exenatide and Weight-Loss

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and now tirzepatide, a dual GLP-1 RA/glucose-dependent insulinotropic polypeptide agonist, have numerous advantages in the treatment of type 2 diabetes and obesity, yet only 11% of patients with type 2 diabetes are prescribed a GLP-1 RA. This narrative review addresses the complexity and cost issues surrounding incretin mimetics to support clinicians.. This narrative review summarizes key trials on the differing effects of incretin mimetics on glycosylated hemoglobin and weight, provides a table with rationale for how to interchange among agents, and summarizes the key factors that guide drug selection beyond guidance from the American Diabetes Association. To support proposed dose interchanges, we preferentially selected high-quality, prospective randomized controlled trials with direct comparisons of agents and doses when available.. Tirzepatide produces the greatest reductions in glycosylated hemoglobin and weight, but its impact on cardiovascular events is still under investigation. Subcutaneous semaglutide and liraglutide are approved for weight loss specifically and are effective in the secondary prevention of cardiovascular disease. Although producing less weight loss, only dulaglutide has effectiveness in the primary and secondary prevention of cardiovascular disease. Semaglutide is the only orally available incretin mimetic; however, the oral formulation produces less weight loss versus its subcutaneous alternative and did not have cardioprotection in its outcomes trial. Although effective in controlling type 2 diabetes, exenatide extended release has the least impact on glycosylated hemoglobin and weight among commonly used agents, while not having cardioprotection. However, exenatide extended release may be preferred on some restrictive insurance formularies.. Although trials have not explicitly studied how to interchange among agents, interchanges can be guided by comparisons between agents' impact on glycosylated hemoglobin and weight. Efficient changes among agents can help clinicians optimize patient-centered care, particularly in the face of changing patient needs and preferences, insurance formularies, and drug shortages.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Prospective Studies; Weight Loss

Obesity is a chronic disease with high prevalence and associated comorbidities, making it a growing global concern. These comorbidities include type 2 diabetes, hypertension, ventilatory dysfunction, arthrosis, venous and lymphatic circulation diseases, depression, and others, which have a negative impact on health and increase morbidity and mortality. GLP-1 agonists, used to treat type 2 diabetes, have been shown to be effective in promoting weight loss in preclinical and clinical studies. This review summarizes numerous studies conducted on the main drugs in the GLP-1 agonists class, outlining the maximum achievable weight loss. Our aim is to emphasize the active role and main outcomes of GLP-1 agonists in promoting weight loss, as well as in improving hyperglycemia, insulin sensitivity, blood pressure, cardio-metabolic, and renal protection. We highlight the pleiotropic effects of these medications, along with their indications, contraindications, and precautions for both diabetic and non-diabetic patients, based on long-term follow-up studies.

Topics: Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Obesity; Peptides; Randomized Controlled Trials as Topic; Weight Loss

Idiopathic intracranial hypertension (IIH) affects predominantly overweight women of childbearing age, causing chronically-disabling headaches and visual loss. Weight loss remains the most effective management strategy, but innovative treatments and randomized control trials (RCTs) remain few. This paper will review recent IIH research.. Pregnancy-related complications, but not losses, are increased in IIH, while symptom severity is not affected. Weight loss of 24% results in normalization of intracranial pressure (ICP) and improvement in papilledema. Prolonged periods of papilledema result in delayed thinning of the ganglion cell layer. Less-invasive telemetry has improved understanding of the positional effects on ICP with rises seen in the supine and lateral positions. Exenatide, a GLP-1 agonist, may reduce ICP and improve symptoms. Venous sinus stenting is increasingly popular but its benefits over CSF diversion remain unclear.. Early involvement of obstetric care is recommended with pregnancy in IIH. Early intervention is required to avoid chronic papilledema that confers worse visual outcomes. Positional changes may affect ICP readings. The use of novel ICP telemetric devices has significant potential in future disease monitoring. The dual benefits of weight loss and ICP reduction with exenatide have significant potential in IIH management. Surgical RCTs are still required.

Topics: Exenatide; Female; Humans; Intracranial Pressure; Papilledema; Pregnancy; Pseudotumor Cerebri; Weight Loss

Aim To determine the antiobesity effect and safety of glucagon-like peptide-1 receptor agonist (GLP-1RA) including liraglutide, exenatide and semaglutide treatment in overweight/obese patients without diabetes. The random-effect model was used to pool data extracted from included literatures. The weighted mean difference (WMD), odds ratio and 95% confidence interval (CI) were used to present the meta-analysis results (PROSPERO registration number: CRD 42020173199). The sources of intertrial heterogeneity, bias and the robustness of results were evaluated by subgroup analysis, sensitivity analysis and regression analysis, respectively. A total of 24 RCTs were recruited in the present analysis which included 5867 patients. The results showed that the treatment of overweight/obese patients without diabetes with GLP-1RAs including liraglutide, exenatide and semaglutide significantly achieved greater weight loss than placebo [WMD=-5.39, 95% CI (-6.82, -3.96)] and metformin [WMD=-5.46, 95% CI (-5.87, -5.05)]. The subgroup analysis showed that semaglutide displayed the most obvious antiobesity effect in terms of weight loss, the reduction of body mass index (BMI) and waist circumference (WC). However, GLP-1RAs treatments had more gastrointestinal adverse events (such as nausea and vomiting) than placebo and Met. The subgroup analysis also represented that semaglutide displayed the lowest risk of gastrointestinal adverse events among three kinds of GLP-1RAs. Our meta-analysis demonstrated that GLP-1RA had a superior antiobesity effect than placebo/Met in overweight/obese patients without diabetes in terms of body weight, BMI, and WC, especially for semaglutide, which had more obvious antiobesity effect and lower GI adverse events than liraglutide and exenatide.

Topics: Anti-Obesity Agents; Exenatide; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide; Obesity; Weight Loss

The global incidence of childhood obesity is increasing. Currently, there are only few established drugs for treating adolescent obesity. Randomized clinical trials (RCTs) comparing pharmacological interventions in children with obesity are scarce; therefore, we aimed to analyze the relative efficacy and adverse reactions of these drugs and compare the effects of each drug on body mass index (BMI).. This meta-analysis focused on the slimming effect, safety, and correlation of metformin, orlistat, exenatide, liraglutide, and topiramate in children with obesity. Several international databases were searched and clinical trials on the treatment of obesity in children in which the drug was administered for ≥ 6 months were included. Changes in BMI before and after treatment were analyzed using a Bayes framework, and the surface under the cumulative ranking was calculated.. Of 2102 relevant articles retrieved, 21 RCTs were included in the study. Compared to other drugs, liraglutide reduced BMI the most in children with obesity. However, it was most associated with drug withdrawal due to adverse events while topiramate was least.. Liraglutide had a higher probability of achieving clinically significant weight loss compared with other drugs while topiramate was superior in safety.

Topics: Adolescent; Anti-Obesity Agents; Child; Exenatide; Humans; Liraglutide; Metformin; Obesity; Orlistat; Topiramate; Weight Loss

Topics: Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Insulin Resistance; Liraglutide; Metformin; Polycystic Ovary Syndrome; Weight Loss

Over recent decades, an improved understanding of the pathophysiology of type 2 diabetes mellitus (T2DM) and glucose regulation has led to innovative research and new treatment paradigms. The discovery of the gut peptide glucagon-like peptide-1 (GLP-1) and its role in glucose regulation paved the way for the class of GLP-1 receptor agonist compounds, or GLP-1RAs. The long-acting GLP-1RAs (dulaglutide, exenatide extended-release, liraglutide, semaglutide [injectable and oral]) are classified as such based on a minimum 24-hour duration of clinically relevant effects after administration. In phase 3 clinical trial programs of long-acting GLP-1RAs, A1C typically was reduced in the range of 1% to 1.5%, with reductions close to 2% in some studies. GLP-1RAs when used alone (without sulfonylureas or insulin) have a low risk of hypoglycemia because, like endogenous GLP-1, their insulinotropic effects are glucose-dependent. In addition to local actions in the gastrointestinal (GI) tract, GLP-1RAs stimulate receptors in the central nervous system to increase satiety, resulting in weight loss. All long-acting GLP-1RAs have, at minimum, been shown to be safe and not increase cardiovascular (CV) risk and most (liraglutide, semaglutide injectable, dulaglutide, albiglutide) have been shown in CV outcomes trials (CVOTs) to significantly reduce the risk of major cardiac adverse events. The class has good tolerability overall, with generally transient GI adverse events being most common. The weekly injectable agents offer scheduling convenience and may promote treatment adherence. One long-acting GLP-1RA is available as an oral daily tablet, which may be preferable for some patients and providers.

