Drug release profile of a novel exenatide long-term drug delivery system (OKV-119) administered to cats.

Beneficial weight-loss properties of glucagon-like peptide-1 receptor agonists (GLP-1RA) in obese people, with corresponding improvements in cardiometabolic risk factors, are well established. OKV-119 is an investigational drug delivery system that is being developed for the long-term delivery of the GLP-1RA exenatide to feline patients. The purpose of this study was to evaluate the drug release characteristics of subcutaneous OKV-119 implants configured to release exenatide for 84 days. Following a 7-day acclimation period, five purpose-bred cats were implanted with OKV-119 protypes and observed for a 112-day study period. Food intake, weekly plasma exenatide concentrations and body weight were measured. Exenatide plasma concentrations were detected at the first measured timepoint (Day 7) and maintained above baseline for over 84 Days. Over the first 28 days, reduced caloric intake and a reduction in body weight were observed in four of five cats. In these cats, a body weight reduction of at least 5% was maintained throughout the 112-day study period. This study demonstrates that a single OKV-119 implant can deliver the GLP-1RA exenatide for a months long duration. Results suggest that exposure to exenatide plasma concentrations ranging from 1.5 ng/ml to 4 ng/ml are sufficient for inducing weight loss in cats.

Ischemia-induced retinal injury is attenuated by Neurovespina, a peptide from the venom of the social wasp Polybia occidentalis.

Neurovespina is a synthetic peptide modified from Occidentalin-1202, a nine amino acid residue peptide isolated from the venom of the social wasp Polybia occidentalis. Previous studies showed that this peptide has a neuroprotective effect on the central nervous system, but its action on the eye has not been explored. So, the objective of this work was to investigate the neuroprotective effect of Neurovespina on the retina and its angiogenic potential in the chicken chorioallantoic membrane (CAM). Retinal ischemia was induced in rats by acute elevation of intraocular pressure (IOP). Electroretinography (ERG) measurements, histopathological and immunohistochemical analysis, and transmission electronic microscopy (TEM) records were performed to check the neuroprotection effect of Neurovespina in the retina of the animals. The angiogenic activity of the peptide was investigated by CAM assay. The results showed that Neurovespina was able to reduce the effects induced by ischemic injury, preventing the reduction of a- and b-waves in the scotopic ERG. Histopathological and immunohistochemistry assays showed that Neurovespina, mainly at 60 µg/ml, protected all layers of the retina. The CAM assay revealed that the peptide promoted the reduction of CAM vessels. So, Neurovespina was able to protect retinal cells from ischemic insult and has an antiangiogenic effect, which can be considered as a promising neuroprotective agent for intravitreal application.

Induced Disassembly of a Virus-like Particle under Physiological Conditions for Venom Peptide Delivery.

Virus-like particles (VLPs) show considerable promise for the in vivo delivery of therapeutic compounds such as bioactive venom peptides. While loading and targeting protocols have been developed for numerous VLP prototypes, induced disassembly under physiological conditions of neutral pH, moderate temperature, and aqueous medium remain a challenge. Here, we implement and evaluate a general mechanism, based on ring-opening metathesis polymerization (ROMP), for controllable VLP disassembly. This mechanism is independent of cell-specific factors or the manipulation of environmental conditions such as pH and temperature that cannot be readily controlled in vivo. The ROMP substrate norbornene is covalently conjugated to surface-exposed lysine residues of a P22 bacteriophage-derived VLP, and ROMP is induced by treatment with the water-soluble ruthenium catalyst AquaMet. Disruption of the P22 shell and release of a GFP reporter is confirmed via native agarose electrophoresis, TEM, and dynamic light scattering (DLS) analyses. Our ROMP disassembly strategy does not depend on the particular structure or morphology of the P22 nanocontainer and is adaptable to other VLP prototypes for the potential delivery of venom peptides for pharmacological applications.

Animal venoms: therapeutic tools for tackling Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative pathology of the central nervous system, mainly involving the selective and progressive loss of dopaminergic neurons from the substantia nigra, resulting in motor and non-motor symptoms. PD remains an incurable ailment; thus, treatments are limited to symptom alleviation. With long-term use, conventional treatments can become inefficient, often triggering possible side effects. Considering these drawbacks, drug discovery constantly turns to nature as a source of efficient therapeutics. Thus, this review explores animal venoms as a rich source of bioactive compounds with potent neuropharmacological profiles for the development of effective adjuvant treatments with fewer side effects, ultimately aiming for the neuroprotection of dopaminergic neurons and the symptomatic relief of PD.

