Diabetes Mellitus, Type 2
Conditions
Brief summary
The aim of the study is to investigate the longterm impact on cardiovascular morbidity and mortality, relevant efficacy parameters (e.g., glycaemic parameters) and safety (e.g., weight and hypoglycaemia) of treatment with linagliptin in patients with type 2 diabetes at elevated cardiovascular risk receiving usual care, and compare outcome against glimepiride.
Interventions
DRUGlinagliptin
linagliptin tablets 5mg QD
DRUGglimepiride
glimepiride over-encapsulated tablet 1-4 mg QD
linagliptin placebo
glimepiride placebo
Sponsors
Eli Lilly and Company
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Type 2 diabetes 2. Elevated glycosylated haemoglobin (HbA1c): 6.5 - 8.5%, inclusive, if treatment naïve or mono-/dual therapy with metformin and/or an alpha-glucosidase inhibitor; 6.5 - 7.5%, inclusive, if treatment with sulphonylurea/glinide in mono- or dual (with metformin OR an alpha-glucosidase inhibitor) therapy) 3. Pre-existing cardiovascular disease OR specified diabetes end-organ damage OR age =\> 70 years OR two or more specified cardiovascular risk factor 4. BMI =\< 45kg/m² 5. age between \>= 40 and =\< 85 years 6. signed and dated written International Conference of Harmonisation( ICF) 7. stable anti-diabetic background for at least 8 wks before study start
Exclusion criteria
1. Type 1 diabetes 2. Treatment with other antidiabetic drugs (e.g. rosiglitazone, pioglitazone, Glucagon-like peptide 1 (GLP-1) analogue/agonists, Dipeptidyl-peptidase IV (DPP-IV) inhibitors or any insulin) prior to informed consent (previous short term use of insulin (up to two weeks) is allowed if taken at least 8 weeks prior informed consent) 3. treatment with any anti-obesity drug less than 3 months before ICF 4. uncontrolled hyperglycemia 5. previous or planned bariatric surgery or intervention 6. current or planned system corticoid treatment 7. change in thyroid hormones treatment 8. acute liver disease or impaired hepatic function 9. pre-planned coronary artery revascularization within 6 months of ICF 10. known hypersensitivity to any of the components 11. Inappropriateness of glimepiride treatment for renal safety issues according to local prescribing information 12. congestive heart failure class III or IV 13. acute or chronic metabolic acidosis 14. hereditary galactose intolerance 15. alcohol or drug abuse 16. participation in another trail with IMP given 2 months before Investigational Medicinal/Medical Product (IMP) start 17. pre-menopausal women who are nursing or pregnant or of child-bearing potential and not willing to use acceptable method of birth control 18. patients considered reliable by the investigator 19. acute coronary syndrome =\< 6 wks before ICF 20. stroke or Transient Ischemic Attack (TIA) =\< 3 months prior to ICF
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The First 3-point Major Adverse Cardiovascular Events (3P-MACE) | From randomization until individual day of trial completion, up to 432 weeks | The first occurrence of any of the following Clinical Event Committee (CEC) confirmed adjudicated components of the primary composite endpoint: CV death (including fatal stroke and fatal myocardial infarction (MI)), non-fatal MI (excluding silent MI), or nonfatal stroke is presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Taking Trial Medication at Trial End, Maintained Glycaemic Control (HbA1c ≤7.0%) Without Need for Rescue Medication, Without >2% Weight Gain, and Without Moderate/Severe Hypoglycaemic Episodes During Maintenance Phase | From Visit 6 (Week 16) to Final visit (Week 432) (Maintenance Phase) | The second key secondary endpoint was a composite endpoint of treatment sustainability, defined as the percentage of patients taking trial medication at trial end, maintained glycaemic control (HbA1c ≤7.0%) without need for rescue medication, without \>2% weight gain, and without moderate/severe hypoglycaemic episodes during maintenance phase. |
| Percentage of Participants Who Were on Trial Medication at Trial End, Maintained Glycaemic Control (HbA1c ≤7.0%) Without Need for Rescue Medication, and Without >2% Weight Gain During Maintenance Phase | From Visit 6 (Week 16) to Final visit (Week 432) (Maintenance Phase) | The third key secondary endpoint was a composite endpoint of treatment sustainability, defined as percentage of patients who were on trial medication at trial end, maintained glycaemic control (HbA1c ≤7.0%) without need for rescue medication, and without \>2% weight gain during maintenance phase. |
| Percentage of Participants With the Occurrence of at Least One Event of 3P-MACE | From randomization until individual day of trial completion, up to 432 weeks | Percentage of participants occurrence of at least one of the following adjudicated components of CV death (including fatal stroke and fatal MI), non-fatal MI (excluding silent MI) and non-fatal stroke is presented as secondary CV endpoint. |
| Percentage of Participants With the Occurrence of at Least One Event of 4P -MACE | From randomization until individual day of trial completion, up to 432 weeks | Percentage of participants occurrence of at least one of the following adjudicated components of CV death (including fatal stroke and fatal MI), non-fatal MI (excluding silent MI), non-fatal stroke, and hospitalisation for unstable angina pectoris is presented as secondary CV endpoint. |
| Percentage of Participants With Occurrence of Any of the Components of the Composite Endpoint of All Adjudication-confirmed Events | From start of the treatment until 7 days after the end of treatment, up to 433 weeks | Percentage of participants with occurrence of any of the following components of the composite endpoint of all adjudication-confirmed events of: * CV death (including fatal stroke and fatal MI) * non-fatal MI * non-fatal stroke * hospitalisation for unstable angina pectoris * TIA * hospitalisation for heart failure * hospitalisation for coronary revascularisation procedures (CABG, PCI) |
