Peripheral Arterial Disease, Type 2 Diabetes
Conditions
Keywords
Type 2 diabetes, Liraglutide, Transcutaneous Oxygen Tension, Peripheral arterial disease, Inflammation, Angiogenesis, Endothelial Dysfunction, Diabetic microvascular complications
Brief summary
STARDUST is an open-label, two-arm randomized controlled trial, aimed at evaluating the effects of liraglutide on peripheral perfusion, as compared with the aggressive treatment of cardio-metabolic risk factors, in people with type 2 diabetes and peripheral artery disease. The potential benefits for participants in the study include the possibility of improving peripheral perfusion with drugs that have been evaluated as effective in controlling diabetes and safe and protective for cardiovascular health. The primary outcome of the study is the change of peripheral transcutaneous oxygen tension between groups at three and six months. Participants in the study will be followed for 6 months in order to evaluate the effects of liraglutide and the change of other secondary outcomes.
Detailed description
An 18-month extension of the follow-up will be performed for all the study population, according to guidelines and good clinical practice. The follow-up will include the glyco-metabolic parameters and the main cardiovascular risk factors, including TcPO2 assessment. Data from this extended observation will be collected for additional analyses (mostly regarding the durability of the effects). Individuals who will be lost during follow-up and/or discontinue or modify the glucose-lowering treatment will be excluded from the analyses.
Interventions
DRUGLiraglutide
Patients in this arm will receive one daily subcutaneous injection of liraglutide. The starting dose is 0.6 mg/dl per day. The dose has to be increased to 1.2 mg/dl per day after the first week of treatment and to 1.8 mg/dl after the second one.
OTHERControl
Patients in this arm will be strictly monitored for atherosclerosis major risk factors, such as hypertension and dyslipidemia, and treated according to current clinical practice.
Sponsors
University of Campania Luigi Vanvitelli
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
35 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* diagnosis of type 2 diabetes within at least 6 months * peripheral arterial disease documented within al least 1 year by doppler ultrasound, angio-CT or arteriography * peripheral transcutaneous oxygen pressure between 30 and 49 mmHg on anterior and/or posterior tibial arteries * Hba1c 6,5-8% * treatment of diabetes with metformin, insulin and/or sulfonylurea
Exclusion criteria
* diagnosis of type 1 diabetes * current treatment with GLP-1 receptor agonists (GLP-1RAs) or dipeptidyl peptidase -4 (DPP-4) inhibitors * GLP-1RAs allergy or intolerance * participation to other clinical studies * history of pancreatitis, thyroid disease, diabetic gastroparesis or inflammatory bowel disease * current or planned pregnancy * acute myocardial infarction and/or acute cerebrovascular disease within 14 days from the screening visit * planned revascularization procedure * renal function with estimated glomerular filtration rate (eGFR) below 15 ml/min * history of cancer and/or oncological treatment within 5 years from the screening visit * current treatment with corticosteroids * psychiatric or other clinical conditions which may interfere with the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Peripheral Transcutaneous Oxygen Pressure | 6 months | Transcutaneous oxygen pressure (mmHg) on the lowest value recorded on anterior or posterior tibial artery after 6 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Glucose Control | 6 months | fasting glucose differences between groups |
