Encapsulation of Exenatide in Poly-(<scp>d,l</scp>-Lactide-Co-Glycolide) Microspheres Produced an Investigational Long-Acting Once-Weekly Formulation for Type 2 Diabetes

DeYoung, Mary Beth; MacConell, Leigh; Sarin, Viren; Trautmann, Michael E.; Herbert, Paul

doi:10.1089/dia.2011.0050

Cited by 222 publications

(211 citation statements)

References 29 publications

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“…The pharmacokinetics of once‐weekly exenatide are shaped by the long‐acting formulation, in which exenatide is incorporated in biodegradable poly‐(D,L‐lactide‐co‐glycolide) polymer microspheres, allowing the continuous release of exenatide with once‐weekly therapy 15. Weekly exenatide administration led to clinically significant improvements in glycaemic control that were evident by week 4, and steady‐state concentration of exenatide at approximately week 8 was consistent with previous studies 16, 17, 18, 19.…”

Section: Discussionmentioning

confidence: 99%

Exenatide once weekly improved 24‐hour glucose control and reduced glycaemic variability in metformin‐treated participants with type 2 diabetes: a randomized, placebo‐controlled trial

Frías

Nakhle²,

Ruggles

et al. 2016

Diabetes Obesity Metabolism

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AimTo assess the effects of once‐weekly exenatide on 24‐hour glucose control and variability.Materials and methodsThis double‐blind, placebo‐controlled trial randomized metformin‐treated adults with type 2 diabetes to once‐weekly exenatide 2.0 mg or placebo. Continuous glucose monitoring (CGM) was performed at baseline and weeks 4 and 10. The primary outcome was change in CGM‐measured 24‐hour mean glucose level.ResultsIn the once‐weekly exenatide (n = 60) and placebo (n = 56) groups (modified intention‐to‐treat population), the baseline glycated haemoglobin (HbA1c) concentrations were 8.2% and 8.0%, respectively, and the fasting plasma glucose (FPG) concentration was 9.86 and 9.32 mmol/L, respectively. Once‐weekly exenatide significantly (p < 0.001) reduced 24‐hour mean glucose level versus placebo (week 4, −1.44 vs −0.29 mmol/L; week 10, −1.71 vs −0.17 mmol/L), with consistent control throughout the week. Once‐weekly exenatide significantly reduced FPG and 2‐hour postprandial glucose (PPG) levels versus placebo at week 4 (FPG, −1.65 vs −0.11 mmol/L; PPG, −1.79 vs −0.11 mmol/L) and week 10 (FPG, −2.32 vs −0.28 mmol/L; PPG, −2.46 vs −0.33 mmol/L). At week 10, once‐weekly exenatide reduced the mean amplitude of glucose excursions (MAGE; −0.84 vs 0.16 mmol/L) and standard deviation (s.d.) of mean glucose (−0.35 vs 0.04 mmol/L). By week 10, once‐weekly exenatide‐treated participants spent more time in euglycaemia (once‐weekly exenatide, 77% vs placebo, 58%), less time in hyperglycaemia (22% vs 42%), and a similar time in hypoglycaemia (0.7% vs 0.3%). Common adverse events were injection‐site nodule (once‐weekly exenatide, 10.0% vs placebo, 0.0%), urinary tract infection (6.7% vs 8.9%) and nausea (6.7% vs 0.0%).ConclusionsIn metformin‐treated participants with type 2 diabetes, once‐weekly exenatide significantly improved daily glucose control and reduced glycaemic variability at weeks 4 and 10, as shown by reductions in 24‐hour glucose, FPG and PPG levels, MAGE and s.d., and increased time spent in euglycaemia.