Topics: Administration, Oral; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Heart Disease Risk Factors; Humans; Immunoglobulin Fc Fragments; Injections; Liraglutide; Recombinant Fusion Proteins; Satiety Response; Weight Loss

The role of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in the treatment of type 1 diabetes mellitus (T1DM), including efficacy and safety evidence, is reviewed.. Currently approved treatment options for glycemic control in T1DM include insulin, which combats insulin deficiency but does not effectively target disease progression or alpha cell dysfunction; and pramlintide, whose use requires multiple daily doses and involves a high likelihood of gastrointestinal side effects. GLP-1 RAs have a unique mechanism of action in T1DM, addressing alpha cell dysfunction and thereby suppressing inappropriate glucagon secretion. GLP-1 RA dosing varies from once weekly to twice daily, and the class is well tolerated in patients with type 2 diabetes. Among the GLP-1 RAs, exenatide and liraglutide have been studied in patients with T1DM, with published evidence consistently demonstrating weight loss, decreases in total daily insulin requirements, and modest improvements in glycemic control. GLP-1 RA therapy appears to be well tolerated in patients with T1DM and is associated with nonsignificant increases in hypoglycemia risk.. GLP-1 RA therapy represents an important add-on therapy option for achieving decreased insulin doses, weight loss, and modest improvements in HbA1c levels without significantly increasing hypoglycemia risk in patients with T1DM. Patients who have detectable C-peptide and/or are overweight or cannot achieve glycemic goals without hypoglycemia have been found to benefit the most from GLP-1 RA therapy. Further studies are warranted to evaluate these agents' potential impact on clinical outcomes such as microvascular and macrovascular complications.

Topics: Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Exenatide; Glucagon; Glucagon-Like Peptide-1 Receptor; Glucagon-Secreting Cells; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Liraglutide; Treatment Outcome; Weight Loss

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.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Peptides; Venoms; Weight Loss

To review the evolution and advancement of GLP-1 receptor agonist (GLP-1RA) therapy, through the lens of randomised controlled trials, from differentiating characteristics, efficacy, safety, tolerability, and cardiovascular outcomes, to evidence gaps and next steps.. Clinical review of published phase 3 or later RCT data studying efficacy, safety, and outcomes of approved GLP-1 RA therapies.. Through a wealth of studies, including both placebo-controlled and active-controlled studies, GLP-1 RAs have demonstrated high glycemic efficacy and ability to facilitate weight loss, with minimal risk of hypoglycemia, potential to restore beta cell function, and evidence for improved cardiovascular outcomes in those at risk.. Over a decade of clinical studies have established the unique contributions of GLP-1 RAs in the treatment of diabetes. Individual differences between the different GLP-1 RAs, in delivery, pharmacokinetic and clinical effects, exist, allowing for tailored approaches to clinical care. The strength of evidence generated through RCTs, both short-term and long-term studies, will continue to evolve and inform our current paradigms in diabetes care.

Topics: Clinical Trials, Phase III as Topic; Diabetes Mellitus; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Liraglutide; Peptides; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Treatment Outcome; Weight Loss

Patients with advanced type 2 diabetes (T2D) and high glycated haemoglobin (HbA1c) values can be difficult to treat because of their severe metabolic disease. This pooled analysis examined the treatment effects of exenatide twice daily (BID), exenatide once weekly (QW) and insulin in patients with high baseline HbA1c (≥10.0%).. This post hoc analysis used pooled data from 12 and 8 randomised controlled trials of exenatide BID and exenatide QW, respectively. Patients with T2D who completed at least 24 weeks of treatment with exenatide BID, exenatide QW or insulin (insulin glargine, insulin detemir or insulin aspart) were categorised by baseline HbA1c. Patients with HbA1c ≥10.0% were included in the analysis.. Both exenatide and insulin reduced HbA1c (mean ± SE reduction: -2.0% ± 0.2% [exenatide] and -2.1% ± 0.2% [insulin] in the exenatide BID studies, and -2.6% ± 0.1% [exenatide] and -2.1% ± 0.2% [insulin] in the exenatide QW studies; all P < .001). Body weight decreased with exenatide and increased with insulin. Systolic blood pressure decreased with exenatide QW. Insulin dose increased over the course of treatment. The most common adverse events with exenatide were gastrointestinal. Insulin was associated with some hypoglycaemia risk. Hypoglycaemia events occurred infrequently with exenatide when given without sulphonylureas.. For patients with high HbA1c, treatment with exenatide or insulin both improved glycaemic control. Given the associated weight loss and low risk of hypoglycaemia, exenatide may be a suitable alternative to treatment with insulin in certain patients with T2D and high HbA1c.

Topics: Blood Pressure; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Peptides; Randomized Controlled Trials as Topic; Systole; Venoms; Weight Loss

Despite the increasing number of medications recently approved to treat obesity among adults, few agents have been formally evaluated in children or adolescents for this indication. Moreover, there is a paucity of guidance in the literature addressing best practices with regard to pediatric obesity pharmacotherapy clinical trial design, and only general recommendations have been offered by regulatory agencies on this topic. The purposes of this article are to (1) offer a background of the current state of the field of pediatric obesity medicine, (2) provide a brief review of the literature summarizing pediatric obesity pharmacotherapy clinical trials, and (3) highlight and discuss some of the unique aspects that should be considered when designing and conducting high-quality clinical trials evaluating the safety and efficacy of obesity medications in children and adolescents. Suggestions are offered in the areas of target population and eligibility criteria, clinical trial end-point selection, trial duration, implementation of lifestyle modification therapy and recruitment and retention of participants. Efforts should be made to design and conduct trials appropriately to ensure that high-quality evidence is generated on the safety and efficacy of various medications used to treat pediatric obesity.

Topics: Anti-Obesity Agents; Body Mass Index; Child; Directive Counseling; Exenatide; Humans; Hypoglycemic Agents; Metformin; Pediatric Obesity; Peptides; Randomized Controlled Trials as Topic; Risk Reduction Behavior; Venoms; Weight Loss

Exenatide once weekly, a glucagon-like peptide-1 receptor agonist (GLP-1RA), is approved as an adjunct to diet and exercise for the treatment of adults with type 2 diabetes mellitus. Exenatide acts by binding to and activating glucagon-like peptide-1 receptors, thereby stimulating glucose-dependent insulin secretion, suppressing glucose-dependent glucagon secretion, slowing gastric emptying, and increasing feelings of satiety. Gradual increases in drug level ("autotitration") after the initiation of a fixed exenatide 2-mg weekly dose achieve minimal effective (~50 pg/mL) and steady-state (~300 pg/mL) concentrations by 2 weeks and 6 to 8 weeks, respectively. The purpose of this study was to examine pharmacodynamic outcomes with exenatide once weekly and to determine whether changes are secondary to weight loss and thus delayed by the sequential nature of responses.. This post hoc analysis evaluated trials in the exenatide once-weekly development program. Outcomes included glycosylated hemoglobin (HbA1c), weight, fasting serum or plasma glucose (FG), lipids, and blood pressure (BP) at weeks 2, 4, and 24. Relationships between changes from baseline in these outcomes and changes in weight were examined. The effect of nausea and vomiting (adverse events characteristic of GLP-1RAs) on weight loss was also assessed.. Pooled data were analyzed from 12 trials in which 2190 patients received exenatide once weekly. Patients had a mean HbA1c level of 8.4% and weight of 87 kg at baseline. Exenatide once weekly produced significant improvements in HbA1c, FG, weight, and systolic BP at weeks 2 and 4, with continuous improvements through week 24. There were no clinically meaningful correlations between weight loss and improvements in pharmacodynamic outcomes at weeks 2, 4, or 24. Patients had significant reductions in weight at weeks 2, 4, and 24 regardless of whether they experienced nausea and/or vomiting during the study, although patients with at least 1 nausea/vomiting event had greater weight loss at week 24 than those who did not.. Improvements in pharmacodynamic end points occurred early in treatment with exenatide once weekly, before steady-state plasma concentrations. These early effects did not seem to be secondary to weight loss and are likely the direct effects of exenatide.

