REducing With MetfOrmin Vascular Adverse Lesions in Type 1 Diabetes (REMOVAL)
Condition: Diabetes Mellitus, Type 1
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1
Intervention: Metformin; Placebo
Intervention description: 3 years treatment duration; 3 years duration
Intervention MeSH terms: Metformin
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 493.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No
Keywords: REMOVAL; metformin; carotid IMT; LDL Cholesterol; endothelial function; retinopathy; HbA1c

Summary:

      The trial is conducted in the United Kingdom (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 HbA1c 7.0%/53 mmol/mol) reduces atherosclerosis, as measured
      by progression of carotid intima-media thickness (cIMT), in adults with confirmed type 1
      diabetes aged 40 years and over at increased risk for cardiovascular disease.
    

Eligibility criteria:

        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 CardioVascular Disease (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 (eGFR) <90 ml/min per 1.73 m^3

          -  Confirmed micro- or macroalbuminuria [according to local assays and reference ranges]

          -  Hypertension (BP >=140/90 millimeters of mercury (mmHg) 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