Safety, tolerability, pharmacodynamics and pharmacokinetics of albiglutide, a long‐acting glucagon‐like peptide‐1 mimetic, in healthy subjects

Bush, Mark A.; Matthews, James L.; Boever, Erika H. De; Dobbins, Robert L.; Hodge, Rebecca J.; Walker, Susan; Holland, M. Claire H.; Gutierrez, M; Stewart, Murray

doi:10.1111/j.1463-1326.2008.00992.x

Cited by 159 publications

(121 citation statements)

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“…Although the relatively limited number of patients with severe renal impairment did experience higher frequencies of GI events compared with patients with mild and moderate renal impairment, there were no new safety concerns identified for albiglutide in this study than were included in similar previous clinical trials (16)(17)(18)(19)(20)(21). Diarrhea (the most common GI event in both treatment groups) and constipation were seen at modestly higher incidences in patients treated with albiglutide than in those treated with sitagliptin; however, there was no marked difference in nausea or vomiting events in either treatment group.…”

Section: Discussionmentioning

confidence: 83%

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confidence: 99%

“…Albiglutide was synthesized through genetic modification that resulted in the attachment of two modified recombinant human GLP-1 fragments linked in tandem to the amino terminus of the coding sequence for human albumin, and it retains GLP-1 glucose-dependent insulinotropic activities both in vitro and in vivo (16). With a half-life of approximately 5 days, the pharmacokinetic profile of albiglutide allows for onceweekly subcutaneous injections (16)(17)(18)(19)(20). To date, reported clinical studies, including a phase I study in patients with varying degrees of renal impairment (GLP108370), have shown albiglutide to be an effective, safe, and tolerable therapy when administered to patients with type 2 diabetes (16)(17)(18)(19)(20)(21).…”

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confidence: 99%

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Efficacy and Safety of the Once-Weekly GLP-1 Receptor Agonist Albiglutide Versus Sitagliptin in Patients With Type 2 Diabetes and Renal Impairment: A Randomized Phase III Study

et al. 2014

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OBJECTIVETo evaluate weekly subcutaneous albiglutide versus daily sitagliptin in renally impaired patients with type 2 diabetes and inadequately controlled glycemia on a regimen of diet and exercise and/or oral antihyperglycemic medications. RESEARCH DESIGN AND METHODSIn this phase III, randomized, double-blind, multicenter, 52-week study, the primary study end point was HbA 1c change from baseline at week 26 in patients with renal impairment, as assessed with estimated glomerular filtration rate and categorized as mild, moderate, or severe ( ‡60 to £89, ‡30 to £59, and ‡15 to £29 mL/min/1.73 m 2 , respectively). Secondary end points included fasting plasma glucose (FPG), weight, achievement of treatment targets, hyperglycemic rescue, and safety. RESULTSBaseline demographics were similar across treatment and renal impairment groups with overall mean age of 63.3 years, BMI of 30.4 kg/m 2 , HbA 1c of 8.2% (66 mmol/mol), and diabetes disease duration of 11.2 years. HbA 1c change from baseline at week 26 was significantly greater for albiglutide than sitagliptin (20.83% vs. 20.52%, P = 0.0003). Decreases in HbA 1c , FPG, and weight were seen through week 52. Time to hyperglycemic rescue through week 52 was significantly longer for albiglutide than sitagliptin (P = 0.0017). Results of safety assessments were similar between groups, and most adverse events (AEs) were mild or moderate. The incidences of gastrointestinal AEs for albiglutide and sitagliptin were as follows: overall, 31.7%, 25.2%; diarrhea, 10.0%, 6.5%; nausea, 4.8%, 3.3%; and vomiting, 1.6%, 1.2%, respectively. CONCLUSIONSOnce-weekly albiglutide therapy in renally impaired patients with type 2 diabetes provided statistically superior glycemic improvement with almost similar tolerability compared with daily sitagliptin therapy.

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confidence: 83%

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Efficacy and Safety of the Once-Weekly GLP-1 Receptor Agonist Albiglutide Versus Sitagliptin in Patients With Type 2 Diabetes and Renal Impairment: A Randomized Phase III Study

et al. 2014

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“…This modification extends the half-life to~5 days and allows weekly dosing [9,10]. Limited data exist that directly compare basal insulin with non-insulin treatments for diabetes.…”

Section: Introductionmentioning

confidence: 99%

HARMONY 4: randomised clinical trial comparing once-weekly albiglutide and insulin glargine in patients with type 2 diabetes inadequately controlled with metformin with or without sulfonylurea