Topics: Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipids; Peptides; Randomized Controlled Trials as Topic; Venoms; Weight Loss

Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is increasingly used in obese or overweight patients with diabetes. However, its safety profile and effects on weight loss in non-diabetic obese or overweight population remain unclear. We aimed to evaluate efficacy and safety of exenatide in obese or overweight participants without diabetes.. We searched up to January 2016 in MEDLINE (Ovid SP), EMBASE (Ovid SP), Cochrane Central Register of Controlled Trials (CENTRAL), some Chinese databases and ClinicalTrials.gov for randomized controlled trials (RCTs) investigating exenatide in obese or overweight participants without diabetes. The primary outcomes included body weight and body mass index (BMI). We pooled data to calculate the mean differences (MDs) with their 95% confidence intervals (CIs). We assessed overall evidence quality of BMI reduction and weight loss according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.. Six randomized controlled trials involving 362 patients were included in the meta- analysis. The follow-up duration ranged from 12 to 24weeks. Compared with control group, a larger body weight loss (MD: -4.47kg; 95% CI: -6.67 to -2.27; P<0.0001), regardless of dosage and population, was achieved by the obese or overweight patients in exenatide group. Exenatide also elicited a greater reduction in. -0.86kg/m(2); 95% CI: -1.39 to -0.33; P=0.001) and waist circumferences (MD: -1.78cm; 95% CI: -3.13 to -0.44; P=0.009) compared with the control. No significant benefits were showed in exenatide group in terms of blood pressure and lipid profiles. Gastrointestinal adverse events were mostly common during the treatment of exenatide.. Exenatide could significantly reduce body weight in obese or overweight participants without diabetes, and might be a safe alternative GLP-1 receptor agonist for weight control in such patients. Larger randomized trials with longer follow-up duration are required to confirm the effectiveness and safety of exenatide.

Topics: Body Weight; Diabetes Mellitus; Exenatide; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Obesity; Overweight; Peptides; Randomized Controlled Trials as Topic; Venoms; Weight Loss

Once-weekly glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown promising results in the treatment of type 2 diabetes. Herein, we compared the efficacy and safety of once-weekly GLP-1RAs with exenatide and liraglutide separately.. We systematically surveyed the pertinent literature using various databases. The randomised controlled trials that compared once-weekly GLP-1RAs with exenatide and liraglutide in type 2 diabetes were included. Our main end-points were control of glycaemia, body weight, hypoglycaemia and gastrointestinal adverse events (AEs).. Our analysis included eight trials involving 5531 patients. Exenatide-long-acting release (LAR), dulaglutide and taspoglutide were more effective than twice-daily exenatide in reducing glycosylated haemoglobin A1c (HbA1c) and fasting blood glucose (FBG) levels and achieving HbA1c targets (< 7.0% and ≤ 6.5%). Liraglutide was as effective as dulaglutide and more effective than exenatide-LAR and albiglutide in controlling glycaemia. With regard to the effectiveness in decreasing body weight, exenatide-LAR, dulaglutide and taspoglutide were similar to exenatide whereas exenatide-LAR, dulaglutide and albiglutide were inferior to liraglutide. Once-weekly GLP-1RAs, exenatide and liraglutide resulted in a similar incidence of hypoglycaemia and of gastrointestinal, serious, or other AEs.. Once-weekly GLP-1RAs were more effective in controlling glycaemia and equally effective in decreasing body weight than twice-daily exenatide but were inferior to liraglutide in controlling these two parameters (dulaglutide was similar with liraglutide in controlling glycaemia). Once-weekly GLP-1RAs, exenatide and liraglutide had a similar risk of causing AEs.

Topics: Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Gastrointestinal Diseases; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Liraglutide; Peptides; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Risk Factors; Treatment Outcome; Venoms; Weight Loss

The increased prevalence of type 2 diabetes follows the increased prevalence of obesity. Both diseases share common pathophysiological pathways; obesity is in most cases the first step, whereas diabetes is the second one. Weight gain occurs during the treatment of diabetes with drugs causing endogenous or exogenous hyperinsulinemia. Insulin and sulfonylurea are making patients more obese and more insulin resistant. Glucagon-like peptide-1 receptor agonists (GLP-1 agonists) and sodium/glucose cotransporter 2 inhibitors (SGLT2 inhibitors) are antidiabetic drugs with weight loss property. GLP-1 agonists mimic an incretin action. They release insulin after a meal during hyperglycemia and suppress glucagon. The weight loss effect is a consequence of central action increased satiety. Some of GLP-1 agonists weight loss is a result of decelerated gastric emptying rate. SGLT2 inhibitors block sodium glucose cotransporter in proximal tubule brush border and produce glucose excretion with urinary loss. Urinary glucose leak results in calories and weight loss. Even a modest weight loss has positive outcome on metabolic features of diabetic patient; such drugs have important role in treatment of type 2 diabetic patients. However, there are some still unresolved questions. The weight loss they produce is modest. Those drugs are expensive and not available to many diabetic patients, they are significantly more expensive compared to "traditional" hypoglycemic drugs. The hypoglycemic endpoint of GLP-1 agonists and SGLT2 inhibitors often requires adding another antidiabetic drug. The most radical and most effective therapy of type 2 diabetes and obesity is bariatric surgery having significant number of diabetes remission.

Topics: Anti-Obesity Agents; Bariatric Surgery; Biological Transport; Clinical Trials as Topic; Comorbidity; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Gastric Emptying; Glucagon; Glucagon-Like Peptide 1; Glucose; Glycosuria; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Kidney Tubules, Proximal; Microvilli; Multicenter Studies as Topic; Obesity; Peptides; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Venoms; Weight Loss

To evaluate the effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on weight reduction in patients with Type 2 diabetes mellitus (Type 2 DM), a network meta-analysis was conducted. MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov were searched from 1950 to October 2013. Randomized controlled trials (RCTs) involving GLP-1 RAs were included if they provided information on body weight. A total of 51 RCTs were included and 17521 participants were enrolled. The mean duration of 51 RCTs was 31 weeks. Exenatide 10 μg twice daily (EX10BID) reduced weight compared with exenatide 5 μg twice daily (EX5BID), liraglutide 0.6 mg once daily (LIR0.6QD), liraglutide-1.2 mg once daily (LIR1.2QD), and placebo treatment, with mean differences of -1.07 kg (95% CI: -2.41, -0.02), -2.38 kg (95% CI: -3.71, -1.06), -1.62 kg (95% CI: -2.79, -0.43), and -1.92 kg (95% CI: -2.61, -1.24), respectively. Reductions of weight treated with liraglutide-1.8 mg once daily (LIR1.8QD) reach statistical significance (-1.43 kg (95% CI: -2.73, -0.15)) versus LIR1.2QD and (-0.98 kg (95% CI: -1.94, -0.02)) versus placebo. Network meta-analysis found that EX10BID, LIR1.8QD, and EX2QW obtained a higher proportion of patients with weight loss than other traditional hypoglycemic agents. Our results suggest GLP-1 RAs are promising candidates for weight control in comparison with traditional hypoglycemic drugs, and EX10BID, LIR1.8QD, and EX2QW rank the top three drugs.

Topics: Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Insulin; Liraglutide; Obesity; Overweight; Peptides; Randomized Controlled Trials as Topic; Receptors, Glucagon; Venoms; Weight Loss

To determine the effects of glucagon-like peptide-1 receptor agonists compared with placebo and other anti-diabetic agents on weight loss in overweight or obese patients with type 2 diabetes mellitus.. Electronic searches were conducted for randomised controlled trials that compared a glucagon-like peptide-1 receptor agonist therapy at a clinically relevant dose with a comparator treatment (other type 2 diabetes treatment or placebo) in adults with type 2 diabetes and a mean body mass index ≥ 25 kg/m2. Pair-wise meta-analyses and mixed treatment comparisons were conducted to examine the difference in weight change at six months between the glucagon-like peptide-1 receptor agonists and each comparator.. In the mixed treatment comparison (27 trials), the glucagon-like peptide-1 receptor agonists were the most successful in terms of weight loss; exenatide 2 mg/week: -1.62 kg (95% CrI: -2.95 kg, -0.30 kg), exenatide 20 μg: -1.37 kg (95% CI: -222 kg, -0.52 kg), liraglutide 1.2 mg: -1.01 kg (95%CrI: -2.41 kg, 0.38 kg) and liraglutide 1.8 mg: -1.51 kg (95% CI: -2.67 kg, -0.37 kg) compared with placebo. There were no differences between the GLP-1 receptor agonists in terms of weight loss.. This review provides evidence that glucagon-like peptide-1 receptor agonist therapies are associated with weight loss in overweight or obese patients with type 2 diabetes with no difference in weight loss seen between the different types of GLP-1 receptor agonists assessed.

