Impact of Metformin on Peripheral Arterial Calcification in Type 1 Diabetes

NCT04583462 | Active Not Recruiting Phase 3

• 2 other identifiers: D201801022018-003121-29
• Study Type: interventional
• Target: 230
• Locations: 1 country
• Sites: 1

Brief Summary

Vascular calcification (VC) is a complication frequently observed in elderly, in chronic kidney disease (CKD) and in diabetes (particularly in type 1 diabetes). VC is a dynamic pathophysiological process that causes cardiovascular morbidity and is an independent risk factor of major amputation. In vitro and human observational studies have suggested a role of metformin in preventing VC. The investigators propose to test the effect of metformin treatment during two years on lower limb arterial calcification evaluated by CT-scan in patients with type 1 diabetes and without CKD. This research is a phase III double blind randomized controlled trial consisting of 2 years double-blind treatment phase (patients randomized to metformin or placebo) in type 1 diabetic patients. The participants and the investigators will be blinded to the study medications taken during the double-blind treatment period

Conditions

Type 1 Diabetes; Peripheral Arterial Calcification

Keywords

Metformin; Peripheral arterial calcification; Type 1 diabetes; Placebo

Outcome Measures

Primary Outcomes (1)

• Change between below-knee arterial calcification score evaluated by CT-scan at T0 and T2years in type 1 diabetic patients treated or not with metformin.

  Below-knee artery calcification scores will be obtained after scanning with a 128-slice multidetector CT scanner without contrast, in a craniocaudal direction, from the bottom of the patella down to the ankle region. The 3-mm cross-sectional slices were separately analyzed. Analysis was performed by radiologists kept blind about the results of the color duplex ultrasonography, laboratory tests, and clinical examinations, using a commercially available software package (Heartbeat CaScore; Philips Healthcare). On cross-sectional images, areas of calcification along below-knee arteries with a density ≥130 Hounsfield units attenuation and a surface \>1 mm2 were identified automatically. Calcification score, determined according to the method described by Agatston et al, will be obtained separately for each of the main below-knee arteries (distal popliteal, anterior tibial, posterior tibial, and peroneal arteries) and added up to obtain the calc

  Change between T0 baseline visit and T2 years

Secondary Outcomes (5)

• Change between below-knee arterial ultrasonographic occlusion score at T0 and T2years in type 1 diabetic patients treated or not with metformin.

  Change between T0 baseline visit and T2 years

• Change between ankle and toe brachial indexes at T0 and T2years in type 1 diabetic patients supplemented or not with metformin.

  Change between T0 baseline visit and T2 years

• Change between pulse wave velocity at T0 and T2years in type 1 diabetic patients supplemented or not with metformin.

  Change between T0 baseline visit and T2 years

• Change between coronary calcification score evaluated by CT-scan at T0 and T2years in type 1 diabetic patients treated or not with metformin.

  Change between T0 baseline visit and T2 years

• Change between below- knee arterial calcification score progression between T0 and T2years with initial below-knee arterial calcification score ≤ and >400 (subgroup analysis)

  Change between T0 baseline visit and T2 years

Study Arms (2)

Metformin

EXPERIMENTAL

Metformin, started at 500 mg per day per os and titrated up to 2000 mg during 2 years (increase of 500 mg every two weeks)

Drug: Metformin

Placebo

PLACEBO COMPARATOR

Placebo (coated tablet similar to metformin tablet titrated following the same schedule as in the experimental arm), started at 500 mg per day per os and titrated up to 2000 mg during 2 years (increase of 500 mg every two weeks)

Drug: Placebo

Interventions

Metformin DRUG

Metformin, started at 500 mg per day per os and titrated up to 2000 mg during 2 years (increase of 500 mg every two weeks)

Also known as: Metformine Arrow LAB 1000 mg

Metformin

Placebo DRUG

Control group : Placebo (coated tablet similar to metformin tablet titrated following the same schedule as in the experimental arm) started at 500 mg per day per os and titrated up to 2000 mg during 2 years (increase of 500 mg every two weeks)

Also known as: Control group

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Type 1 diabetes
• Women and Men ≥ 18 years old and ≤ 80 years old with:
• Complications: diabetic retinopathy and/or nephropathy (with creatinine clearance ≥ 60 mL/mn) and/or neuropathy and/or peripheral arterial occlusive disease and/or cardiopathy and/or stroke and/or
• cardiovascular risk factors : hypertension and/or dyslipidemia (HDL \< 0.35g/L or LDL \> 1.9g/L or treated dyslipidemia) and/or tobacco use (old or active smoking greater than 5 pack years) and/or
• Diabetes duration \>20 years
• For women in childbearing age, effective contraception during the whole trial
• Signed written informed consent
• Affiliation of a social security regime (AME excluded)

You may not qualify if:

• Known metformin contra-indication: severe liver insufficiency -CHILD B or C, heart failure (FEVG\<45%) or history of pulmonary edema, respiratory insufficiency with history of acute respiratory failure or patients receiving oxygen therapy, chronic ethylism, lactic acidosis
• Know sensitivity to metformin or to any of its excipients or placebo excipients (lactose)
• Indication or history of lower limb angioplasty (with stenting) and/or bypass
• HbA1c of less than 3 months \>11%
• Chronic inflammatory disease or chronic immune-suppressive drugs intake
• Pregnancy woman (confirmed by a sanguine beta-human chorionic gonadotropin test) or breastfeeding woman
• Patient under legal protection measure (tutorship or curatorship) or deprived of freedom
• Unable to consent

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

Pitié Salpêtrière Hospital, AP-HP, Diabetology department

Paris, 75013, France

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 1

Interventions

Metformin; Control Groups

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Epidemiologic Research Design; Epidemiologic Methods; Investigative Techniques; Research Design; Methods

Study Officials

• Olivier OB Bourron, Doctor

  Assistance Publique - Hôpitaux de Paris

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 5, 2020
• First Posted: October 12, 2020
• Study Start: June 2, 2021
• Primary Completion (Estimated): September 29, 2027
• Study Completion (Estimated): October 29, 2027
• Last Updated: November 24, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Beginning 3 months and ending 3 years following article publication. Requests out of these time frame can also be submitted to the sponsor
• Access Criteria: Researchers who provide a methodologically sound proposal.

Locations

FR (1)