title: Metformin versus placebo in combination with insulin analogues in patients with type 2 diabetes mellitus-the randomised, blinded Copenhagen Insulin and Metformin Therapy (CIMT) trial.
abstract: OBJECTIVE
  To assess the effect of metformin versus placebo both in combination with insulin analogue treatment on changes in carotid intima-media thickness (IMT) in patients with type 2 diabetes.
  
  
  METHODS
  Investigator-initiated, randomised, placebo-controlled trial with a 2 × 3 factorial design conducted at eight hospitals in Denmark.
  
  
  METHODS
  412 participants with type 2 diabetes (glycated haemoglobin (HbA1c) ≥ 7.5% (≥ 58 mmol/mol); body mass index >25 kg/m2) were in addition to open-labelled insulin treatment randomly assigned 1:1 to 18 months blinded metformin (1 g twice daily) versus placebo, aiming at an HbA1c ≤ 7.0% (≤ 53 mmol/mol).
  
  
  RESULTS
  The primary outcome was change in the mean carotid IMT (a marker of subclinical cardiovascular disease). HbA1c, insulin dose, weight and hypoglycaemic and serious adverse events were other prespecified outcomes.
  
  
  RESULTS
  Change in the mean carotid IMT did not differ significantly between the groups (between-group difference 0.012 mm (95% CI -0.003 to 0.026), p=0.11). HbA1c was more reduced in the metformin group (between-group difference -0.42% (95% CI -0.62% to -0.23%), p<0.001)), despite the significantly lower insulin dose at end of trial in the metformin group (1.04 IU/kg (95% CI 0.94 to 1.15)) compared with placebo (1.36 IU/kg (95% CI 1.23 to 1.51), p<0.001). The metformin group gained less weight (between-group difference -2.6 kg (95% CI -3.3 to -1.8), p<0.001). The groups did not differ with regard to number of patients with severe or non-severe hypoglycaemic or other serious adverse events, but the metformin group had more non-severe hypoglycaemic episodes (4347 vs 3161, p<0.001).
  
  
  CONCLUSIONS
  Metformin in combination with insulin did not reduce carotid IMT despite larger reduction in HbA1c, less weight gain, and smaller insulin dose compared with placebo plus insulin. However, the trial only reached 46% of the planned sample size and lack of power may therefore have affected our results.
  
  
  BACKGROUND
  NCT00657943; Results.
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark Department of Endocrinology, Hvidovre, Copenhagen University Hospital, Hvidovre, Denmark Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark Department of Paediatrics, Hvidovre, Copenhagen University Hospital, Hvidovre, Denmark.
authors.forename: Louise
authors.initials: L
authors.lastname: Lundby-Christensen
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark Department of Cardiology, Nephrology and Endocrinology, Nordsjællands University Hospital-Hillerød, Hillerød, Denmark Department of Health, University of Aarhus, Denmark.
authors.forename: Lise
authors.initials: L
authors.lastname: Tarnow
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark.
authors.forename: Trine W
authors.initials: TW
authors.lastname: Boesgaard
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Ingelheim, Germany.
authors.forename: Søren S
authors.initials: SS
authors.lastname: Lund
authors.affiliation: Department of Physiology and Nuclear Medicine, Frederiksberg, Copenhagen University Hospital, Frederiksberg, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Wiinberg
authors.affiliation: Department of Endocrinology, Bispebjerg, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Hans
authors.initials: H
authors.lastname: Perrild
authors.affiliation: Department of Endocrinology, Bispebjerg, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Thure
authors.initials: T
authors.lastname: Krarup
authors.affiliation: Department of Endocrinology, Hvidovre, Copenhagen University Hospital, Hvidovre, Denmark.
authors.forename: Ole
authors.initials: O
authors.lastname: Snorgaard
authors.affiliation: Department of Endocrinology, Hvidovre, Copenhagen University Hospital, Hvidovre, Denmark.
authors.forename: Birthe
authors.initials: B
authors.lastname: Gade-Rasmussen
authors.affiliation: Department of Cardiology, Nephrology and Endocrinology, Nordsjællands University Hospital-Hillerød, Hillerød, Denmark University of Copenhagen, Copenhagen, Denmark.
authors.forename: Birger
authors.initials: B
authors.lastname: Thorsteinsson
authors.affiliation: Department of Cardiology, Nephrology and Endocrinology, Nordsjællands University Hospital-Hillerød, Hillerød, Denmark Department of Medicine, Gentofte, Copenhagen University Hospital, Hellerup, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Røder
authors.affiliation: Department of Endocrinology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Elisabeth R
authors.initials: ER
authors.lastname: Mathiesen
authors.affiliation: Department of Endocrinology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Tonny
authors.initials: T
authors.lastname: Jensen
authors.affiliation: University of Copenhagen, Copenhagen, Denmark Department of Endocrinology, Herlev, Copenhagen University Hospital, Herlev, Denmark The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Vestergaard
authors.affiliation: Department of Medicine, University Hospital Køge, Køge, Denmark.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Hedetoft
authors.affiliation: Department of Medicine, University Hospital Køge, Køge, Denmark.
authors.forename: Leif
authors.initials: L
authors.lastname: Breum
authors.affiliation: Department of Medicine, Gentofte, Copenhagen University Hospital, Hellerup, Denmark.
authors.forename: Elsebeth
authors.initials: E
authors.lastname: Duun
authors.affiliation: Department of Medicine, Gentofte, Copenhagen University Hospital, Hellerup, Denmark.
authors.forename: Simone B
authors.initials: SB
authors.lastname: Sneppen
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark University of Copenhagen, Copenhagen, Denmark The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.affiliation: Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark Department of Cardiology, Nephrology and Endocrinology, Nordsjællands University Hospital-Hillerød, Hillerød, Denmark.
authors.forename: Bianca
authors.initials: B
authors.lastname: Hemmingsen
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark.
authors.forename: Bendix
authors.initials: B
authors.lastname: Carstensen
authors.affiliation: Department of Endocrinology, Hvidovre, Copenhagen University Hospital, Hvidovre, Denmark University of Copenhagen, Copenhagen, Denmark.
authors.forename: Sten
authors.initials: S
authors.lastname: Madsbad
authors.affiliation: Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Gluud
authors.affiliation: Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Jørn
authors.initials: J
authors.lastname: Wetterslev
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark University of Copenhagen, Copenhagen, Denmark Department of Endocrinology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Allan
authors.initials: A
authors.lastname: Vaag
authors.affiliation: Department of Endocrinology, Hvidovre, Copenhagen University Hospital, Hvidovre, Denmark Department of Endocrinology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Almdal
mesh_terms: D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D059168:Carotid Intima-Media Thickness / Q000706:statistics & numerical data; D003718:Denmark; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D006442:Glycated Hemoglobin / Q000187:drug effects; D006801:Humans; D007003:Hypoglycemia / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000627:therapeutic use*; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin
keywords: ULTRASONOGRAPHY