Diabetes Mellitus, Type 1
Conditions
Keywords
REMOVAL, metformin, carotid IMT, LDL Cholesterol, endothelial function, retinopathy, HbA1c
Brief 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.
Interventions
DRUGMetformin
3 years treatment duration
DRUGPlacebo
3 years duration
Sponsors
NHS Greater Glasgow and Clyde
Juvenile Diabetes Research Foundation
Imperial College London
University of Wisconsin, Madison
University of Dundee
Merck Serono S.A., Geneva
Itamar-Medical, Israel
University of Western Ontario, Canada
University of Melbourne
Steno Diabetes Center Copenhagen
Maastricht University Medical Center
University of Glasgow
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Averaged Mean Far Wall Common Carotid Artery Intima-media Thickness (cIMT) | 0, 12 months, 24 months, 36 months | Progression of averaged mean far wall common carotid artery intima media thickness IMT (mean cIMT) measured using B mode ultrasonography with a 7.0 MHz or higher broadband linear array transducer and concurrent recording of 3-lead electrocardiogram (ECG). Longitudinal images of the common carotid artery will be obtained at anterior, lateral and posterior angles at baseline, 12, 24 and 36 months using Meijer's arc to standardize the transducer angle. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Weight | Baseline, Year 1, Year 2, Year 3 | Measured at sites using calibrated weighing scales |
| Change in Insulin Dose | Baseline, Year 1, Year 2, Year 3 | Units/ kg body weight Extracted by study nurses from the Study Diary and reported on the study CRF using dedicated fields |
| Change in Endothelial Function | Baseline, Year 1, Year 3 | In some centres (Arbitrary units) Reactive Hyperaemia Index using the ENDOPAT device (Itamar, Israel) |
| Number of Participants With Retinopathy and at Least a 2 Stage Progression in Retinopathy From Baseline to 36 Months | Baseline, Year 3 | Two color 45° field retinal photographs (fields 1 and 2) from each eye at 0 and 36 months graded at the University of Wisconsin Ocular Epidemiology Reading Center (OERC) using the modified Airlie House classification scheme and the Early Treatment Diabetic Retinopathy Severity scale. |
| Change in LDL Cholesterol | Baseline, Year 3 | mmol/L Centrally assayed at the University of Glasgow |
| Change in Estimated Glomerular Filtration Rate | Baseline, Year 1, Year 2, Year 3 | Number of participants developing new microalbuminuria; change in absolute concentration Calculated using the MDRD equation1 based on creatinine measured in accredited local laboratories |
| Change in HbA1c | Baseline, Year 3 | Measured in accredited local laboratories participating in DCCT-aligned quality control programmes. |
Countries
Australia, Canada, Denmark, Netherlands, United Kingdom
Participant flow
Pre-assignment details
493 participants where enrolled and consented. All participants entered a 3 month Run In phase with placebo. Participants who remained eligible were randomly assigned to receive metformin or placebo for 3 years. 65 participants where ineligible to be randomized.
Participants by arm
| Arm | Count |
|---|---|
| Metformin Oral Metformin (as Glucophage 500mg x 2 bd) titrated from initial 500mg to target 2000mg daily
Metformin: 3 years treatment duration 219 of 428 randomised were assigned to Metformin Group | 219 |
| Placebo Placebo: 3 years duration 209 of the 428 randomised were assigned to Placebo | 209 |
| Total | 428 |
Baseline characteristics
| Characteristic | Metformin | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 219 Participants | 209 Participants | 428 Participants |
| Age, Continuous | 55.2 years STANDARD_DEVIATION 8.5 | 55.8 years STANDARD_DEVIATION 8.8 | 55.5 years STANDARD_DEVIATION 8.7 |
| Baseline HbA1c | 64.8 mmol/mol | 64.7 mmol/mol | 64.75 mmol/mol |
| Blood Pressure | 130.5 Systolic BP (mmHg) STANDARD_DEVIATION 15 | 128.5 Systolic BP (mmHg) STANDARD_DEVIATION 14.6 | 129.5 Systolic BP (mmHg) STANDARD_DEVIATION 14.8 |
| BMI | 28.4 kg/m2 STANDARD_DEVIATION 4.5 | 28.5 kg/m2 STANDARD_DEVIATION 4.1 | 28.5 kg/m2 STANDARD_DEVIATION 4.3 |
| Daily Insulin Dose | 0.63 units/kg | 0.68 units/kg | 0.66 units/kg |
| Diabetes Diagnosis Duration | 33.4 years STANDARD_DEVIATION 11 | 34.3 years STANDARD_DEVIATION 10.5 | 33.85 years STANDARD_DEVIATION 10.75 |
| Diabetic Retinopathy | 51 participants | 58 participants | 109 participants |
| eGFR | 92.9 ml/min/1.73m2 STANDARD_DEVIATION 20.9 | 91.1 ml/min/1.73m2 STANDARD_DEVIATION 21.6 | 92 ml/min/1.73m2 STANDARD_DEVIATION 21.3 |