Topics: Adult; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Male; Peptides; Randomized Controlled Trials as Topic; Venoms; Weight Loss

Incretin therapies such as glucagon-like peptide 1 (GLP-1) agonists are commonly used for the treatment of type 2 diabetes mellitus. GLP-1 mimetics, besides improving glycemic control, have been shown to influence multiple pathways regulating blood pressure (BP). We investigated the GLP-1 analogs effects on BP from published randomized studies using a meta-analytic approach.. Thirty-three trials (12,469 patients) that assessed the efficacy of GLP-1 analogs on glycemic control (HbA1C) over 12-56 weeks that met additional criteria, including the availability of standardized sitting BP assessment and weight parameters, were identified. Comparator therapy included oral antiglycemic drugs or placebo. The weighted mean difference (WMD) in systolic BP (SBP) change was calculated using a random-effects model after performing a test for heterogeneity.. Forty-one percent of patients were treated with liraglutide (0.3-3mg once daily), whereas 59% were treated with exenatide (5-10 µg twice daily or 2mg weekly). GLP-1 treatment achieved a greater SBP reduction than comparator therapy (WMD = 2.22mm Hg; 95% confidence interval (CI) = -2.97 to -1.47). In the pooled analysis, GLP-1 had beneficial effects on weight loss (WMD = -2.56kg; 95% CI = -3.12 to -2.00), HbA1c reduction (WMD = -0.41%; 95% CI = -0.78 to -0.04) but was associated with a heart rate increase (WMD = 1.30 bpm; 95% CI = 0.26-2.33). In a separate meta-regression analysis, the degree of SBP change was not related to baseline BP, weight loss, or improvement in HbA1C.. This meta-analysis provides evidence that GLP-1 analogs reduce sitting SBP. These findings may support potentially favorable long-term cardiovascular outcomes.

Topics: Biomarkers; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Peptides; Time Factors; Treatment Outcome; Venoms; Weight Loss

Effective, evidence-based management of type 2 diabetes (T2D) requires the integration of the best available evidence with clinical experience and patient preferences.. Studies published from 2000 to 2012 evaluating glucagon-like peptide-1 receptor agonists (GLP-1RAs) or dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) were identified using PubMed. The author contextualized the study findings with his clinical experience.. Incretin-based therapy targets multiple dysfunctional organs in T2D. Injectable GLP-1RAs provide substantial glycemic control and weight reduction; while oral DPP-4 inhibitors provide moderate glycemic control and weight neutrality. Both classes are effective, well tolerated, and associated with a low incidence of hypoglycemia when used alone or in combination with other antidiabetes agents. GLP-1RAs are associated with transient nausea and, like DPP-4 inhibitors, rare pancreatitis.. Data indicate and clinical experience confirms that incretins are well tolerated in appropriate patients and provide sustained glycemic control and weight loss or weight neutrality throughout T2D progression.

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Linagliptin; Liraglutide; Peptides; Piperidines; Purines; Pyrazines; Quinazolines; Receptors, Glucagon; Sitagliptin Phosphate; Treatment Outcome; Triazoles; Uracil; Venoms; Weight Loss

GLP-1 receptors agonists have been a substantial change in treatment of type 2 diabetes mellitus, and its weekly administration has broken pre-established schemes. Daily exenatide is administered every 12 hours (BID) subcutaneously, while weekly exenatide is administered once a week. Both molecules share a common mechanism of action but have differential effects on basal and postprandial glucose. We review the major clinical trials with both exenatide BID and weekly exenatide. It can be concluded that exenatide BID shows a hypoglycemic effect similar to other treatments for type 2 DM but adding significant weight loss with low incidence of hypoglycemia. Weekly exenatide decreases HbA1c similar to liraglutide but larger than exenatide BID, both glargine and biphasic insulin, sitagliptin, and pioglitazone, maintaining weight loss and adding to gastrointestinal intolerance the induration at the injection site as a side effect.

Topics: Delayed-Action Preparations; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Administration Schedule; Exenatide; Female; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Insulin; Insulin Glargine; Insulin, Long-Acting; Liraglutide; Male; Metformin; Peptides; Pioglitazone; Receptors, Glucagon; Thiazolidinediones; Venoms; Weight Loss

Exenatide once weekly is the first glucose-lowering agent available to patients with type 2 diabetes mellitus (T2DM) which is administered once per week. This long-acting formulation contains the same active ingredient as exenatide twice daily, except that the exenatide is encapsulated in dissolvable microspheres. Following subcutaneous injection, exenatide once weekly microspheres remain in place under the skin and slowly degrade, releasing active exenatide continuously into circulation. In randomized clinical trials, exenatide once weekly was associated with significant glycaemic improvement and moderate weight loss in patients with T2DM when administered as monotherapy or in combination with a variety of oral antidiabetic agents. Exenatide once weekly also lowered blood glucose more effectively than titrated basal insulin in patients on metformin or metformin plus sulphonylurea background therapy. Gastrointestinal side effects (nausea, vomiting and diarrhoea) were the most common tolerability issues associated with exenatide once weekly administration, but they occurred at lower rates than in patients on other glucagon-like peptide receptor agonists (i.e., exenatide twice daily or liraglutide). Issues regarding the place of exenatide once weekly in T2DM pharmacotherapy are discussed.

Topics: Blood Glucose; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Diarrhea; Drug Administration Schedule; Drug Therapy, Combination; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Male; Metformin; Middle Aged; Nausea; Peptides; Randomized Controlled Trials as Topic; Treatment Outcome; Venoms; Vomiting; Weight Loss

The efficacy and safety of glucagon-like peptide (GLP)-1 receptor agonists for weight loss in adult patients without diabetes is reviewed.. GLP-1 receptor agonists have been associated with significant weight loss in patients with diabetes, raising the question of whether these agents could be used for weight loss in patients without diabetes. The mechanism by which GLP-1 receptor agonists induce weight loss is believed to be related to multiple actions involving the brain and gastrointestinal tract, with the primary action related to an increase in satiety. Trials examining the effects of GLP-1 receptor agonists for weight loss have compared exenatide, liraglutide, and orlistat. Of the studies completed to date, the majority of patients have been enrolled in trials involving liraglutide. Based on the reviewed literature, both exenatide 10 μg twice daily and liraglutide in dosages of up to 3 mg daily resulted in significant weight loss in patients without diabetes. A decrease in the proportion of patients with prediabetes was also found in studies of liraglutide. Nausea and vomiting were the most frequently reported adverse events in patients from these studies. Symptomatic hypoglycemia was reported in only one study with liraglutide in patients without diabetes and was not objectively confirmed by laboratory data. A higher frequency of psychiatric disorders, specifically insomnia, was reported by patients taking high doses of liraglutide.. GLP-1 receptor agonists offer a reasonable alternative for nondiabetic patients not able to achieve weight-loss goals with lifestyle modifications alone.

Topics: Adult; Dose-Response Relationship, Drug; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Lactones; Life Style; Liraglutide; Obesity; Orlistat; Peptides; Receptors, Glucagon; Treatment Outcome; Venoms; Weight Loss

Type 2 diabetes (T2DM) is a disease of epidemic proportion associated with significant morbidity and excess mortality. Optimal glucose control reduces the risk of microvascular and possibly macrovascular complications due to diabetes. However, glycemic control is rarely optimal and several therapeutic interventions for the treatment of diabetes cause hypoglycemia and weight gain; some may exacerbate cardiovascular risk. Exenatide (synthetic exendin-4) is a glucagon- like peptide-1 receptor (GLP-1R) agonist developed as a first-in-class diabetes therapy. This review presents an overview of the evolution of exenatide as a T2DM treatment, beginning with the seminal preclinical discoveries and continuing through to clinical pharmacology investigations and phase 3 clinical trials. In patients with T2DM, exenatide enhanced glucose-dependent insulin secretion, suppressed inappropriately elevated glucagon secretion, slowed gastric emptying, and enhanced satiety. In controlled phase 3 clinical trials ranging from 12 to 52 weeks, 10-mcg exenatide twice daily (ExBID) reduced mean HbA1c by -0.8% to -1.7% as monotherapy or in combination with metformin (MET), sulfonylureas (SFU), and/or thiazolidinediones (TZD); with mean weight losses of -1.2 kg to -8.0 kg. In controlled phase 3 trials ranging from 24 to 30 weeks, a 2-mg once-weekly exenatide formulation (ExQW) reduced mean HbA1c by -1.3% to -1.9%, with mean weight reductions of -2.3 to -3.7 kg. Exenatide was generally well-tolerated. The most common side effects were gastrointestinal in nature, mild, and transient. Nausea was the most prevalent adverse event. The incidence of hypoglycemia was generally low. By building upon early observations exenatide was successfully developed into an effective diabetes therapy.

