title: Dose response of continuous subcutaneous infusion of recombinant glucagon-like peptide-1 in combination with metformin and sulphonylurea over 12 weeks in patients with type 2 diabetes mellitus.
abstract: OBJECTIVE
  Any differences observed between natural glucagon-like peptide-1 (GLP-1) and studies obtained with analogues might call for renewed considerations concerning the use and design of such analogues. Thus, we aimed to evaluate the dose-response relationship of recombinant glucagon-like peptide-1 (7-36) amide (rGLP-1) administered by continuous subcutaneous infusion (CSCI) in subjects with type 2 diabetes.
  
  
  METHODS
  We compared the efficacy and safety of three doses of recombinant GLP-1, ranging from 1.25 to 5.0 pmol/kg/min (pkm) and placebo, given by continuous subcutaneous infusion over 3 months in combination with metformin and sulphonylurea (SU), to lower haemoglobin A1c (HbA1c), fasting plasma glucose and weight in 95 type 2 diabetes patients with inadequate glycaemic control.
  
  
  RESULTS
  The mean decreases in HbA1c at endpoint (week 12) were significantly greater for all three rGLP-1 dose groups when each was compared with the placebo group, with the greatest decrease occurring in the 5.0 pkm dose group (-1.3%, s.d. ± 0.18, p < 0.001). The mean decreases in fasting plasma glucose from baseline to endpoint were significantly greater for all three rGLP-1 dose groups than for the placebo group, with the greatest decrease occurring in the 5.0 pkm dose group (-26.0 mg/dl, s.d. ± 8.5, p = 0.02). Body weight was significantly reduced by 1.8 kg (s.d. ± 1.3) in the 1.25 pkm dose group only (p = 0.04).
  
  
  CONCLUSIONS
  Administration of rGLP-1 by CSCI over a 12-week period in combination with metformin and an SU had a dose dependent effect in lowering HbA1c and fasting plasma glucose. However, administration of rGLP-1 by CSCI may be less effective with respect to lowering of body weight compared with the daily and once weekly analogues.
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: S S
authors.initials: SS
authors.lastname: Torekov
authors.forename: J J
authors.initials: JJ
authors.lastname: Holst
authors.forename: M R
authors.initials: MR
authors.lastname: Ehlers
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives*; D006442:Glycated Hemoglobin / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D055104:Infusions, Subcutaneous; D008297:Male; D008687:Metformin / Q000008:administration & dosage*; D008875:Middle Aged; D013453:Sulfonylurea Compounds / Q000008:administration & dosage*; D013997:Time Factors
chemical_list: D001786:Blood Glucose; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008687:Metformin; D013453:Sulfonylurea Compounds; C517652:hemoglobin A1c protein, human
keywords: GLP-1; GLP-1 analogue; antidiabetic drug; antiobesity drug; clinical trial; dose-response relationship