| Existing Cardiovascular Disease | 30 participants | 22 participants | 52 participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment Australia | 32 participants | 30 participants | 62 participants |
| Region of Enrollment Canada | 55 participants | 55 participants | 110 participants |
| Region of Enrollment Denmark | 4 participants | 4 participants | 8 participants |
| Region of Enrollment Netherlands | 16 participants | 15 participants | 31 participants |
| Region of Enrollment United Kingdom | 112 participants | 105 participants | 217 participants |
| Sex: Female, Male Female | 90 Participants | 85 Participants | 175 Participants |
| Sex: Female, Male Male | 129 Participants | 124 Participants | 253 Participants |
| Total Cholesterol | 4 mmol/L STANDARD_DEVIATION 0.88 | 4 mmol/L STANDARD_DEVIATION 0.93 | 4 mmol/L STANDARD_DEVIATION 0.91 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 219 | 2 / 209 |
| other Total, other adverse events | 112 / 219 | 52 / 209 |
| serious Total, serious adverse events | 34 / 219 | 31 / 209 |
Outcome results
Primary
Change in Averaged Mean Far Wall Common Carotid Artery Intima-media Thickness (cIMT)
Progression of averaged mean far wall common carotid artery intima media thickness IMT (mean cIMT) measured using B mode ultrasonography with a 7.0 MHz or higher broadband linear array transducer and concurrent recording of 3-lead electrocardiogram (ECG). Longitudinal images of the common carotid artery will be obtained at anterior, lateral and posterior angles at baseline, 12, 24 and 36 months using Meijer's arc to standardize the transducer angle.
Time frame: 0, 12 months, 24 months, 36 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Metformin | Change in Averaged Mean Far Wall Common Carotid Artery Intima-media Thickness (cIMT) | Baseline | 0.773 mm | Standard Deviation 0.14 |
| Metformin | Change in Averaged Mean Far Wall Common Carotid Artery Intima-media Thickness (cIMT) | 24 Months | 0.792 mm | Standard Deviation 0.145 |
| Metformin | Change in Averaged Mean Far Wall Common Carotid Artery Intima-media Thickness (cIMT) | 12 Months | 0.782 mm | Standard Deviation 0.147 |
| Metformin | Change in Averaged Mean Far Wall Common Carotid Artery Intima-media Thickness (cIMT) | 36 Months | 0.793 mm | Standard Deviation 0.134 |
| Placebo | Change in Averaged Mean Far Wall Common Carotid Artery Intima-media Thickness (cIMT) | 36 Months | 0.820 mm | Standard Deviation 0.177 |
| Placebo | Change in Averaged Mean Far Wall Common Carotid Artery Intima-media Thickness (cIMT) | Baseline | 0.791 mm | Standard Deviation 0.183 |
| Placebo | Change in Averaged Mean Far Wall Common Carotid Artery Intima-media Thickness (cIMT) | 12 Months | 0.788 mm | Standard Deviation 0.174 |
| Placebo | Change in Averaged Mean Far Wall Common Carotid Artery Intima-media Thickness (cIMT) | 24 Months | 0.823 mm | Standard Deviation 0.187 |
Secondary
Change in Endothelial Function
In some centres (Arbitrary units) Reactive Hyperaemia Index using the ENDOPAT device (Itamar, Israel)
Time frame: Baseline, Year 1, Year 3
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Metformin | Change in Endothelial Function | Baseline | 2.28 RHI (Arbitrary units) | Standard Deviation 0.74 |
| Metformin | Change in Endothelial Function | 36 Months | 2.17 RHI (Arbitrary units) | Standard Deviation 0.69 |
| Placebo | Change in Endothelial Function | Baseline | 2.24 RHI (Arbitrary units) | Standard Deviation 0.75 |
| Placebo | Change in Endothelial Function | 36 Months | 2.24 RHI (Arbitrary units) | Standard Deviation 0.73 |
Secondary
Change in Estimated Glomerular Filtration Rate
Number of participants developing new microalbuminuria; change in absolute concentration Calculated using the MDRD equation1 based on creatinine measured in accredited local laboratories
Time frame: Baseline, Year 1, Year 2, Year 3
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Metformin | Change in Estimated Glomerular Filtration Rate | Baseline | 92.9 ml/min/1.73m2 | Standard Deviation 20.9 |
| Metformin | Change in Estimated Glomerular Filtration Rate | 36 Months | 92.1 ml/min/1.73m2 | Standard Deviation 20.8 |
| Placebo | Change in Estimated Glomerular Filtration Rate | Baseline | 91.1 ml/min/1.73m2 | Standard Deviation 21.6 |
| Placebo | Change in Estimated Glomerular Filtration Rate | 36 Months | 87.2 ml/min/1.73m2 | Standard Deviation 19.6 |
Secondary
Change in HbA1c
Measured in accredited local laboratories participating in DCCT-aligned quality control programmes.