| Weight Change | 6 months | Weight value at 6 months minus value at baseline |
| BMI Change | 6 months | BMI value at 6 months minus value at baseline |
| Waist Circumference Change | 6 months | Waist circumference value at 6 months minus value at baseline |
| Systolic Blood Pressure Change | 6 months | systolic blood pressure value at 6 months minus value at baseline |
| Lipid Profile | 6 months | total cholesterol after 6 months |
| C-reactive Protein (CRP) Change | 6 months | CRP value at 6 months minus value at baseline |
| HbA1c Glucose Control | 6 months | HbA1c values after 6 months |
| Estimated Glomerular Filtration Rate | 6 months | estimated glomerular filtration rate after 6 months |
| Angiogenesis | 6 months | vascular endothelial growth factor (VEGF) after 6 months |
| Ankle-brachial Index (ABI) Change | 6 months | ABI value after 6 months minus value at baseline ABI evaluation was obtained dividing the leg systolic pressure by the arm systolic pressure, both detected through a doppler probe and a sphygmomanometer. Normal ABI ranges from 1.0 to 1.4. ABI values above 1.4 suggest a noncompressible calcified vessel. ABI value below 0.9 is considered diagnostic of PAD. |
| Sexual Hormonal Profile | 6 months | Sexual hormone binding protein after 6 months |
| Male Sexual Function | 6 months | Erectile function (IIEF-5) score at 6 months Male patients will perform a self-assessment test (IIEF-5) of their erectile function and overall satisfaction with sexual life, referring to the previous 6 months. Erectile dysfunction (ED) will be classified based on the total questionnaire score. The highest score available is 25, the lowest is 0. Any score ranging from 25 and 22 refers to the absence of ED. Any score ≤ 21 will indicate the presence of ED \[mild (score 21-17), mild-moderate (score 16 -12), moderate (score 11-8) and severe (score 7-1)\]. The IIEF-5 questionnaire will be administered at visit 2 (week 0) and at the end of the study (week 24). |
| Female Sexual Function | 6 months | Female sexual function (FSFI) after 6 months Female sexual function will be studied through the FSFI questionnaire which assesses sexual activity over the past 4 weeks and includes 19 questions. The questionnaire will investigate six distinct domains (sexual desire, arousal, lubrication, orgasm, satisfaction and pain), and provide a total score indicative of global sexual function. Points are assigned for each answer (from 1 to 5 for 1-2 questions, from 0 to 5 for 3-19): the sum of the scores for each domain is multiplied by a domain factor (desire 0.6, arousal 0.3, lubrication 0.3 orgasm 0.4, satisfaction 0.4, pain 0.4). The six domain scores are added up, and the total score may vary from 2.0 to 36.0 points. A total FSFI score \< 26.55 will be used to classify the presence of female sexual dysfunction. The FSFI questionnaire will be administered at visit 2 (week 0) and at the end of the study (week 24). |
| 6-minute Walking Test | 6 months | 6-minutes walking distance after 6 months |
| Renal Function | 6 months | creatinine levels after 6 months |
Countries
Italy
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Liraglutide Group Patients in this arm will receive liraglutide, according to the current clinical practice.
Liraglutide: Patients in this arm will receive one daily subcutaneous injection of liraglutide. The starting dose is 0.6 mg/dl per day. The dose has to be increased to 1.2 mg/dl per day after the first week of treatment and to 1.8 mg/dl after the second one. | 27 |
| Control Group Patients in this arm will be strictly monitored with optimization of the therapy for atherosclerosis major risk factors.