Topics: Animals; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Metformin; Mice; Mice, Knockout; Models, Animal; Nausea; Peptides; Sulfonylurea Compounds; Thiazolidinediones; Venoms; Weight Loss

Recent research has indicated that appetite-regulating hormones from the gut may have therapeutic potential. The incretin hormone, glucagon-like peptide-1 (GLP-1), appears to be involved in both peripheral and central pathways mediating satiation. Several studies have also indicated that GLP-1 levels and responses to meals may be altered in obese subjects. Clinical trial results have shown further that two GLP-1 receptor agonists (GLP-1 RAs), exenatide and liraglutide, which are approved for the treatment of hyperglycemia in patients with type 2 diabetes, also produce weight loss in overweight subjects without diabetes. Thus, GLP-1 RAs may provide a new option for pharmacological treatment of obesity.

Topics: Animals; Eating; Exenatide; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Liraglutide; Obesity; Peptides; Receptors, Glucagon; Satiation; Signal Transduction; Venoms; Weight Loss

Anti-diabetic drugs have, in addition to their well-known glucose lowering-effect, different effects in the rest of cardiovascular factors that are associated with diabetes mellitus. Glucagon-like peptide-1 (GLP-1) receptor agonists have recently been incorporated to the therapeutic arsenal of type 2 diabetes mellitus. The objective of this review is to summarize the available evidence on the effect of the GLP-1 receptor agonists on different cardiovascular risk factors, mediated by the effect of GLP-1 receptor agonists on the control of hyperglycaemia and the GLP-1 receptor agonists effect on other cardiovascular risk factors (weight control, blood pressure control, lipid profile and all other cardiovascular risk biomarkers). In addition, we present the emerging evidence with regards to the impact that GLP-1 receptor agonists therapy could have in the reduction of cardiovascular events and the currently ongoing studies addressing this issue.

Topics: Blood Glucose; Brain; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dyslipidemias; Exenatide; Gastric Emptying; Glucagon-Like Peptide 1; Heart; Humans; Hypertension; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Liraglutide; Liver; Meta-Analysis as Topic; Obesity; Peptides; Risk; Venoms; Weight Loss

In people with type 2 diabetes mellitus (T2DM), the incretin effect is reduced, but the recent advent of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide (GLP)-1 agonists/analogues has enabled restoration of at least some of the function of the incretin system, with accompanying improvements in glycaemic control. Two GLP-1 receptor agonists/analogues are currently approved for the treatment of T2DM-exenatide (Byetta®, Eli Lilly & Co., Indianapolis, IN, US) and liraglutide (Victoza®, Novo Nordisk, Bagsvaerd, Denmark); a once-weekly formulation of exenatide (Bydureon®, Eli Lilly & Co.) has also been approved by the European Medicines Agency. The National Institute for Health and Clinical Excellence (NICE) has recently published guidance on the use of liraglutide in T2DM, based on evidence from the Liraglutide Effect and Action in Diabetes (LEAD) Phase III trial programme, which compared liraglutide with existing glucose-lowering therapies, such as exenatide and insulin glargine. The LEAD programme reported HbA1c reductions from 0.8 to 1.5% with liraglutide (1.2 and 1.8 mg), accompanied by low rates of hypoglycaemia and some weight loss; side effects were primarily gastrointestinal in nature (e.g. nausea and diarrhoea). Based on the findings of the LEAD studies and the NICE recommendation, liraglutide now represents an important therapy widely available in the UK for certain patient groups, including those with a body mass index (BMI) ≥35.0 kg/m(2) , and patients with a BMI <35 kg/m(2) who are considered unsuitable for insulin and are failing to meet targets for glycaemic control with oral agents. NICE guidelines still suggest that most patients without considerable obesity (BMI <35 kg/m(2) ) are probably best managed using insulin therapy. Evidence also suggests a future role for GLP-1 mimetics in combination with basal insulin.

Topics: Algorithms; Diabetes Mellitus, Type 2; Drug Administration Schedule; Evidence-Based Medicine; Exenatide; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Detemir; Insulin Glargine; Insulin, Long-Acting; Liraglutide; Male; Peptides; Randomized Controlled Trials as Topic; United Kingdom; Venoms; Weight Loss

The objective of this systematic review was to assess the published literature on the effectiveness of exenatide twice daily (exenatide) in clinical practice, specifically its effects on haemoglobin A1c (A1C), fasting glucose (FG), weight, systolic blood pressure (SBP), medication use, hospitalization and cardiovascular disease (CVD) outcomes. A systematic literature search using the MEDLINE database of English language literature published between January 2005 and May 2011 was performed. The review included retrospective or prospective observational studies that included 100 or more patients per treatment group. A total of 15 studies meeting the inclusion criteria were identified. The studies revealed significant reductions of -0.4 to -0.9% in A1C, -10 mg/dl in FG, -2 to -11 kg in body weight and -2 to -11 mmHg in SBP. Statistically significant reductions in the use or dosage of either oral glucose-lowering medications or insulin after initiating exenatide treatment were found in every observational study that assessed medication changes, including reductions in dosage of up to 75% in sulphonylureas dosages, 22% in metformin, 66% in thiazolidinediones (TZD) or TZD combination therapy and 75% in prandial insulin. Exenatide-treated patients experienced significantly lower rates of all-cause and CVD-related hospitalization and CVD events than patients treated with other therapies overall. In this review of observational studies, exenatide initiation was associated with significant reductions in clinically relevant outcomes. Improvements in A1C, FG, weight and SBP in the observational studies in this review were consistent with improvements observed in controlled clinical trials.

Topics: Blood Glucose; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Female; Glycated Hemoglobin; Hospitalization; Humans; Hypoglycemic Agents; Male; Peptides; United States; Venoms; Weight Loss

To determine whether treatment with agonists of glucagon-like peptide-1 receptor (GLP-1R) result in weight loss in overweight or obese patients with or without type 2 diabetes mellitus.. Systematic review with meta-analyses.. Electronic searches (Cochrane Library, Medline, Embase, and Web of Science) and manual searches (up to May 2011). Review methods Randomised controlled trials of adult participants with a body mass index of 25 or higher; with or without type 2 diabetes mellitus; and who received exenatide twice daily, exenatide once weekly, or liraglutide once daily at clinically relevant doses for at least 20 weeks. Control interventions assessed were placebo, oral antidiabetic drugs, or insulin.. Three authors independently extracted data. We used random effects models for the primary meta-analyses. We also did subgroup, sensitivity, regression, and sequential analyses to evaluate sources of intertrial heterogeneity, bias, and the robustness of results after adjusting for multiple testing and random errors.. 25 trials were included in the analysis. GLP-1R agonist groups achieved a greater weight loss than control groups (weighted mean difference -2.9 kg, 95% confidence interval -3.6 to -2.2; 21 trials, 6411 participants). We found evidence of intertrial heterogeneity, but no evidence of bias or small study effects in regression analyses. The results were confirmed in sequential analyses. We recorded weight loss in the GLP-1R agonist groups for patients without diabetes (-3.2 kg, -4.3 to -2.1; three trials) as well as patients with diabetes (-2.8 kg, -3.4 to -2.3; 18 trials). In the overall analysis, GLP-1R agonists had beneficial effects on systolic and diastolic blood pressure, plasma concentrations of cholesterol, and glycaemic control, but did not have a significant effect on plasma concentrations of liver enzymes. GLP-1R agonists were associated with nausea, diarrhoea, and vomiting, but not with hypoglycaemia.. The present review provides evidence that treatment with GLP-1R agonists leads to weight loss in overweight or obese patients with or without type 2 diabetes mellitus.

