Diabetes, Diabetes Mellitus, Type 2
Conditions
Brief summary
This trial is conducted in Africa, Asia, Europe, and North and South America. The aim of this trial is to determine the long term effect of liraglutide on cardiovascular events in subjects with type 2 diabetes.
Interventions
DRUGliraglutide
Maximum dose of 1.8 mg liraglutide, injected subcutaneously (under the skin) once daily. Administered in addition to the subject's standard treatment
DRUGplacebo
Maximum dose of 1.8 mg placebo, injected subcutaneously (under the skin) once daily. Administered in addition to the subject's standard treatment
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
- Type 2 diabetes - Age min. 50 years at screening and concomitant cardiovascular, cerebrovascular or peripheral vascular disease or chronic renal failure or chronic heart failure OR age min. 60 years at screening and other specified risk factors of cardiovascular disease - HbA1c: 7.0% or above - Anti-diabetic drug naive or treated with one or more oral anti-diabetic drugs (OADs) or treated with human NPH insulin or long-acting insulin analogue or premixed insulin, alone or in combination with OAD(s)
Exclusion criteria
- Type 1 diabetes - Use of a glucagon-like peptide-1 (GLP-1) receptor agonist (exenatide, liraglutide or other) or pramlintide or any dipeptidyl peptidase 4 (DPP-4) inhibitor within the 3 months prior to screening (trial start) - Use of insulin other than human NPH insulin or long-acting insulin analogue or premixed insulin within 3 months prior to screening. Short-term use of other insulin during this period in connection with intercurrent illness is allowed, at Investigator's discretion
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time From Randomisation to First Occurrence of Cardiovascular Death, Non-fatal Myocardial Infarction, or Non-fatal Stroke (a Composite Cardiovascular Outcome) | from randomisation (visit 3; month 0) to last contact (visit 16; up to month 60+30 days) | Time from randomisation to first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (a composite cardiovascular outcome). The percentage of subjects experiencing a first event of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (a composite cardiovascular outcome) is presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time From Rand. to First Occurrence of an Expanded Composite Cardiovascular Outcome Defined as Either Cardiovascular Death, Non-fatal Myocardial Infarction, Non-fatal Stroke, Revascularisation, Hospitalisation for Unstable Angina or for Heart Failure. | from randomisation (visit 3; month 0) to last contact (visit 16; up to month 60+30 days) | Time from randomisation to first occurrence of an expanded composite cardiovascular outcome defined as either cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularisation, hospitalisation for unstable angina or for heart failure. The percentage of subjects experiencing first occurrence of an expanded composite cardiovascular outcome defined as either cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularisation, hospitalisation for unstable angina or for heart failure is presented. |
| Time From Randomisation to All Cause Death | from randomisation (visit 3; month 0) to last contact (visit 16; up to month 60+30 days) | Time from randomisation to all cause death. The percentage of subjects with a death by any cause (all-cause death) is presented. |
| Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome | from randomisation (visit 3; month 0) to last contact (visit 16; up to month 60+30 days) | Time from randomisation to each individual component of the expanded composite cardiovascular outcome. The percentage of subjects experiencing each of the individual component of the expanded composite cardiovascular outcome (defined as either cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularisation, hospitalisation for unstable angina or heart failure) is presented. |
| Time From Randomisation to First Occurrence of a Composite Microvascular Outcome | from randomisation (visit 3; month 0) to last contact (visit 16; up to month 60+30 days) | Time from randomisation to first occurrence of a composite microvascular outcome, defined as any one of the following: * new onset of persistent macroalbuminuria * persistent doubling of serum creatinine * need for continuous renal replacement therapy * death due to renal disease * need for retinal photocoagulation or treatment with intravitreal agents * vitreous haemorrhage * diabetes-related blindness The percentage of subjects experiencing a first occurrence of a composite microvascular outcome is presented. |
| Time From Randomisation to Each Individual Component of the Composite Microvascular Outcome and to the Retinopathy and Nephropathy Composite Outcomes Separately. | from randomisation (visit 3; month 0) to last contact (visit 16; up to month 60+30 days) | Time from randomisation to each individual component of the composite microvascular outcome and to the retinopathy and nephropathy composite outcomes separately. The percentage of subjects experiencing each individual component of the composite microvascular outcome are presented. |
Countries
Australia, Austria, Belgium, Brazil, Canada, China, Czechia, Denmark, Finland, France, Germany, Greece, India, Ireland, Israel, Italy, Mexico, Netherlands, Norway, Poland, Puerto Rico, Romania, Russia, Serbia, South Africa, South Korea, Spain, Sweden, Taiwan, Turkey (Türkiye), United Arab Emirates, United Kingdom, United States
Participant flow
Recruitment details
410 sites in 32 countries across the 4 regions recruited subjects. Number of sites that recruited subjects is given in parenthesis. Europe (143), North America (135) (US, Canada) , Asia (33) (China, Taiwan, Korea, India) and Rest of the world (99) (Brazil, Mexico, Australia, South Africa, Turkey, Russian Federation, United Arab Emirates).
