The Metformin-FMD Trial

Study Overview
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Brief Summary
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In acute myocardial infarction early restoration of coronary blood flow is the most effective strategy to limit infarct-size. Paradoxically, reperfusion itself also aggravates myocardial injury and contributes to final infarct size, a process termed 'reperfusion injury'. Ischemia and reperfusion (IR)-induced endothelial dysfunction seems to play a pivotal role in this process, resulting in vasoconstriction and reduced blood flow to the already ischemic tissue. Recently, it has been shown that the glucose-lowering drug metformin is able to limit IR-injury in murine models of myocardial infarction, probably by increased formation of the endogenous nucleoside adenosine. In the current research proposal, the investigators aim to translate this finding to the human in vivo situation, using flow-mediated dilation (FMD) of the brachial artery as a well-validated model of (endothelial) IR-injury.

Official Title
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Can Metformin Prevent Endothelial Ischemia and Reperfusion Injury? The Metformin-FMD Trial

Conditions
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Ischemia Reperfusion Injury, Endothelial Function

Intervention / Treatment
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* Drug: Metformin
* Drug: Pretreatment with metformin in combination of infusion of caffeine.
* Drug: No pretreatment with metformin in combination with infusion of caffeine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 30-50 years Written informed consent Exclusion Criteria: Smoking Hypertension (in supine position: systolic BP > 140 mmHg, diastolic BP > 90 mmHg) Hyperlipidaemia (fasting total cholesterol > 5.5 mmol/L or random > 6.5 mmol/L) Diabetes Mellitus (fasting glucose > 7.0 mmol/L or random glucose > 11.0 mmol/L) History of any cardiovascular disease Concomitant use of medication Renal dysfunction (MDRD < 60 ml/min) Professional athletes

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pretreatment with metformin<br>Pretreatment with metformin 500 mg three times a day for 3 days. | Drug: Metformin<br>* metformin 500 mg three times a day, for 3 days<br>|
| No Intervention: No pretreatment.<br>no intervention | |
| Active Comparator: Pretreatment with Metformin/caffeine<br>to study whether caffeine (4 mg/kg intravenously over 10 minutes) attenuates the protective effect of metformin (500 mg three times a day for 3 days) on FMD after ischemia/reperfusion | Drug: Pretreatment with metformin in combination of infusion of caffeine.<br>* Pretreatment with metformin 500 mg three times a day for 3 days, in combination with pretreatment with caffeine (4 mg/kg intravenously over 10 minutes) prior to FMD measurement<br>|
| Other: No metformin, only pretreatment with caffeine<br>No pretreatment with metformin, FMD measurement after forearm ischemia/reperfusion and infusion of caffeine (4 mg/kg intravenously over 10 minutes). | Drug: No pretreatment with metformin in combination with infusion of caffeine<br>* No pretreatment with metformin in combination with pretreatment with caffeine (4 mg/kg intravenously over 10 minutes).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metformin-FMD trial: The effect of pretreatment with metformin on FMD of the brachial artery after forearm ischemia and reperfusion. | Metformin-FMD trial: To study the effect of oral pretreatment with metformin (500 mg three times ad ay for 3 days) on flow mediated dilation of the brachial artery after 20 minutes of forearm ischemia and 20 minutes of reperfusion in healthy volunteers. | approx. 6 months | 
| Control trial: the effect of caffeine on the protective effect of metformin on FMD after ischemia and reperfusion. | Control trial: when metformin displays a protective effect on endothelial function, we will conduct a second experiment to study whether caffeine, an adenosine receptor antagonist, attenuates the protective effect of metformin on flow mediated dilation after 20 minutes of ischemia and 20 minutes of reperfusion in healthy volunteers. | approx. 6 months |