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Advances in Therapy Mar 2014A new formulation of exenatide has become available recently that is the first antidiabetic medication for type 2 diabetes mellitus (T2DM) dosed on a weekly schedule.... (Review)
Review
INTRODUCTION
A new formulation of exenatide has become available recently that is the first antidiabetic medication for type 2 diabetes mellitus (T2DM) dosed on a weekly schedule. This review summarizes the pharmacology, efficacy, and safety of exenatide once weekly (exenatide QW). The results are interpreted in terms of the pathophysiology of T2DM, as well as the pharmacology of the new formulation.
METHODS
Relevant literature on exenatide QW and diabetes was identified through PubMed database searches from inception until September 2013.
DISCUSSION
In the new once-weekly formulation of exenatide, the exenatide molecule is dispersed in microspheres. Following subcutaneous injection, these microspheres degrade in situ and slowly release active agent. In clinical trials, therapy with exenatide QW as monotherapy or in combination with other antidiabetic treatments was associated with reductions in glycated hemoglobin (-1.3% to -1.9%), fasting plasma glucose (-32 to -41 mg/dL), and body weight (-2.0 to -3.7 kg). These outcomes were achieved without an associated increase in the rate of hypoglycemic episodes, except when exenatide QW was used in combination with sulfonylureas. The primary tolerability issues in the trials were gastrointestinal adverse events, particularly during the first weeks of use, although the rate of nausea during startup with exenatide QW was lower than that with the related agents, exenatide twice daily and liraglutide once daily.
CONCLUSIONS
Exenatide QW may be particularly well suited to patients who desire the benefits associated with glucagon-like peptide-1 receptor agonists, including significant glycemic control, low risk of hypoglycemia, and moderate weight loss, but prefer the convenience of once-weekly dosing.
Topics: Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Humans; Hypoglycemic Agents; Peptides; Venoms
PubMed: 24535624
DOI: 10.1007/s12325-014-0101-4 -
Drug Design, Development and Therapy 2021To explore the effect of the glucagon-like peptide-1 receptor agonist exenatide on coagulation function and platelet aggregation in patients with type 2 diabetes...
OBJECTIVE
To explore the effect of the glucagon-like peptide-1 receptor agonist exenatide on coagulation function and platelet aggregation in patients with type 2 diabetes mellitus (T2DM).
METHODS
Thirty patients with newly diagnosed T2DM were enrolled as the case group, and 30 healthy people with matching age and sex were selected as the control group. Patients in the case group received exenatide treatment for 8 weeks. The general clinical data and biochemical indicators of all subjects were collected; and their peripheral blood platelet count, coagulation index, nitric oxide (NO), platelet membrane glycoprotein (CD62p), platelet activation complex-1 (PAC-1) and platelet aggregation induced by collagen, epinephrine (EPI), arachidonic acid (AA), and adenosine diphosphate (ADP) were detected.
RESULTS
The fibrinogen, CD62p, PAC-1, and platelet aggregation rates of the case group (pretreatment) are higher than those in the control group (EPI 77.90±6.31 vs 60.15±5.37, ADP 52.89±9.36 vs 47.90±6.16, and AA 76.09±3.14 vs.55.18±3.55); and the NO level is lower in the case group than in the control group (<0.05, respectively). After 8 weeks of exenatide treatment in the case group, the CD62p, PAC-1, and platelet aggregation rates were lower than before the treatment (EPI: 61.96±8.94 vs 77.90±6.31 and AA: 50.98±6.73 vs 76.09±3.14); and the NO level was higher than before the treatment (<0.05, respectively). Pearson correlation analysis showed that the changes in platelet aggregation rates (Δ EPI and ΔAA) of the patients in the case group after 8 weeks of exenatide treatment were positively correlated with the changes in body mass index, waist circumference, weight, blood lipids, fasting plasma glucose, haemoglobin A1c, fibrinogen, CD62p, and PAC-1 and negatively correlated with the changes in high-density lipoprotein and NO (<0.05). Multiple linear regression analysis showed that the changes in NO, CD62p and PAC-1 were independent risk factors affecting the changes in platelet aggregation rates.
CONCLUSION
The GLP-1R agonist exenatide can inhibit the activation state of platelets in patients with T2DM and inhibit thrombosis, which is beneficial to reduce the risk of cardiovascular events.
Topics: Adult; Blood Coagulation; Case-Control Studies; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Male; Middle Aged; Nitric Oxide; P-Selectin; Platelet Aggregation
PubMed: 34285470
DOI: 10.2147/DDDT.S312347 -
Physiological Reports Mar 2023The inotropic effects of glucagon have been recognized for many years, but it has remained unclear whether glucagon signaling is beneficial to cardiac function. We...