Pre-assignment details
All subjects received placebo (0.6 mg/day) during the open labeled run-in period of 2-3 weeks and were instructed on how to administer the trial product. During this period the subjects demonstrated that they could adhere to the injection regimen in the trial.
Participants by arm
| Arm | Count |
|---|---|
| Liraglutide Subjects received liraglutide once daily by subcutaneous injection in the abdomen, thigh or upper arm, at any time of the day and irrespective of meals, for a treatment period of 42 to 60 months. It was recommended to keep the time of injection consistent from day to day. Liraglutide was initiated at a dose of 0.6 mg and up-titrated to 1.2 mg after 1 week and to 1.8 mg after one additional week up to 42-60 months. | 4,668 |
| Placebo Subjects received placebo (matched to liraglutide) daily by subcutaneous injection in the abdomen, thigh or upper arm, at any time of the day and irrespective of meals, for a treatment period of 42 to 60 months. It was recommended to keep the time of injection consistent from day to day. Placebo was initiated at a dose of 0.6 mg and up-titrated to 1.2 mg after 1 week and to 1.8 mg after one additional week up to 42-60 months. | 4,672 |
| Total | 9,340 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Alive | 127 | 142 |
| Overall Study | Lost to Follow-up | 8 | 9 |
| Overall Study | Withdrawn - does not allow contact | 4 | 8 |
Baseline characteristics
| Characteristic | Liraglutide | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 64.2 years STANDARD_DEVIATION 7.2 | 64.4 years STANDARD_DEVIATION 7.2 | 64.3 years STANDARD_DEVIATION 7.2 |
| Age, Customized 85 years and over | 17 Participants | 25 Participants | 42 Participants |
| Age, Customized Between 18 and 64 years | 2512 Participants | 2499 Participants | 5011 Participants |
| Age, Customized Between 65 to 84 years | 2139 Participants | 2148 Participants | 4287 Participants |
| Sex: Female, Male Female | 1657 Participants | 1680 Participants | 3337 Participants |
| Sex: Female, Male Male | 3011 Participants | 2992 Participants | 6003 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 684 / 4,668 | 210 / 4,672 |
| serious Total, serious adverse events | 2,320 / 4,668 | 2,354 / 4,672 |
Outcome results
Primary
Time From Randomisation to First Occurrence of Cardiovascular Death, Non-fatal Myocardial Infarction, or Non-fatal Stroke (a Composite Cardiovascular Outcome)
Time from randomisation to first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (a composite cardiovascular outcome). The percentage of subjects experiencing a first event of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (a composite cardiovascular outcome) is presented.
Time frame: from randomisation (visit 3; month 0) to last contact (visit 16; up to month 60+30 days)
Population: All randomised subjects.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Liraglutide | Time From Randomisation to First Occurrence of Cardiovascular Death, Non-fatal Myocardial Infarction, or Non-fatal Stroke (a Composite Cardiovascular Outcome) | 13.0 percentage of subjects |
| Placebo | Time From Randomisation to First Occurrence of Cardiovascular Death, Non-fatal Myocardial Infarction, or Non-fatal Stroke (a Composite Cardiovascular Outcome) | 14.9 percentage of subjects |
Comparison: The primary endpoint was evaluated using the Cox regression model to estimate the hazard ratio (HR) (liraglutide/placebo) and the 2-sided 95% confidence interval (CI) including treatment group as factor. Non-inferiority of liraglutide versus placebo was considered confirmed, if the upper limit of the two-sided 95% CI for the hazard ratio was below 1.3 or if the p-value for the one-sided test of H0: HR \>=1.3 against Ha: HR \<1.3 was less than 2.5% (or equivalent to 5% in two-sided test).p-value: <0.00195% CI: [0.778, 0.968]Regression, Cox
Comparison: If non-inferiority was established for the primary outcome, a test for superiority was performed. Superiority of liraglutide versus placebo was considered confirmed, if the upper limit of the two-sided 95% CI for the hazard ratio was below 1.0 or equivalent if the p-value for the one-sided test of H0: HR \>=1.0 against Ha: HR \<1.0 was less than 2.5% (or equivalent to 5% in two-sided test).p-value: 0.00595% CI: [0.778, 0.968]Regression, Cox
Secondary
Time From Randomisation to All Cause Death
Time from randomisation to all cause death. The percentage of subjects with a death by any cause (all-cause death) is presented.
