title: Cardiovascular, renal and gastrointestinal effects of incretin-based therapies: an acute and 12-week randomised, double-blind, placebo-controlled, mechanistic intervention trial in type 2 diabetes.
abstract: BACKGROUND
  Incretin-based therapies, that is, glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors, are relatively novel antihyperglycaemic drugs that are frequently used in type 2 diabetes management. Apart from glucose-lowering, these agents exhibit pleiotropic actions that may have favourable and unfavourable clinical consequences. Incretin-based therapies have been associated with heart rate acceleration, heart failure, acute renal failure and acute pancreatitis. Conversely, these agents may reduce blood pressure, glomerular hyperfiltration, albuminuria and hepatic steatosis. While large-sized cardiovascular safety trials can potentially identify the clinical significance of some of these pleiotropic actions, small-sized mechanistic studies are important to understand the (patho)physiological rationale of these findings. The current protocol describes a mechanistic study to assess cardiovascular, renal and gastrointestinal effects, and mechanisms of incretin-based therapies in type 2 diabetes.
  
  
  METHODS
  60 patients with type 2 diabetes will undergo acute and prolonged randomised, double-blind, intervention studies. The acute intervention will consist of intravenous administration of the GLP-1 receptor agonist exenatide or placebo. For the prolonged intervention, patients will be randomised to 12-week treatment with the GLP-1 receptor agonist liraglutide, the DPP-4 inhibitor sitagliptin or matching placebos. For each examined organ system, a primary end point is defined. Primary cardiovascular end point is change in resting heart rate variability assessed by beat-to-beat heart rate monitor and spectral analyses software. Primary renal end point is change in glomerular filtration rate assessed by the classic inulin clearance methodology. Primary gastrointestinal end points are change in pancreatic exocrine function assessed by MRI-techniques (acute intervention) and faecal elastase-1 levels (12-week intervention). Secondary end points include systemic haemodynamics, microvascular function, effective renal plasma flow, renal tubular function, pancreatic volume and gallbladder emptying-rate.
  The study is approved by the local Ethics Review Board (VU University Medical Center, Amsterdam) and conducted in accordance with the Declaration of Helsinki and Good Clinical Practice.
  
  
  BACKGROUND
  NCT01744236.
authors.affiliation: Department of Internal Medicine, Diabetes Centre, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Mark M
authors.identifier: http://orcid.org/0000-0001-8236-8842
authors.initials: MM
authors.lastname: Smits
authors.affiliation: Department of Internal Medicine, Diabetes Centre, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Lennart
authors.initials: L
authors.lastname: Tonneijck
authors.affiliation: Department of Internal Medicine, Diabetes Centre, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Marcel H A
authors.initials: MH
authors.lastname: Muskiet
authors.affiliation: Department of Health Sciences, EMGO Institute for Health and Care Research, VU University Amsterdam, Amsterdam, The Netherlands Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Trynke
authors.initials: T
authors.lastname: Hoekstra
authors.affiliation: Department of Internal Medicine, Diabetes Centre, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Mark H H
authors.initials: MH
authors.lastname: Kramer
authors.affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Indra C
authors.initials: IC
authors.lastname: Pieters
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Djuna L
authors.initials: DL
authors.lastname: Cahen
authors.affiliation: Department of Internal Medicine, Diabetes Centre, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Michaela
authors.initials: M
authors.lastname: Diamant
authors.affiliation: Department of Internal Medicine, Diabetes Centre, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Daniël H
authors.initials: DH
authors.lastname: van Raalte
mesh_terms: D000328:Adult; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use; D004311:Double-Blind Method; D000077270:Exenatide; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects*; D006321:Heart / Q000187:drug effects*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D054795:Incretins / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects*; D000069450:Liraglutide / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000627:therapeutic use; D012107:Research Design; D000068900:Sitagliptin Phosphate / Q000627:therapeutic use; D016896:Treatment Outcome; D014688:Venoms / Q000627:therapeutic use
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D054795:Incretins; D010455:Peptides; D014688:Venoms; D000069450:Liraglutide; D000077270:Exenatide; D000068900:Sitagliptin Phosphate