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Section: Discussionmentioning

confidence: 99%

Exenatide once weekly improved 24‐hour glucose control and reduced glycaemic variability in metformin‐treated participants with type 2 diabetes: a randomized, placebo‐controlled trial

Frías

Nakhle²,

Ruggles

et al. 2016

Diabetes Obesity Metabolism

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“…19 Once-weekly exenatide was developed by encapsulating exenatide in microspheres of a biodegradable polymer, resulting in sustained drug delivery over a period of weeks after subcutaneous injection. 18 …”

Section: Study Drugmentioning

confidence: 99%

“…16 A small increase in heart rate has been observed with GLP-1 receptor agonists, which appears to be a class effect. 17 The EXenatide Study of Cardiovascular Event Lowering (EXSCEL) will evaluate the effect of a once-weekly formulation of exenatide (Bydureon) 18 on major cardiovascular events when given in addition to usual care.…”

Section: Introductionmentioning

confidence: 99%

Rationale and design of the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) trial

Holman

Bethel

George

et al. 2016

American Heart Journal

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The primary efficacy hypothesis is that exenatide once-weekly is superior to usual care with respect to the primary composite cardiovascular endpoint. EXSCEL is powered to detect a 15% relative risk reduction in the exenatide once weekly group, with 85% power and a 2-sided 5% alpha. The primary safety hypothesis is that exenatide onceweekly is noninferior to usual care with respect to the primary cardiovascular composite endpoint. Noninferiority will be concluded if the upper limit of the confidence interval is <1.30. 4EXSCEL will assess whether exenatide once-weekly can reduce cardiovascular events in patients with T2DM with a broad range of cardiovascular risk. It will also provide longterm safety information on exenatide once-weekly in people with T2DM. ClinicalTrials.gov Identifier: NCT011443385

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“…Encapsulation of the active molecule, exenatide, into biodegradable poly (D, L-lactideco-glycolide) microspheres enables the continuous release of exenatide from the once-weekly formulation [22].…”

Section: Exenatidementioning

confidence: 99%

Effects of Glucagon-Like Peptide-1 Receptor Agonists on β-Cell Function in Patients with Type 2 Diabetes

Grandy¹,

Shaunik²

2015

J Diabetes Metab

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Type 2 diabetes (T2D) is characterized by insulin resistance and a progressive decline in pancreatic β-cell function. Over time, upregulation of insulin secretion is no longer sufficient to compensate for insulin resistance, leading to fasting hyperglycemia, while β-cell function continues to deteriorate. Effective treatments targeting the underlying pathophysiology of T2D involve early lifestyle interventions and a combination of therapies to counteract insulin resistance and progressive deterioration of β cells. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are one class of antihyperglycemic agents that target multiple pathways, mediating clinical benefits for patients with T2D. This review summarizes the effects of treatment with various GLP-1RAs, including exenatide (twice daily and once weekly), liraglutide, dulaglutide, and lixisenatide, on β-cell function in patients with T2D. β-cell function was assessed in randomized controlled trials and their extension studies using a variety of methods, including glucose and arginine clamp techniques, proinsulin-to-insulin ratio, and homeostatic model assessment of β-cell function (HOMA-B). Exenatide twice daily and liraglutide both improved first-and second-phase insulin secretory responses. In addition, numerous studies reported significant improvements in HOMA-B with exenatide (twice daily and once weekly; range of relative change from baseline: +28-50%; range of absolute change: +5-40%) or liraglutide (range of change vs. placebo: +13-43%). Improvements in HOMA-B were also observed with the newer GLP-1RAs dulaglutide and lixisenatide. In contrast to the effects on HOMA-B, treatment with GLP-1RAs had a lesser effect on insulin sensitivity. Taken together, the results suggest that glucagon-like peptide-1 analogs have a greater effect on β-cell function than insulin sensitivity.

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Encapsulation of Exenatide in Poly-(d,l-Lactide-Co-Glycolide) Microspheres Produced an Investigational Long-Acting Once-Weekly Formulation for Type 2 Diabetes

Cited by 222 publications

References 29 publications

Exenatide once weekly improved 24‐hour glucose control and reduced glycaemic variability in metformin‐treated participants with type 2 diabetes: a randomized, placebo‐controlled trial

Exenatide once weekly improved 24‐hour glucose control and reduced glycaemic variability in metformin‐treated participants with type 2 diabetes: a randomized, placebo‐controlled trial

Rationale and design of the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) trial

Effects of Glucagon-Like Peptide-1 Receptor Agonists on β-Cell Function in Patients with Type 2 Diabetes

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