| Time to First Occurrence of Any of the Components of the Composite Endpoint of All Adjudication-confirmed Events | From start of the treatment until 7 days after the end of treatment, up to 433 weeks | Time to first occurrence of any of the following components of the composite endpoint of all adjudication-confirmed events of: * CV death (including fatal stroke and fatal MI) * non-fatal MI * non-fatal stroke * hospitalisation for unstable angina pectoris * Transient ischaemic attack (TIA) * hospitalisation for heart failure * hospitalisation for coronary revascularisation procedures (CABG, PCI) |
| Change From Baseline to Final Visit in Hemoglobin A1c (HbA1c) | Baseline and week 432 | Change from baseline to final visit in HbA1c is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment. |
| Change From Baseline to Final Visit in Fasting Plasma Glucose (FPG) | Baseline and week 432 | Change from baseline to final visit in fasting plasma glucose (FPG) is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment. |
| Change From Baseline to Final Visit Fasting Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol and High-density Lipoprotein (HDL) Cholesterol | Baseline and week 432 | Change from baseline to final visit in total cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment. |
| The First 4-point (4P)- MACE | From randomization until individual day of trial completion, up to 432 weeks | The first key secondary endpoint was time to first occurrence of any of the following adjudicated components of the composite endpoint: CV death (including fatal stroke and fatal MI), non-fatal stroke, non-fatal MI (excluding silent MI), or hospitalisation for unstable angina pectoris. |
| Change From Baseline to Final Visit in Creatinine | Baseline and week 432 | Change from baseline to final visit in creatinine is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment. |
| Change From Baseline to Final Visit in Estimated Glomerular Filtration Rate (eGFR) | Baseline and week 432 | Change from baseline to final visit in eGFR is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment. |
| Change From Baseline to Final Visit in Urine Albumin Creatinine Ratio (UACR) | Baseline and week 432 | Change from baseline to final visit in UACR is presented as secondary diabetes-related endpoint. Least square mean is adjusted geometric mean (gMean) ratio. The Final Visit value referred to the last value obtained on-treatment. |
| Percentage of Participants With Transition in Albuminuria Classes | Baseline and week 432 | Percentage of patients with transition in albuminuria classes is presented as secondary endpoint. Data for last value on treatment (LVOT) to baseline (base) is presented. |
| Change From Baseline of Insulin Secretion Rate (ISR) at Fixed Glucose Concentration at 208 Weeks | Baseline and week 208 | The endpoint change from baseline of ISR at fixed glucose concentration at 208 weeks as derived from a 3-hour meal tolerance test is Beta-cell function sub-study endpoint. |
| Percentage of Participants With Occurrence of Accelerated Cognitive Decline at End of Follow-up | 433 weeks | Occurrence of accelerated cognitive decline based on regression based index (RBI) score at end of follow-up (a dichotomous outcome measure; presence or absence of accelerated cognitive decline) is Cognition sub-study endpoint. |
| Continuous Glucose Monitoring (CGM) Sub-study: Change From Baseline in the Inter-quartile Range of Diurnal Glucose Variability (Milligrams/ Deciliter) to End of Study | Baseline | Baseline data for the continuous glucose monitoring sub-study was collected and analyzed. However, the participant number was far less than original planned. The study was stopped early around week 64 (V9) due to recruitment issues and data were not pre-specified to be analyzed and reported at week 64 time point as target was with an estimated time point of 432 weeks for primary or secondary end points. Thus this endpoint was not analysed and only the baseline data collected were analysed and the results are reported in this CGM substudy endpoint. |
| CGM Sub-study : Change From Baseline in the Inter-quartile Range of Diurnal Glucose Variability (Millimoles/ Litre) to End of Study | Baseline | Baseline data for the continuous glucose monitoring sub-study was collected and analyzed. However, the participant number was far less than original planned. The study was stopped early around week 64 (V9) due to recruitment issues and data were not pre-specified to be analyzed and reported at week 64 time point as target was with an estimated time point of 432 weeks for primary or secondary end points. Thus this endpoint was not analysed and only the baseline data collected were analysed and the results are reported in this CGM substudy endpoint. |
| Change From Baseline to Final Visit in Triglycerides | Baseline and week 432 | Change from baseline to final visit in triglycerides is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment. |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Czechia, Finland, France, Georgia, Germany, Greece, Hong Kong, Hungary, India, Ireland, Israel, Italy, Japan, Malaysia, Mexico, Netherlands, New Zealand, Norway, Peru, Philippines, Portugal, Romania, Russia, Serbia, Slovakia, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Tunisia, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
This multicentre, multinational, randomised, double-blind, double-dummy, parallel group,comparator-controlled trial compared Linagliptin versus (vs.) Glimepiride, predominantly on metformin background treatment in participants with type 2 diabetes mellitus (T2DM) at elevated cardiovascular (CV) risk receiving usual care.