Time frame: from randomisation (visit 3; month 0) to last contact (visit 16; up to month 60+30 days)
Population: All randomised subjects
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Liraglutide | Time From Randomisation to All Cause Death | 8.2 percentage of subjects |
| Placebo | Time From Randomisation to All Cause Death | 9.6 percentage of subjects |
95% CI: [0.739, 0.971]Regression, Cox
Secondary
Time From Randomisation to Each Individual Component of the Composite Microvascular Outcome and to the Retinopathy and Nephropathy Composite Outcomes Separately.
Time from randomisation to each individual component of the composite microvascular outcome and to the retinopathy and nephropathy composite outcomes separately. The percentage of subjects experiencing each individual component of the composite microvascular outcome are presented.
Time frame: from randomisation (visit 3; month 0) to last contact (visit 16; up to month 60+30 days)
Population: All randomised subjects
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Liraglutide | Time From Randomisation to Each Individual Component of the Composite Microvascular Outcome and to the Retinopathy and Nephropathy Composite Outcomes Separately. | New onset of persistent macroalbuminuria | 3.4 Percentage of subjects |
| Liraglutide | Time From Randomisation to Each Individual Component of the Composite Microvascular Outcome and to the Retinopathy and Nephropathy Composite Outcomes Separately. | Retinopathy composite | 2.3 Percentage of subjects |
| Liraglutide | Time From Randomisation to Each Individual Component of the Composite Microvascular Outcome and to the Retinopathy and Nephropathy Composite Outcomes Separately. | Need for continuous renal-replacement therapy | 1.2 Percentage of subjects |
| Liraglutide | Time From Randomisation to Each Individual Component of the Composite Microvascular Outcome and to the Retinopathy and Nephropathy Composite Outcomes Separately. | Treatment with photocoagulation/intravitreal agent | 2.1 Percentage of subjects |
| Liraglutide | Time From Randomisation to Each Individual Component of the Composite Microvascular Outcome and to the Retinopathy and Nephropathy Composite Outcomes Separately. | Persistent doubling of serum creatinine | 1.9 Percentage of subjects |
| Liraglutide | Time From Randomisation to Each Individual Component of the Composite Microvascular Outcome and to the Retinopathy and Nephropathy Composite Outcomes Separately. | Development of diabetes-related blindness | 0.0 Percentage of subjects |
| Liraglutide | Time From Randomisation to Each Individual Component of the Composite Microvascular Outcome and to the Retinopathy and Nephropathy Composite Outcomes Separately. | Death due to renal disease | 0.2 Percentage of subjects |
| Liraglutide | Time From Randomisation to Each Individual Component of the Composite Microvascular Outcome and to the Retinopathy and Nephropathy Composite Outcomes Separately. | Vitreous haemorrhage | 0.7 Percentage of subjects |
| Liraglutide | Time From Randomisation to Each Individual Component of the Composite Microvascular Outcome and to the Retinopathy and Nephropathy Composite Outcomes Separately. | Nephropathy composite | 5.7 Percentage of subjects |
| Placebo | Time From Randomisation to Each Individual Component of the Composite Microvascular Outcome and to the Retinopathy and Nephropathy Composite Outcomes Separately. | Vitreous haemorrhage | 0.5 Percentage of subjects |
| Placebo | Time From Randomisation to Each Individual Component of the Composite Microvascular Outcome and to the Retinopathy and Nephropathy Composite Outcomes Separately. | Nephropathy composite | 7.2 Percentage of subjects |
| Placebo | Time From Randomisation to Each Individual Component of the Composite Microvascular Outcome and to the Retinopathy and Nephropathy Composite Outcomes Separately. | New onset of persistent macroalbuminuria | 4.6 Percentage of subjects |
