Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
03MT024
Study information
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
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.
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
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details below to request a patient information sheet
Condition
Type 2 diabetes
Intervention
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.
Intervention type
Drug
Phase
Phase II
Drug names
Metformin, gliclazide
Primary outcome measure
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 measures
No secondary outcome measures
Overall trial start date
09/03/2004
Overall trial end date
09/03/2006
Reason abandoned (if study stopped)
Eligibility
Participant 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
Participant type
Patient
Age group
Adult
Gender
Male
Target number of participants
20 men with type 2 diabetes
Participant 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
Recruitment start date
09/03/2004
Recruitment end date
09/03/2006
Locations
Countries of recruitment
United Kingdom
Trial participating centre
Division of Cardiovascular and Medical Sciences
Glasgow
G12 8QQ
United Kingdom
Sponsor information
Organisation
Greater Glasgow Health Board (North Glasgow University Hospitals Division) (UK)
Sponsor details
300 Balgray Hill Road
Glasgow
G12 3UR
United Kingdom
Sponsor type
Government
Website
Funders
Funder type
Charity
Funder name
British Heart Foundation (BHF) (UK) (ref: PG/03/114/16038)
Alternative name(s)
BHF
Funding Body Type
private sector organisation
Funding Body Subtype
foundation
Location
United Kingdom
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list
2011 results in http://www.ncbi.nlm.nih.gov/pubmed/21455728
Publication citations
-
Results
Boyle JG, Logan PJ, Jones GC, Small M, Sattar N, Connell JM, Cleland SJ, Salt IP, AMP-activated protein kinase is activated in adipose tissue of individuals with type 2 diabetes treated with metformin: a randomised glycaemia-controlled crossover study., Diabetologia, 2011, 54, 7, 1799-1809, doi: 10.1007/s00125-011-2126-4.