Control: Patients in this arm will be strictly monitored for atherosclerosis major risk factors, such as hypertension and dyslipidemia, and treated according to current clinical practice. | 28 |
| Total | 55 |
Baseline characteristics
| Characteristic | Control Group | Liraglutide Group | Total |
|---|---|---|---|
| Age, Continuous | 65.0 years | 66 years | 65 years |
| Duration of diabetes | 10.0 years | 11.0 years | 10 years |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 6 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Male | 22 Participants | 21 Participants | 43 Participants |
| TcPO2 | 40.5 mmHg STANDARD_DEVIATION 5.7 | 40.0 mmHg STANDARD_DEVIATION 5.9 | 40.3 mmHg STANDARD_DEVIATION 5.8 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 27 | 0 / 28 |
| other Total, other adverse events | 0 / 27 | 0 / 28 |
| serious Total, serious adverse events | 0 / 27 | 0 / 28 |
Outcome results
Primary
Peripheral Transcutaneous Oxygen Pressure
Transcutaneous oxygen pressure (mmHg) on the lowest value recorded on anterior or posterior tibial artery after 6 months
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide Group | Peripheral Transcutaneous Oxygen Pressure | 54.2 mmHg | Standard Deviation 5.9 |
| Control Group | Peripheral Transcutaneous Oxygen Pressure | 43.4 mmHg | Standard Deviation 4.8 |
p-value: <0.00195% CI: [8, 14.5]t-test, 2 sided
p-value: <0.00195% CI: [1.26, 2.9]Chi-squared
Secondary
6-minute Walking Test
6-minutes walking distance after 6 months
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide Group | 6-minute Walking Test | 364 meters | Standard Deviation 13.7 |
| Control Group | 6-minute Walking Test | 340 meters | Standard Deviation 11.5 |
p-value: <0.00195% CI: [21.8, 28.3]t-test, 2 sided
Secondary
Angiogenesis
vascular endothelial growth factor (VEGF) after 6 months
Time frame: 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Liraglutide Group | Angiogenesis | 124 pg/mL |
| Control Group | Angiogenesis | 68.4 pg/mL |
p-value: <0.00195% CI: [59.9, 115.1]t-test, 2 sided
Secondary
Ankle-brachial Index (ABI) Change
ABI value after 6 months minus value at baseline ABI evaluation was obtained dividing the leg systolic pressure by the arm systolic pressure, both detected through a doppler probe and a sphygmomanometer. Normal ABI ranges from 1.0 to 1.4. ABI values above 1.4 suggest a noncompressible calcified vessel. ABI value below 0.9 is considered diagnostic of PAD.
Time frame: 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Liraglutide Group | Ankle-brachial Index (ABI) Change | 0.9 ratio |
| Control Group | Ankle-brachial Index (ABI) Change | 1 ratio |
p-value: 0.1895% CI: [-0.09, 0.01]t-test, 2 sided
Secondary
BMI Change
BMI value at 6 months minus value at baseline
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide Group | BMI Change | 28.7 Kg/m2 | Standard Deviation 4 |
| Control Group | BMI Change | 27.7 Kg/m2 | Standard Deviation 4.4 |
p-value: 0.195% CI: [-1.7, 0.1]t-test, 2 sided
Secondary
C-reactive Protein (CRP) Change
CRP value at 6 months minus value at baseline
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide Group | C-reactive Protein (CRP) Change | 0.5 mg/dL | Standard Deviation 0.5 |
| Control Group | C-reactive Protein (CRP) Change | 0.8 mg/dL | Standard Deviation 0.5 |
p-value: 0.0295% CI: [-0.7, -0.07]t-test, 2 sided
Secondary
Estimated Glomerular Filtration Rate
estimated glomerular filtration rate after 6 months
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide Group | Estimated Glomerular Filtration Rate | 71 mL/min/1.73 m^2 | Standard Deviation 18.4 |
| Control Group | Estimated Glomerular Filtration Rate | 74.7 mL/min/1.73 m^2 | Standard Deviation 13.4 |
p-value: 0.2595% CI: [-8.5, 2.3]t-test, 2 sided
Secondary
Female Sexual Function
Female sexual function (FSFI) after 6 months Female sexual function will be studied through the FSFI questionnaire which assesses sexual activity over the past 4 weeks and includes 19 questions. The questionnaire will investigate six distinct domains (sexual desire, arousal, lubrication, orgasm, satisfaction and pain), and provide a total score indicative of global sexual function. Points are assigned for each answer (from 1 to 5 for 1-2 questions, from 0 to 5 for 3-19): the sum of the scores for each domain is multiplied by a domain factor (desire 0.6, arousal 0.3, lubrication 0.3 orgasm 0.4, satisfaction 0.4, pain 0.4). The six domain scores are added up, and the total score may vary from 2.0 to 36.0 points. A total FSFI score \< 26.55 will be used to classify the presence of female sexual dysfunction. The FSFI questionnaire will be administered at visit 2 (week 0) and at the end of the study (week 24).
