Effects of Once-Weekly Dosing of a Long-Acting Release Formulation of Exenatide on Glucose Control and Body Weight in Subjects With Type 2 Diabetes

Kim, Dennis; MacConell, Leigh; Zhuang, Dongliang; Kothare, Prajakti A.; Trautmann, Michael E.; Fineman, Mark; Taylor, Kristin

doi:10.2337/dc06-2375

Cited by 417 publications

(363 citation statements)

References 28 publications

Supporting

Mentioning

337

Contrasting

Unclassified

Order By: Relevance

“…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. Continuous exposure of exenatide translated into similar glucose‐lowering effects at the beginning and end of the week.…”

Section: Discussionsupporting

confidence: 87%

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 87%

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

View full text Add to dashboard Cite

show abstract

“…A second study comparing a 16-vs. 24-h GLP-1 infusion in patients indicated that greater efficacy could be achieved with sustained 24-h coverage (38), with no evidence of tachyphylaxis or loss of activity. Finally, treatment with exendin-LAR has been reported to reduce A1C as much as 2% in the high-dose group (39). Since the half-life for exendin-LAR was reported to be 14 -15 days, the data confirms that sustained exposure to a GLP-1 analogue has potential for profound efficacy.…”

Section: Fig 5 Cnto736 Is Present In the Area Of The Hypothalamus Amentioning

confidence: 56%

Protein Engineering Strategies for Sustained Glucagon-Like Peptide-1 Receptor–Dependent Control of Glucose Homeostasis

Picha¹,

Cunningham²,

Drucker³

et al. 2008

Diabetes

View full text Add to dashboard Cite

OBJECTIVE-We have developed a novel platform for display and delivery of bioactive peptides that links the biological properties of the peptide to the pharmacokinetic properties of an antibody. Peptides engineered in the MIMETIBODY platform have improved biochemical and biophysical properties that are quite distinct from those of Fc-fusion proteins. CNTO736 is a glucagon-like peptide 1 (GLP-1) receptor agonist engineered in our MIMETIBODY platform. It retains many activities of native GLP-1 yet has a significantly enhanced pharmacokinetic profile. Our goal was to develop a long-acting GLP-1 receptor agonist with sustained efficacy. RESEARCH DESIGN AND METHODS-In vitro and in vivo activity of CNTO736 was evaluated using a variety of rodent cell lines and diabetic animal models.RESULTS-Acute pharmacodynamic studies in diabetic rodents demonstrate that CNTO736 reduces fasting and postprandial glucose, decreases gastric emptying, and inhibits food intake in a GLP-1 receptor-specific manner. Reduction of food intake following CNTO736 dosing is coincident with detection of the molecule in the circumventricular organs of the brain and activation of c-fos in regions protected by the blood-brain barrier. Diabetic rodents dosed chronically with CNTO736 have lower fasting and postprandial glucose and reduced body weight. CONCLUSIONS-Takentogether, our data demonstrate that CNTO736 produces a spectrum of GLP-1 receptor-dependent actions while exhibiting significantly improved pharmacokinetics relative to the native GLP-1 peptide. Diabetes 57: [1926][1927][1928][1929][1930][1931][1932][1933][1934] 2008 D rug development strategies for therapeutic peptides continue to be challenging despite advances in technologies such as pegylation and lipidation (1-4). Although important biological processes are regulated by peptides, successful development of peptide drugs has been limited and transformation of a metabolically labile peptide into a drug remains challenging. In contrast, considerable advances have been made in the development of antibody therapeutics (5,6). A technology that could link the activity of a target peptide with the pharmacokinetic characteristics of an antibody would be a valuable addition to tools available for drug discovery. To address this need, we developed the MI-METIBODY platform as a novel technology for the display and delivery of bioactive peptides. Using protein design tools, we linked an antibody Fc domain to a bioactive glucagon-like peptide 1 (GLP-1) analog and engineered the construct for optimal biochemical and biophysical properties.GLP-1 is a 30 -amino acid peptide secreted from L-cells of the intestine following nutrient ingestion (7-10). GLP-1 is rapidly degraded in vivo with a half-life of Ͻ2 min and cleared via the kidney (11,12). When circulating glucose concentrations are elevated, GLP-1 increases insulin and decreases glucagon secretion from the pancreas and slows gastric emptying, thereby reducing glucose appearance in the circulation and enhancing glucose clearance from the circul...

show abstract

“…As seen consistently in previous studies [6,7,11,13,14], vildagliptin was weight-neutral. Although vildagliptin is thought to act primarily through increasing plasma levels of the active form of GLP-1 and GLP-1 agonists can lead to substantial weight loss [20], the degree of GLP-1 receptor signalling induced by the more physiological levels of GLP-1 achieved with vildagliptin may underlie the lack of weight gain but be insufficient to elicit significant weight loss.…”

Section: Discussionmentioning

confidence: 99%

Comparison of vildagliptin and acarbose monotherapy in patients with Type 2 diabetes: a 24‐week, double‐blind, randomized trial

et al. 2008

View full text Add to dashboard Cite

Aims To compare the efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor, vildagliptin, with the alpha glucosidase inhibitor, acarbose, in drug-naive patients with Type 2 diabetes.Methods This multi-centre, randomized, double-blind, parallel-arm study compared the efficacy and tolerability of vildagliptin (100 mg daily, given as 50 mg twice daily, n = 441) and acarbose (up to 300 mg daily, given as three equally divided doses, n = 220) during 24-week treatment in drug-naive patients with Type 2 diabetes.Results Monotherapy with vildagliptin or acarbose decreased glycated haemoglobin (HbA 1c ) (baseline ≈ 8.6%) to a similar extent during 24-week treatment. The adjusted mean change from baseline to end-point (AM Δ ) in HbA 1c was − 1.4 ± 0.1% and − 1.3 ± 0.1% in patients receiving vildagliptin and acarbose, respectively, meeting the statistical criterion for non-inferiority (upper limit of 95% confidence interval for between-treatment difference ≤ 0.4%). The decrease in fasting plasma glucose was similar with acarbose ( − 1.5 ± 0.2 mmol/l) and vildagliptin ( − 1.2 ± 0.1 mmol/l). Body weight did not change in vildagliptin-treated patients ( − 0.4 ± 0.1 kg) but decreased in acarbose-treated patients ( − 1.7 ± 0.2 kg, P < 0.001 vs. vildagliptin). The proportion of patients experiencing any adverse event (AE) was 35% vs. 51% in patients receiving vildagliptin or acarbose, respectively; gastrointestinal AEs were significantly more frequent with acarbose (25.5%) than vildagliptin (12.3%, P < 0.001). No hypoglycaemia was reported for either group. ConclusionsVildagliptin is effective and well tolerated in patients with Type 2 diabetes, demonstrating similar glycaemic reductions to acarbose, but with better tolerability. Diabet. Med. 25, 435-441 (2008)

show abstract

Effects of Once-Weekly Dosing of a Long-Acting Release Formulation of Exenatide on Glucose Control and Body Weight in Subjects With Type 2 Diabetes

Cited by 417 publications

References 28 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

Protein Engineering Strategies for Sustained Glucagon-Like Peptide-1 Receptor–Dependent Control of Glucose Homeostasis

Comparison of vildagliptin and acarbose monotherapy in patients with Type 2 diabetes: a 24‐week, double‐blind, randomized trial

Contact Info

Product

Resources

About