Pre-assignment details
All participants were screened for eligibility to participate in the trial. Participants attended specialist sites which would then ensure that all participants met all inclusion/exclusion criteria. Participants were not to be randomised to trial treatment if any one of the specific entry criteria were not met.
Participants by arm
| Arm | Count |
|---|---|
| Linagliptin After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of 5 milligram (mg) linagliptin plus 1 over-encapsulated tablet of placebo matching glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. | 3,023 |
| Glimepiride After 2-4 weeks placebo run-in phase, participants were administered 1 tablet of placebo matching linagliptin plus 1 over-encapsulated tablet of 1 to 4 mg glimepiride, which was uptitrated in 4-week intervals during the first 16 weeks of treatment to the next dose. Both doses were administered once daily orally up to an estimated 432 weeks treatment period. | 3,010 |
| Total | 6,033 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Discontinuation From Study (Treated Set) | Consent Withdrawn (Status Alive) | 49 | 37 |
| Discontinuation From Study (Treated Set) | Consent Withdrawn (Status Unknown) | 14 | 12 |
| Discontinuation From Study (Treated Set) | LostToFollowUpfor3P-MACE(StatusAlive) | 38 | 35 |
| Discontinuation From Study (Treated Set) | LostToFollowUpfor3P-MACE(StatusUnknown) | 8 | 8 |
| Discontinuation From Study (Treated Set) | Not treated | 5 | 4 |
| Discontinuation From Study (Treated Set) | Site Closure (Status Alive) | 15 | 22 |
| Discontinuation From Study (Treated Set) | Site Closure (Status Unknown) | 0 | 1 |
| Discontinuation From Treatment | Adverse Event | 457 | 523 |
| Discontinuation From Treatment | Lack of Efficacy | 61 | 41 |
| Discontinuation From Treatment | Lost to Follow-up | 24 | 28 |
| Discontinuation From Treatment | Not treated | 5 | 4 |
| Discontinuation From Treatment | Other than listed above | 230 | 211 |
| Discontinuation From Treatment | Protocol Violation | 46 | 47 |
| Discontinuation From Treatment | Withdrawal by Subject | 309 | 328 |
Baseline characteristics
| Characteristic | Glimepiride | Total | Linagliptin |
|---|---|---|---|
| Age, Continuous | 64.2 Years STANDARD_DEVIATION 9.5 | 64.0 Years STANDARD_DEVIATION 9.5 | 63.9 Years STANDARD_DEVIATION 9.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 513 Participants | 1032 Participants | 519 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2487 Participants | 4982 Participants | 2495 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 10 Participants | 19 Participants | 9 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 108 Participants | 214 Participants | 106 Participants |
| Race (NIH/OMB) Asian | 530 Participants | 1061 Participants | 531 Participants |
| Race (NIH/OMB) Black or African American | 169 Participants | 324 Participants | 155 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 3 Participants | 8 Participants | 5 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 10 Participants | 19 Participants | 9 Participants |
| Race (NIH/OMB) White | 2190 Participants | 4407 Participants | 2217 Participants |
| Sex: Female, Male Female | 1229 Participants | 2414 Participants | 1185 Participants |
| Sex: Female, Male Male | 1781 Participants | 3619 Participants | 1838 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 308 / 3,023 | 336 / 3,010 |
| other Total, other adverse events | 2,376 / 3,023 | 2,504 / 3,010 |
| serious Total, serious adverse events | 1,403 / 3,023 | 1,448 / 3,010 |
Outcome results
Primary
The First 3-point Major Adverse Cardiovascular Events (3P-MACE)
The first occurrence of any of the following Clinical Event Committee (CEC) confirmed adjudicated components of the primary composite endpoint: CV death (including fatal stroke and fatal myocardial infarction (MI)), non-fatal MI (excluding silent MI), or nonfatal stroke is presented.
