An overview of once-weekly glucagon-like peptide-1 receptor agonists-available efficacy and safety data and perspectives for the future

Madsbad, Sten; Kielgast, Urd; Asmar, Meena; Deacon, Carolyn F.; Torekov, Signe S.; Holst, Jens J.

doi:10.1111/j.1463-1326.2011.01357.x

Cited by 181 publications

(149 citation statements)

References 69 publications

(230 reference 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: 86%

“…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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Section: Discussionmentioning

confidence: 86%

mentioning

confidence: 99%

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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“…These modifications give semaglutide an extended half‐life of approximately one week,13 making it suitable for once‐weekly administration 14, 15. Once‐weekly administration may improve patient compliance and quality of life,16, 17 compared with first‐generation GLP‐1RAs that require once‐/twice‐daily dosing 18. Semaglutide is associated with dose‐dependent reductions in HbA1c and body weight in individuals with diabetes 19.…”

Section: Introductionmentioning

confidence: 99%

Effects of once‐weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity

Blundell

Finlayson

Axelsen

et al. 2017

Diabetes Obesity Metabolism

369

370

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AimThe aim of this trial was to investigate the mechanism of action for body weight loss with semaglutide.Materials and methodsThis randomised, double‐blind, placebo‐controlled, two‐period crossover trial investigated the effects of 12 weeks of treatment with once‐weekly subcutaneous semaglutide, dose‐escalated to 1.0 mg, in 30 subjects with obesity. Ad libitum energy intake, ratings of appetite, thirst, nausea and well‐being, control of eating, food preference, resting metabolic rate, body weight and body composition were assessed.ResultsAfter a standardised breakfast, semaglutide, compared with placebo, led to a lower ad libitum energy intake during lunch (−1255 kJ; P < .0001) and during the subsequent evening meal (P = .0401) and snacks (P = .0034), resulting in a 24% reduction in total energy intake across all ad libitum meals throughout the day (−3036 kJ; P < .0001). Fasting overall appetite suppression scores were improved with semaglutide vs placebo, while nausea ratings were similar. Semaglutide was associated with less hunger and food cravings, better control of eating and a lower preference for high‐fat foods. Resting metabolic rate, adjusted for lean body mass, did not differ between treatments. Semaglutide led to a reduction from baseline in mean body weight of 5.0 kg, predominantly from body fat mass.ConclusionAfter 12 weeks of treatment, ad libitum energy intake was substantially lower with semaglutide vs placebo with a corresponding loss of body weight observed with semaglutide. In addition to reduced energy intake, likely mechanisms for semaglutide‐induced weight loss included less appetite and food cravings, better control of eating and lower relative preference for fatty, energy‐dense foods.

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“…The utility of these linkers was demonstrated by t 1/2 extension of exenatide, a 39-aa peptide that is a potent glucagon-like peptide-1 (GLP-1) agonist (19). Because exenatide requires twice daily injections in humans, there is considerable interest in developing once-weekly GLP-1 agonists (20). We produced both releasable [7A (Scheme 3), Mod = PhSO 2 −] and stable N α -azido-linker exenatides by on-resin solidphase peptide synthesis acylation of the N terminus of exenatide and attached them to four-branch PEG 40kDa -DBCO to give the releasable [8A (Scheme 3), Mod = PhSO 2 −] and stable conjugates (SI Text 8).…”

mentioning

confidence: 99%

Predictable and tunable half-life extension of therapeutic agents by controlled chemical release from macromolecular conjugates

Santi

Schneider

Reid

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

177

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Conjugation to macromolecular carriers is a proven strategy for improving the pharmacokinetics of drugs, with many stable polyethylene glycol conjugates having reached the market. Stable conjugates suffer several limitations: loss of drug potency due to conjugation, confining the drug to the extracellular space, and the requirement for a circulating conjugate. Current research is directed toward overcoming such limitations through releasable conjugates in which the drug is covalently linked to the carrier through a cleavable linker. Satisfactory linkers that provide predictable cleavage rates tunable over a wide time range that are useful for both circulating and noncirculating conjugates are not yet available. We describe such conjugation linkers on the basis of a nonenzymatic β-elimination reaction with preprogrammed, highly tunable cleavage rates. A set of modular linkers is described that bears a succinimidyl carbonate group for attachment to an amine-containing drug or prodrug, an azido group for conjugation to the carrier, and a tunable modulator that controls the rate of β-eliminative cleavage. The linkers provide predictable, tunable release rates of ligands from macromolecular conjugates both in vitro and in vivo, with half-lives spanning from a range of hours to >1 y at physiological pH. A circulating PEG conjugate achieved a 56-fold half-life extension of the 39-aa peptide exenatide in rats, and a noncirculating s.c. hydrogel conjugate achieved a 150-fold extension. Using slow-cleaving linkers, the latter may provide a generic format for once-a-month dosage forms of potent drugs. The releasable linkers provide additional benefits that include lowering C max and pharmacokinetic coordination of drug combinations. metronomic chemotherapy | implant M any drugs and drug candidates are suboptimal or ineffective because of a short duration of action. For example, peptides and proteins with promising therapeutic value often have serum half-lives of only minutes to hours. One solution to this problem involves conjugation to carriers such as polyethylene glycol (PEG), the Fc portion of IgG, serum albumin, and other longlived macromolecules. The large carriers retard kidney filtration and hence increase plasma half-life of the attached drug. Much success has been realized thus far with PEG as the macromolecular carrier. PEG is nontoxic and nonimmunogenic, and the plasma half-life is a function of hydrodynamic size. Conjugation of drugs to PEG with molecular mass ∼40 kDa has been successfully used with peptides, nucleic acids, and small molecules and can afford half-lives of up to ∼7 d in humans; as of 2011, 10 PEGylated peptide-based drugs were approved by the Food and Drug Administration (FDA) and ∼40 were in clinical trials (1, 2).All of the currently marketed PEG-protein conjugates are permanently PEGylated. Attachment of large PEG moieties often reduces activity of the drug, and higher concentrations of conjugate are necessary to achieve the required biological activity. A further limitation is that permanen...

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An overview of once-weekly glucagon-like peptide-1 receptor agonists-available efficacy and safety data and perspectives for the future

Cited by 181 publications

References 69 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

Effects of once‐weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity

Predictable and tunable half-life extension of therapeutic agents by controlled chemical release from macromolecular conjugates

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