On the form and bio-mechanics of venom-injection elements.

A wide variety of animals-from insects to snakes-crucially depend on their ability to inject venom into their target, be it their prey or their predator. To effectively deliver their venom, venomous animals use a specialized biomechanical element whose tip must penetrate through the integument of the target. During this process, the tip of the venom-injection element (VIE) is subject to local forces, which may deform it and cause considerable structural damage to the VIE, with devastating consequences for the survival of the animal or, in the case of eusocial insects, to the colony. Hence, it is plausible that millions of years of evolution have carefully 'shaped' the architecture of VIEs across different taxa toward a similar mechanical function, namely, to effectively resist the mechanical forces exerted on the tip. The present study aims to identify such a common architecture by analyzing the form-function relationships in various biological VIEs. A universal structural modeling, which quantifies the fundamental geometrical characteristics of a wide range of VIEs is constituted, and a theoretical mechanical framework that analytically correlates these characteristics with the material stress fields is introduced. This investigation reveals that the architecture of biological VIEs reduces the magnitude of applied stresses and confines the maximal stress to the near-tip region of the element. The presented analytical approach and modeling can be straightforwardly applied to various other types of bio-mechanical elements and can potentially be employed for developing a new class of microscopic injection elements for bio-medical and engineering applications. STATEMENT OF SIGNIFICANCE: Venomous animals-both vertebrate and invertebrate-use an extremely wide variety of venom-injection elements to incapacitate their prey or predator. Despite the clear differences in their typical dimensions, shapes, and evolutionary paths, all venom-injection elements have evolved to perform a single mechanical function, namely, to penetrate a target surface. Accordingly, the architecture of many such elements appears to follow similar principles and their material exhibits similar stress characteristics upon biologically relevant mechanical loadings. The current study introduces a theoretical model that draws connections between the 'universal' structural characteristics of such elements and their bio-mechanical functions. It is found that all examined venom-injection elements provide extreme load-bearing capabilities and unusual post-failure functionalities, which are in good agreement with the wide range of numerical and experimental findings from the literature. The emerging theoretical insights from this study thus shed light on the biomechanical origins of the naturally evolved forms of various biological organisms, including bee and wasp stingers, spider and snake fangs, porcupine fish spines, and scorpion stingers.

Valuing injection frequency and other attributes of type 2 diabetes treatments in Australia: a discrete choice experiment.

BACKGROUND: Multiple pharmacotherapy options are available to control blood glucose in Type 2 Diabetes Mellitus (T2DM). Patients and prescribers may have different preferences for T2DM treatment attributes, such as mode and frequency of administration, based on their experiences and beliefs which may impact adherence. As adherence is a pivotal issue in diabetes therapy, it is important to understand what patients value and how they trade-off the risks and benefits of new treatments. This study aims to investigate the key drivers of choice for T2DM treatments, with a focus on injection frequency, and explore patients' associated willingness-to-pay. METHODS: A discrete choice experiment (DCE) was used to present patients with a series of trade-offs between different treatment options, injectable and oral medicines that were made up of 10 differing levels of attributes (frequency and mode of administration, weight change, needle type, storage, nausea, injection site reactions, hypoglycaemic events, instructions with food and cost). A sample of 171 Australian consenting adult T2DM patients, of which 58 were receiving twice-daily injections of exenatide and 113 were on oral glucose-lowering treatments, completed the national online survey. An error components model was used to estimate the relative priority and key drivers of choice patients place on different attributes and to estimate their willingness to pay for new treatments. RESULTS: Injection frequency, weight change, and nausea were shown to be important attributes for patients receiving injections. Within this cohort, a once-weekly injection generated an additional benefit over a twice-daily injection, equivalent to a weighted total willingness to pay of AUD$22.35 per month. CONCLUSIONS: Based on the patient preferences, the importance of frequency of administration and other non-health benefits can be valued. Understanding patient preferences has an important role in health technology assessment, as the identification of the value as well as the importance weighting for each treatment attribute may assist with funding decisions beyond clinical trial outcomes.

