Diabetes Mellitus, Type 2
Conditions
Brief summary
The general aim of the present study is to investigate the impact of 4 weeks treatment with linagliptin (5 mg) on endothelial function in patients with type 2 diabetes mellitus. In the current trial this effect of linagliptin treatment on endothelial function will be compared against both the sulfonylurea glimepiride and against placebo, which has not been tested in a trial before; as also is the case for other DPP-4 inhibitors. Besides placebo, glimepiride was chosen as a comparator, as it is one compound of the second most used oral antidiabetic drug class.
Interventions
DRUGPlacebo
Placebo matching Glimepiride
DRUGLinagliptin
given once daily for 28 days
DRUGGlimepiride
1 mg for 7 days followed by uptitration to 2 mg (given for following 21 days)
Sponsors
Eli Lilly and Company
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Type 2 diabetic male and female patients according to the following criteria: Based upon a complete medical history and clinical laboratory tests 2. Age \>= 18 and Age \<= 65 years 3. Body mass index \>= 25 \<= 35 kg/m2 4. HbA1c \<= 7.5% 5. Treatment with metformin (=1500 mg daily) for \<= 3 months 6. Signed and dated written informed consent prior to admission to the study in accordance with GCP and the local legislation. For female patients of childbearing potential: 7. Use of acceptable method of contraception (Pearl-Index \<1).
Exclusion criteria
1. Treatment with any glucose-lowering drug except for metformin within prior 3 months. 2. Any finding of the medical examination (including blood pressure, pulse rate and electrocardiogram) deviating from normal and of clinical relevance. 3. Any evidence of a clinically relevant acute concomitant disease 4. History of cardiovascular disease (e.g. coronary artery disease history of acute myocard infarction or stroke, peripheral vascular disease). 5. History of major diabetic complications (e.g. nephropathy, retinopathy) 6. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, immunological or hormonal disorders (except: hypertension treated with angiotensin receptor blocker or angiotensin-converting-enzyme inhibitors, hyperlipidemia with statin therapy, thyroid hormone replacement therapy, all stable for at least three months prior to screening). 7. Surgery of the gastrointestinal tract (except appendectomy). 8. Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders. 9. History of relevant orthostatic hypotension, fainting spells or blackouts. 10. Chronic or relevant acute infections. 11. History of relevant allergy/hypersensitivity (including allergy to drug or its excipients). 12. Intake of drugs with a long half-life (\> 24 hours) within at least one month or less than 10 half-lives of the respective drug prior to administration or during the trial. 13. Participation in another trial with an investigational drug within one month prior to administration or during the trial. 14. Smoker (\>= 1 cigarettes or \>= 1 cigars or \>= 1 pipes/day). 15. Alcohol abuse (more than 60 g/day). 16. Drug abuse. 17. Blood donation (more than 100 mL within four weeks prior to administration or during the trial). 18. Excessive physical activities (within one week prior to administration or during the trial). 19. Any laboratory value outside the reference range that is of clinical relevance.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Flow Mediated Vasodilation (FMD) Under Fasted Condition on Day 28 | baseline and day 28 for each treatment arm | Endothelial function under fasted condition was measured with flow mediated vasodilation (FMD). The change from baseline was calculated as the value on Day 28 divided by the respective value at baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Flow Mediated Vasodilation (FMD) 2 h Post Meal on Day 28 | baseline and day 28 for each treatment arm | Endothelial function 2 hours post meal was measured with flow mediated vasodilation (FMD). The change from baseline was calculated as the value on Day 28 divided by the respective value at baseline. |
| Change From Baseline in 2 Hours Post Meal Endothelial Independent Vasodilation (EIDV) on Day 28 | baseline and day 28 for each treatment arm | Endothelial function 2h post-meal was measured by endothelial independent vasodilation (EIDV). The change from baseline was calculated as the value on Day 28 divided by the respective value at baseline. |
| Number of Patients With Adverse Events | up to 20 weeks | Number of patients with any adverse events |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Total Participants All study participants | 42 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Period 1 Including Washout | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 1 |
| Period 2 Including Washout | Adverse Event | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Total Participants |
|---|---|
| Age, Continuous | 60.3 years STANDARD_DEVIATION 6 |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 40 | 20 / 41 | 9 / 40 |
| serious Total, serious adverse events | 0 / 40 | 0 / 41 | 0 / 40 |
Outcome results
Primary
Change From Baseline in Flow Mediated Vasodilation (FMD) Under Fasted Condition on Day 28
Endothelial function under fasted condition was measured with flow mediated vasodilation (FMD). The change from baseline was calculated as the value on Day 28 divided by the respective value at baseline.
