 90 days after treatment initiation | 
| Pulse wave velocity |  | 90 days after treatment initiation | 
| Glomerular filtration rate |  | 90 days after treatment initiation | 
| Tubular function |  | 90 days after treatment initiation | 
| KIM-1 | Marker of renal damage | 90 days after treatment initiation | 
| Exocrine pancreas function |  | 90 days after treatment initiation |