| Placebo | Time From Randomisation to Each Individual Component of the Composite Microvascular Outcome and to the Retinopathy and Nephropathy Composite Outcomes Separately. | Persistent doubling of serum creatinine | 2.1 Percentage of subjects |
| Placebo | Time From Randomisation to Each Individual Component of the Composite Microvascular Outcome and to the Retinopathy and Nephropathy Composite Outcomes Separately. | Need for continuous renal-replacement therapy | 1.4 Percentage of subjects |
| Placebo | Time From Randomisation to Each Individual Component of the Composite Microvascular Outcome and to the Retinopathy and Nephropathy Composite Outcomes Separately. | Death due to renal disease | 0.1 Percentage of subjects |
| Placebo | Time From Randomisation to Each Individual Component of the Composite Microvascular Outcome and to the Retinopathy and Nephropathy Composite Outcomes Separately. | Retinopathy composite | 2.0 Percentage of subjects |
| Placebo | Time From Randomisation to Each Individual Component of the Composite Microvascular Outcome and to the Retinopathy and Nephropathy Composite Outcomes Separately. | Treatment with photocoagulation/intravitreal agent | 1.8 Percentage of subjects |
| Placebo | Time From Randomisation to Each Individual Component of the Composite Microvascular Outcome and to the Retinopathy and Nephropathy Composite Outcomes Separately. | Development of diabetes-related blindness | 0.02 Percentage of subjects |
Comparison: Analysis for percentage of subjects experiencing a composite nephropathy event was done by Cox regression model with treatment as fixed factor.95% CI: [0.666, 0.918]Regression, Cox
Comparison: Analysis for percentage of subjects experiencing a new onset of persistant macroalbuminaria event was done by Cox regression model with treatment as fixed factor.95% CI: [0.602, 0.905]Regression, Cox
Comparison: Analysis for percentage of subjects experiencing persistent doubling of serum creatinine was done by Cox regression model with treatment as fixed factor.95% CI: [0.667, 1.189]Regression, Cox
Comparison: Analysis for percentage of subjects experiencing a need for continuous renal-replacement therapy was done by Cox regression model with treatment as fixed factor.95% CI: [0.607, 1.244]Regression, Cox
Comparison: Analysis for percentage of subjects experiencing death due to renal disease was done by Cox regression model with treatment as fixed factor.95% CI: [0.521, 4.869]Regression, Cox
Comparison: Analysis for percentage of subjects experiencing composite retinopathy was done by Cox regression model with treatment as fixed factor.95% CI: [0.869, 1.519]Regression, Cox
Comparison: Analysis for percentage of subjects experiencing treatment with photocoagulation or intravitreal agents was done by Cox regression model with treatment as fixed factor.95% CI: [0.869, 1.546]Regression, Cox
Comparison: Analysis for percentage of subjects experiencing development of diabetes-related blindness was done by Cox regression model with treatment as fixed factor.95% CI: [0.004, 30.847]Regression, Cox
Comparison: Analysis for percentage of subjects experiencing vitreous haemorrhage was done by Cox regression model with treatment as fixed factor.95% CI: [0.845, 2.502]Regression, Cox
Secondary
Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome
Time from randomisation to each individual component of the expanded composite cardiovascular outcome. The percentage of subjects experiencing each of the individual component of the expanded composite cardiovascular outcome (defined as either cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularisation, hospitalisation for unstable angina or heart failure) is presented.