Time frame: Baseline, Year 3
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Metformin | Change in HbA1c | Baseline | 8.1 %units | Standard Deviation 0.9 |
| Metformin | Change in HbA1c | 36 Months | 8.1 %units | Standard Deviation 0.9 |
| Placebo | Change in HbA1c | Baseline | 8.0 %units | Standard Deviation 0.8 |
| Placebo | Change in HbA1c | 36 Months | 8.1 %units | Standard Deviation 0.8 |
Secondary
Change in Insulin Dose
Units/ kg body weight Extracted by study nurses from the Study Diary and reported on the study CRF using dedicated fields
Time frame: Baseline, Year 1, Year 2, Year 3
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Metformin | Change in Insulin Dose | Baseline | 0.36 units/kg | Standard Deviation 0.26 |
| Metformin | Change in Insulin Dose | 36 Months | 0.62 units/kg | Standard Deviation 0.26 |
| Placebo | Change in Insulin Dose | 36 Months | 0.67 units/kg | Standard Deviation 0.3 |
| Placebo | Change in Insulin Dose | Baseline | 0.68 units/kg | Standard Deviation 0.3 |
Secondary
Change in LDL Cholesterol
mmol/L Centrally assayed at the University of Glasgow
Time frame: Baseline, Year 3
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Metformin | Change in LDL Cholesterol | Baseline | 2.23 mmol/L | Standard Deviation 0.7 |
| Metformin | Change in LDL Cholesterol | 36 Months | 2.07 mmol/L | Standard Deviation 0.83 |
| Placebo | Change in LDL Cholesterol | Baseline | 2.25 mmol/L | Standard Deviation 0.72 |
| Placebo | Change in LDL Cholesterol | 36 Months | 2.21 mmol/L | Standard Deviation 0.71 |
Secondary
Change in Weight
Measured at sites using calibrated weighing scales
Time frame: Baseline, Year 1, Year 2, Year 3
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Metformin | Change in Weight | Baseline | 83.9 kg | Standard Deviation 15.4 |
| Metformin | Change in Weight | 36 Months | 82.0 kg | Standard Deviation 15.4 |
| Placebo | Change in Weight | Baseline | 83.5 kg | Standard Deviation 13.7 |
| Placebo | Change in Weight | 36 Months | 83.2 kg | Standard Deviation 13.8 |
Secondary
Number of Participants With Retinopathy and at Least a 2 Stage Progression in Retinopathy From Baseline to 36 Months
Two color 45° field retinal photographs (fields 1 and 2) from each eye at 0 and 36 months graded at the University of Wisconsin Ocular Epidemiology Reading Center (OERC) using the modified Airlie House classification scheme and the Early Treatment Diabetic Retinopathy Severity scale.
Time frame: Baseline, Year 3
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Metformin | Number of Participants With Retinopathy and at Least a 2 Stage Progression in Retinopathy From Baseline to 36 Months | Baseline | 191 Participants |
| Metformin | Number of Participants With Retinopathy and at Least a 2 Stage Progression in Retinopathy From Baseline to 36 Months | 36 Months | 8 Participants |
| Placebo | Number of Participants With Retinopathy and at Least a 2 Stage Progression in Retinopathy From Baseline to 36 Months | Baseline | 190 Participants |
| Placebo | Number of Participants With Retinopathy and at Least a 2 Stage Progression in Retinopathy From Baseline to 36 Months | 36 Months | 10 Participants |