Time frame: From randomization until individual day of trial completion, up to 432 weeks
Population: Treated set (TS): All patients treated with at least one dose of trial drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Linagliptin | The First 3-point Major Adverse Cardiovascular Events (3P-MACE) | 20.7 Events/ 1000 patients-years |
| Glimepiride | The First 3-point Major Adverse Cardiovascular Events (3P-MACE) | 21.2 Events/ 1000 patients-years |
p-value: <0.000195.47% CI: [0.84, 1.14]Regression, Cox
p-value: 0.381395.47% CI: [0.84, 1.14]Regression, Cox
Secondary
CGM Sub-study : Change From Baseline in the Inter-quartile Range of Diurnal Glucose Variability (Millimoles/ Litre) to End of Study
Baseline data for the continuous glucose monitoring sub-study was collected and analyzed. However, the participant number was far less than original planned. The study was stopped early around week 64 (V9) due to recruitment issues and data were not pre-specified to be analyzed and reported at week 64 time point as target was with an estimated time point of 432 weeks for primary or secondary end points. Thus this endpoint was not analysed and only the baseline data collected were analysed and the results are reported in this CGM substudy endpoint.
Time frame: Baseline
Population: The sub-study was stopped early and required target with an estimated time point of 432 weeks was not achieved for this endpoint. Thus the data were not unblinded and only the baseline data collected were reported overall and not by treatment arm for this endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Linagliptin | CGM Sub-study : Change From Baseline in the Inter-quartile Range of Diurnal Glucose Variability (Millimoles/ Litre) to End of Study | 2.45 Millimoles/ Litre (mmol/L) | Standard Deviation 0.7 |
Secondary
Change From Baseline of Insulin Secretion Rate (ISR) at Fixed Glucose Concentration at 208 Weeks
The endpoint change from baseline of ISR at fixed glucose concentration at 208 weeks as derived from a 3-hour meal tolerance test is Beta-cell function sub-study endpoint.
Time frame: Baseline and week 208
Population: Meal tolerance test(MTT) last observation carried forward(LOCF) set: Randomised and treated patients with one dose of study drug and signed the sub-study Informed Consent with valid baseline and on-treatment MTT. If values taken after rescue medication intake will be set to missing, last observed on-treatment value was carry forwarded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Linagliptin | Change From Baseline of Insulin Secretion Rate (ISR) at Fixed Glucose Concentration at 208 Weeks | 11.07 Picomol/ minute/meter^2 (pmol/min/m²) | Standard Error 15.07 |
| Glimepiride | Change From Baseline of Insulin Secretion Rate (ISR) at Fixed Glucose Concentration at 208 Weeks | 6.95 Picomol/ minute/meter^2 (pmol/min/m²) | Standard Error 13.76 |
p-value: 0.840295% CI: [-36.46, 44.71]ANCOVA
Secondary
Change From Baseline to Final Visit Fasting Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol and High-density Lipoprotein (HDL) Cholesterol
Change from baseline to final visit in total cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.
Time frame: Baseline and week 432
Population: TS w/o duplicates, participants on treatment
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Linagliptin | Change From Baseline to Final Visit Fasting Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol and High-density Lipoprotein (HDL) Cholesterol | LDL cholesterol | -6.1 mg/dL | Standard Error 0.6 |
| Linagliptin | Change From Baseline to Final Visit Fasting Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol and High-density Lipoprotein (HDL) Cholesterol | HDL cholesterol | 0.7 mg/dL | Standard Error 0.2 |
| Linagliptin | Change From Baseline to Final Visit Fasting Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol and High-density Lipoprotein (HDL) Cholesterol | Total cholesterol | -5.4 mg/dL | Standard Error 0.7 |
| Glimepiride | Change From Baseline to Final Visit Fasting Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol and High-density Lipoprotein (HDL) Cholesterol | LDL cholesterol | -6.5 mg/dL | Standard Error 0.6 |
| Glimepiride | Change From Baseline to Final Visit Fasting Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol and High-density Lipoprotein (HDL) Cholesterol | HDL cholesterol | 0.3 mg/dL | Standard Error 0.2 |
| Glimepiride | Change From Baseline to Final Visit Fasting Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol and High-density Lipoprotein (HDL) Cholesterol | Total cholesterol | -0.5 mg/dL | Standard Error 0.7 |
Comparison: LDL cholesterol, this was the fifth step in a pre-defined hierarchical testing approach.p-value: 0.6495.47% CI: [-1.3, 2.1]ANCOVA
Comparison: HDL cholesterol, this was the fifth step in a pre-defined hierarchical testing approach.p-value: 0.049795% CI: [0, 1]ANCOVA
Comparison: Total cholesterol, this was the fifth step in a pre-defined hierarchical testing approach.p-value: 0.682395% CI: [-2.4, 1.6]ANCOVA
Secondary
Change From Baseline to Final Visit in Creatinine
Change from baseline to final visit in creatinine is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.
