Bedtime administration of NN2211, a long-acting GLP-1 derivative, substantially reduces fasting and postprandial glycemia in type 2 diabetes

Abstract

Glucagon-like peptide 1 (GLP-1) is a potent glucoselowering 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 AUC130-1530 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 mealrelated (∼ 12 h postadministration) glycemia by modifying insulin secretion, delaying gastric emptying, and suppressing prandial glucagon secretion.