Dataset Information

A glycosylated Fc-fused glucagon-like peptide-1 receptor agonist exhibits equivalent glucose lowering to but fewer gastrointestinal side effects than dulaglutide.

ABSTRACT:

Aim

To evaluate the pharmacokinetic and pharmacodynamic properties of a novel glycosylated Fc-fused glucagon-like peptide-1(GLP-1-gFc) receptor agonist with distinctive receptor binding affinity, designed to improve in vivo stability and safety relative to the commercial GLP-1 analogue dulaglutide, and assess its safety profile and pharmacokinetics in healthy humans.

Materials and methods

We constructed GLP-1-gFc and determined its binding affinity and potency using in vitro instrumental and cell-based analyses followed by in vivo comparison of the glucose-lowering and gastrointestinal side effects between GLP-1-gFc and dulaglutide. A phase 1 clinical trial was conducted to confirm the efficacy and safety profile of GLP-1-gFc.

Results

GLP-1-gFc showed 10-fold less binding affinity and 4-fold less potency than dulaglutide in in vitro. A potency-adjusted dose delayed HbA1c increase comparable with that of dulaglutide (Change for 6 weeks: 2.4 mg/kg GLP-1-gFc, 4.34 ± 0.40 vs. 0.6 mg/kg dulaglutide, 4.26 ± 0.22; n.s.). However, the equivalent efficacy dose and higher dose did not induce malaise-related responses (blueberry bar consumption, g/mouse: 2.4 mg/kg GLP-1-gFc, 0.15% ± 0.03% vs. 0.6 mg/kg dulaglutide, 0.04% ± 0.01%; P < .01) or QT interval changes (mean at 14-20 hours, mSc: 0.28 mg/kg GLP-1-gFc, 0.0-8.0 vs. 0.07 mg/kg dulaglutide, 8.0-27.7; n.s.), observed as safety variables in rats and monkeys, compared with those of dulaglutide. Glucose reductions in an oral glucose tolerance test were significant at day 3 postdose without severe gastrointestinal adverse events and pulse rate changes in healthy subjects.

Conclusions

These results suggest that GLP-1-gFc could be used as a novel GLP-1 receptor agonist with better safety than dulaglutide to maximize therapeutic benefits in subjects with type 2 diabetes.

SUBMITTER: An IB

PROVIDER: S-EPMC7383507 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Publications

A glycosylated Fc-fused glucagon-like peptide-1 receptor agonist exhibits equivalent glucose lowering to but fewer gastrointestinal side effects than dulaglutide.

An In Bok IB Byun Mi Sun MS Yang Sang In SI Choi Yuri Y Woo Jung Won JW Jang Hak Chul HC Sung Young Chul YC

Diabetes, obesity & metabolism 20200603 8

<h4>Aim</h4>To evaluate the pharmacokinetic and pharmacodynamic properties of a novel glycosylated Fc-fused glucagon-like peptide-1(GLP-1-gFc) receptor agonist with distinctive receptor binding affinity, designed to improve in vivo stability and safety relative to the commercial GLP-1 analogue dulaglutide, and assess its safety profile and pharmacokinetics in healthy humans.<h4>Materials and methods</h4>We constructed GLP-1-gFc and determined its binding affinity and potency using in vitro instr ...[more]

PMID: 32314505

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Project description:BACKGROUND:Dulaglutide is a new, long-acting glucagon-like peptide analogue in the treatment of type 2 diabetes. It is available in two doses, 0.75 and 1.5 mg, given by injection once weekly. This systematic review reports the effectiveness and safety of dulaglutide in type 2 diabetes in dual and triple therapy. METHODS:MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, and conference abstracts were searched from 2005 to August 2014, and updated in January 2015. Company websites and references of included studies were checked for potentially relevant studies. European Medicines Agency and US Food and Drug Administration websites were searched. RESULTS:Four trials were included. All were manufacturer-funded randomized controlled trials from the Assessment of Weekly Administration of Dulaglutide in Diabetes (AWARD) program. AWARD-1 compared dulaglutide 1.5 mg against exenatide 10 µg twice daily and placebo, AWARD-2 compared dulaglutide 0.75 and 1.5 mg against insulin glargine, AWARD-5 compared dulaglutide 0.75 and 1.5 mg against sitagliptin 100 mg and placebo, and AWARD-6 compared dulaglutide 1.5 mg against liraglutide 1.8 mg. The duration of follow-up in the trials ranged from 26 to 104 weeks. The primary outcome of all the included trials was change in HbA1c. At 26 weeks, greater HbA1c reductions were seen with dulaglutide than with twice daily exenatide (dulaglutide 1.5/0.75 mg: -1.5%/-1.3%; exe: 0.99%) and sitagliptin (1.5/0.75 mg -1.22%/-1.01%; sitagliptin: -0.6%). HbA1c change was greater with dulaglutide 1.5 mg (-1.08%) than with glargine (-0.63%), but not with dulaglutide 0.75 mg (-0.76%). Dulaglutide 1.5 mg was found to be noninferior to liraglutide 1.8 mg. More patients treated with dulaglutide achieved HbA1c targets of <7% and ≤6.5%. Reduction in weight was greater with dulaglutide than with sitagliptin and exenatide. Hypoglycemia was infrequent. The main adverse events were nausea, diarrhea, and vomiting. CONCLUSION:Dulaglutide is effective in the treatment of patients with type 2 diabetes but we need long follow-up data for safety concerns.

Dataset Information

A glycosylated Fc-fused glucagon-like peptide-1 receptor agonist exhibits equivalent glucose lowering to but fewer gastrointestinal side effects than dulaglutide.

Aim

Materials and methods

Results

Conclusions

Publications

A glycosylated Fc-fused glucagon-like peptide-1 receptor agonist exhibits equivalent glucose lowering to but fewer gastrointestinal side effects than dulaglutide.

Similar Datasets

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