Diabetes Mellitus, Type 2
Conditions
Brief summary
The aim of the study is to investigate the longterm impact on cardiovascular morbidity, mortality and renal function of treatment with linagliptin in a selected population of patients with Type 2 diabetes mellitus (T2DM) and to compare outcomes against placebo, on a background of standard of care.
Interventions
DRUGPlacebo
placebo matching tablets
DRUGLinagliptin
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
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Documented diagnosis of T2DM before visit 1(screening). 2. Male or female patients who are drug-naïve or pre-treated with any antidiabetic background medication, excluding treatment with Glucagon-like Peptide 1 (GLP-1) receptor agonists, Dipeptidyl-peptidase 4 (DPP-4) inhibitors or Sodium Glucose Linked Transporter 2 (SGLT-2) inhibitors if =\> consecutive 7 days. 3. Stable antidiabetic background medication (unchanged daily dose) for at least 8 weeks prior to randomization. If insulin is part of the background therapy, the average daily insulin dose should not have changed by more than 10% within the 8 weeks prior to randomization compared with the daily insulin dose at randomization. 4. HbA1c of =\> 6.5% and \<= 10.0% at Visit 1 (screening) 5. Age =\> 18 years at Visit 1(screening). For Japan only: Age =\> 20 years at Visit 1 6. Body Mass Index (BMI) \<= 45 kg/m2 at Visit 1 (screening) 7. Signed and dated written informed consent by date of Visit 1(screening) in accordance with Good Clinical Practice (GCP) and local legislation prior to any study related procedure 8. High risk of cardiovascular (CV) events defined by: 1) albuminuria (micro or macro) and previous macrovascular disease and/or 2) impaired renal function with predefined Urine Albumin Creatinine Ratio (UACR)
Exclusion criteria
1. Type 1 diabetes mellitus. 2. Treatment (=\> 7 consecutive days) with GLP-1 receptor agonists, other DPP-4 inhibitors or SGLT-2 inhibitors prior to informed consent. Note: This also includes clinical trials where these antidiabetic drugs have been provided to the patient. 3. Active liver disease or impaired hepatic function, defined by serum levels of either Alanine Transaminase (ALT) (SGPT), Aspartate transaminase (AST) (SGOT), or alkaline phosphatase (AP) =\> 3 x upper limit of normal (ULN) as determined at Visit 1. 4. Estimated Glomerular filtration Rate (eGFR) \<15 ml/min/1.73 m2 (severe renal impairment or End Stage Renal Disease (ESRD), Modification of Diet in Renal Disease (MDRD) formula), as determined during screening at Visit 1 and/or the need for maintenance dialysis. 5. Any previous (or planned within next 12 months) bariatric surgery (open or laparoscopic) or intervention (gastric sleeve). 6. Pre-planned coronary artery re-vascularisation (PCI, CABG) or any previous PCI and/or CABG \<= 2 months prior informed consent. 7. Known hypersensitivity or allergy to the investigational products or its excipients. 8. Any previous or current alcohol or drug abuse that would interfere with trial participation in the opinion of the investigator. 9. Participation in another trial with an investigational drug ongoing or within 2 months prior to visit 1 (screening). 10. Pre-menopausal women (last menstruation = 1 year prior to informed consent) who are nursing or pregnant, are of child-bearing potential and are not practicing an acceptable method of birth control (acceptable methods of birth control include tubal ligation, transdermal patch, intra uterine devices/systems (IUDs/IUSs), oral, implantable or injectable contraceptives, sexual abstinence (if allowed by local authorities), double barrier method and vasectomised partner) or do not plan to continue using acceptable method of birth control throughout the study and do not agree to submit to periodic pregnancy testing during participation in the trial. 11. Patients considered unreliable by the investigator concerning the requirements for follow up during the study and/or compliance with study drug administration, have a life expectancy less than 5 years for non-CV causes, or have cancer other than non-melanoma skin cancer within last 3 years, or has any other condition than mentioned which in the opinion of the investigator, would not allow safe participation in the study. 12. Acute coronary syndrome (ACS), diagnosed \<= 2 months prior to visit 1 (screening). 13. Stroke or Transient Ischemic Attack (TIA) \<= 3 months prior to visit 1 (screening).