Topics: Anti-Obesity Agents; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Obesity; Overweight; Peptides; Receptors, Glucagon; Treatment Outcome; Venoms; Weight Loss

The two classes of incretin-related therapies, dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have become important treatment options for patients with type 2 diabetes. Sitagliptin, saxagliptin, vildagliptin and linagliptin, the available DPP-4 inhibitors, are oral medications, whereas the GLP-1 RAs-twice-daily exenatide, once-weekly exenatide and once-daily liraglutide-are administered subcutaneously. By influencing levels of GLP-1 receptor stimulation, these medications lower plasma glucose levels in a glucose-dependent manner with low risk of hypoglycaemia, affecting postprandial plasma glucose more than most other anti-hyperglycaemic medications. Use of GLP-1 RAs has been shown to result in greater glycaemic improvements than DPP-4 inhibitors, probably because of higher levels of GLP-1 receptor activation. GLP-1 RAs can also produce significant weight loss and may reduce blood pressure and have beneficial effects on other cardiovascular risk factors. Although both classes are well tolerated, DPP-4 inhibitors may be associated with infections and headaches, whereas GLP-1 RAs are often associated with gastrointestinal disorders, primarily nausea. Pancreatitis has been reported with both DPP-4 inhibitors and GLP-1 RAs, but a causal relationship between use of incretin-based therapies and pancreatitis has not been established. In clinical trials, liraglutide has shown efficacy and tolerability and resulted in certain significant benefits when compared with exenatide and sitagliptin.

Topics: Administration, Oral; Blood Glucose; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Administration Schedule; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Liraglutide; Male; Peptides; Randomized Controlled Trials as Topic; Risk Factors; Venoms; Weight Loss

Incretin-based therapies have a glucose-dependent mode of action that results in excellent glucose-lowering efficacy with very low risk of hypoglycaemia, and weight neutrality [dipeptidyl peptidase-4 (DPP-4) inhibitors] or weight loss [glucagon-like peptide-1 (GLP-1) receptor agonists], in people with type 2 diabetes mellitus (T2DM). Patient-reported outcomes (PROs) complement physician evaluations of efficacy and tolerability and offer insights into the subjective experience of using modern diabetes treatments. We conducted a systematic search of clinical trials of the GLP-1 receptor agonists liraglutide, exenatide and long-acting exenatide, one of which included the oral DPP-4 inhibitor sitagliptin as a comparator. No other PRO data for DPP-4 inhibitors were identified. This review summarizes PRO data from eight clinical trials, the majority of which used the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and/or Impact of Weight on Quality of Life-Lite (IWQOL-Lite) to evaluate patient experience. People with T2DM were highly satisfied with modern incretin-based therapies compared with traditional therapies. Treatment satisfaction (including perceptions of convenience and flexibility) was high and generally higher with GLP-1 agonists in association with their greater glucose-lowering efficacy and tendency to facilitate weight loss. Weight-related quality of life (QoL) also improved in people using incretin therapies. The glycaemic improvements achieved with GLP-1 receptor agonists, coupled with the low incidence of hypoglycaemia and ability to cause weight loss, seemed to offset potential concern about injections. It is plausible that superior patient-reported benefits found in clinical trials may translate into improved, clinically meaningful, long-term outcomes through increased treatment acceptability. Long-term, prospective data are needed to ascertain whether this is the case in practice.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Administration Schedule; Exenatide; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Liraglutide; Male; Medication Adherence; Patient Satisfaction; Peptides; Pyrazines; Self Care; Sitagliptin Phosphate; Surveys and Questionnaires; Treatment Outcome; Triazoles; Venoms; Weight Loss

To evaluate the potential role of exenatide for weight loss in overweight or obese adults without diabetes.. PubMed (1946-August 2012) and EMBASE (1974-August 2012) were used to conduct a literature search utilizing the terms exenatide, weight loss, obesity, and overweight. Additional references were identified by bibliographic review of relevant articles.. Studies assessing the use of exenatide in adult subjects without type 2 diabetes or polycystic ovary syndrome and reporting effects on body weight were included.. Five studies were identified that reported use of exenatide in nondiabetic adults and included weight change as an outcomes measure. In all 5 of these studies, subjects taking exenatide experienced statistically significant weight loss, which ranged from 2.0 ± 2.8 to 5.1 ± 0.5 kg. Two of the trials were randomized, placebo-controlled studies; 1 trial was a randomized, open-label investigation; 1 study had a prospective, open-label cohort design; and the remaining study was a chart review. Adverse events experienced with exenatide were primarily gastrointestinal in nature, although each trial reported the drug to be well tolerated.. Obesity continues to be a national epidemic, while choices for effective pharmacologic treatments are extremely limited. Exenatide appears to have promising effects on weight in overweight or obese adults without type 2 diabetes. Further investigations with large, placebo-controlled trials assessing long-term weight loss as a primary outcome are warranted.

Topics: Adult; Anti-Obesity Agents; Body Weight; Clinical Trials as Topic; Exenatide; Humans; Obesity; Overweight; Peptides; Venoms; Weight Loss

The prevalence of obesity and diabetes is epidemic. Severe insulin resistance (defined as the need for > or = 200 units of insulin per day to achieve glycemic control) is commonly seen with obesity and can complicate diabetes management. The management of patients with diabetes who have severe insulin resistance is difficult, and at times frustrating, and requires a multifaceted approach. Weight loss is the best treatment option, which can be a challenging task for patients to achieve and maintain. Medications that decrease insulin needs like metformin, thiazolidinediones, or pramlintide may help, but some patients also need high doses of insulin. This article reviews these different treatment options and provides practical advice on weight loss, use of insulin sensitizers, and use of U-500 insulin.

Topics: Amyloid; Bariatric Surgery; Diabetes Mellitus; Diet, Reducing; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Exercise; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Islet Amyloid Polypeptide; Liraglutide; Metformin; Obesity; Peptides; Thiazolidinediones; Treatment Failure; Venoms; Weight Loss

Type 2 diabetes mellitus and comorbidities related to overweight/obesity are risk factors for the development of cardiovascular disease (CVD). In addition to insulin resistance and progressive beta-cell failure as key factors in the pathogenesis of type 2 diabetes mellitus, defects in the incretin system are now known to contribute as well. Lifestyle modifications including diet and exercise are often insufficient for reducing glucose and weight, and most patients with type 2 diabetes will require pharmacotherapy to treat their hyperglycemia. Goals of therapy should be to reduce blood glucose to as low as possible, for as long as possible, without weight gain and hypoglycemia, and correcting cardiovascular risk factors. Numerous antidiabetes medications lower blood glucose; however, many are associated with weight gain and do not address risk factors present for CVD. Newer pharmacotherapies include the glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and amylinomimetics. The GLP-1 receptor agonists and amylinomimetics reduce glucose while promoting weight loss and improving other cardiovascular risk factors with a low incidence of hypoglycemia. The DPP-4 inhibitors effectively lower glucose and are weight neutral.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Life Style; Liraglutide; Obesity; Overweight; Peptides; Receptors, Glucagon; Venoms; Weight Loss

Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone mainly released from the distal ileum, jejunum, and colon in response to food ingestion. It is categorized as an incretin due to its activation of GLP-1 receptors in pancreatic beta-cells leading to insulin exocytosis in a glucose-dependent manner. Exenatide (synthetic exendin-4) is a subcutaneously injected GLP-1 receptor agonist that shares 50% homology with GLP-1. It is derived from lizard venom and stimulates the GLP-1 receptor for prolonged periods. The present review aims to enumerate exenatide-instigated weight loss, summarize the known mechanisms of exenatide-induced weight loss, and elaborate on its possible application in the pharmacotherapy of obesity.. A search through PubMed was performed using exenatide and weight loss as search terms. A second search was performed using exenatide and mechanisms or actions as search terms.. In addition to exenatide's action to increase insulin secretion in individuals with elevated levels of plasma glucose, clinical trials have reported consistent weight loss associated with exenatide treatment. Studies have found evidence that exenatide decreases energy intake and increases energy expenditure, but findings on which predominates to cause weight loss are often inconsistent and controversial.. Further research on the effects of exenatide treatment on energy intake and expenditure are recommended to better understand the mechanisms through which exenatide causes weight loss.

Topics: Animals; Diabetes Mellitus, Type 2; Energy Intake; Energy Metabolism; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Lizards; Obesity; Peptides; Receptors, Glucagon; Venoms; Weight Loss

Several drugs that act on the incretin hormonal system are now licensed in the UK as add-on therapy for patients with type 2 diabetes mellitus and inadequate glycaemic control. Liraglutide (Victoza--Novo Nordisk) is a recently licensed long-acting glucagon-like peptide-1 (GLP-1) mimetic that can be given once daily as a subcutaneous injection, as part of either dual or triple therapy. Advertising claims that use of the drug leads to "reductions in weight"; "reductions in systolic blood pressure"; and "improvements in beta-cell function", as well as reductions in blood glucose concentrations. Here we assess the evidence for these claims and consider whether liraglutide has a role in the management of patients with type 2 diabetes.

