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

NCT ID: NCT04146155

Last Updated: 2021-07-07

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 200 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-05-01
• Study Completion Date: 2021-12-31

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.

Conditions

Type 2 Diabetes; Peripheral Vascular Disorder Due to Diabetes Mellitus

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Liraglutide+standard-of-care treatment

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.

Group Type: EXPERIMENTAL

Liraglutide+standard-of-care treatment

Intervention Type: DRUG

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

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.

Group Type: ACTIVE_COMPARATOR

standard-of-care treatment

Intervention Type: OTHER

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.

Interventions

Liraglutide+standard-of-care treatment

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.

Intervention Type: DRUG

standard-of-care treatment

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.

Intervention Type: OTHER

Other Intervention Names

Victoza

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.

• Minimum Eligible Age: 40 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Second Affiliated Hospital, School of Medicine, Zhejiang University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Chao Zheng, MD,PhD

Role: PRINCIPAL_INVESTIGATOR

the Second Affiliated Hospital Zhejiang University Schoolof Medicine

Youjin Pan, MD.

Role: PRINCIPAL_INVESTIGATOR

Second Affiliated Hospital of Wenzhou Medical University

Xia Li, MD,PhD

Role: PRINCIPAL_INVESTIGATOR

Central South University

Li Li, MD.

Role: PRINCIPAL_INVESTIGATOR

Ningbo Hospital of Zhejiang University

Locations

The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University

Wenzhou, Zhejiang, China

Site Status: RECRUITING

Countries

China

Central Contacts

Chao Zheng, MD, PhD

Role: CONTACT

wallbb_1022@163.com

8615057585907

Facility Contacts

Youjin Pan, MD.

Role: primary

526623800@qq.com

86057788002723

Mengte Shi, MD.

Role: backup

smt198853@163.com

86057788002713

References

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.

Reference Type: DERIVED

PMID: 34693515 (View on PubMed)

Other Identifiers

zhengchao

Identifier Type: -

Identifier Source: org_study_id