Condition category
Nutritional, Metabolic, Endocrine
Date applied
Date assigned
Last edited
Retrospectively registered
Overall trial status
Recruitment status
No longer recruiting
Publication status

Plain English Summary

Not provided at time of registration

Trial website

Contact information



Primary contact

Dr James Boyle


Contact details

Division of Cardiovascular and Medical Sciences
Glasgow Cardiovascular Research Centre
University of Glasgow
G12 8QQ
United Kingdom

Additional identifiers

EudraCT number number

Protocol/serial number


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


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


Secondary study design

Randomised controlled trial

Trial setting


Trial type


Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet


Type 2 diabetes


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



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


Overall trial end date


Reason abandoned (if study stopped)


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


Age group




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


Recruitment end date



Countries of recruitment

United Kingdom

Trial participating centre

Division of Cardiovascular and Medical Sciences
G12 8QQ
United Kingdom

Sponsor information


Greater Glasgow Health Board (North Glasgow University Hospitals Division) (UK)

Sponsor details

300 Balgray Hill Road
G12 3UR
United Kingdom

Sponsor type




Funder type


Funder name

British Heart Foundation (BHF) (UK) (ref: PG/03/114/16038)

Alternative name(s)


Funding Body Type

private sector organisation

Funding Body Subtype

Trusts, charities, foundations (both public and private)


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

Publication citations

  1. 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.

Additional files

Editorial Notes