The inotropic effects of glucagon have been recognized for many years, but it has remained unclear whether glucagon signaling is beneficial to cardiac function. We evaluated the effects of glucagon alone and in combination with the glucagon-like peptide 1 (GLP-1) receptor agonist exenatide in the isolated perfused rat heart. The isolated perfused rat heart was used to investigate the initial inotropic and chronotropic effects of glucagon and exenatide during aerobic perfusion, and recovery of contractile function following ischaemia/reperfusion. Glucagon, but not exenatide, elicited an acute chronotropic and inotropic response during aerobic perfusion of the rat heart. Compared with control, glucagon improved recovery of left ventricular developed pressure (LVDP) by 33% (p < 0.05) and rate-pressure product (RPP) by 66% (p < 0.001) following ischaemia/reperfusion and amplified the mild recovery enhancement elicited by exenatide in a dose-dependent manner. Glucagon shows inotropic properties in the isolated perfused rat heart and improves contractile recovery following ischaemia/reperfusion, both alone and when co-administered with a GLP-1 receptor agonist. Glucagon and exenatide, a GLP-1 receptor agonist, combine to stimulate greater recovery of postischaemic contractile function in the Langendorff heart. Glucagon was inotropic and chronotropic, yet this initial effect decreased over time and did not account for the increased contractility observed postischaemia/reperfusion.
Topics: Rats; Animals; Exenatide; Glucagon; Glucagon-Like Peptide-1 Receptor; Heart; Reperfusion; Myocardial Contraction; Ischemia
PubMed: 36946315
DOI: 10.14814/phy2.15597 -
The Journal of Clinical Endocrinology... May 2022Sodium-glucose cotransporter-2 inhibitors (SGLT2i) cause less weight loss than expected based on urinary calorie excretion. This may be explained by SGLT2i-induced... (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) cause less weight loss than expected based on urinary calorie excretion. This may be explained by SGLT2i-induced alterations in central reward and satiety circuits, leading to increased appetite and food intake. Glucagon-like peptide-1 receptor agonists are associated with reduced appetite and body weight, mediated by direct and indirect central nervous system (CNS) effects.
OBJECTIVE
We investigated the separate and combined effects of dapagliflozin and exenatide on the CNS in participants with obesity and type 2 diabetes.
METHODS
This was a 16-week, double-blind, randomized, placebo-controlled trial. Obese participants with type 2 diabetes (n = 64, age 63.5 ± 0.9 years, BMI 31.7 ± 0.6 kg/m2) were randomized (1:1:1:1) to dapagliflozin 10 mg with exenatide-matched placebo, exenatide twice daily 10 µg with dapagliflozin-matched placebo, dapagliflozin and exenatide, or double placebo. Using functional MRI, the effects of treatments on CNS responses to viewing food pictures were assessed after 10 days and 16 weeks of treatment.
RESULTS
After 10 days, dapagliflozin increased, whereas exenatide decreased CNS activation in the left putamen. Combination therapy had no effect on responses to food pictures. After 16 weeks, no changes in CNS activation were observed with dapagliflozin, but CNS activation was reduced with dapagliflozin-exenatide in right amygdala.
CONCLUSION
The early increase in CNS activation with dapagliflozin may contribute to the discrepancy between observed and expected weight loss. In combination therapy, exenatide blunted the increased CNS activation observed with dapagliflozin. These findings provide further insights into the weight-lowering mechanisms of SGLT2i and GLP-1 receptor agonists.
Topics: Benzhydryl Compounds; Blood Glucose; Brain; Cues; Diabetes Mellitus, Type 2; Double-Blind Method; Exenatide; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Middle Aged; Obesity; Sodium-Glucose Transporter 2 Inhibitors; Weight Loss
PubMed: 35134184
DOI: 10.1210/clinem/dgac043 -
Journal of Diabetes Investigation Mar 2020To evaluate the efficacy and safety of once-weekly (q.w.) extended-release exenatide after switching from twice-daily (b.i.d.) exenatide in patients with type 2 diabetes. (Clinical Trial)
Clinical Trial
AIMS/INTRODUCTION
To evaluate the efficacy and safety of once-weekly (q.w.) extended-release exenatide after switching from twice-daily (b.i.d.) exenatide in patients with type 2 diabetes.