Glucagon-Like Peptide-1 Receptor Agonist and Glucagon Increase Glucose-Stimulated Insulin Secretion in Beta Cells via Distinct Adenylyl Cyclases.

Diabetes mellitus is a chronic disease in which the pancreas no longer produces enough insulin. Pancreatic alpha cell mass increases in response to insufficient insulin secretion. However, the reason for this increase is not clear. It is possible that the increased alpha-cells may stimulate compensatory insulin release in response to the insufficient insulin such as insulin resistance. In this study, we investigated whether glucagon and glucagon-like peptide-1 (GLP-1), hormones produced by alpha cells, contribute to insulin secretion in INS-1 cells, a beta cell line. We confirmed that alpha cell area in the pancreatic islets and glucagon secretion were increased in HFD-induced obese mice. Co-treatment with glucagon and exendin-4 (Ex-4), a GLP-1 receptor agonist, additively increased glucose-stimulated insulin secretion in INS-1 cells. In parallel, cAMP production was also additively increased by co-treatment with these hormones. The increase of insulin secretion by Ex-4 in the presence of high glucose was inhibited by 2'5'-dideoxyadenosine, a transmembrane adenylyl cyclase inhibitor, but not by KH-7, a soluble adenylyl cyclase inhibitor. The increase of insulin secretion by glucagon in INS-1 cells was inhibited by both 2'5'-dideoxyadenosine and KH-7. We suggest that glucagon and GLP-1 produced from alpha cells additively increase cAMP and insulin secretion in the presence of high glucose via distinct adenylyl cyclases in INS-1 cells, and this may contribute to the compensatory increase of insulin secretion by an increase of pancreatic alpha cell mass under conditions of insulin resistance.

The use of low molecular weight protamine to enhance oral absorption of exenatide.

Although oral delivery of exenatide has significant advantages, its poor permeability through intestinal epithelial membranes and rapid digestion by pepsin and ereptase in the gastrointestinal tract make effective oral delivery of exenatide a formidable challenge. In this study, we constructed a zinc ion (Zn2+) and exenatide complex functionalized nanoparticle (NP) oral delivery system to overcome the above-mentioned issue. Polyethylene glycol-poly(lactic-co-glycolic acid) (PEG-PLGA) was used as a drug carrier to escape enzymatic degradation in the gastrointestinal tract, and low molecular weight protamine (LMWP) was used as a functional group to increase penetration of NPs into the intestinal epithelium. The functionalized NPs exhibited significantly improved penetration across the intestinal epithelium, as shown by cell uptake and transmembrane transport experiments. Moreover, a significant hypoglycemic effect was observed in diabetic rats. The relative bioavailability of the orally administered functionalized NPs vs. subcutaneous injection was 7.44%, 29-fold that of the exenatide-Zn2+ solution group. These findings indicate that our modification could effectively improve exenatide treatment.

Symbiotic polydnavirus and venom reveal parasitoid to its hyperparasitoids.

Symbiotic relationships may provide organisms with key innovations that aid in the establishment of new niches. For example, during oviposition, some species of parasitoid wasps, whose larvae develop inside the bodies of other insects, inject polydnaviruses into their hosts. These symbiotic viruses disrupt host immune responses, allowing the parasitoid's progeny to survive. Here we show that symbiotic polydnaviruses also have a downside to the parasitoid's progeny by initiating a multitrophic chain of interactions that reveals the parasitoid larvae to their enemies. These enemies are hyperparasitoids that use the parasitoid progeny as host for their own offspring. We found that the virus and venom injected by the parasitoid during oviposition, but not the parasitoid progeny itself, affected hyperparasitoid attraction toward plant volatiles induced by feeding of parasitized caterpillars. We identified activity of virus-related genes in the caterpillar salivary gland. Moreover, the virus affected the activity of elicitors of salivary origin that induce plant responses to caterpillar feeding. The changes in caterpillar saliva were critical in inducing plant volatiles that are used by hyperparasitoids to locate parasitized caterpillars. Our results show that symbiotic organisms may be key drivers of multitrophic ecological interactions. We anticipate that this phenomenon is widespread in nature, because of the abundance of symbiotic microorganisms across trophic levels in ecological communities. Their role should be more prominently integrated in community ecology to understand organization of natural and managed ecosystems, as well as adaptations of individual organisms that are part of these communities.

