REducing with MetfOrmin Vascular
Adverse Lesions in Type 1 diabetes mellitus

Cardiovascular disease (CVD) is the commonest cause of premature death in type
1 diabetes (T1DM). Population-based data from 19,248 individuals with the
condition in Scotland indicate ten year absolute CVD event rates of 16.7% and
12.7% respectively in men and women aged 40-60 years, rising to 49% and 39% in
those aged over 60 years. These rates are 3-5 fold higher than in the general
population. Few randomized controlled trials (RCTs) have directly addressed
myocardial infarction (MI) and stroke prevention in T1DM.
Metformin has many of the properties desirable for an adjunct oral agent to be
added in with insulin therapy to improve metabolic control. Data from ourselves
and others show that it may: (i) reduce insulin dose (by 6 units) for a given
achieved HbA1c; (ii) promote weight stabilization; (iii) be associated with low
rates of hypoglycaemia; and (iv) reduce LDL cholesterol * by 0.5 mmol/L (20
mg/dL) - even on a background of statin
therapy. There is considerable evidence that it may also provide direct and
potentially beneficial cardiovascular effects at least in type 2 diabetes -
particularly as demonstrated in the UK Prospective Diabetes Study (UKPDS).

Primary objective:
To test for the first time in a double-blind randomized, placebo controlled
trial whether three years treatment with metformin 1000 mg bd added to titrated
insulin therapy (towards target HbA1c 7.0%/ 53 mmol/mol) reduces
atherosclerosis, as measured by progression of carotid Intima Media Thickness
(IMT), in adults with confirmed T1DM aged 40 years and over at increased risk
for CVD.
Secondary and tertiary objective:
To examine over this period the effect of metformin on other markers of
diabetic micro- and macrovascular complications and intermediate
disease- related biomarkers. The composite secondary endpoint will provide
clinically meaningful information on the potential of metformin to influence
clinical practice in this condition.

Randomized, double-blind, placebo controlled trial

Metformin as Glucophage 500mg two tablets twice daily (=1000mg twice daily) or
matching placebo tablets, added to standard insulin therapy. Participants will
be asked to titrate up the medication according to usual practice with
metformin i.e. they will take one tablet with the evening meal for one week;
this will then be increased to additional tablets at weekly intervals with the
morning meal, evening meal and then morning meal until a dose of 1000 mg twice
daily is achieved.

Patients will have to visit the research ward 5 times over a period of three
years. The remaining visits will be planned together with their standard
outpatient visits. Furthermore, patients will be called regelurly, in
particular at initiation of the study, to monitor their glucose-regulation.
Additional blood will be withdrawn (approximately 60 ml in total spread over 5
withdrawals). Potential risks are hematoma, which is reversible. Treatment of
metformin can lead to hypoglycemia when added to standard insulin therapy.
These episodes will be kept to a mininum by excluding those patients with a
hypoglycemia anawareness and to monitor patients frequently when therapy is
initiated. Rare complications of metformin therapy are elevated liver enzymes
and lactic acidosis. The former is reversible and will be discovered at an
early stage, since these levels will be monitored frequently after initiation
of therapy. Lactic acidosis is associated with impaired kidney function.
Patients with kidney function will be excluded from the study. Furthermore,
patients will be instructed to contact the study doctor when there is a risk of
deterioration of kidney function, i.e. when contrast is given for diagnostic
testing and when a new drug is started.
Potential benefits: patients will more closely than conventional followed with
regard to glucose regulation and cardiovascular risk.