REducing With MetfOrmin Vascular Adverse Lesions in Type 1 Diabetes (REMOVAL)

• Change in HbA1c [ Time Frame: Baseline, Year 1, Year 2, Year 3 ] [ Designated as safety issue: No ]
• Change in LDL Cholesterol [ Time Frame: Baseline, Year 1, Year 2, Year 3 ] [ Designated as safety issue: No ]
• Change in albuminuria & estimated glomerular filtration rate [ Time Frame: Baseline, Year 1, Year 2, Year 3 ] [ Designated as safety issue: No ]
  Number of participants developing new microalbuminuria; change in absolute concentration
• Change in retinopathy stage [ Time Frame: Baseline, Year 3 ] [ Designated as safety issue: No ]
  ETDRS grade
• Change in weight [ Time Frame: Baseline, Year 1, Year 2, Year 3 ] [ Designated as safety issue: No ]
• Change in insulin dose [ Time Frame: Baseline, Year 1, Year 2, Year 3 ] [ Designated as safety issue: No ]
• Change in endothelial function [ Time Frame: Baseline, Year 1, Year 3 ] [ Designated as safety issue: No ]
  RHI units

The trial is conducted in the UK, Australia, Canada, Denmark and the Netherlands. The aim is to test whether 3 years treatment with metformin added to titrated insulin therapy (towards target HbA1c7.0%/53 mmol/mol) reduces atherosclerosis, as measured by progression of carotid IMT, in adults with confirmed type 1 diabetes aged 40 years and over at increased risk for cardiovascular disease.

• Drug: Metformin
  3 years treatment duration
  Other Name: Glucophage
• Drug: Placebo
  3 years duration

• Experimental: Metformin
  Oral Metformin (as Glucophage 500mg x 2 bd) titrated from initial 500mg to target 2000mg daily
  Intervention: Drug: Metformin
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo

Inclusion Criteria:

• Type 1 Diabetes for five years or more*
• Age 40 years or above
• 7.0 =< HbA1c <10.0% (53 - 86 mmol/mol)

AND 3 or more of the following ten CVD risk factors:

• BMI >27 kg/m^2
• Current HbA1c >8.0% (64 mmol/mol)
• Known CVD/peripheral vascular disease
• Current smoker
• Estimated glomerular filtration rate <90 ml/min per 1.73 m^3
• Confirmed micro- or macroalbuminuria [according to local assays and reference ranges]
• Hypertension (BP >=140/90mmHg or established on antihypertensive treatment)
• Dyslipidaemia [total cholesterol >=5.0 mmol/L (200 mg/dL);OR HDL cholesterol <1.20 mmol/L (46mg/dL) [MEN]; OR <1.30 mmol/L (50 mg/dL) [WOMEN]; or triglycerides >=1.7 mmol/L (150mg/dL); or established on lipid-lowering treatment)]
• Strong family history of CVD (at least one parent, biological aunt/ uncle, or sibling with myocardial infarction or stroke aged <60 years)
• Duration of diabetes > 20 years

Exclusion Criteria:

• eGFR < 45 ml/min/1.73m2
• woman of childbearing age not on effective contraception
• Pregnancy and/or lactation
• Acute coronary syndrome or Stroke/Transient Ischaemic Attack within the last three months
• NYHA stage 3 or 4 heart failure
• Significant hypoglycaemia unawareness
• Impaired cognitive function/ unable to give informed consent
• Previous carotid surgery/ inability to capture adequate carotid images
• Estimated glomerular filtration < 45ml/min/1.73m^2 (MDRD)
• Gastroparesis
• History of lactic acidosis
• Other contraindications to metformin (hepatic impairment, known hypersensitivity to metformin, acute illness such as dehydration, severe infection, shock, acute cardiac failure or suspected tissue hypoxia)
• Any coexistent life threatening condition including prior diagnosis of cancer within two years
• History of alcohol problem or drug abuse

• NHS Greater Glasgow and Clyde
• Juvenile Diabetes Research Foundation
• Imperial College London
• University of Wisconsin School of Medicine and Public Health
• University of Dundee
• Merck Serono S.A., Geneva
• Itamar-Medical, Israel
• University of Western Ontario, Canada
• University of Melbourne
• Steno Diabetes Center
• Maastricht University Medical Center