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to the First Occurrence of Any of the Following Adjudication-confirmed Components of the Primary Composite Endpoint 3-point Major Adverse Cardiovascular (CV) Events (3-point MACE): CV Death, Non-fatal Myocardial Infarction (MI) or Non-fatal Stroke. | From randomization to individual end of observation; up to 4.3 years | Time to event analysis of patients with first occurrence of any of the following adjudication-confirmed components of the primary composite endpoint (3-point MACE): CV death, non-fatal MI or non-fatal stroke. The percentage of observed patients with first occurrence of any of the following adjudication-confirmed components of the primary composite endpoint (3-point MACE) was reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to the First Occurrence of Any of the Following Adjudication-confirmed Components: Renal Death, Sustained End Stage Renal Disease (ESRD), or Sustained Decrease of 40% or More in Estimated Glomerular Filtration Rate (eGFR). | From randomization to individual end of observation; up to 4.3 years | Time to the first occurrence of any of the following adjudication-confirmed components: renal death, sustained ESRD, or sustained decrease of 40% or more in eGFR. The percentage of observed patients with first occurrence of any of the following adjudication-confirmed components: renal death, sustained ESRD, or sustained decrease of 40% or more in eGFR was reported. |
Countries
Argentina, Brazil, Bulgaria, Canada, Chile, China, Colombia, Croatia, Czechia, Germany, Hungary, Israel, Japan, Malaysia, Mexico, Netherlands, Poland, Portugal, Romania, Russia, South Africa, South Korea, Spain, Taiwan, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Prior to initiation of any trial-related procedure, all patients were informed about the trial verbally and in writing by the investigator. The patients signed and dated the informed consent before any study related procedures.
Pre-assignment details
Patients with documented diagnosis of Type 2 Diabetes Mellitus (T2DM) at high risk of cardiovascular (CV) events and who met all the inclusion criteria and did not meet any of the exclusion criteria could be enrolled in the trial.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients were administered Placebo matching Linagliptin 5 mg film-coated tablet orally once daily.
At Visit 2, patients received one treatment box sufficient for 12 weeks treatment (plus 1 week reserve).
At Visit 3 (until trial end) patients received 2 medication boxes sufficient for 24 weeks treatment (plus 2 weeks reserve). | 3,485 |
| Linagliptin Patients were administered Linagliptin 5 milligram (mg) film-coated tablet orally once daily.
At Visit 2, patients received one treatment box sufficient for 12 weeks treatment (plus 1 week reserve).
At Visit 3 (until trial end) patients received 2 medication boxes sufficient for 24 weeks treatment (plus 2 weeks reserve). | 3,494 |
| Total | 6,979 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Discontinuation From Treatment | Adverse event/ CV outcome event | 402 | 362 |
| Discontinuation From Treatment | Non compliance | 24 | 15 |
| Discontinuation From Treatment | Not Treated | 7 | 5 |
| Discontinuation From Treatment | Other reason than specified | 196 | 176 |
| Discontinuation From Treatment | Withdrawal by Subject | 333 | 281 |
| Discontinuation From Trial | Not Treated | 7 | 5 |
| Discontinuation From Trial | Patient lost to follow-up for MACE | 55 | 36 |
Baseline characteristics
| Characteristic | Linagliptin | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 66.1 years STANDARD_DEVIATION 9.05 | 65.9 years STANDARD_DEVIATION 9.1 | 65.6 years STANDARD_DEVIATION 9.14 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1227 Participants | 2501 Participants | 1274 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2267 Participants | 4478 Participants | 2211 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 159 Participants | 315 Participants | 156 Participants |
| Race (NIH/OMB) Asian | 307 Participants | 640 Participants | 333 Participants |
| Race (NIH/OMB) Black or African American | 194 Participants | 411 Participants | 217 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 7 Participants | 17 Participants | 10 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2827 Participants | 5596 Participants | 2769 Participants |
| Sex: Female, Male Female | 1346 Participants | 2589 Participants | 1243 Participants |
| Sex: Female, Male Male | 2148 Participants | 4390 Participants | 2242 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 253 / 3,485 | 250 / 3,494 |
| other Total, other adverse events | 1,422 / 3,485 | 1,434 / 3,494 |
| serious Total, serious adverse events | 1,343 / 3,485 | 1,293 / 3,494 |
Outcome results
Primary
Time to the First Occurrence of Any of the Following Adjudication-confirmed Components of the Primary Composite Endpoint 3-point Major Adverse Cardiovascular (CV) Events (3-point MACE): CV Death, Non-fatal Myocardial Infarction (MI) or Non-fatal Stroke.