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide Group | Female Sexual Function | 20.4 score on a scale | Standard Deviation 1.4 |
| Control Group | Female Sexual Function | 21.2 score on a scale | Standard Deviation 1.3 |
Secondary
Glucose Control
fasting glucose differences between groups
Time frame: 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Liraglutide Group | Glucose Control | 118.5 mg/dL |
| Control Group | Glucose Control | 117 mg/dL |
p-value: 0.5295% CI: [-14.3, 7.4]t-test, 2 sided
Secondary
HbA1c Glucose Control
HbA1c values after 6 months
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide Group | HbA1c Glucose Control | 6.7 percentage of HbA1c | Standard Deviation 0.7 |
| Control Group | HbA1c Glucose Control | 6.8 percentage of HbA1c | Standard Deviation 0.8 |
p-value: 0.0695% CI: [-0.8, 0.01]t-test, 2 sided
Secondary
Lipid Profile
total cholesterol after 6 months
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide Group | Lipid Profile | 142.3 mg/dL | Standard Deviation 40.6 |
| Control Group | Lipid Profile | 158.8 mg/dL | Standard Deviation 55.1 |
p-value: 0.7295% CI: [-32.6, 22.9]t-test, 2 sided
Secondary
Male Sexual Function
Erectile function (IIEF-5) score at 6 months Male patients will perform a self-assessment test (IIEF-5) of their erectile function and overall satisfaction with sexual life, referring to the previous 6 months. Erectile dysfunction (ED) will be classified based on the total questionnaire score. The highest score available is 25, the lowest is 0. Any score ranging from 25 and 22 refers to the absence of ED. Any score ≤ 21 will indicate the presence of ED \[mild (score 21-17), mild-moderate (score 16 -12), moderate (score 11-8) and severe (score 7-1)\]. The IIEF-5 questionnaire will be administered at visit 2 (week 0) and at the end of the study (week 24).
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide Group | Male Sexual Function | 12.4 score on a scale | Standard Deviation 5.7 |
| Control Group | Male Sexual Function | 12.5 score on a scale | Standard Deviation 4.6 |
p-value: 0.0695% CI: [-0.09, 2.6]t-test, 2 sided
Secondary
Renal Function
creatinine levels after 6 months
Time frame: 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Liraglutide Group | Renal Function | 1 mg/dL |
| Control Group | Renal Function | 0.8 mg/dL |
p-value: 0.1295% CI: [-0.04, 0.3]t-test, 2 sided
Secondary
Sexual Hormonal Profile
Sexual hormone binding protein after 6 months
Time frame: 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Liraglutide Group | Sexual Hormonal Profile | 45 nmol/L |
| Control Group | Sexual Hormonal Profile | 49.5 nmol/L |
p-value: 0.0695% CI: [-0.6, 18.1]t-test, 2 sided
Secondary
Systolic Blood Pressure Change
systolic blood pressure value at 6 months minus value at baseline
Time frame: 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Liraglutide Group | Systolic Blood Pressure Change | 130 mmHg |
| Control Group | Systolic Blood Pressure Change | 130 mmHg |
p-value: 0.9995% CI: [-5.8, 5.8]t-test, 2 sided
Secondary
Waist Circumference Change
Waist circumference value at 6 months minus value at baseline
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide Group | Waist Circumference Change | 108.9 cm | Standard Deviation 10.3 |
| Control Group | Waist Circumference Change | 104.1 cm | Standard Deviation 11.6 |
p-value: 0.8195% CI: [-2.8, 3.5]t-test, 2 sided
Secondary
Weight Change
Weight value at 6 months minus value at baseline
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide Group | Weight Change | 78.5 Kg | Standard Deviation 14.4 |
| Control Group | Weight Change | 80.7 Kg | Standard Deviation 12.5 |
p-value: 0.3395% CI: [-3.6, 1.2]t-test, 2 sided