Efficacy and Safety of Liraglutide in Type 2 Diabetes With Lower Extremity Arterial Disease

Zhejiang University

Status and phase: Unknown; Phase 4

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

Treatments: Other: standard-of-care treatment; Drug: Liraglutide+standard-of-care treatment

Study type: Interventional

Funder types: Other

Identifiers

NCT04146155

zhengchao

Details and patient eligibility

About

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.

Full 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.

Enrollment: 200 estimated patients

Sex: All

Ages: 40+ years old

Volunteers: Accepts Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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200 participants in 2 patient groups

Liraglutide+standard-of-care treatment

Experimental group

Description:

Intervention: 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.

Treatment:

Drug: Liraglutide+standard-of-care treatment

standard-of-care treatment

Active Comparator group

Description:

standard-of-care treatment with the exception of incretin and SGLT2i therapies. This approach expect to yield similar glycemic control in the two study groups.

Treatment:

Other: standard-of-care treatment