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/m 2 , HbA 1c 6.5 ؎ 0.6%, in a double-blind, placebo-controlled, crossover design. A single injection (10 g/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 ⅐ kg ؊1 ⅐ min P atients with type 2 diabetes experience relative insulin deficiency as well as delayed and blunted meal-related insulin response (1). Glucagon excess contributes to the elevated fasting and postprandial glycemia (2). Because of a marked and glucosedependent insulinotropic action and a restraining effect on glucagon release, glucagon like peptide-1 (GLP-1) is an obvious candidate for the treatment of type 2 diabetes (3). In addition, GLP-1 delays gastric emptying and reduces appetite in patients with type 2 diabetes also in nonemetic doses (4). Continuous intravenous infusion and repeated subcutaneous injections of GLP-1 (7-36 amide) effectively reduce fasting plasma glucose as well as meal-related glycemia (3,5). Even in patients with type 2 diabetes and secondary failure of sulfonylurea treatment, GLP-1 has been demonstrated to reduce glycemia effectively (6).Increased ␤-cell function has been reported after overnight GLP-1 infusion, as measured by homeostasis model assessment (HOMA) and by first-and second-phase insulin secretion (7). The secretagogue effect is achieved by a concomitant increase of basal (nonpulsatile) and highfrequency pulsatile insulin release in patients with type 2 diabetes (8). In a study of ultradian insulin pulsatility, GLP-1 was reported to restore glucose entrainment in individuals with impaired glucose tolerance (9), indicating preferential effects on the coordination of insulin release.GLP-1 is rapidly cleaved by dipeptidyl-peptidase IV after both intravenous and subcutaneous injections, and the development of long-acting derivatives is needed for clinical use. NN2211 is an acylated GLP-1 derivative with prolonged action due to a combination of albumin binding, metabolic stability, and slow release from the injection site. NN2211 has shown a favorable pharmacokinetic

Alpha cell function in health and disease: influence of glucagon-like peptide-1

“…In contrast, subcutaneous injection of the acylated derivative of GLP-1, liraglutide, did not affect fasting glucagon or glucagon during graded glucose infusions in patients with type 2 diabetes [4]. However, in another study, bedtime injection of liraglutide modestly decreased postmeal glucagon [100]. Zander and colleagues reported the first longer-term study of GLP-1 based therapy in patients with type 2 diabetes [101].…”

Diabesity: therapeutic options

“…Liraglutide is 97% homologous to human GLP-1, with only a single amino acid substitution and a glutamate-spaced fatty acid chain to distinguish it from the native peptide [105]. These modifications slow the degradation of liraglutide by DPP-4, thereby extending plasma half-life to 13 h [106][107][108][109].Liraglutide produces clinically meaningful reductions in HbA1c and body weight relative to placebo [91,92,[110][111][112]. In a double-blind, placebocontrolled, 52-week study evaluating the effects of liraglutide or glimepiride as first-line monotherapy in 746 people with type 2 diabetes, body weight was reduced by 2.05 ± 4.40 and 2.45 ± 4.37 kg in the liraglutide 1.2 and 1.8 mg cohorts respectively, compared with weight gain of 1.12 ± 4.24 kg in those receiving glimepiride 8 mg (p < 0.0001 for both vs. glimepiride).…”

Gut-Derived Incretin Hormones and New Therapeutic Approaches

“…After a single injection the half-life of liraglutide is 11-15 h, with a decrease in glucagon, an increase in insulin, and lowering of 24-h glucose profiles in persons with type 2 diabetes following once-daily administration (10). After 12 weeks of administration, HbA 1c levels decrease to a similar extent to that seen with sulfonylureas but with weight loss rather than weight gain (11 Two newer products, CJC-1131 and Albugon, exhibit covalent binding to albumin. CJC-1131, which is currently in phase 2 clinical trials, was developed by the research company ConjuChem based on their DAC (drug affinity construct) technology, leading to decreased clearance.…”