title: Sustained influence of metformin therapy on circulating glucagon-like peptide-1 levels in individuals with and without type 2 diabetes.
abstract: To investigate, in the Carotid Atherosclerosis: Metformin for Insulin Resistance (CAMERA) trial (NCT00723307), whether the influence of metformin on the glucagon-like peptide (GLP)-1 axis in individuals with and without type 2 diabetes (T2DM) is sustained and related to changes in glycaemia or weight, and to investigate basal and post-meal GLP-1 levels in patients with T2DM in the cross-sectional Diabetes Research on Patient Stratification (DIRECT) study.
  
  
  
  CAMERA was a double-blind randomized placebo-controlled trial of metformin in 173 participants without diabetes. Using 6-monthly fasted total GLP-1 levels over 18 months, we evaluated metformin's effect on total GLP-1 with repeated-measures analysis and analysis of covariance. In the DIRECT study, we examined active and total fasting and 60-minute post-meal GLP-1 levels in 775 people recently diagnosed with T2DM treated with metformin or diet, using Student's t-tests and linear regression.
  
  
  
  In CAMERA, metformin increased total GLP-1 at 6 (+20.7%, 95% confidence interval [CI] 4.7-39.0), 12 (+26.7%, 95% CI 10.3-45.6) and 18 months (+18.7%, 95% CI 3.8-35.7), an overall increase of 23.4% (95% CI 11.2-36.9; P < .0001) vs placebo. Adjustment for changes in glycaemia and adiposity, individually or combined, did not attenuate this effect. In the DIRECT study, metformin was associated with higher fasting active (39.1%, 95% CI 21.3-56.4) and total GLP-1 (14.1%, 95% CI 1.2-25.9) but not post-meal incremental GLP-1. These changes were independent of potential confounders including age, sex, adiposity and glycated haemoglobin.
  
  
  
  In people without diabetes, metformin increases total GLP-1 in a sustained manner and independently of changes in weight or glycaemia. Metformin-treated patients with T2DM also have higher fasted GLP-1 levels, independently of weight and glycaemia.
authors.affiliation: MRC Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Health, University of Oxford, Oxford, UK.
authors.forename: David
authors.initials: D
authors.lastname: Preiss
authors.affiliation: Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, UK.
authors.forename: Adem
authors.initials: A
authors.lastname: Dawed
authors.affiliation: BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Welsh
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Heggie
authors.affiliation: NIHR Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, UK.
authors.forename: Angus G
authors.initials: AG
authors.lastname: Jones
authors.affiliation: Department of Epidemiology and Biostatistics, VU Medical Center, Amsterdam, The Netherlands.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Dekker
authors.affiliation: Department of Clinical Sciences, Genetic and Molecular Epidemiology, Lund University, Malmö, Sweden.
authors.forename: Robert
authors.initials: R
authors.lastname: Koivula
authors.affiliation: Section of Metabolic Genetics, Faculty of Health Sciences, Novo Nordisk Foundation Centre for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Tue H
authors.initials: TH
authors.lastname: Hansen
authors.affiliation: BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Stewart
authors.affiliation: Diabetes Trials Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
authors.forename: Rury R
authors.initials: RR
authors.lastname: Holman
authors.affiliation: Department of Clinical Sciences, Genetic and Molecular Epidemiology, Lund University, Malmö, Sweden.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Franks
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Walker
authors.affiliation: Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, University of Dundee, Dundee, UK.
authors.forename: Ewan R
authors.initials: ER
authors.lastname: Pearson
authors.affiliation: BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Naveed
authors.initials: N
authors.lastname: Sattar
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D004311:Double-Blind Method; D005215:Fasting / Q000378:metabolism; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000187:drug effects* / Q000378:metabolism; D006442:Glycated Hemoglobin / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D008875:Middle Aged; D010455:Peptides; D019518:Postprandial Period / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D036341:Intercellular Signaling Peptides and Proteins; D008687:Metformin; D010455:Peptides; C576018:CKGGRAKDC-GG-D(KLAKLAK)2; C517652:hemoglobin A1c protein, human
keywords: 
  GLP-1; antidiabetic drug; metformin