The increasing interest in the development of GLP-1-based analogues for the treatment of diabetes will result in the testing of these analogues in normal and diabetic subjects over the next several years. This section of glucagon.com will focus on the results of these studies following publication of the data in the peer-reviewed scientific literature.
Six week infusion of native GLP-1 in Type 2 Diabetes
Native GLP-1 has been infused by the subcutaneous route (4.8 pmol/kg/min) using a portable insulin pump in a non-randomized study of subjects with Type 2 diabetes over the age of 40 (mean age 55) with mean initial HbA1c of about 9%, and mean fasting glucose ~14 mM. Oral antidiabetic medication was discontinued 3 weeks prior to the study. In GLP-1-infused subjects, plasma levels of GLP-1 rose from ~ 19 pM to 197 pM by week 1, and 282 pM at week 6. Six weeks of GLP-1 infusion resulted in significant improvements in fasting (decrease of 4.3 mM glucose) and 8 h mean glucose (decrease of 5.5 mM), fasting and mean 8h free fatty acids, a reduction in HbA1c from 9.2% to 7.9%, a decrease in fructosamine from 349 uM to 282 uM, and a reduction in gastric emptying.
Multiple parameters of beta cell function, including C-peptide responses to glucose and arginine improved in the GLP-1-treated patients. See Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002 Mar 9;359(9309):824-30
Twelve week infusion of GLP-1 in elderly subjects
A clinical trial of native GLP-1 was carried out in 16 patients with type 2 diabetes treated with oral hypoglycemic agents. Eight patients (aged 75 +/- 2 years, BMI 27 +/ 1 kg/m(2)) continued on their usual glucose-lowering therapy and eight patients (aged 73 +/- 1 years, BMI 27 + 1 kg/m(2), discontinued their hypoglycemic medications and received GLP-1 by continuous subcutaneous infusion, at varying doses, for 12 weeks. Primary end points were HbA(1c) and blood glucose determinations. HbA(1c) levels (7.1%) and body weight were equally maintained in both groups however the GLP-1-treated group had much less hypoglycemia. GLP-1 enhanced glucose-induced insulin secretion and insulin-mediated glucose disposal. See Effects of 3 Months of Continuous Subcutaneous Administration of Glucagon-Like Peptide 1 in Elderly Patients With Type 2 Diabetes. Diabetes Care. 2003 Oct;26(10):2835-2841
NN2211, subsequently renamed Liraglutide, is an acylated albumin-bound human GLP-1 analog that exhibits a prolonged duration of action in preclinical rodent studies. For information on studies with this GLP-1R agonist, see Liraglutide
Exendin-4, subsequently renamed Exenatide, is a naturally occurring DP IV-resistant GLP-1 analog, lizard exendin-4, has been examined in both short term and more prolonged administration regimens in man. To review basic studies and preclinical investigation, see Exendin-4
For an overview of the Exendin-4 data in man, see Exendin-4: Human data
CJC-1131: GLP-1-albumin drug affinity complex (DAC) technology. GLP-1 is a GLP-1 analogue engineered for covalent coupling to albumin. The GLP-1 albumin compound retains the ability to bind to and activate the GLP-1 receptor, and appears to exhibit highly similar biological actions, compared to native GLP-1, when assessed using cells in vitro, or rodents in vivo. For an overview of CJC-1131, see Development and characterization of a glucagon-like Peptide 1-albumin conjugate: the ability to activate the glucagon-like Peptide 1 receptor in vivo. Diabetes. 2003 Mar;52(3):751-9. See CJC-1131
ZP10, Zealand Pharma, and Aventis
ZP10 is an exendin-4 derivative being developed by Zealand Pharmaceuticals. A licensing deal with Aventis was announced on June 25 2003, whereby Aventis received global rights to and responsibility for commercialization of ZP10 (AVE-10). See the Zealand Press Release and the Sanofi update of AVE-0010 Phase 2 Data from Septmber 2007
Roche, Beaufour Ipsen and BIM51077
BIM51077 is a human GLP-1 derivative, originally developed and taken through Phase 1 studies by Ipsen, now licensed to Roche, as outlined in their Oct 21 2003 Press Release.
LY315902 is a Lilly DPP-IV-resistant GLP-1 analogue and LY307161 SR is a sustained release formulation of a GLP-1 analog suitable for once daily administration; LY307161 efficacy has been examined in human clinical trials. In data presented at the 2002 ADA Meeting in San Francisco, the pharmacokinetic/-dynamic effects of a single 4.5 mg LY307161 SR was evaluated in 9 patients with Type 2 diabetes, mean age 60, BMI 30.3, HbA1c 7.3, treated with diet (7) and/or metformin (2) over a period of 21 days. Food intake on test days was identical for each individual. In all but one patient, blood glucose was lowered to near-normal levels throughout the duration of the test days (day 6 and day 21). No hypoglycemia was observed and the average body weight of the patients declined by 2.1 + 0.5 kg. Nevertheless, Eli Lilly announced it was discontinuing the GLP-1 analogue clinical program at the time it disclosed its intent on Friday Sept 20 2002 to partner with Amylin in the clinical development of exendin-4 (AC2993-Exenatide).