Topics: Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Liraglutide; Nausea; Peptides; Practice Guidelines as Topic; Venoms; Vomiting; Weight Loss

A systematic review of the literature, in combination with a meta-analysis of randomized controlled trials comparing treatments with placebo, was conducted to provide an update on the clinical efficacy and safety of incretin-based medications in adult patients with type 2 diabetes.. A literature search (2000-2009) identified 38 placebo-controlled trials (phase II or later - parallel design) comparing exenatide (n = 8), liraglutide (n = 7), vildagliptin (n = 11) and sitagliptin (n = 12) with placebo. Outcomes were change from baseline in HbA(1c) and in weight, and the number of patient-reported hypoglycemic episodes. HbA(1c) and weight outcomes were analyzed as weighted mean differences (WMD), and the number of hypoglycemic episodes as relative risks (RR).. Patients receiving liraglutide showed greater reduction in HbA(1c) in comparison to placebo (WMD = -1.03, 95% confidence interval, CI = -1.16 to -0.90, p < 0.001) than those on sitagliptin (WMD = -0.79, 95% CI = -0.93 to -0.65, p < 0.001), exenatide (WMD = -0.75, 95% CI = -0.83 to -0.67, p < 0.001) or vildagliptin (WMD = -0.67, 95% CI = -0.83 to -0.52, p < 0.001). Weight was statistically significantly negatively associated with exenatide (WMD = -1.10, 95% CI = -1.32 to -0.87, p < 0.001) and positively associated with sitagliptin (WMD = 0.60, 95% CI = 0.33-0.87, p < 0.001) and vildagliptin (WMD = 0.56, 95% CI = 0.27-0.84, p < 0.001). The number of patient-reported hypoglycemic episodes was statistically significantly associated with the use of sitagliptin (RR = 2.56, 95% CI = 1.23-5.33, p = 0.01) and exenatide (RR = 2.40, 95% CI = 1.30-4.11, p = 0.002).. Incretin-based therapies are effective in glycemic control and also offer other advantages such as weight loss (exenatide and liraglutide). This may have an important impact on patient adherence to medication.

Topics: Adamantane; Adult; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Liraglutide; Nitriles; Peptides; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Triazoles; Venoms; Vildagliptin; Weight Loss

Exenatide is an incretin mimetic that activates glucagon-like-peptide-1 receptors. It blunts the postprandial rise of plasma glucose by increasing glucose-dependent insulin secretion, suppressing inappropriately high glucagon secretion and delaying gastric emptying.. In seven clinical trials performed in 2845 adult patients with type 2 diabetes mellitus who were inadequately controlled by a sulphonylurea and/or metformin (glycosylated haemoglobin, HbA1c

Topics: Blood Glucose; Body Weight; C-Reactive Protein; Diabetes Mellitus, Type 2; Exenatide; Fasting; Female; Glucagon; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Male; Peptides; Randomized Controlled Trials as Topic; Venoms; Weight Loss

Tight diabetes control sometimes comes with a price: weight gain and hypoglycemia. Two of the three major recent trials that looked at the relationship between intensive diabetes control and cardiovascular events reported significant weight gain among the intensively treated groups. There is a growing concern that the weight gain induced by most diabetes medications diminishes their clinical benefits. On the other hand, there is a claim that treating diabetes with medications that are weight neutral or induces weight loss or less weight gain while minimizing those that increase body weight may emerge as the future direction for treating overweight and obese patients with diabetes. This review clarifies the weight effect of each of the currently available diabetes medications, and explains the mechanism of action behind this effect. Despite the great variability among reviewed clinical trials, the currently available evidence is quite sufficient to demonstrate the change in body weight in association with most of the currently available medications. This review also provides some guidelines on using diabetes medications during weight management programs.

Topics: Abdominal Fat; Benzamides; Body Weight; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Exenatide; Glucagon-Like Peptide 1; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Insulin; Metformin; Obesity; Peptides; Randomized Controlled Trials as Topic; Sulfonylurea Compounds; Thiazolidinediones; Venoms; Weight Gain; Weight Loss

The benefits and drawbacks of exenatide as an alternative to insulin in the treatment of poorly regulated type 2 diabetes are reviewed. Exenatide and insulin have equal effects on HbA1c but exenatide causes weight-loss and improved postprandial glucose control. Nausea is reported by nearly half of patients treated with exenatide. Exenatide can be considered in the overweight patient without extremely elevated HbA1c but nausea could pose a substantial hurdle for successful treatment.

Topics: Adult; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Evidence-Based Medicine; Exenatide; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Peptides; Treatment Outcome; Venoms; Weight Loss

Among the challenges in improving outcomes in patients with diabetes is effectively implementing existing pharmacotherapies. However, current therapies for diabetes are often limited by adverse effects such as edema, hypoglycemia, and weight gain. Understanding the role of the incretin effect on the pathophysiology of diabetes has led to the development of new therapeutic agents. Exenatide is the first in a new class of agents termed "incretin mimetics," which replicate several glucoregulatory effects of the endogenous incretin hormone, glucagon-like peptide-1. In clinical trials, patients with type 2 diabetes treated with exenatide demonstrate sustained improvements in glycemic control, with reductions in fasting and postprandial glucose levels and improvements in glycosylated hemoglobin levels. Improvements in glycemic control with exenatide are coupled with reductions in body weight. Lipid parameters, blood pressure, and C-reactive protein have been shown to improve favorably in patients treated with exenatide. The sustained glycemic improvements and progressive reduction in body weight with exenatide treatment support a shift toward a more favorable cardiovascular risk profile and may have a positive impact on decreasing the risk of associated long-term complications.

Topics: C-Reactive Protein; Comorbidity; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin; Obesity; Peptides; Protein Binding; Risk Factors; Venoms; Weight Loss

Glucagon-like peptide-1 (7-36) amide (GLP-1) is a gut hormone, released postprandially,which stimulates insulin secretion and insulin gene expression as well as pancreatic B-cell growth. Together with glucose-dependent insulinotropic polypeptide (GIP), it is responsible for the incretin effect which is the augmentation of insulin secretion following oral administration of glucose. Patients with Type 2 diabetes have greatly impaired or absent incretin-mediated insulin secretion which is mainly as a result of decreased secretion of GLP-1. However,the insulinotropic action of GLP-1 is preserved in patients with Type 2 diabetes,and this has encouraged attempts to treat Type 2 diabetic patients with GLP-1.GLP-1 also possesses a number of potential advantages over existing agents for the treatment of Type 2 diabetes. In addition to stimulating insulin secretion and promoting pancreatic B-cell mass, GLP-1 suppresses glucagon secretion,delays gastric emptying and inhibits food intake. Continuous intravenous and subcutaneous administration significantly improves glycaemic control and causes reductions in both HbA1c and body weight. However, GLP-1 is metabolized extremely rapidly in the circulation by the enzyme dipeptidyl peptidase IV(DPP-IV). This is the probable explanation for the short-lived effect of single doses of native GLP-1, making it an unlikely glucose-lowering agent. The DPP-IV resistant analogue, exenatide, has Food and Drug Administration (FDA) approval for the treatment of Type 2 diabetes and selective DPP-IV inhibitors are underdevelopment. Both approaches have demonstrated remarkable efficacy in animal models and human clinical studies. Both are well tolerated and appear to have advantages over current therapies for Type 2 diabetes, particularly in terms of the effects on pancreatic B-cell restoration and potential weight loss.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin-Secreting Cells; Peptides; Venoms; Weight Loss

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.. We investigated the separate and combined effects of dapagliflozin and exenatide on the CNS in participants with obesity and type 2 diabetes.. 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.. 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.. 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

This study sought to evaluate the effect of 52 weeks of exenatide extended release (XR) on the maintenance of meal replacement therapy (MRT)-induced BMI reduction in adolescents with severe obesity.. In this randomized, double-blind, placebo-controlled trial, 100 participants aged 12 to 18 years with BMI ≥ 1.2 × 95th percentile were enrolled in a short-term MRT run-in phase. Those who achieved ≥5% BMI reduction during the run-in were then randomized to 52 weeks of exenatide XR 2.0 mg or placebo weekly. Both groups also received lifestyle therapy. The prespecified primary end point was mean percent change in BMI from randomization (post run-in) to 52 weeks in the intention-to-treat population.. A total of 100 participants were enrolled, and 66 (mean age 16 = [SD 1.5] years; 47% female) achieved ≥5% BMI reduction with MRT and were randomized (33 to exenatide XR and 33 to placebo). From randomization (post run-in) to 52 weeks, mean BMI increased 4.6% and 10.1% in the exenatide XR and placebo groups, respectively. The placebo-subtracted exenatide XR treatment effect was -4.1% (95% CI: -8.6% to 0.5%, p = 0.078).. Although not achieving statistical significance, exenatide XR, compared with placebo, may partly mitigate the propensity toward BMI rebound in adolescents who achieved initial weight loss with dietary intervention.