MATERIALS AND METHODS
This was an investigator-initiated, prospective, single-arm, multicenter study. Individuals with type 2 diabetes who had been treated with exenatide b.i.d. for at least 3 months were enrolled and switched to exenatide q.w. for 24 weeks. The primary end-point was change in HbA1c at week 24 to test the glucose-lowering effect of exenatide q.w. versus exenatide b.i.d.
RESULTS
A total of 58 Japanese individuals with type 2 diabetes completed the study. Glycated hemoglobin was reduced by 0.2% at week 24 (7.2 ± 1.2% vs 7.0 ± 1.2% [56 ± 13 vs 53 ± 13 mmol/mol], 95% confidence interval -0.4 to -0.03%, P < 0.005 for non-inferiority, P = 0.01 for superiority). Fasting plasma glucose was reduced by 12 mg/dL at week 24 (154 ± 46 vs 142 ± 46 mg/dL, P = 0.02). β-Cell function assessed by homeostasis model assessment of β-cell function and C-peptide index was significantly improved at week 24. The incidence of self-reported hypoglycemia was reduced, and treatment satisfaction assessed by the Diabetes Treatment Satisfaction Questionnaire and Diabetes Medication Satisfaction Questionnaire was improved at week 24, with no change in body weight. There was no serious adverse event related to the study drug.
CONCLUSIONS
Switching from exenatide b.i.d. to exenatide q.w. resulted in a reduction in glycated hemoglobin, fasting plasma glucose and the incidence of hypoglycemia, and improvement in β-cell function and treatment satisfaction in patients with type 2 diabetes. These findings will be useful for selecting optimal treatment in individuals with type 2 diabetes.
Topics: Blood Glucose; Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Middle Aged; Prospective Studies; Treatment Outcome
PubMed: 31518492
DOI: 10.1111/jdi.13146 -
International Immunopharmacology Feb 2023Obesity is associated with multiple comorbidities, such as metabolic abnormalities and cognitive dysfunction. Moreover, accumulating evidence indicates that...
The GLP-1 receptor agonist exenatide ameliorates neuroinflammation, locomotor activity, and anxiety-like behavior in mice with diet-induced obesity through the modulation of microglial M2 polarization and downregulation of SR-A4.
Obesity is associated with multiple comorbidities, such as metabolic abnormalities and cognitive dysfunction. Moreover, accumulating evidence indicates that neurodegenerative disorders are associated with chronic neuroinflammation. GLP-1 receptor agonists (RAs) have been extensively studied as a treatment for type 2 diabetes. Emerging evidence has demonstrated a protective effect of GLP-1 RAs on neurodegenerative disease, which is independent of its glucose-lowering effects. In this study, we aimed to examine the effects of a long-acting GLP-1 RA, exenatide, on high-fat diet (HFD)-induced neuroinflammation and related brain function impairment. First, mice treated with exenatide exhibited significantly reduced HFD-increased body weight and blood glucose. In an open field test, exenatide treatment ameliorated the reduction in local motor activity and anxiety in HFD-fed mice. Moreover, HFD induced astrogliosis, microgliosis, and upregulation of IL-1β, IL-6 and TNF-α in hippocampus and cortex. Exenatide treatment reduced HFD-induced astrogliosis and IL-1β and TNF-α expressions. Moreover, exenatide increased phosphor-ERK and M2-type microglia marker arginase-1 expression in the hippocampus and cortex. In addition, we found that scavenger receptor-A4 protein expression was induced by HFD and was subsequently inhibited by exenatide. SR-A4 knockout reversed the locomotor activity impairment but not the anxiety behavior caused by HFD consumption. SR-A4 knockout also reduced HFD-induced neuroinflammation, as shown by the reduced expression of GFAP and IBA-1 compared with that in wild-type control mice. These results demonstrate that exenatide decreases HFD-increased neuroinflammation and promotes anti-inflammatory M2 differentiation. The inhibition of SR-A4 by exenatide exerts anti-inflammatory activity.
Topics: Mice; Animals; Exenatide; Microglia; Glucagon-Like Peptide-1 Receptor; Neuroinflammatory Diseases; Down-Regulation; Diabetes Mellitus, Type 2; Tumor Necrosis Factor-alpha; Neurodegenerative Diseases; Gliosis; Obesity; Diet, High-Fat; Glucagon-Like Peptide 1; Locomotion; Anxiety; Mice, Inbred C57BL
PubMed: 36587502
DOI: 10.1016/j.intimp.2022.109653 -
British Journal of Clinical Pharmacology Mar 2017The aim of the present analysis was to develop a core population pharmacokinetic model for the pharmacokinetic properties of immediate-release (IR) exenatide, which can...
