Hypothesis: Does metformin added to titrated insulin therapy [towards target HbA1c 7.0% (53 mmol/mol)] reduce progression of atheroma as measured by carotid artery intima-media thickness (cIMT) in adults with T1DM at risk of cardiovascular disease?
Secondary and tertiary objectives: to examine the effect of metformin on other markers of diabetic micro- and macrovascular complications and intermediate disease-related biomarkers.
Design and method
Randomized, double-blind, placebo controlled trial.
Primary endpoint cIMT: For the primary endpoint of cIMT there will be a baseline measurement and repeat measurements at year 1, 2 and 3. All those with a baseline and at least one follow up measurement will be included in the analysis.
1. Type 1 diabetes for five years or more*
2. age ≥ 40 years
3. 7.0 ≤ HbA1c < 10.0% (53-86 mmol/mol)
*defined as diagnosis below age 40 years AND insulin use within 1 year of diagnosis
AND three or more of the following ten CVD risk factors:
1. BMI > 27 kg/m2
2. current HbA1c > 8.0% (64 mmol/mol)
3. known CVD/ peripheral vascular disease
4. current smoker
5. estimated glomerular filtration rate < 90 ml/min per 1.73 m2 (MDRD equation)
6. confirmed micro- or macroalbuminuria [according to local assays and reference
ranges - see Appendix 5]
7. hypertension (BP ≥ 140/ 90 mmHg or established on antihypertensive treatment)
- total cholesterol ≥ 5.0 mmol/L (200 mg/dL);
- OR HDL cholesterol < 1.2 mmol/L (46 mg/dL) [men] or < 1.3 mmol/L (50 mg/dL) [women];
- OR triglycerides ≥ 1.7 mmol/L (150 mg/dL); or established on lipid-lowering treatment
(ix) strong family history of CVD (at least one parent, biological aunt/ uncle, or sibling
with myocardial infarction or stroke aged < 60 years)
(x) duration of diabetes > 20 years.
Expected ending and outcome
Three years per participant (plus one month placebo single-blind in third month of three month Run-In period). cIMT differences over time, with 95% confidence intervals and p-values. Primary outcome regression model extended to assess whether metabolic effects could explain differences in progression of cIMT.
Sponsor: NHS Greater Glasgow and Clyde Board / University of Glasgow, DD1
Chief Investigator: John Petrie, Professor of Diabetic Medicine, University of Glasgow; Honorary Consultant in Diabetes NHS Greater Glasgow and Clyde, UK