Time frame: Baseline and week 432
Population: TS w/o duplicates, participants on treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Linagliptin | Change From Baseline to Final Visit in Creatinine | 0.08 mg/dL | Standard Error 0.01 |
| Glimepiride | Change From Baseline to Final Visit in Creatinine | 0.09 mg/dL | Standard Error 0.01 |
Comparison: This was the fifth step in a pre-defined hierarchical testing approach.p-value: 0.516595% CI: [-0.03, 0.01]ANCOVA
Secondary
Change From Baseline to Final Visit in Estimated Glomerular Filtration Rate (eGFR)
Change from baseline to final visit in eGFR is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.
Time frame: Baseline and week 432
Population: TS w/o duplicates, participants on treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Linagliptin | Change From Baseline to Final Visit in Estimated Glomerular Filtration Rate (eGFR) | -4.0 mL/minute/1.73 meter^2 | Standard Error 0.3 |
| Glimepiride | Change From Baseline to Final Visit in Estimated Glomerular Filtration Rate (eGFR) | -5.0 mL/minute/1.73 meter^2 | Standard Error 0.3 |
Comparison: This was the fifth step in a pre-defined hierarchical testing approach.p-value: 0.516595% CI: [0.2, 1.8]ANCOVA
Secondary
Change From Baseline to Final Visit in Fasting Plasma Glucose (FPG)
Change from baseline to final visit in fasting plasma glucose (FPG) is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.
Time frame: Baseline and week 432
Population: TS w/o duplicates considering all available data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Linagliptin | Change From Baseline to Final Visit in Fasting Plasma Glucose (FPG) | 12.4 Milligram/ deciliter (mg/dL) | Standard Error 0.9 |
| Glimepiride | Change From Baseline to Final Visit in Fasting Plasma Glucose (FPG) | 19.7 Milligram/ deciliter (mg/dL) | Standard Error 0.9 |
Comparison: This was the fifth step in a pre-defined hierarchical testing approach.p-value: <0.000195% CI: [-9.7, -4.8]ANCOVA
Secondary
Change From Baseline to Final Visit in Hemoglobin A1c (HbA1c)
Change from baseline to final visit in HbA1c is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.
Time frame: Baseline and week 432
Population: TS w/o duplicates considering all available data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Linagliptin | Change From Baseline to Final Visit in Hemoglobin A1c (HbA1c) | 0.06 Percentage glycosylated hemoglobin (%) | Standard Error 0.02 |
| Glimepiride | Change From Baseline to Final Visit in Hemoglobin A1c (HbA1c) | 0.15 Percentage glycosylated hemoglobin (%) | Standard Error 0.02 |
Comparison: This was the fifth step in a pre-defined hierarchical testing approach.p-value: 0.002395% CI: [-0.15, -0.03]ANCOVA
Secondary
Change From Baseline to Final Visit in Triglycerides
Change from baseline to final visit in triglycerides is presented as secondary diabetes-related endpoint. Least square mean is adjusted mean. The Final Visit value referred to the last value obtained on-treatment.
Time frame: Baseline and week 432
Population: TS w/o duplicates, participants on treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Linagliptin | Change From Baseline to Final Visit in Triglycerides | 1.7 mg/dL | Standard Error 2.2 |
| Glimepiride | Change From Baseline to Final Visit in Triglycerides | 5.2 mg/dL | Standard Error 2.2 |
Comparison: This was the fifth step in a pre-defined hierarchical testing approach.p-value: 0.267895% CI: [-9.6, 2.7]ANCOVA
Secondary
Change From Baseline to Final Visit in Urine Albumin Creatinine Ratio (UACR)
Change from baseline to final visit in UACR is presented as secondary diabetes-related endpoint. Least square mean is adjusted geometric mean (gMean) ratio. The Final Visit value referred to the last value obtained on-treatment.