AIM
The aim of the present analysis was to develop a core population pharmacokinetic model for the pharmacokinetic properties of immediate-release (IR) exenatide, which can be used in subsequent analyses of novel sustained-release formulations.
METHODS
Data from eight clinical trials, evaluating a wide range of doses and different administration routes, were available for analysis. All modelling and simulations were conducted using the nonlinear mixed-effect modelling program NONMEM. External model validation was performed using data from the phase III clinical trials programme through standard visual predictive checks.
RESULTS
The pharmacokinetics of IR exenatide was described by a two-compartment model, and the absorption of subcutaneous exenatide was described with a sequential zero-order rate constant followed by a saturable nonlinear absorption process. Drug elimination was characterized by two parallel routes (linear and nonlinear), with significant relationships between renal function and the linear elimination route, and between body weight and volume of distribution. For a subject with normal renal function, the linear clearance was estimated to be 5.06 l hr . The nonlinear elimination was quantified with a Michaelis-Menten constant (K ) of 567 pg ml and a maximum rate of metabolism (V ) of 1.6 μg h . For subcutaneous administration, 37% of the subcutaneous dose is absorbed via the zero-order process, and the remaining 63% via the nonlinear pathway.
CONCLUSIONS
The present analysis provides a comprehensive population pharmacokinetic model for exenatide, expanding the elimination process to include both linear and nonlinear components, providing a suitable platform for a broad range of concentrations and patient conditions that can be leveraged in future modelling efforts of sustained-release exenatide formulations.
Topics: Adolescent; Adult; Aged; Clinical Trials as Topic; Computer Simulation; Dose-Response Relationship, Drug; Exenatide; Female; Humans; Hypoglycemic Agents; Male; Middle Aged; Models, Biological; Nonlinear Dynamics; Peptides; Venoms; Young Adult
PubMed: 27650681
DOI: 10.1111/bcp.13135 -
Advances in Clinical and Experimental... May 2021Microvascular dysfunction is one of the most serious complications of diabetic retinopathy (DR). As a novel treatment drug for type 2 diabetes, exenatide possesses...
BACKGROUND
Microvascular dysfunction is one of the most serious complications of diabetic retinopathy (DR). As a novel treatment drug for type 2 diabetes, exenatide possesses protective properties against retinal neurodegeneration. Sphingosine-1-phosphate receptor 2 (S1PR2) could regulate blood glucose in diabetes, and inhibition of S1PR2 is involved in the treatment of diabetes. However, the mechanism of exenatide in human retinal vascular endothelial cells (hRVECs) has not been fully defined.
OBJECTIVES
We tested the hypothesis that S1PR2 plays a vital role in high glucose (HG)-induced hRVECs, and that exenatide could ameliorate HG-induced hRVEC injury by regulating S1PR2 production.
MATERIAL AND METHODS
The hRVECs underwent HG-stimulation. Quantitative real-time polymerase chain reaction (RT-qPCR) and western blot were performed to examine the expression of S1PR2. Oxidative stress levels, inflammatory markers and cell apoptosis were detected using reactive oxygen species (ROS) staining, enzyme-linked immunosorbent assay (ELISA) kits and TUNEL staining.
RESULTS
High glucose increased the level of S1PR2 in hRVECs and reduced the expression of glucagon-like peptide-1 receptor (GLP1R) compared to the control group. Exenatide decreased the level of S1PR2 induced by HG. Sphingosine-1 blocked the effects of exenatide, alleviating the ROS and cell apoptosis induced by HG. JTE-013 treatment protected hRVECs from injury by HG. The inhibitory effects of exenatide on S1PR2 expression lessened HG-induced hRVEC injury.
CONCLUSIONS
The results demonstrate a possible mechanism of exenatide mediated inhibition of S1PR2 synthesis, and support S1PR2 as a novel target for treating DR.
Topics: Apoptosis; Diabetes Mellitus, Type 2; Endothelial Cells; Exenatide; Glucose; Humans; Inflammation; Oxidative Stress; Reactive Oxygen Species; Sphingosine-1-Phosphate Receptors
PubMed: 33984196
DOI: 10.17219/acem/133483 -
JCI Insight Jan 2020Friedreich ataxia is an autosomal recessive neurodegenerative disease associated with a high diabetes prevalence. No treatment is available to prevent or delay disease...