Time frame: baseline and day 28 for each treatment arm
Population: Efficacy set (ES)- included all patients of the TS who provided at least 1 observation for at least 1 primary, secondary, or other efficacy endpoint without important protocol violations relevant for the statistical evaluation of these endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Linagliptin 5 mg | Change From Baseline in Flow Mediated Vasodilation (FMD) Under Fasted Condition on Day 28 | 0.885 percentage |
| Glimepiride 1-4 mg | Change From Baseline in Flow Mediated Vasodilation (FMD) Under Fasted Condition on Day 28 | 1.002 percentage |
| Placebo | Change From Baseline in Flow Mediated Vasodilation (FMD) Under Fasted Condition on Day 28 | 1.002 percentage |
p-value: 0.540390% CI: [0.633, 1.235]ANOVA
p-value: 0.540290% CI: [0.632, 1.235]ANOVA
p-value: 0.998990% CI: [0.715, 1.397]ANOVA
Secondary
Change From Baseline in 2 Hours Post Meal Endothelial Independent Vasodilation (EIDV) on Day 28
Endothelial function 2h post-meal was measured by endothelial independent vasodilation (EIDV). The change from baseline was calculated as the value on Day 28 divided by the respective value at baseline.
Time frame: baseline and day 28 for each treatment arm
Population: Efficacy set (ES)- included all patients of the TS who provided at least 1 observation for at least 1 primary, secondary, or other efficacy endpoint without important protocol violations relevant for the statistical evaluation of these endpoints.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Linagliptin 5 mg | Change From Baseline in 2 Hours Post Meal Endothelial Independent Vasodilation (EIDV) on Day 28 | 1.003 percentage |
| Glimepiride 1-4 mg | Change From Baseline in 2 Hours Post Meal Endothelial Independent Vasodilation (EIDV) on Day 28 | 1.053 percentage |
| Placebo | Change From Baseline in 2 Hours Post Meal Endothelial Independent Vasodilation (EIDV) on Day 28 | 0.981 percentage |
p-value: 0.298290% CI: [-0.13, 0.03]ANOVA
p-value: 0.660190% CI: [-0.059, 0.101]ANOVA
p-value: 0.141290% CI: [-0.009, 0.152]ANOVA
Secondary
Change From Baseline in Flow Mediated Vasodilation (FMD) 2 h Post Meal on Day 28
Endothelial function 2 hours post meal was measured with flow mediated vasodilation (FMD). The change from baseline was calculated as the value on Day 28 divided by the respective value at baseline.
Time frame: baseline and day 28 for each treatment arm
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Linagliptin 5 mg | Change From Baseline in Flow Mediated Vasodilation (FMD) 2 h Post Meal on Day 28 | 1.262 Percentage |
| Glimepiride 1-4 mg | Change From Baseline in Flow Mediated Vasodilation (FMD) 2 h Post Meal on Day 28 | 1.045 Percentage |
| Placebo | Change From Baseline in Flow Mediated Vasodilation (FMD) 2 h Post Meal on Day 28 | 1.009 Percentage |
p-value: 0.388590% CI: [0.84, 1.738]ANOVA
p-value: 0.310590% CI: [0.868, 1.801]ANOVA
p-value: 0.874990% CI: [0.721, 1.485]ANOVA
Secondary
Number of Patients With Adverse Events
Number of patients with any adverse events
Time frame: up to 20 weeks
Population: Treated set (TS)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Linagliptin 5 mg | Number of Patients With Adverse Events | 11 participants |
| Glimepiride 1-4 mg | Number of Patients With Adverse Events | 25 participants |
| Placebo | Number of Patients With Adverse Events | 14 participants |
| REP - Linagliptin 5 mg | Number of Patients With Adverse Events | 4 participants |
| REP - Glimepiride 1-4 mg | Number of Patients With Adverse Events | 7 participants |
| Rep - Placebo | Number of Patients With Adverse Events | 7 participants |