Exendin-4 relieves the inhibitory effects of high glucose on the proliferation and osteoblastic differentiation of periodontal ligament stem cells.

BACKGROUND: With the impaired regenerative potential in patients with diabetes mellitus (DM), Periodontal ligament stem cells (PDLSCs) are regarded as an attractive source of stem cells for periodontal cytotherapy. Recent studies have shown that Exendin-4 (Ex-4) exerts cell-protective effects and bone remodeling ability on many types of cells. The aim of this study was to investigate whether Ex-4 alleviates the inhibition of high glucose on the proliferation and osteogenic differentiation of PDLSCs. METHODS: PDLSCs were incubated in medium supplemented with 5.5 mM d-glucose (NG), 30 mM d-glucose (HG), NG plus Ex-4, and HG plus different concentration (1, 10, 20, 100 nM) of Ex-4 respectively. Cell proliferation was detected by CCK-8 assay and cell cycle analysis. Osteogenesis was assessed by Alizarin Red S staining and evaluation of the mRNA expression of Runx2, ALP and Osx at day 7, 14 and 21. Intracellular level of reactive oxygen species (ROS) was detected using 5-(and-6)-chloromethyl-2',7'-dichlorodihydro-fluorescein diacetate (CMH2DCF-DA). RESULTS: The proliferation ability, mineralized nodules forming capacity and the mRNA expression of Runx2, ALP and Osx of PDLSCs in HG group were decreased, the ROS level was increased compared to NG group. With the treatment of Ex-4, the HG-inhibited proliferation ability and osteogenic differentiation ability of PDLSCs were significantly reversed, the HG-increased ROS level could be down-regulated. Moreover, Ex-4 enhanced the osteogenic differentiation of normal PDLSCs. CONCLUSIONS: Ex-4 alleviates the inhibitory effect of HG on the proliferation and osteoblastic differentiation of PDLSCs, and has a significant enhance in the osteoblastic differentiation of normal PDLSCs, giving new insights into the possible therapeutic method of diabetic periodontitis.

Exenatide with Metformin Ameliorated Visceral Adiposity and Insulin Resistance.

BACKGROUND: To study the effectiveness of exenatide with metformin and sequential treatment with exenatide and glargine added to metformin and their influence on insulin sensitivity and adipose distribution. METHODS: 20 newly diagnosed obese type 2 diabetic patients were enrolled, and 2-month washout treatment of metformin, 6-month exenatide treatment, and 6-month glargine treatment were administrated sequentially accompanied with previous metformin. Glucolipid metabolic parameters were compared among groups. Adipose distribution was quantified with computerized tomography according to anatomy, dividing into visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), adding up to total adipose tissue (TAT). RESULTS: The 6-month exenatide treatment dramatically ameliorated the glucose and lipid profile, improved insulin sensitivity, and mainly decreased VAT and also the ratio of VAT/SAT (RVS). The following 6-month glargine treatment increased VAT. The whole 12-month sequential treatment with exenatide and glargine added to metformin basically improved the insulin sensitivity and glucolipid control though VAT rebounded at the end, however without deteriorating the other parameters. CONCLUSION: Exenatide is an ideal treatment for obese type 2 diabetic patients in the aspect of adipose tissue distribution. Sequential treatment of exenatide and glargine could be an alternative for low-income patients who cannot afford GLP-1 agonist for long time. This trial is registered with ChiCTR-OOC-17013679.

Exenatide once weekly for smoking cessation: study protocol for a randomized clinical trial.