Friedreich ataxia is an autosomal recessive neurodegenerative disease associated with a high diabetes prevalence. No treatment is available to prevent or delay disease progression. Friedreich ataxia is caused by intronic GAA trinucleotide repeat expansions in the frataxin-encoding FXN gene that reduce frataxin expression, impair iron-sulfur cluster biogenesis, cause oxidative stress, and result in mitochondrial dysfunction and apoptosis. Here we examined the metabolic, neuroprotective, and frataxin-inducing effects of glucagon-like peptide-1 (GLP-1) analogs in in vivo and in vitro models and in patients with Friedreich ataxia. The GLP-1 analog exenatide improved glucose homeostasis of frataxin-deficient mice through enhanced insulin content and secretion in pancreatic β cells. Exenatide induced frataxin and iron-sulfur cluster-containing proteins in β cells and brain and was protective to sensory neurons in dorsal root ganglia. GLP-1 analogs also induced frataxin expression, reduced oxidative stress, and improved mitochondrial function in Friedreich ataxia patients' induced pluripotent stem cell-derived β cells and sensory neurons. The frataxin-inducing effect of exenatide was confirmed in a pilot trial in Friedreich ataxia patients, showing modest frataxin induction in platelets over a 5-week treatment course. Taken together, GLP-1 analogs improve mitochondrial function in frataxin-deficient cells and induce frataxin expression. Our findings identify incretin receptors as a therapeutic target in Friedreich ataxia.
Topics: Adolescent; Adult; Aged; Animals; Brain; Cerebellum; Disease Models, Animal; Exenatide; Female; Friedreich Ataxia; Ganglia, Spinal; Gene Expression Regulation; Gene Knock-In Techniques; Glucagon-Like Peptide 1; Humans; Insulin; Insulin-Secreting Cells; Iron; Iron-Binding Proteins; Male; Mice; Mice, Knockout; Middle Aged; Mitochondria; Oxidative Stress; Reactive Oxygen Species; Trinucleotide Repeat Expansion; Young Adult; Frataxin
PubMed: 31877117
DOI: 10.1172/jci.insight.134221 -
Journal of Managed Care & Specialty... Sep 2018This article provides an overview of the efficacy and safety of once-weekly glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in the treatment of type 2 diabetes... (Review)
Review
UNLABELLED
This article provides an overview of the efficacy and safety of once-weekly glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in the treatment of type 2 diabetes mellitus (T2DM). GLP-1 RAs stimulate pancreatic GLP-1 receptors, which increases insulin secretion, delays gastric emptying, and increases satiety. As a class, GLP-1 RAs lower A1c levels and have been associated with reductions in weight and blood pressure and reduced fluctuations in glucose levels, and they have a low risk of hypoglycemia. Exenatide extended release (ER) and dulaglutide monotherapy have shown similar or superior reductions in A1c and weight compared with various oral antidiabetic drugs (OADs). Semaglutide has been shown to reduce both A1c and body weight compared with placebo and, in head-to-head studies versus both exenatide ER and dulaglutide, showed greater reductions in A1c and body weight. Once-weekly GLP-1 RAs have also been evaluated as add-on therapy in the continuum of care for the treatment of T2DM in combination with a variety of background medications, including 1 or more OADs (metformin, sulfonylureas, and/or thiazolidinediones), basal insulin, and prandial insulin. Gastrointestinal adverse events (e.g., nausea, vomiting, and diarrhea) are the most common side effects with once-weekly GLP-1 RAs. Rates of hypoglycemia, and especially major/severe hypoglycemia, are low with once-weekly GLP-1 RAs but, as expected, are higher when used in combination with sulfonylureas or insulin. These once-weekly GLP-1 RAs provide a safe and effective treatment option for patients with T2DM and may offer improved convenience and possibly greater adherence compared with daily GLP-1 RAs.
DISCLOSURES
This supplement was funded by Novo Nordisk. Handelsman reports research grants from Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Grifols, Janssen, Lexicon, Merck, Novo Nordisk, Regeneron, and Sanofi; speaker fees from Amarin, Amgen, AstraZeneca, Boehringer Ingelheim-Lilly, Janssen, Merck, Novo Nordisk, Regeneron, and Sanofi; and has served in advisory capacity to Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Eisai, Intarcia, Janssen, Lilly, Merck, Merck-Pfizer, Novo Nordisk, Regeneron, and Sanofi. Cannon reports speaker fees and owns stock in Novo Nordisk. Shannon reports consultant and speaker fees from Novo Nordisk and Boehringer Ingelheim-Lilly Alliance. Schneider reports advisory board fees from Intarcia, Lilly, and Novo Nordisk. Wyne has nothing to disclose.
Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycemic Index; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Recombinant Fusion Proteins; Treatment Outcome
PubMed: 30156445
DOI: 10.18553/jmcp.2018.24.9-a.s14