Bedtime Administration of NN2211, a Long-Acting GLP-1 Derivative, Substantially Reduces Fasting and Postprandial Glycemia in Type 2 Diabetes

  1. Claus B. Juhl1,
  2. Malene Hollingdal1,
  3. Jeppe Sturis2,
  4. Grethe Jakobsen2,
  5. Henrik Agersø2,
  6. Johannes Veldhuis3,
  7. Niels Pørksen1 and
  8. Ole Schmitz14
  1. 1Medical Department M (Endocrinology and Diabetes), Århus University Hospital, Århus, Denmark
  2. 2Novo Nordisk A/S, Bagsværd, Denmark
  3. 3Department of Medicine, General Clinical Research Center and Center for Biometrical Technology, University of Virginia, Charlottesville, Virginia
  4. 4Institute of Clinical Pharmacology, University of Århus, Århus, Denmark

    Abstract

    Glucagon-like peptide 1 (GLP-1) is a potent glucose-lowering agent of potential interest for the treatment of type 2 diabetes. To evaluate actions of NN2211, a long-acting GLP-1 derivative, we examined 11 patients with type 2 diabetes, age 59 ± 7 years (mean ± SD), BMI 28.9 ± 3.0 kg/m2, HbA1c 6.5 ± 0.6%, in a double-blind, placebo-controlled, crossover design. A single injection (10 μg/kg) of NN2211 was administered at 2300 h, and profiles of circulating insulin, C-peptide, glucose, and glucagon were monitored during the next 16.5 h. A standardized mixed meal was served at 1130 h. Efficacy analyses were performed for the fasting (7–8 h) and mealtime (1130–1530 h) periods. Insulin secretory rates (ISR) were estimated by C-peptide deconvolution analysis. Glucose pulse entrainment (6 mg · kg−1 · min−1 every 10 min) was evaluated by 1-min sampled measurements of insulin concentrations from 0930 to 1030 h and subsequent time series analysis of the insulin concentration profiles. All results are given as NN2211 versus placebo; statistical analyses were performed by analysis of variance. In the fasting state, plasma glucose was significantly reduced (6.9 ± 1.0 vs. 8.1 ± 1.0 mmol/l; P = 0.004), ISR was increased (179 ± 70 vs. 163 ± 66 pmol/min; P = 0.03), and plasma glucagon was unaltered (19 ± 4 vs. 20 ± 4 pg/ml; P = 0.17) by NN2211. Meal-related area under the curve (AUC)1130–1530 h for glucose was markedly reduced (30.6 ± 2.4 vs. 39.9 ± 7.3 mmol · l−1 · h−1; P < 0.001), ISR AUC1130–1530 h was unchanged (118 ± 32 vs. 106 ± 27 nmol; P = 0.13), but the increment (relative to premeal values) was increased (65 ± 22 vs. 45 ± 11 nmol; P = 0.04). Glucagon AUC1130–1530 h was suppressed (77 ± 18 vs. 82 ± 17 pmol · l−1 · h−1; P = 0.04). Gastric emptying was significantly delayed as assessed by AUC1130–1530 h of 3-ortho-methylglucose (400 ± 84 vs. 440 ± 70 mg · l−1 · h−1; P = 0.02). During pulse entrainment, there was a tendency to increased high frequency regularity of insulin release as measured by a greater spectral power and autocorrelation coefficient (0.05 < P < 0.10). The pharmacokinetic profile of NN2211, as assessed by blood samplings for up to 63 h postdosing, was as follows: T1/2 = 10.0 ± 3.5 h and Tmax = 12.4 ± 1.7 h. Two patients experienced gastrointestinal side effects on the day of active treatment. In conclusion, the long-acting GLP-1 derivative NN2211 effectively reduces fasting as well as meal-related (∼12 h postadministration) glycemia by modifying insulin secretion, delaying gastric emptying, and suppressing prandial glucagon secretion.

    Footnotes

    • Address correspondence and reprint requests to Claus B. Juhl, Medical Department M, Århus University Hospital, Noerrebrogade 44, Århus C, Denmark. E-mail: cbj{at}dadlnet.dk.

      Received for publication 20 June 2001 and accepted in revised form 11 October 2001.

      During conduction of the trial and the time of manuscript submission, J.S., G.J., and H.A. all were full-time employees of Novo Nordisk A/S and hold stock in Novo Nordisk A/S.

      ApEn, approximate entropy; AUC, area under the curve; ELISA, enzyme-linked immunosorbent assay; GLP-1, glucagon-like peptide 1; HOMA, homeostasis model assessment; ISR, insulin secretory rates.

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