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The clinical development program of lixisenatide: a once-daily glucagon-like Peptide-1 receptor agonist.

ABSTRACT: Lixisenatide (AVE0010) is a once-daily glucagon-like peptide-1 (GLP-1) receptor agonist used in the treatment of type 2 diabetes. Phase II dose-finding and pharmacodynamic studies identified the 20 µg once-daily dose as having the optimum combination of efficacy, convenience and tolerability. Lixisenatide was prospectively investigated in a series of 11 multinational, randomised, controlled phase III trials (GLP-1 agonist AVE0010 in paTients with type 2 diabetes mellitus for Glycemic cOntrol and sAfety evaLuation [GetGoal] programme) that included a direct head-to-head study with exenatide. The GetGoal programme established the efficacy and safety profile of lixisenatide 20 µg once daily across the spectrum of patients with type 2 diabetes, including patients not treated with anti-diabetic agents, those failing on oral agents and as an adjunct to basal insulin therapy. The main efficacy endpoints were met in all studies, with the baseline to endpoint reductions in HbA1c consistently ranging from 0.7% to 1.0%. In a head-to-head comparison with exenatide 10 ?g twice daily, lixisenatide 20 ?g once daily was non-inferior for HbA1c reduction, achieved with threefold fewer patients with symptomatic hypoglycemia events and better gastrointestinal tolerability. Three randomised trials of lixisenatide treatment added to basal insulin showed significantly improved glycemic control over placebo, with pronounced postprandial glucose reductions and good tolerability. Discontinuations for adverse events were consistently low, ranging from 2.5% to 10.4%. As the provision of individualized care moves center stage in diabetes management, lixisenatide with once-daily dosing, a single maintenance dose and fixed-dose pens offers an important treatment option for type 2 diabetes.

SUBMITTER: Bain SC

PROVIDER: S-EPMC4269639 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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The clinical development program of lixisenatide: a once-daily glucagon-like Peptide-1 receptor agonist.

Bain Stephen C SC

Diabetes therapy : research, treatment and education of diabetes and related disorders 20140716 2

Lixisenatide (AVE0010) is a once-daily glucagon-like peptide-1 (GLP-1) receptor agonist used in the treatment of type 2 diabetes. Phase II dose-finding and pharmacodynamic studies identified the 20 µg once-daily dose as having the optimum combination of efficacy, convenience and tolerability. Lixisenatide was prospectively investigated in a series of 11 multinational, randomised, controlled phase III trials (GLP-1 agonist AVE0010 in paTients with type 2 diabetes mellitus for Glycemic cOntrol and ...[more]

PMID: 25027491

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Project description:Aims/introductionThe prevalence and pathophysiological background of type 2 diabetes mellitus vary across ethnicities, and can affect treatment responses. Adding lixisenatide to basal insulin (BI) in type 2 diabetes mellitus patients has shown improvements in glycated hemoglobin (HbA1c) and postprandial glycemic (PPG) excursions, without increasing hypoglycemic events. We aim to compare the efficacy of lixisenatide in Asian and white patients inadequately controlled with basal insulin.Materials and methodsAn individual-level pooled analysis of two multi-national phase III studies, GetGoal-L and GetGoal-L-C, was carried out to assess the efficacy of lixisenatide versus placebo as an add-on treatment to BI ± metformin in Asian and white patients with type 2 diabetes mellitus. Change in HbA1c, 2-h PPG and PPG excursion were analyzed, along with possible predictors of glycemic control.ResultsPooled data showed that baseline characteristics were similar between Asian and white patients with the exception of bodyweight, body mass index and BI dose being higher in white patients. After 24 weeks, lixisenatide reduced HbA1c in both ethnic groups, with no statistically significant difference between the two groups (Asian patients least squares mean difference -0.49, 95% confidence interval -0.68 to - 0.30 and white patients least squares mean difference -0.45, 95% confidence interval -0.63 to - 0.26; P = 0.6287). Similarly, no significant difference was found in 2-h PPG reduction between both groups (least squares mean difference for Asian vs white patients: -3.37 vs -3.93; P = 0.3203). Treatment with lixisenatide contributed to HbA1c reduction of -0.56% after adjustment of baseline HbA1c level in Asian patients, and -0.41% in white patients.ConclusionsAdding lixisenatide to BI significantly reduced HbA1c and 2-h PPG levels in both Asian and white participants with type 2 diabetes mellitus. No differences in treatment effect were observed between the two populations.

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.

Project description:BackgroundOrforglipron is a novel once-daily oral non-peptide glucagon-like peptide-1 receptor agonist with several recently published randomized controlled trials (RCTs) evaluating its role in diabetes and obesity. No meta-analysis has analyzed the efficacy and safety of orforglipron; this meta-analysis aimed to address this knowledge gap.MethodsA systematic search was conducted in electronic databases to identify RCTs that included individuals with obesity who were administered orforglipron and compared to either a placebo or an active comparator. The primary outcome of interest was the percent change in body weight.ResultsFrom 12 initially screened articles, data from three RCTs involving 774 people were analyzed with a follow-up duration of up to 36 weeks. Compared to placebo, patients receiving orforglipron 12 mg/day (mean difference (MD), MD -5.48%, 95% CI [-7.64, -3.33], p < 0.01), 24 mg/day (MD -8.51%, 95% confidence interval (CI) [-9.88, -7.14], p < 0.01), 36 mg/day (MD -8.84%, 95% CI [-11.68, -6.00], p < 0.01) and 45 mg/day (MD -8.24%, 95% CI [-12.84, -3.63], p < 0.01) had a significantly greater percent reduction in body weight. The percentage of patients being able to achieve >15% weight loss from baseline was significantly higher with orforglipron 24 mg/day [Odds ratio (OR) 21.90 (95% CI [4.06, 118.15], p = 0.0003), 36 mg/day (OR 17.43, 95% CI [3.18, 95.66], p = 0.001) and 45 mg/day (OR 23.17, 95% CI [4.37, 123.03], p = 0.0002). Total but not severe adverse events were significantly higher with all the doses of orforglipron compared to placebo, with the hazard ratios being higher with higher doses. Gastrointestinal side-effects were predominant side effects, being dose-dependent, with nausea, vomiting, constipation, and gastroesophageal reflux being the predominant ones.ConclusionOrforglipron at 24-45 mg/day doses is an effective weight loss medication. The efficacy versus side effect profile suggests that 24-36 mg/day is the most optimal dose for orforglipron as an anti-obesity medicine.

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The clinical development program of lixisenatide: a once-daily glucagon-like Peptide-1 receptor agonist.

Publications

The clinical development program of lixisenatide: a once-daily glucagon-like Peptide-1 receptor agonist.

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