title: Acute renal effects of the GLP-1 receptor agonist exenatide in overweight type 2 diabetes patients: a randomised, double-blind, placebo-controlled trial.
abstract: This study aimed to investigate the acute renal effects of the glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide in type 2 diabetes patients.
  
  
  
  We included overweight (BMI 25-40 kg/m(2)) men and postmenopausal women, aged 35-75 years with type 2 diabetes (HbA1c 48-75 mmol/mol; 6.5-9.0%) and estimated GFR ≥ 60 ml min(-1) 1.73 m(-2). Exenatide or placebo (NaCl solution, 154 mmol/l) was administrated intravenously in an acute, randomised, double-blind, placebo-controlled trial conducted at the Diabetes Center VU University Medical Center (VUMC). GFR (primary endpoint) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippurate clearance, respectively, based on timed urine sampling. Filtration fraction (FF) and effective renal vascular resistance (ERVR) were calculated, and glomerular hydrostatic pressure (PGLO) and vascular resistance of the afferent (RA) and efferent (RE) renal arteriole were estimated. Tubular function was assessed by absolute and fractional excretion of sodium (FENa), potassium (FEK) and urea (FEU), in addition to urine osmolality, pH and free water clearance. Renal damage markers, BP and plasma glucose were also determined.
  
  
  
  Of the 57 patients randomised by computer, 52 were included in the final analyses. Exenatide (n = 24) did not affect GFR (mean difference +2 ± 3 ml min(-1) 1.73 m(-2), p = 0.489), ERPF, FF, ERVR or PGLO, compared with placebo (n = 28). Exenatide increased RA (p < 0.05), but did not change RE. Exenatide increased FENa, FEK, urine osmolality and pH, while FEU, urinary flow and free water clearance were decreased (all p < 0.05). Osmolar clearance and renal damage makers were not affected. Diastolic BP and mean arterial pressure increased by 3 ± 1 and 6 ± 2 mmHg, respectively, whereas plasma glucose decreased by 1.4 ± 0.1 mmol/l (all p < 0.05).
  
  
  
  Exenatide infusion does not acutely affect renal haemodynamics in overweight type 2 diabetes patients at normal filtration levels. Furthermore, acute GLP-1RA administration increases proximal sodium excretion in these patients.
  
  
  
  ClincialTrials.gov NCT01744236 FUNDING : The research leading to these results has been funded from: (1) the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement number 282521 - the SAFEGUARD project; and (2) the Dutch Kidney Foundation, under grant agreement IP12.87.
authors.affiliation: Department of Internal Medicine/Diabetes Center, VU University Medical Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, the Netherlands. l.tonneijck@vumc.nl.
authors.forename: Lennart
authors.initials: L
authors.lastname: Tonneijck
authors.affiliation: Department of Internal Medicine/Diabetes Center, VU University Medical Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, the Netherlands.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Smits
authors.affiliation: Department of Internal Medicine/Diabetes Center, VU University Medical Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, the Netherlands.
authors.forename: Marcel H A
authors.initials: MHA
authors.lastname: Muskiet
authors.affiliation: Department of Health Sciences and the 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 Center, VU University Medical Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, the Netherlands.
authors.forename: Mark H H
authors.initials: MHH
authors.lastname: Kramer
authors.affiliation: Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors.forename: A H Jan
authors.initials: AHJ
authors.lastname: Danser
authors.affiliation: Department of Internal Medicine/Diabetes Center, VU University Medical Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, the Netherlands.
authors.forename: Michaela
authors.initials: M
authors.lastname: Diamant
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center, Utrecht, the Netherlands.
authors.forename: Jaap A
authors.initials: JA
authors.lastname: Joles
authors.affiliation: Department of Internal Medicine/Diabetes Center, VU University Medical Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, the Netherlands.
authors.forename: Daniël H
authors.initials: DH
authors.lastname: van Raalte
mesh_terms: D000328:Adult; D000368:Aged; D001794:Blood Pressure / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004311:Double-Blind Method; D000077270:Exenatide; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D000067757:Glucagon-Like Peptide-1 Receptor / Q000037:antagonists & inhibitors*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D050177:Overweight / Q000503:physiopathology; D010455:Peptides / Q000627:therapeutic use*; D015990:Placebo Effect; D014688:Venoms / Q000627:therapeutic use*
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; D000077270:Exenatide
keywords: Diabetes; Exenatide; GLP-1 receptor agonist; Glomerular filtration rate; Glomerular hyperfiltration; Glucagon-like peptide-1; Renal function; Renal haemodynamics; Type 2 diabetes