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11 February 2012
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| [ Print-friendly version ] |
| The effects of metformin on vascular function and adipocyte AMP-activated protein kinase (AMPK) activation in type 2 diabetes |
| ISRCTN | ISRCTN51336867 |
| ClinicalTrials.gov identifier | |
| Public title | The effects of metformin on vascular function and adipocyte AMP-activated protein kinase (AMPK) activation in type 2 diabetes |
| Scientific title | The effects of metformin on vascular function and adipocyte AMP-activated protein kinase (AMPK) activation in type 2 diabetes: a randomised, double blind, glycaemia-controlled crossover trial |
| Acronym | N/A |
| Serial number at source | 03MT024 |
| Study hypothesis | Epidemiological studies have suggested that overweight type 2 diabetic patients may have fewer cardiovascular events on metformin compared with sulphonylureas. The mechanisms of metformin action have yet to be fully elucidated, although recent data have implicated AMP-kinase activation as a potential mediator of metformin action in hepatocytes and skeletal myocytes. We propose to take this a step further. We will conduct a double-blind randomised glycaemia-controlled crossover study in 20 overweight type 2 diabetic patients comparing interventions of metformin with a sulphonylurea. In this group we will study resistance artery endothelial function ex vivo, based on the hypothesis that metformin will augment NO-dependent vasorelaxation. In addition, we will quantify AMPK activity in fat cell lysates from the same patients to clarify whether metformin regulates this kinase in adipocytes. Together, these data will increase our understanding of metformin's vascular action and may pave the way for novel therapeutic targeting of AMPK in the context of metabolic and vascular pathophysiology. |
| Lay summary | Not provided at time of registration |
| Ethics approval | North Glasgow University Hospitals NHS Trust Ethics Committee approved on the 20th January 2004 (ref: 03/154/2) |
| Study design | Single centre randomised double blind controlled crossover trial |
| Countries of recruitment | United Kingdom |
| Disease/condition/study domain | Type 2 diabetes |
| Participants - inclusion criteria |
1. Body mass index (BMI) range 27 - 40 kg/m2
2. HbA1c greater than 7% but less than 11% (Diabetes Control and Complications Trial [DCCT]) at screening 3. Previously treated with diet alone or oral monotherapy (i.e., metformin or sulphonylurea). Subjects on monotherapy had discontinued medication during the six-week run-in period. 4. Males, aged between 50 - 70 years |
| Participants - exclusion criteria |
1. Subjects on warfarin treatment
2. Subjects treated with insulin currently or in the previous 12 months 3. Previous intolerance of metformin or sulphonylurea 4. Presence of contra-indication to metformin therapy for example renal disease or congestive cardiac failure 5. Cardiovascular event (i.e., electrocardiogram (ECG)/troponin proven myocardial infarction [MI] or cerebrovascular accident [CVA]) in previous 6 months |
| Anticipated start date | 09/03/2004 |
| Anticipated end date | 09/03/2006 |
| Status of trial | Completed |
| Patient information material | Not available in web format, please use the contact details below to request a patient information sheet |
| Target number of participants | 20 men with type 2 diabetes |
| Interventions |
The study was single-centre and had a randomised, double blind, glycaemia-controlled crossover design. After full explanation of experimental procedures aided by a subject information sheet, written informed consent was obtained. Each subject was issued with details of the study as well as the investigators' contact telephone numbers. Patients on monotherapy discontinued medication during a six-week run-in period. After this period, patients were randomised to receive metformin (500 mg three times daily) or gliclazide (80 mg twice daily with a lunchtime placebo capsule to ensure blinding) for ten weeks, aiming for a similar reduction in HbA1c. Each drug had a two week dose titration as follows:
Week 1: Gliclazide 80 mg once daily with breakfast, metformin 500 mg once daily with breakfast Week 2: Gliclazide 80 mg once daily with breakfast and dummy capsule at lunch, metformin 500 mg twice daily with breakfast and lunch Weeks 3 - 10: Gliclazide 80 mg twice daily at breakfast and evening meal and dummy capsule at lunch, metformin 500 mg three times daily with breakfast, lunch and evening meal Subjects were asked to inform the investigators of any medication started or discontinued during the study period. No specific advice on lifestyle was given at the time of randomisation. Study randomisation: Randomisation and tablet supply was co-ordinated by the hospital pharmacy. Metformin and gliclazide capsules of identical appearance were manufactured by the pharmac. A computerised randomisation list was made. Randomisation codes were put into sealed envelopes and stored by the pharmacist. Medication bottles were numbered, and allocation was done in sequence. Unblinding was performed at the end of the study period. Subject visits: The study required subjects to attend the Clinical Investigation and Research Unit, University of Glasgow on a total of nine occasions: Week 0 - Screening visit Week 1 - Start of phase 1 Week 5 - Interim visit Week 10 - End of phase 1 (with biopsy) Week 12 - Stitch removal Week 16 - Start of phase 2 Week 21 - Interim visit Week 26 - End of phase 2 (with biopsy) Week 28 - Stitch removal Patients were contacted by telephone at two weeks and attended the CIRU for a brief assessment at five weeks during each phase to check on any side effects and to assess glycaemic control. Any patient with significant osmotic symptoms or a fasting blood glucose of greater than 15 mM would have been withdrawn from the study. Patients were then required to attend the CIRU at 08:30 hours at the end of the ten week study phase having fasted from midnight (and having abstained from alcohol, caffeine and moderate/heavy exercise in the preceding 72 hours) for clinical measures, adipose biopsy and blood sampling for biochemical analysis. Taxis were available to transfer volunteers to and from the CIRU. Snacks were provided at the CIRU when the study protocol was completed. Following a six-week washout phase, the groups were crossed over. |
| Primary outcome measure(s) |
Measured at the end of each 10-week study phase:
1. Body mass index 2. Blood pressure 3. Analysis of routine blood samples (fasting venous blood samples for urea, creatinine, electrolytes, total cholesterol, triglycerides, high density lipoprotein [HDL]-cholesterol, loew density lipoprotein [LDL]-cholesterol, glucose, liver function tests and HbA1C) 4. Analysis of non-routine blood samples (total adiponectin, tumour necrotising factor-alpha [TNF-a], interleukin-6 [IL-6] and asymmetric dimethyl-arginine [ADMA]) 5. Pulse wave velocity (PWV) 6. Wire myography 7. Adipose AMPK activity assays |
| Secondary outcome measure(s) | No secondary outcome measures |
| Sources of funding | British Heart Foundation (BHF) (UK) (ref: PG/03/114/16038) |
| Trial website | |
| Publications | 2011 results in http://www.ncbi.nlm.nih.gov/pubmed/21455728 |
| Contact name | Dr James Boyle |
| Address |
Division of Cardiovascular and Medical Sciences
Glasgow Cardiovascular Research Centre University of Glasgow |
| City/town | Glasgow |
| Zip/Postcode | G12 8QQ |
| Country | United Kingdom |
| Sponsor | Greater Glasgow Health Board (North Glasgow University Hospitals Division) (UK) |
| Address | 300 Balgray Hill Road |
| City/town | Glasgow |
| Zip/Postcode | G12 3UR |
| Country | United Kingdom |
| Sponsor website: | http://www.nhsggc.org.uk |
| Date applied | 19/06/2010 |
| Last edited | 11/10/2011 |
| Date ISRCTN assigned | 29/06/2010 |
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| © 2012 ISRCTN unless otherwise stated. | |
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