Time to event analysis of patients with first occurrence of any of the following adjudication-confirmed components of the primary composite endpoint (3-point MACE): CV death, non-fatal MI or non-fatal stroke. The percentage of observed patients with first occurrence of any of the following adjudication-confirmed components of the primary composite endpoint (3-point MACE) was reported.
Time frame: From randomization to individual end of observation; up to 4.3 years
Population: Treated set (TS): All patients treated with at least one dose of trial medication. If no trial medication was taken at site during the visit, but the medication kit was dispensed to the patient and not all trial medication was returned, the patient was included in the TS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to the First Occurrence of Any of the Following Adjudication-confirmed Components of the Primary Composite Endpoint 3-point Major Adverse Cardiovascular (CV) Events (3-point MACE): CV Death, Non-fatal Myocardial Infarction (MI) or Non-fatal Stroke. | 12.1 percentage of participants |
| Linagliptin | Time to the First Occurrence of Any of the Following Adjudication-confirmed Components of the Primary Composite Endpoint 3-point Major Adverse Cardiovascular (CV) Events (3-point MACE): CV Death, Non-fatal Myocardial Infarction (MI) or Non-fatal Stroke. | 12.4 percentage of participants |
Comparison: Cox proportional hazard regression model was performed to compare the effect of linagliptin versus placebo. Model included randomised treatment and geographical region as factors. Breslow's method was used for dealing with ties. First hypothesis (non-inferiority of the primary endpoint) was to be tested at the one-sided alpha-level of 2.5%. In case of significance the next set of hypotheses (two separate hypothesis tests) were to be tested with a sequentially rejective multiple test procedure.p-value: 0.000295% CI: [0.89, 1.17]Regression, Cox
Comparison: Cox proportional hazard regression model was performed to compare the effect of linagliptin versus placebo. Model included randomised treatment and geographical region as factors. Breslow's method was used for dealing with ties. First hypothesis (non-inferiority of the primary endpoint) was to be tested at the one-sided alpha-level of 2.5%. In case of significance the next set of hypotheses (two separate hypothesis tests) were to be tested with a sequentially rejective multiple test procedure.p-value: 0.630195% CI: [0.89, 1.17]Regression, Cox
Secondary
Time to the First Occurrence of Any of the Following Adjudication-confirmed Components: Renal Death, Sustained End Stage Renal Disease (ESRD), or Sustained Decrease of 40% or More in Estimated Glomerular Filtration Rate (eGFR).
Time to the first occurrence of any of the following adjudication-confirmed components: renal death, sustained ESRD, or sustained decrease of 40% or more in eGFR. The percentage of observed patients with first occurrence of any of the following adjudication-confirmed components: renal death, sustained ESRD, or sustained decrease of 40% or more in eGFR was reported.
Time frame: From randomization to individual end of observation; up to 4.3 years
Population: TS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to the First Occurrence of Any of the Following Adjudication-confirmed Components: Renal Death, Sustained End Stage Renal Disease (ESRD), or Sustained Decrease of 40% or More in Estimated Glomerular Filtration Rate (eGFR). | 8.8 percentage of participants |
| Linagliptin | Time to the First Occurrence of Any of the Following Adjudication-confirmed Components: Renal Death, Sustained End Stage Renal Disease (ESRD), or Sustained Decrease of 40% or More in Estimated Glomerular Filtration Rate (eGFR). | 9.4 percentage of participants |
Comparison: Cox proportional hazard regression model was performed to compare the effect of linagliptin versus placebo. Model included randomised treatment and geographical region as factors. Breslow's method was used for dealing with ties. First hypothesis (non-inferiority of the primary endpoint) was to be tested at the one-sided alpha-level of 2.5%. In case of significance the next set of hypotheses (two separate hypothesis tests) were to be tested with a sequentially rejective multiple test procedure.p-value: 0.691895% CI: [0.89, 1.22]Regression, Cox