Time frame: Baseline and week 432
Population: TS w/o duplicates, participants on treatment
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Linagliptin | Change From Baseline to Final Visit in Urine Albumin Creatinine Ratio (UACR) | 1.52 mg/ gcrea | Geometric Coefficient of Variation 1.83 |
| Glimepiride | Change From Baseline to Final Visit in Urine Albumin Creatinine Ratio (UACR) | 1.57 mg/ gcrea | Geometric Coefficient of Variation 1.83 |
Comparison: This was the fifth step in a pre-defined hierarchical testing approach.p-value: 0.292195% CI: [0.91, 1.03]ANCOVA
Secondary
Continuous Glucose Monitoring (CGM) Sub-study: Change From Baseline in the Inter-quartile Range of Diurnal Glucose Variability (Milligrams/ Deciliter) to End of Study
Baseline data for the continuous glucose monitoring sub-study was collected and analyzed. However, the participant number was far less than original planned. The study was stopped early around week 64 (V9) due to recruitment issues and data were not pre-specified to be analyzed and reported at week 64 time point as target was with an estimated time point of 432 weeks for primary or secondary end points. Thus this endpoint was not analysed and only the baseline data collected were analysed and the results are reported in this CGM substudy endpoint.
Time frame: Baseline
Population: The sub-study was stopped early and required target with an estimated time point of 432 weeks was not achieved for this endpoint. Thus the data were not unblinded and only the baseline data collected were reported overall and not by treatment arm for this endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Linagliptin | Continuous Glucose Monitoring (CGM) Sub-study: Change From Baseline in the Inter-quartile Range of Diurnal Glucose Variability (Milligrams/ Deciliter) to End of Study | 44.2 Milligrams/ deciliter (mg/ dL) | Standard Deviation 12.6 |
Secondary
Percentage of Participants Taking Trial Medication at Trial End, Maintained Glycaemic Control (HbA1c ≤7.0%) Without Need for Rescue Medication, Without >2% Weight Gain, and Without Moderate/Severe Hypoglycaemic Episodes During Maintenance Phase
The second key secondary endpoint was a composite endpoint of treatment sustainability, defined as the percentage of patients taking trial medication at trial end, maintained glycaemic control (HbA1c ≤7.0%) without need for rescue medication, without \>2% weight gain, and without moderate/severe hypoglycaemic episodes during maintenance phase.
Time frame: From Visit 6 (Week 16) to Final visit (Week 432) (Maintenance Phase)
Population: TS without duplicates (TS w/o duplicates), patients who are off-drug or died prior to regular study stop were handled as non-completers considered failure (NCF).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Linagliptin | Percentage of Participants Taking Trial Medication at Trial End, Maintained Glycaemic Control (HbA1c ≤7.0%) Without Need for Rescue Medication, Without >2% Weight Gain, and Without Moderate/Severe Hypoglycaemic Episodes During Maintenance Phase | 16.0 Percentage of participants (%) |
| Glimepiride | Percentage of Participants Taking Trial Medication at Trial End, Maintained Glycaemic Control (HbA1c ≤7.0%) Without Need for Rescue Medication, Without >2% Weight Gain, and Without Moderate/Severe Hypoglycaemic Episodes During Maintenance Phase | 10.2 Percentage of participants (%) |
p-value: <0.000195.47% CI: [1.43, 1.96]Regression, Logistic
Secondary
Percentage of Participants Who Were on Trial Medication at Trial End, Maintained Glycaemic Control (HbA1c ≤7.0%) Without Need for Rescue Medication, and Without >2% Weight Gain During Maintenance Phase
The third key secondary endpoint was a composite endpoint of treatment sustainability, defined as percentage of patients who were on trial medication at trial end, maintained glycaemic control (HbA1c ≤7.0%) without need for rescue medication, and without \>2% weight gain during maintenance phase.
Time frame: From Visit 6 (Week 16) to Final visit (Week 432) (Maintenance Phase)
Population: TS w/o duplicates (NCF)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Linagliptin | Percentage of Participants Who Were on Trial Medication at Trial End, Maintained Glycaemic Control (HbA1c ≤7.0%) Without Need for Rescue Medication, and Without >2% Weight Gain During Maintenance Phase | 17.4 Percentage of participants (%) |
| Glimepiride | Percentage of Participants Who Were on Trial Medication at Trial End, Maintained Glycaemic Control (HbA1c ≤7.0%) Without Need for Rescue Medication, and Without >2% Weight Gain During Maintenance Phase | 14.1 Percentage of participants (%) |
Comparison: This was the fifth step in a pre-defined hierarchical testing approach.p-value: 0.000495.47% CI: [1.11, 1.48]Regression, Logistic
Secondary
Percentage of Participants With Occurrence of Accelerated Cognitive Decline at End of Follow-up
Occurrence of accelerated cognitive decline based on regression based index (RBI) score at end of follow-up (a dichotomous outcome measure; presence or absence of accelerated cognitive decline) is Cognition sub-study endpoint.