BACKGROUND: Cigarette smoking is the greatest preventable cause of morbidity and premature mortality in the United States. Approved pharmacological treatments for smoking cessation are marginally effective, underscoring the need for improved pharmacotherapies. A novel approach might use glucagon-like peptide-1 (GLP-1) agonists, which reduce alcohol and drug use in preclinical studies. GLP-1 is produced in the intestinal L-cells and in the hindbrain. The peptide maintains glucose homeostasis and reduces food intake. Several GLP-1 agonists are used clinically to treat type 2 diabetes and obesity, but none have been tested in humans to reduce smoking. AIMS: We will examine whether extended-release exenatide reduces smoking, craving, and withdrawal symptoms, as well as cue-induced craving for cigarettes. METHODS: We will enroll prediabetic and/or overweight treatment seeking smokers (n = 90) into a double-blind, placebo-controlled, randomized clinical trial. Participants will be randomized in a 1:1 ratio to receive exenatide or placebo. All participants will receive transdermal nicotine replacement therapy (NRT) and behavioral counseling. Abstinence from smoking (verified via expired CO level of ≤5 ppm), craving (Questionnaire of Smoking Urges score), and withdrawal symptoms (Wisconsin Scale of Withdrawal Symptoms score) will be assessed weekly during 6 weeks of treatment and at 1 and 4 weeks posttreatment. Cue-induced craving for cigarettes will be assessed at baseline and at 3 weeks of treatment following virtual reality exposure. EXPECTED OUTCOMES: We hypothesize that exenatide will increase the number of participants able to achieve complete smoking abstinence above that achieved via standard NRT and that exenatide will reduce craving and withdrawal symptoms, as well as cue-induced craving for cigarettes.

Sustained exenatide delivery via intracapsular microspheres for improved survival and function of microencapsulated porcine islets.

The ability of glucagon-like peptide-1 analogs to enhance glucose-dependent insulin secretion and to inhibit ß cell apoptosis could be of potential benefit for islet transplantation. In this study, we investigated the effect of sustained local delivery of exenatide, a synthetic exendin-4, on the in vitro viability and function of encapsulated porcine islets. Prior to encapsulation, we fabricated exenatide-loaded poly(latic-co-glycolic acid) microspheres, and investigated their release behavior with different initial drug-loading amounts. Exenatide-loaded microspheres, exhibiting a sustained release over 21 days, were subsequently chosen and co-encapsulated with porcine islets in alginate microcapsules. During the 21-day period, the islets co-encapsulated with the exenatide-loaded microspheres exhibited improved survival and glucose-stimulated insulin secretion, compared to those without. This suggested that the intracapsular sustained delivery of exenatide via microspheres could be a promising strategy for improving survival and function of microencapsulated porcine islets for islet xenotransplantation.

Exendin-4-encapsulated dissolving microneedle arrays for efficient treatment of type 2 diabetes.

Dissolving microneedles (DMNs) are microscopic needles capable of delivering encapsulated compounds and releasing them into the skin in a minimally invasive manner. Most studies indicate that encapsulating therapeutics in DMNs is an efficacious approach; however, the importance of evaluating the activity of encapsulated compounds, during the fabrication process, has not been examined in detail. Conducting an analysis of thermal, chemical, and physical stress factors, including temperature, pH, and the interaction of the polymer and therapeutics mixture during preparation, is essential for retaining the activity of encapsulated therapeutics during and after fabrication. Here, we optimised the thermal, chemical, and physical parameters for the fabrication of exendin-4 (Ex-4)-encapsulated DMNs (Ex-4 DMNs). Ex-4, a peptide agonist of glucagon-like peptide (GLP) receptor, is used for glycaemic control in patients with type 2 diabetes. Our findings indicate that optimising the parameters involved in DMN fabrication retained the activity of Ex-4 by up to 98.3 ± 1.5%. Ex-4 DMNs reduced the blood-glucose level in diabetic mice with efficiency similar to that of a subcutaneous injection. We believe that this study paves way for the commercialisation of an efficient and minimally invasive treatment for patients with type 2 diabetes.

Mitochondrial Dysfunction in Diabetic Cardiomyopathy: Effect of Mesenchymal Stem Cell with PPAR-γ Agonist or Exendin-4.

