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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
200
Liraglutide is available if pre-filled pens (6 mg/ml) as a solution for injection (Victoza®). One ml of solution contains 6 mg of Liraglutide (human glucagon-like peptide-1 analogue produced by recombinant DNA technology in Saccharomyces cerevisiae). One pre-filled pen contains 18 mg Liraglutide in 3 ml. Liraglutide is added to existing standard-of-care treatment containing one or more oral anti-hyperglycemic agents or insulin or a combination of these agents with the exception of other incretin and SGLT2i therapies in accordance with local clinical practice guidelines.
Standard-of-care treatment including: metformin should be given as the first line therapy as long as it is tolerated and not contraindicated; other agents, including sulfonylureas or glucosidase inhibitor or insulin, should be added to metformin .Glycemic control will be managed by the investigators in accordance with local clinical practice guidelines by the adjustment of concomitant glucose-lowering agents or the addition of new antidiabetic medications with the exception of incretin and SGLT2i therapies. This approach expect to yield similar glycemic control in the two study groups.
The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University
Wenzhou, Zhejiang, China
RECRUITINGInitial and absolute claudication distance
The primary outcome measures used to assess efficacy were pain-free walking distance (distance walked to the onset of symptoms, or the initial claudication distance \[ICD\]) and the maximum distance walked (absolute claudication distance \[ACD\]) on standardized treadmill testing. Evaluation of walking performance was accomplished with standardized treadmill testing. A constant speed of 3.2 km/h (2mile/h) and a fixed incline of 12.5% were used.
Time frame: 24 weeks
Assess the effects on ABI of a six month treatment with Liraglutide compared to control group (standard-of-care treatment).
ankle-brachial index is ratio of ankle systolic pressure to arm systolic pressure: using a 10-12 cm sphygmomanometer cuff placed just above the ankle and a doppler instrument used to measure the systolic pressure of the posterior tibial and dorsalis pedis arteries of each leg. These pressures are then normalized to the higher brachial pressure of either arm to form the ankle-brachial index (ABI). The index leg is often defined as the leg with the lower ABI.
Time frame: 24 weeks
Assess the effects on endothelial function of a six month treatment with Liraglutide compared to control group (standard-of-care treatment).
Assess the effects on endothelial function of a six month treatment with Liraglutide compared to conventional treatment, assessed as the baseline corrected change in endothelial function by flow-mediated vasodilation (FMD) of the brachial artery at 6 months.
Time frame: 24 weeks
Muscle microvascular perfusion by CEU
Contrast enhanced ultrasound (CEU) performed by experienced radiologists is used for contrast ultrasonographic examination of skeletal muscle.
Time frame: 24 weeks
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).
Circulating progenitor cells (EPCs) will be quantified using flow cytometry before and after 6 month treatment GLP-1 receptor agonist or conventional therapy (control group). Briefly, after erythrocyte lysis, peripheral blood will be stained with 10µL fluorescein isothiocyanate-conjugated anti-human CD34 mAb, 10µL phycoethrin-conjugated anti-human KDR mAb, and 10µL allophycocyanin-conjugated anti-CD133 mAb.
Time frame: 24 weeks
Changes from baseline in HbA1c
Change from baseline to last assessment during the treatment period in HbA1c
Time frame: 24 weeks
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