Time frame: 433 weeks
Population: Full analysis set cognition(FAS-COG): Randomised and treated patients with one dose of study drug, baseline assessment (the z-scores, A\&E or Mini-mental state examination(MMSE) can be calculated), years of formal education with baseline MMSE≥24 and at least one on-treatment assessment (of which at least one of the RBI scores can be calculated).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Linagliptin | Percentage of Participants With Occurrence of Accelerated Cognitive Decline at End of Follow-up | 27.8 Percentage of participants (%) |
| Glimepiride | Percentage of Participants With Occurrence of Accelerated Cognitive Decline at End of Follow-up | 27.6 Percentage of participants (%) |
Comparison: This was the fifth step in a pre-defined hierarchical testing approach.p-value: 0.911295% CI: [0.86, 1.18]Regression, Logistic
Secondary
Percentage of Participants With Occurrence of Any of the Components of the Composite Endpoint of All Adjudication-confirmed Events
Percentage of participants with occurrence of any of the following components of the composite endpoint of all adjudication-confirmed events of: * CV death (including fatal stroke and fatal MI) * non-fatal MI * non-fatal stroke * hospitalisation for unstable angina pectoris * TIA * hospitalisation for heart failure * hospitalisation for coronary revascularisation procedures (CABG, PCI)
Time frame: From start of the treatment until 7 days after the end of treatment, up to 433 weeks
Population: TS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Linagliptin | Percentage of Participants With Occurrence of Any of the Components of the Composite Endpoint of All Adjudication-confirmed Events | 17.1 Percentage of participants (%) |
| Glimepiride | Percentage of Participants With Occurrence of Any of the Components of the Composite Endpoint of All Adjudication-confirmed Events | 17.8 Percentage of participants (%) |
Secondary
Percentage of Participants With the Occurrence of at Least One Event of 3P-MACE
Percentage of participants occurrence of at least one of the following adjudicated components of CV death (including fatal stroke and fatal MI), non-fatal MI (excluding silent MI) and non-fatal stroke is presented as secondary CV endpoint.
Time frame: From randomization until individual day of trial completion, up to 432 weeks
Population: TS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Linagliptin | Percentage of Participants With the Occurrence of at Least One Event of 3P-MACE | 11.8 Percentage of participants (%) |
| Glimepiride | Percentage of Participants With the Occurrence of at Least One Event of 3P-MACE | 12.0 Percentage of participants (%) |
Secondary
Percentage of Participants With the Occurrence of at Least One Event of 4P -MACE
Percentage of participants occurrence of at least one of the following adjudicated components of CV death (including fatal stroke and fatal MI), non-fatal MI (excluding silent MI), non-fatal stroke, and hospitalisation for unstable angina pectoris is presented as secondary CV endpoint.
Time frame: From randomization until individual day of trial completion, up to 432 weeks
Population: TS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Linagliptin | Percentage of Participants With the Occurrence of at Least One Event of 4P -MACE | 13.2 Percentage of participants (%) |
| Glimepiride | Percentage of Participants With the Occurrence of at Least One Event of 4P -MACE | 13.3 Percentage of participants (%) |
Secondary
Percentage of Participants With Transition in Albuminuria Classes
Percentage of patients with transition in albuminuria classes is presented as secondary endpoint. Data for last value on treatment (LVOT) to baseline (base) is presented.
