The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men

Diabetologia. 2002 Feb;45(2):195-202. doi: 10.1007/s00125-001-0719-z.


Aims/hypothesis: Glucagon-like peptide-1 (GLP-1), a polypeptide hormone secreted by the l-cells in the gastrointestinal tract, has shown promising effects as a new treatment modality for patients with Type II (non-insulin-dependent) diabetes mellitus. However, the pharmacokinetic profile of native GLP-1 with a rapid elimination has limited its therapeutic potential. NN2211 is a fatty acid derivative of GLP-1, which pre-clinically has shown a protracted pharmacokinetic profile, while maintaining its biological activity. This study aimed to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of NN2211 in healthy male subjects following seven days treatment.

Methods: In a double-blind, randomized, dose escalation, placebo controlled study, healthy male subjects were enrolled at five consecutive dose levels of NN2211 (1.25, 5.0, 7.5, 10.0, 12.5 microg/kg). Six subjects were allocated at random at each dose level to active or placebo treatment with a ratio of 2:1. Dosing with NN2211 was performed on day 1, and days 5-11. The 84-h pharmacokinetics and 24-h glucose and insulin profiles were assessed on day 1 and day 11.

Results: Following s. c. administration the half-life of NN2211 was found to be 12.6 +/- 1.1 h, with a subsequent accumulation index after a daily dose for seven days of 1.4-1.5. There were dose-proportional increases in exposure (AUC and C(max)) with increasing doses. Overall, there were no statistically significant differences from placebo in the 24-h glucose and insulin profiles. In subjects treated with NN2211 rather than placebo, there was a higher incidence of adverse events, most notably dizziness and adverse events related to the gastrointestinal system. There were no serious adverse events but three subjects were nonetheless withdrawn because of dizziness, fever and nausea. There were no clinically relevant changes in vital signs, ECG parameters, physical examination or safety laboratory parameters. A significantly lower diuresis was observed in the actively treated subjects, without a clinically relevant change in packed cell volume.

Conclusions/interpretation: This study shows NN2211 has a pharmacokinetic profile supporting a daily dose in human beings, but also that subjects treated with NN2211 rather than placebo, had a higher incidence of adverse events, most notably dizziness and adverse events related to the gastrointestinal system.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Adult
  • Area Under Curve
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Glucagon / adverse effects
  • Glucagon / analogs & derivatives
  • Glucagon / pharmacokinetics
  • Glucagon / pharmacology*
  • Glucagon-Like Peptide 1
  • Humans
  • Liraglutide
  • Male
  • Middle Aged
  • Peptide Fragments / pharmacokinetics
  • Placebos
  • Protein Precursors / pharmacokinetics
  • Reference Values
  • Safety


  • Blood Glucose
  • Peptide Fragments
  • Placebos
  • Protein Precursors
  • Liraglutide
  • Glucagon-Like Peptide 1
  • Glucagon