efficacy and safety of liraglutide in type 2 diabetes with lower extremity arterial disease

Conditions: Type 2 Diabetes; Peripheral Vascular Disorder Due to Diabetes Mellitus

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.

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.

Keywords: glucagon-like peptide-1 claudication peripheral vascular disease