Time frame: Baseline and week 432
Population: TS w/o duplicates, participants on treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Linagliptin | Percentage of Participants With Transition in Albuminuria Classes | Base(<30mg/gcrea)LVOT(>=30 to<=300mg/gcrea) | 14.1 Percentage of participants (%) |
| Linagliptin | Percentage of Participants With Transition in Albuminuria Classes | Base (>=30 to <=300 mg/gcrea) LVOT(>300 mg/gcrea) | 3.5 Percentage of participants (%) |
| Linagliptin | Percentage of Participants With Transition in Albuminuria Classes | Base (>=30 to <=300 mg/gcrea) LVOT(<30mg/gcrea) | 5.4 Percentage of participants (%) |
| Linagliptin | Percentage of Participants With Transition in Albuminuria Classes | Base (>300 mg/gcrea) LVOT (<30 mg/gcrea) | 0.1 Percentage of participants (%) |
| Linagliptin | Percentage of Participants With Transition in Albuminuria Classes | Base (<30 mg/gcrea) LVOT (>300 mg/gcrea) | 1.4 Percentage of participants (%) |
| Linagliptin | Percentage of Participants With Transition in Albuminuria Classes | Base (>300 mg/gcrea) LVOT(>=30 to<=300mg/gcrea) | 0.8 Percentage of participants (%) |
| Linagliptin | Percentage of Participants With Transition in Albuminuria Classes | Base(>=30to<=300mg/gcrea)LVOT(>=30to<=300mg/gcrea) | 12.7 Percentage of participants (%) |
| Linagliptin | Percentage of Participants With Transition in Albuminuria Classes | Base (>300 mg/gcrea) LVOT(>300 mg/gcrea) | 3.4 Percentage of participants (%) |
| Linagliptin | Percentage of Participants With Transition in Albuminuria Classes | Base (<30mg/gcrea) LVOT (<30mg/gcrea) | 58.4 Percentage of participants (%) |
| Glimepiride | Percentage of Participants With Transition in Albuminuria Classes | Base (>300 mg/gcrea) LVOT(>300 mg/gcrea) | 2.7 Percentage of participants (%) |
| Glimepiride | Percentage of Participants With Transition in Albuminuria Classes | Base (<30mg/gcrea) LVOT (<30mg/gcrea) | 57.7 Percentage of participants (%) |
| Glimepiride | Percentage of Participants With Transition in Albuminuria Classes | Base(<30mg/gcrea)LVOT(>=30 to<=300mg/gcrea) | 16.0 Percentage of participants (%) |
| Glimepiride | Percentage of Participants With Transition in Albuminuria Classes | Base (<30 mg/gcrea) LVOT (>300 mg/gcrea) | 1.4 Percentage of participants (%) |
| Glimepiride | Percentage of Participants With Transition in Albuminuria Classes | Base (>=30 to <=300 mg/gcrea) LVOT(<30mg/gcrea) | 5.1 Percentage of participants (%) |
| Glimepiride | Percentage of Participants With Transition in Albuminuria Classes | Base(>=30to<=300mg/gcrea)LVOT(>=30to<=300mg/gcrea) | 12.1 Percentage of participants (%) |
| Glimepiride | Percentage of Participants With Transition in Albuminuria Classes | Base (>=30 to <=300 mg/gcrea) LVOT(>300 mg/gcrea) | 3.7 Percentage of participants (%) |
| Glimepiride | Percentage of Participants With Transition in Albuminuria Classes | Base (>300 mg/gcrea) LVOT (<30 mg/gcrea) | 0.3 Percentage of participants (%) |
| Glimepiride | Percentage of Participants With Transition in Albuminuria Classes | Base (>300 mg/gcrea) LVOT(>=30 to<=300mg/gcrea) | 0.9 Percentage of participants (%) |
Secondary
The First 4-point (4P)- MACE
The first key secondary endpoint was time to first occurrence of any of the following adjudicated components of the composite endpoint: CV death (including fatal stroke and fatal MI), non-fatal stroke, non-fatal MI (excluding silent MI), or hospitalisation for unstable angina pectoris.
Time frame: From randomization until individual day of trial completion, up to 432 weeks
Population: TS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Linagliptin | The First 4-point (4P)- MACE | 23.4 Events/ 1000 patients-years |
| Glimepiride | The First 4-point (4P)- MACE | 23.7 Events/ 1000 patients-years |
p-value: 0.433495.47% CI: [0.86, 1.14]Regression, Cox
Secondary
Time to First Occurrence of Any of the Components of the Composite Endpoint of All Adjudication-confirmed Events
Time to first occurrence of any of the following components of the composite endpoint of all adjudication-confirmed events of: * CV death (including fatal stroke and fatal MI) * non-fatal MI * non-fatal stroke * hospitalisation for unstable angina pectoris * Transient ischaemic attack (TIA) * hospitalisation for heart failure * hospitalisation for coronary revascularisation procedures (CABG, PCI)
Time frame: From start of the treatment until 7 days after the end of treatment, up to 433 weeks
Population: TS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Linagliptin | Time to First Occurrence of Any of the Components of the Composite Endpoint of All Adjudication-confirmed Events | 31.1 Events/ 1000 patients-years |
| Glimepiride | Time to First Occurrence of Any of the Components of the Composite Endpoint of All Adjudication-confirmed Events | 32.4 Events/ 1000 patients-years |
Comparison: This was the fifth step in a pre-defined hierarchical testing approach.p-value: 0.524995% CI: [0.85, 1.09]Regression, Cox