Therapy targeting mitochondria may provide novel ways to treat diabetes and its complications. Bone marrow-derived mesenchymal stem cells (MSCs), the peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists and exendin-4; an analog of glucagon-like peptide-1 have shown cardioprotective properties in many cardiac injury models. So, we evaluated their effects in diabetic cardiomyopathy (DCM) in relation to mitochondrial dysfunction. This work included seven groups of adult male albino rats: the control group, the non-treated diabetic group, and the treated diabetic groups: one group was treated with MSCs only, the second with pioglitazone only, the third with MSCs and pioglitazone, the forth with exendin-4 only and the fifth with MSCs and exendin-4. All treatments were started after 6 weeks from induction of diabetes and continued for the next 4 weeks. Blood samples were collected for assessment of glucose, insulin, and cardiac enzymes. Hearts were removed and used for isolated heart studies, and gene expression of: myocyte enhancer factor-2 (Mef2), peroxisome proliferator-activated receptor gamma coactivator1-alpha (PGC1α), nuclear factor kappa B (NFKB) and autophagic markers: light chain 3 (LC3) and beclin by real-time reverse transcription-polymerase chain reaction. The cardiac mitochondrial protein levels of cardiolipin and uncoupler protein 2 (UCP2) were assessed by ELISA and western blot technique, respectively. Treated groups showed significant improvement in left ventricular function associated with improvement in the cardiac injury and myopathic markers compared to the non treated diabetic group. NFKB was down-regulated while cardiolipin, PGC1α, LC.3 and beclin were up-regulated in all treated groups. These data suggest that the cardioprotective effects of MSCs, exendin-4 or pioglitazone based on their ability to improve mitochondrial functions through targeting inflammatory and autophagy signaling. The co- administration of pioglitazone or exendin-4 with MSCs showed significant superior improvement compared with MSCs alone, indicating the ability to use them in supporting cardioprotective effects of MSCs.

Efficacy and tolerability of the new autoinjected suspension of exenatide once weekly versus exenatide twice daily in patients with type 2 diabetes.

AIMS: To simplify administration of aqueous exenatide once weekly, which requires reconstitution, the exenatide microspheres have been reformulated in a ready-to-use autoinjector with a Miglyol diluent (exenatide QWS-AI). This study compared the efficacy and safety of exenatide QWS-AI with the first-in-class glucagon-like peptide-1 receptor agonist exenatide twice daily (BID). MATERIALS AND METHODS: This randomized, open-label, controlled study in patients with type 2 diabetes using diet and exercise or taking stable oral glucose-lowering medication randomized patients 3:2 to either exenatide QWS-AI (2 mg) or exenatide BID (10 µg) for 28 weeks. The primary outcome was the 28-week change in glycated haemoglobin (HbA1c). A subset of patients completed a standardized meal test for postprandial and pharmacokinetic assessments. RESULTS: A total of 375 patients (mean HbA1c, 8.5% [69 mmol/mol]; body mass index, 33.2 kg/m2 ; diabetes duration, 8.5 years) received either exenatide QWS-AI (n = 229) or exenatide BID (n = 146); HbA1c was reduced by -1.4% and -1.0%, respectively (least-squares mean difference, -0.37%; P = .0072). More patients achieved HbA1c <7.0% with exenatide QWS-AI (49.3%) than with exenatide BID (43.2%; P = .225). Body weight was reduced in both groups (P = .37 for difference). Gastrointestinal adverse events (AEs) were reported in 22.7% (exenatide QWS-AI) and 35.6% (exenatide BID) of patients; fewer patients in the exenatide QWS-AI group withdrew because of AEs than in the exenatide BID group. Minor hypoglycaemia occurred most often with concomitant sulfonylurea use. CONCLUSIONS: Exenatide QWS-AI was associated with a greater reduction in HbA1c, similar weight loss and a favorable gastrointestinal AE profile compared with exenatide BID.

Efficacy and Safety of ITCA 650, a Novel Drug-Device GLP-1 Receptor Agonist, in Type 2 Diabetes Uncontrolled With Oral Antidiabetes Drugs: The FREEDOM-1 Trial.

