title: Metformin in adults with type 1 diabetes: Design and methods of REducing with MetfOrmin Vascular Adverse Lesions (REMOVAL): An international multicentre trial.
abstract: Cardiovascular (CV) disease is a major cause of reduced life expectancy in type 1 diabetes (T1D). Intensive insulin therapy prevents CV complications but is constrained by hypoglycaemia and weight gain. Adjunct metformin reduces insulin dose requirement and stabilizes weight but there are no data on its cardiovascular effects. We have therefore initiated an international double-blind, randomized, placebo-controlled trial (REMOVAL: REducing with MetfOrmin Vascular Adverse Lesions in type 1 diabetes) to examine whether metformin reduces progression of atherosclerosis in adults with T1D. Individuals ≥40 years of age with T1D for ≥5 years are eligible if they have ≥3 of 10 specified CV risk factors. The enrolment target is 500 participants in 17 international centres.
  
  
  
  After 12 weeks of single-blind placebo-controlled run-in, participants with ≥ 70% adherence are randomized to metformin or matching placebo for 3 years with insulin titrated towards HbA1c 7.0% (53 mmol/mol). The primary endpoint is progression of averaged mean far wall common carotid intima-media thickness (cIMT) measured by ultrasonography at baseline, 12, 24 and 36 months. This design provides 90% power to detect a mean difference of 0.0167 mm in cIMT progression between treatment arms (α = 0.05), assuming that up to 20% withdraw or discontinue treatment. Other endpoints include HbA1c, weight, LDL cholesterol, insulin requirement, progression of retinopathy, endothelial function and frequency of hypoglycaemia.
  
  
  
  REMOVAL is the largest clinical trial of adjunct metformin therapy in T1D to date and will provide clinically meaningful information on its potential to impact CV disease and other complications.
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
authors.forename: John R
authors.initials: JR
authors.lastname: Petrie
authors.affiliation: Institute of Cardiovascular Science, University College London, London, UK.
authors.forename: Nish
authors.initials: N
authors.lastname: Chaturvedi
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Ford
authors.affiliation: St Joseph's Health Care, London, Ontario, Canada.
authors.forename: Irene
authors.initials: I
authors.lastname: Hramiak
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Alun D
authors.initials: AD
authors.lastname: Hughes
authors.affiliation: NHMRC Clinical Trials Centre, University of Sydney, Australia.
authors.forename: Alicia J
authors.initials: AJ
authors.lastname: Jenkins
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Barbara
authors.initials: B
authors.lastname: E Klein
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Ron
authors.initials: R
authors.lastname: Klein
authors.affiliation: Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, Canada.
authors.forename: Teik Chye
authors.initials: TC
authors.lastname: Ooi
authors.affiliation: Steno Diabetes Center and the University of Copenhagen, Copenhagen, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Rossing
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Naveed
authors.initials: N
authors.lastname: Sattar
authors.affiliation: Department of Internal Medicine and Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Coen D A
authors.initials: CD
authors.lastname: Stehouwer
authors.affiliation: Institute of Genetics and Molecular Medicine, University of Edinburgh, UK.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Colhoun
mesh_terms: D000328:Adult; D050197:Atherosclerosis / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D059168:Carotid Intima-Media Thickness; D008078:Cholesterol, LDL / Q000097:blood; D002985:Clinical Protocols; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000150:complications* / Q000188:drug therapy; D018450:Disease Progression; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006442:Glycated Hemoglobin / Q000187:drug effects; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007328:Insulin / Q000008:administration & dosage / Q000097:blood; D008297:Male; D008687:Metformin / Q000008:administration & dosage*; D008875:Middle Aged; D012307:Risk Factors; D016037:Single-Blind Method
chemical_list: D001786:Blood Glucose; D008078:Cholesterol, LDL; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin; C517652:hemoglobin A1c protein, human
keywords: adjunct therapy; cardiovascular; carotid intima media thickness; clinical trial; complications; endothelial function; hypoglycaemia metformin; type 1 diabetes; weight