Clinical trial NCT04146155: Efficacy and Safety of Liraglutide in Type 2 Diabetes With Lower Extremity Arterial Disease
Official title: Liraglutide Efficacy and Action on Type 2 Diabetes With Peripheral Atherosclerotic intErmittent Claudication (LEADPACE STUDY): a Prospective, 24-week, Multicenter, Randomized, Controlled Clinical Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Type 2 Diabetes
Peripheral Vascular Disorder Due to Diabetes Mellitus
Keywords: Glucagon-like peptide-1
Claudication
Peripheral vascular disease
Lead sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University
Sponsor class: OTHER
First posted: 2019-10-31
Enrollment: 200
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Diabetic lower extremity arterial disease ( DLEAD ), is a common complication of type 2 diabetes. However, DLEAD remains less studied than other diabetic vascular complications; and only few randomised controlled trials (RCTs) have dealt with major lower-limb adverse events as prespecified endpoints. Studies have suggested that glucagon-like peptide-1 (GLP-1) analogues have a protective effect on the development of atherosclerosis, potentially mediated via the GLP-1 receptors expressed on endothelial cells, smooth muscle cells, and in monocytes/macrophages. The investigators aim to evaluate the improvement of lower extremity ischemia in patients with type 2 diabetes mellitus complicated with lower limb vascular lesions after liraglutide, compared with the standard-of-care treatment group.

Detailed description: GLP-1 is an incretin hormone that mediates glucose-stimulated insulin secretion.Accumulating data from both animal and human studies confirmed a beneficial effect of GLP-1 on myocardium, endothelium and vasculature, suggesting the potential ameliorative effect of peripheral atherosclerosis. In our preliminary studies shown that liraglutide, a long-acting GLP-1R agonist (GLP1RA), stimulate endothelial proliferation and angiogenesis. The study aims to test the hypothesis that sustained activation of the GLP-1R enhances microvascular perfusion, promotes angiogenesis, leading to increased walking distance and limb perfusion in diabetes patients with peripheral arterial disease (PAD). Eligible patients will be randomized 1:1 to with or without liraglutide treatment by a 6-month follow-up. The primary endpoints are the change in initial and absolute claudication distance and assessment of limb ischemia at 6 months compared with baseline. This trial will collect important mechanistic and clinical information on the safety and efficacy of liraglutide in T2DM patients with PAD.

Eligibility criteria: Inclusion Criteria:

* Informed consent
* type 2 diabetes (1999 WHO criteria)
* 7.5≤HbA1c ≤14%
* Age \> 40 years
* lower extremity PAD with symptom
* Absence of distal arterial pulse.
* ABI less than 0.9 or the value decreased by more than 15% after treadmill test.
* Presence of stenosis or occlusion of lower extremity arteries as determined by Duplex ultrasound imaging or lower extremity CTA; or lower extremity DSA(Digital Substraction Angiography).

Exclusion Criteria:

* Type 1 diabetes
* Other Concomitant illness:

  1) poorly controlled hypertension: \>160 mmHg systolic blood pressure and/or\>100 mmHg diastolic blood pressure (with or without long-term oral antihypertensive drugs); 2) Chronic heart failure NYHA class (III-IV); 3) An acute coronary or cerebro-vascular event within the previous 6 months; 4) hematological malignancies such as acute or chronic myeloid leukemia, or any other hematological disorders that would interfere with the determination of circulating EPC levels; 5) Personal history of non-familial medullary thyroid carcinoma; 6) Immunological disorders such as lupus, psoriasis, scleroderma and rheumatoid arthritis which would interfere with the determination of circulating EPC levels; 7) Chronic haemodialysis or chronic peritoneal dialysis; 8) End stage liver disease, presence of acute or chronic liver disease or recent history of the following: ALT level ≥ 3 times the upper limit of normal, or AST level ≥ 3 times the upper limit of normal; 9) Severe gastrointestinal diseases, such as gastrointestinal ulcer, gastrointestinal bleeding, pyloric stenosis, gastric bypass surgery; 10) History of chronic pancreatitis or idiopathic acute pancreatitis; 11) Any acute condition or exacerbation of chronic condition that would in the Investigator's opinion interfere with the initial trial visit schedule and procedures; 12) Inability to walk on a tredamill without grade at a speed of at least 3.2 km/h for at least 2 minutes.
* Drugs: 1) Known or suspected hypersensitivity to trial products or related products ; 2) Use of GLP-1 receptor agonist (exenatide (BID or OW), liraglutide, or other) within 6 months prior to screening; 3).Alcohol or drugs abuse.
* 4. Acute decompensation of glycaemic control requiring immediate intensification of treatment to prevent acute complications of diabetes (eg diabetes ketoacidosis) within 90 days prior to screening.
* Recent (within 6 months) surgery or trauma.
* Pregnancy and lactation.
* Psychiatric disorders
* Simultaneous participation in any other clinical trial of an investigational agent.

Primary outcomes:
measure: Initial and absolute claudication distance
timeFrame: 24 weeks
Secondary outcomes:
measure: Assess the effects on ABI of a six month treatment with Liraglutide compared to control group (standard-of-care treatment).
timeFrame: 24 weeks
measure: Assess the effects on endothelial function of a six month treatment with Liraglutide compared to control group (standard-of-care treatment).
timeFrame: 24 weeks
measure: Muscle microvascular perfusion by CEU
timeFrame: 24 weeks
measure: Assess the effects on the endothelial circulating progenitor cells concentration of a six month treatment with Liraglutide compared to control group (standard-of-care treatment).
timeFrame: 24 weeks
measure: Changes from baseline in HbA1c
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Wenzhou
country: China
facility: The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University
state: Zhejiang
Study officials:
affiliation: the Second Affiliated Hospital Zhejiang University Schoolof Medicine
name: Chao Zheng, MD,PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Second Affiliated Hospital of Wenzhou Medical University
name: Youjin Pan, MD.
role: PRINCIPAL_INVESTIGATOR
affiliation: Central South University
name: Xia Li, MD,PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ningbo Hospital of Zhejiang University
name: Li Li, MD.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kanie T, Mizuno A, Takaoka Y, Suzuki T, Yoneoka D, Nishikawa Y, Tam WWS, Morze J, Rynkiewicz A, Xin Y, Wu O, Providencia R, Kwong JS. Dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists and sodium-glucose co-transporter-2 inhibitors for people with cardiovascular disease: a network meta-analysis. Cochrane Database Syst Rev. 2021 Oct 25;10(10):CD013650. doi: 10.1002/14651858.CD013650.pub2.