OBJECTIVE: ITCA 650 (exenatide in osmotic mini-pump) continuously delivers exenatide subcutaneously for 3-6 months. Two doses of ITCA 650 were compared with placebo in patients with uncontrolled type 2 diabetes. RESEARCH DESIGN AND METHODS: This 39-week, phase 3, double-blind, placebo-controlled trial randomized 460 patients aged 18-80 years with glycated hemoglobin (HbA1c) 7.5-10% [58-86 mmol/mol] 1:1:1 to placebo, ITCA 650 40 µg/day, or ITCA 650 60 µg/day. Primary end point was change in HbA1c at 39 weeks. RESULTS: Least squares (LS) mean change from baseline HbA1c was -1.1% [-12.2 mmol/mol] and -1.2% [-13.2 mmol/mol] for ITCA 650 40 and 60 µg/day, respectively (P < 0.001 vs. placebo -0.1% [-1.3 mmol/mol]). In a prespecified analysis, greater HbA1c reductions occurred in patients not receiving sulfonylureas (SUs) versus those receiving SUs (-1.7% vs. -1.2% [-18.6 and -13.1 mmol/mol]). At week 39, HbA1c <7% [53 mmol/mol] was attained in 37%, 44%, and 9% of ITCA 650 40 µg/day, ITCA 650 60 µg/day, and placebo groups, respectively (P < 0.001 each dose vs. placebo). LS mean change from baseline body weight was -2.3 kg and -3.0 kg for ITCA 650 40 and 60 µg/day, respectively (P ≤ 0.015 vs. placebo -1.0 kg). Nausea was the most common adverse event (AE) and subsided over time. Discontinuation for gastrointestinal AEs occurred in 7.2% with ITCA and 1.3% with placebo. Most AEs associated with procedures to place and remove ITCA 650 were mild and transient. CONCLUSIONS: ITCA 650 significantly reduced HbA1c and weight compared with placebo and was well tolerated in patients with uncontrolled type 2 diabetes on oral antidiabetes medications.

Pharmacokinetic drug evaluation of exenatide for the treatment of type 2 diabetes.

INTRODUCTION: Glucagon-like peptide-1 (GLP-1) receptor analogs are a group of therapeutic agents which mimic endogenous GLP-1, exerting their effect by the stimulation of the GLP-1 receptor with a wide distribution. Its activation increases insulin releasing dependent on blood glucose levels, suppression of glucagon secretion and a reduction of hepatic glucose output. It delays gastric emptying and increases satiety. Exenatide is the synthetic version of exendin-4, a natural peptide with similar properties to human GLP-1. There are two pharmaceutical forms, for subcutaneous injection: twice daily and once weekly. Clinical practice guidelines recommend them because of a high efficacy reducing hyperglycemia, low risk of hypoglycemia and a significative weight loss effect. Gastrointestinal adverse events are the most common beside injection site-related. Their cost is the main limitation to use. Areas covered: We review the recent literature investigating the pharmacokinetics and pharmacodynamics and efficacy-safety studies of exenatide twice daily and once weekly in type 2 diabetes Expert opinion: GLP-1 receptor analogs are now positioned as an effective and safe drug for the treatment of type 2 diabetes. Exenatide significally reduces HbA1c and fasting plasma glucose. Additionally, it produces moderate weight loss and decreases blood pressure. One weekly formulation may improve compliance while cost is still a limitation. EXSCEL trial has shown that, despite cardiovascular safety, exenatide do not exhibits cardiovascular benefits.

Insulin secretion predicts the response to therapy with exenatide plus pioglitazone, but not to basal/bolus insulin in poorly controlled T2DM patients: Results from the Qatar study.

The present study aims to identify predictors for response to combination therapy with pioglitazone plus exenatide vs basal/bolus insulin therapy in T2DM patients who are poorly controlled with maximum/near-maximum doses of metformin plus a sulfonylurea. Participants in the Qatar study received a 75-g OGTT with measurement of plasma glucose, insulin and C-peptide concentration at baseline and were then randomized to receive either treatment with pioglitazone plus exenatide or basal/bolus insulin therapy for one year. Insulin secretion measured with plasma C-peptide concentration during the OGTT was the strongest predictor of response to combination therapy (HbA1c ≤ 7.0%) with pioglitazone plus exenatide. A 54% increase in 2-hour plasma C-peptide concentration above the fasting level identified subjects who achieved the glycaemic goal (HbA1c < 7.0%) with 82% sensitivity and 79% specificity. Only baseline HbA1c was a predictor of response to basal/bolus insulin therapy. Thus, the increment in 2-hour plasma C-peptide concentration above the fasting level provides a useful tool to identify poorly controlled T2DM patients who can achieve glycaemic control without insulin therapy, and thereby, can be used to individualize antihyperglycaemic therapy in poorly controlled T2DM patients.