Time frame: from randomisation (visit 3; month 0) to last contact (visit 16; up to month 60+30 days)
Population: All the randomised subjects.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Liraglutide | Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome | Cardiovascular death | 4.7 percentage of subjects |
| Liraglutide | Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome | Non-fatal stroke | 3.4 percentage of subjects |
| Liraglutide | Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome | Non-fatal myocardial infarction | 6.0 percentage of subjects |
| Liraglutide | Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome | Unstable angina pectoris (hospitalisation) | 2.6 percentage of subjects |
| Liraglutide | Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome | Coronary revascularisation | 8.7 percentage of subjects |
| Liraglutide | Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome | Heart failure (hospitalisation) | 4.7 percentage of subjects |
| Placebo | Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome | Coronary revascularisation | 9.4 percentage of subjects |
| Placebo | Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome | Cardiovascular death | 6.0 percentage of subjects |
| Placebo | Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome | Unstable angina pectoris (hospitalisation) | 2.7 percentage of subjects |
| Placebo | Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome | Non-fatal stroke | 3.8 percentage of subjects |
| Placebo | Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome | Heart failure (hospitalisation) | 5.3 percentage of subjects |
| Placebo | Time From Randomisation to Each Individual Component of the Expanded Composite Cardiovascular Outcome | Non-fatal myocardial infarction | 6.8 percentage of subjects |
Comparison: Analysis for percentage of subjects experiencing cardiovascular death was done by Cox regression model with treatment as fixed factor.95% CI: [0.656, 0.934]Regression, Cox
Comparison: Analysis for percentage of subjects experiencing non-fatal stroke was done by Cox regression model with treatment as fixed factor95% CI: [0.721, 1.107]Regression, Cox
Comparison: Analysis for percentage of subjects experiencing non-fatal myocardial infarction was done by Cox regression model with treatment as fixed factor95% CI: [0.747, 1.031]Regression, Cox
Comparison: Analysis for percentage of subjects experiencing hospitalisation for unstable angina pectoris was done by Cox regression model with treatment as fixed factor95% CI: [0.763, 1.258]Regression, Cox
Comparison: Analysis for percentage of subjects experiencing coronary revascularisation was done by Cox regression model with treatment as fixed factor95% CI: [0.797, 1.044]Regression, Cox
Comparison: Analysis for percentage of subjects experiencing hospitalisation for heart failure was done by Cox regression model with treatment as fixed factor95% CI: [0.727, 1.046]Regression, Cox
Secondary
Time From Randomisation to First Occurrence of a Composite Microvascular Outcome
Time from randomisation to first occurrence of a composite microvascular outcome, defined as any one of the following: * new onset of persistent macroalbuminuria * persistent doubling of serum creatinine * need for continuous renal replacement therapy * death due to renal disease * need for retinal photocoagulation or treatment with intravitreal agents * vitreous haemorrhage * diabetes-related blindness The percentage of subjects experiencing a first occurrence of a composite microvascular outcome is presented.
Time frame: from randomisation (visit 3; month 0) to last contact (visit 16; up to month 60+30 days)
Population: All randomised subjects.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Liraglutide | Time From Randomisation to First Occurrence of a Composite Microvascular Outcome | 7.6 Percentage of subjects |
| Placebo | Time From Randomisation to First Occurrence of a Composite Microvascular Outcome | 8.9 Percentage of subjects |
Comparison: Analysis for percentage of subjects experiencing a first microvascular event was done by Cox regression model with treatment as fixed factor.95% CI: [0.73, 0.969]Regression, Cox
Secondary
Time From Rand. to First Occurrence of an Expanded Composite Cardiovascular Outcome Defined as Either Cardiovascular Death, Non-fatal Myocardial Infarction, Non-fatal Stroke, Revascularisation, Hospitalisation for Unstable Angina or for Heart Failure.
Time from randomisation to first occurrence of an expanded composite cardiovascular outcome defined as either cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularisation, hospitalisation for unstable angina or for heart failure. The percentage of subjects experiencing first occurrence of an expanded composite cardiovascular outcome defined as either cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularisation, hospitalisation for unstable angina or for heart failure is presented.
Time frame: from randomisation (visit 3; month 0) to last contact (visit 16; up to month 60+30 days)
Population: All randomised subjects.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Liraglutide | Time From Rand. to First Occurrence of an Expanded Composite Cardiovascular Outcome Defined as Either Cardiovascular Death, Non-fatal Myocardial Infarction, Non-fatal Stroke, Revascularisation, Hospitalisation for Unstable Angina or for Heart Failure. | 20.3 percentage of subjects |
| Placebo | Time From Rand. to First Occurrence of an Expanded Composite Cardiovascular Outcome Defined as Either Cardiovascular Death, Non-fatal Myocardial Infarction, Non-fatal Stroke, Revascularisation, Hospitalisation for Unstable Angina or for Heart Failure. | 22.7 percentage of subjects |
95% CI: [0.807, 0.962]Regression, Cox