Weissman¹,

Carr

et al. 2014

Diabetologia

113

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Aims/hypothesis The aim of this study was to compare the efficacy and safety of once-weekly albiglutide with once-daily insulin glargine (A21Gly,B31Arg,B32Arg human insulin) in patients with type 2 diabetes inadequately controlled on metformin with or without sulfonylurea. Methods This was a randomised, open-label, multicentre (n=222), parallel-group, non-inferiority out-patient clinical trial, with 779 patients enrolled in the study. The study was conducted in 222 centres located in four countries. Patients aged ≥18 years with type 2 diabetes treated with metformin (±sulfonylurea) for at least 3 months with a baseline HbA 1c 7.0-10.0% (53.0-85.8 mmol/mol) were randomly assigned (2:1) via a computer-generated randomisation sequence with a voice response system to receive albiglutide (30 mg once a week, n=504) or insulin glargine (10 U once a day, n=241) added to current therapy. Participants and investigators were not masked to treatment assignment. Doses of each medication were adjusted on the basis of the glycaemic response. The primary endpoint was change from baseline in HbA 1c at week 52. Results In the albiglutide group, HbA 1c declined from 8.28± 0.90% (67.0±9.8 mmol/mol) (mean±SD) at baseline to 7.62± 1.12% (59.8±12.2 mmol/mol) at week 52. A similar reduction occurred in the insulin glargine group (8.36±0.95% to 7.55± 1.04% [67.9±10.4 to 59.0±11.4 mmol/mol]). The modeladjusted treatment difference of 0.11% (95% CI −0.04%, 0.27%) (1.2 mmol/mol [95% CI −0.4, 3.0 mmol/mol]) indicated non-inferiority of albiglutide to insulin glargine based on the pre-specified non-inferiority margin of 0.3% (3.3 mmol/mol, p=0.0086). Body weight increased in the insulin glargine group and decreased in the albiglutide group, with a mean treatment difference of −2.61 kg (95% CI −3.20, −2.02; p<0.0001). Documented symptomatic hypoglycaemia occurred in a higher proportion of patients in the insulin glargine group than in the albiglutide group (27.4% vs 17.5%, p=0.0377). Conclusions/interpretation Albiglutide was non-inferior to insulin glargine at reducing HbA 1c at week 52, with modest weight loss and less hypoglycaemia. Both drugs were well tolerated. Albiglutide may be considered an alternative to insulin glargine in this patient population. Trial registration: ClinicalTrials.gov NCT00838916 (completed) Funding: This study was planned and conducted by GlaxoSmithKline.

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“…An amino acid substitution at position eight of the GLP-1 dimer creates resistance to dipeptidyl peptidase-4 (DPP-4) degradation. Albiglutide has a half-life of ;5 days, allowing for weekly dosing (19)(20)(21)(22)(23). In a phase 2b dose-ranging study, once-weekly albiglutide was associated with numerically greater improvement in HbA 1c versus twice-daily exenatide and substantially less nausea and vomiting (22).…”

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Advancing Basal Insulin Replacement in Type 2 Diabetes Inadequately Controlled With Insulin Glargine Plus Oral Agents: A Comparison of Adding Albiglutide, a Weekly GLP-1 Receptor Agonist, Versus Thrice-Daily Prandial Insulin Lispro

et al. 2014

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OBJECTIVEGLP-1 receptor agonists may provide an alternative to prandial insulin for advancing basal insulin therapy. Harmony 6 was a randomized, open-label, activecontrolled trial testing once-weekly albiglutide vs. thrice-daily prandial insulin lispro as an add-on to titrated once-daily insulin glargine. RESEARCH DESIGN AND METHODSPatients taking basal insulin (with or without oral agents) with HbA 1c 7-10.5% (53-91 mmol/mol) entered a glargine standardization period, followed by randomization to albiglutide, 30 mg weekly (n = 282), subsequently uptitrated to 50 mg, if necessary, or thrice-daily prandial lispro (n = 281) while continuing metformin and/or pioglitazone. Glargine was titrated to fasting plasma glucose of <5.6 mmol/L, and lispro was adjusted based on glucose monitoring. The primary end point was the difference in the HbA 1c change from baseline at week 26. RESULTSAt week 26, HbA 1c decreased from baseline by 20.82 6 SE 0.06% (9.0 mmol/mol) with albiglutide and 20.66 6 0.06% (7.2 mmol/mol) with lispro; treatment difference, 20.16% (95% CI 20.32 to 0.00; 1.8 mmol/mol; P < 0.0001), meeting the noninferiority end point (margin, 0.4%). Weight decreased with albiglutide but increased with lispro (20.73 6 0.19 kg vs. +0.81 6 0.19 kg). The mean glargine dose increased from 47 to 53 IU (albiglutide) and from 44 to 51 IU (lispro). Adverse events for albiglutide versus lispro included severe hypoglycemia (0 vs. 2 events), documented symptomatic hypoglycemia (15.8% vs. 29.9%), nausea (11.2% vs. 1.4%), vomiting (6.7% vs. 1.4%), and injection site reactions (9.5% vs. 5.3%). CONCLUSIONSWeekly albiglutide is a simpler therapeutic option than thrice-daily lispro for advancing basal insulin glargine therapy, resulting in comparable HbA 1c reduction with weight loss and lower hypoglycemia risk.

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Safety, tolerability, pharmacodynamics and pharmacokinetics of albiglutide, a long‐acting glucagon‐like peptide‐1 mimetic, in healthy subjects

Abstract: Albiglutide has a half-life that favours once weekly or less frequent dosing with an acceptable safety/tolerability profile in non-diabetic subjects.

Cited by 159 publications

References 30 publications

Efficacy and Safety of the Once-Weekly GLP-1 Receptor Agonist Albiglutide Versus Sitagliptin in Patients With Type 2 Diabetes and Renal Impairment: A Randomized Phase III Study

Efficacy and Safety of the Once-Weekly GLP-1 Receptor Agonist Albiglutide Versus Sitagliptin in Patients With Type 2 Diabetes and Renal Impairment: A Randomized Phase III Study

HARMONY 4: randomised clinical trial comparing once-weekly albiglutide and insulin glargine in patients with type 2 diabetes inadequately controlled with metformin with or without sulfonylurea

Advancing Basal Insulin Replacement in Type 2 Diabetes Inadequately Controlled With Insulin Glargine Plus Oral Agents: A Comparison of Adding Albiglutide, a Weekly GLP-1 Receptor Agonist, Versus Thrice-Daily Prandial Insulin Lispro

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