Topics: Adolescent; Double-Blind Method; Exenatide; Female; Humans; Hypoglycemic Agents; Male; Obesity, Morbid; Treatment Outcome; Weight Loss

Sodium-glucose cotransporter-2 inhibitors induce less weight loss than expected. This may be explained by sodium-glucose cotransporter-2 inhibitor-induced alterations in central reward- and satiety circuits, leading to increased appetite and food intake. Glucagon-like peptide-1 receptor agonists reduce appetite and body weight because of direct and indirect effects on the brain. We investigated the separate and combined effects of dapagliflozin and exenatide on the brain in response to the anticipation and consumption of food in people with obesity and type 2 diabetes.. As part of a larger study, this was a 16 week, double-blind, randomized, placebo-controlled trial. Subjects with obesity and type 2 diabetes were randomized (1:1:1:1) to dapagliflozin 10 mg with exenatide-matched placebo, exenatide twice-daily 10 μg with dapagliflozin-matched placebo, dapagliflozin plus exenatide, or double placebo. Using functional magnetic resonance imaging, the effects of treatments on brain responses to the anticipation of food and food receipt were assessed after 10 days and 16 weeks.. After 10 days, dapagliflozin increased activation in right amygdala and right caudate nucleus in response to the anticipation of food, and tended to decrease activation in right amygdala in response to actual food receipt. After 16 weeks, no changes in brain activation were observed with dapagliflozin. Dapagliflozin plus exenatide reduced activation in right caudate nucleus and amygdala to the anticipation of food, and decreased activation in the right amygdala in response to food receipt after 16 weeks.. The dapagliflozin-induced changes in brain activation may contribute to the discrepancy between observed and expected weight loss with dapagliflozin. Exenatide blunted the dapagliflozin-induced changes in brain activation, which may contribute to the additional weight loss with combined treatment.

Topics: Benzhydryl Compounds; Blood Glucose; Brain; Diabetes Mellitus, Type 2; Double-Blind Method; Exenatide; Glucose; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Obesity; Sodium; Sodium-Glucose Transporter 2 Inhibitors; Weight Loss

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) induce less weight loss than expected. This may be explained by SGLT2i-induced alterations in central reward and satiety circuits, contributing to increased appetite and food intake. This hyperphagia may be specific to high-calorie foods. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are associated with lower preferences for high-calorie foods, and with decreased activation in areas regulating satiety and reward in response to high-calorie food pictures, which may reflect this lower preference for energy-dense foods. To optimize treatment, we need a better understanding of how intake is controlled, and how [(un)healthy] food choices are made. The aim of the study was to investigate the effects of dapagliflozin, exenatide, and their combination on brain activation in response to low-calorie food pictures.. We performed an exploratory analysis of a larger, 16-week, double-blind, randomized, placebo-controlled trial. Sixty-eight subjects with obesity and type 2 diabetes were randomized to dapagliflozin, exenatide, dapagliflozin plus exenatide, or double placebo. Using functional MRI, the effects of treatments on brain responses to low-calorie food pictures were assessed after 10 days and 16 weeks.. Dapagliflozin versus placebo decreased activity in response to low-calorie food pictures, in the caudate nucleus, insula, and amygdala after 10 days, and in the insula after 16 weeks. Exenatide versus placebo increased activation in the putamen in response to low-calorie food pictures after 10 days, but not after 16 weeks. Dapagliflozin plus exenatide versus placebo had no effect on brain responses, but after 10 days dapagliflozin plus exenatide versus dapagliflozin increased activity in the insula and amygdala in response to low-calorie food pictures.. Dapagliflozin decreased activation in response to low-calorie food pictures, which may reflect a specific decreased preference for low-calorie foods, in combination with the previously found increased activation in response to high-calorie foods, which may reflect a specific preference for high-calorie foods, and may hamper SGLT2i-induced weight loss. Exenatide treatment increased activation in response to low-calorie foods. Combination treatment may lead to more favorable brain responses to low-calorie food cues, as we observed that the dapagliflozin-induced decreased response to low-calorie food pictures had disappeared.

Topics: Benzhydryl Compounds; Brain; Diabetes Mellitus, Type 2; Exenatide; Glucosides; Humans; Hypoglycemic Agents; Sodium-Glucose Transporter 2 Inhibitors; Weight Loss

The majority of Polycystic ovary syndrome (PCOS) are overweight or obese with increased infertility and high risk of pregnancy complications. We aim to compare efficacy of metformin and exenatide on spontaneous pregnancy rate, overall pregnancy rate after assisted reproductive technology treatment (ART) and pregnancy outcomes in overweight or obese infertility PCOS.. In this long-term follow-up study, 160 overweight or obese infertility Chinese PCOS were randomized to exenatide or metformin treatment for 12 weeks. Afterward, all were treated with metformin alone until pregnancy confirmed and followed until delivery. If patients failed spontaneous pregnancy during the second 12 weeks, ART could be offered until end of 64 weeks. The primary outcome was spontaneous pregnancy rate.. At week 24, 29.2% of women in exenatide group conceived spontaneously while 14.7% in metformin group (p = 0.03). At week 64, total pregnancy rates were 79.2% in exenatide group and 76% in metformin group without significant difference (p = 0.65). Between two groups, there was no significant difference of pregnancy outcomes (p > 0.05). A stepwise logistic regression showed that spontaneous pregnancy was positively associated with body weight reduction and HOMA-IR improvement in either group.. In overweight or obese infertility Chinese PCOS, 12 weeks pregestational exenatide treatment resulted in more spontaneous pregnancy likely due to greater weight reduction and improvement of insulin resistance compared with metformin treatment without obvious benefit on overall pregnancy rate after ART or pregnancy outcomes of successful conceived women.. This clinical trial was registered at Chinese Clinical Trials Registry (ChiCTR-IIR-16008084) on 13/3/2016.

Topics: Exenatide; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Infertility, Female; Metformin; Obesity; Overweight; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Outcome; Pregnancy Rate; Weight Loss

As there is significant heterogeneity in the weight loss response to pharmacotherapy, one of the most important clinical questions in obesity medicine is how to predict an individual's response to pharmacotherapy. The present study examines patterns of weight loss among overweight and obese women who demonstrated early robust response to twice daily exenatide treatment compared to those treated with hypocaloric diet and matched placebo injections.. We randomized 182 women (BMI 25-48 kg/m2) to treatment with exenatide alone or matched placebo injections plus hypocaloric diet. In both treatment groups, women who demonstrated ≥ 5% weight loss at 12 weeks were characterized as high responders and those who lost ≥10% of body weight were classified as super responders. Our primary outcome was long-term change in body weight among early high responders to either treatment. An exploratory metabolomic analysis was also performed.. We observed individual variability in weight loss with both exenatide and hypocaloric diet plus placebo injections. There was a trend toward a higher percentage of subjects who achieved ≥ 5% weight loss with exenatide compared to diet (56% of those treated with exenatide, 76% of those treated with diet, p = 0.05) but no significant difference in those who achieved ≥ 10% weight loss (23% of individuals treated with exenatide and 36% of those treated with diet, p = 0.55). In both treatment groups, higher weight loss at 3 months of treatment predicted super responder status (diet p=0.0098, exenatide p=0.0080). Both treatment groups also demonstrated similar peak weight loss during the study period. We observed lower cysteine concentrations in the exenatide responder group (0.81. In a population of early high responders, longer term weight loss with exenatide treatment is similar to that achieved with a hypocaloric diet.. www.clinicaltrialsgov, identifier NCT01590433.

Topics: Adult; Anti-Obesity Agents; Body Mass Index; Combined Modality Therapy; Cysteine; Diet, Reducing; Double-Blind Method; Exenatide; Female; Humans; Metabolomics; Middle Aged; Obesity; Overweight; Treatment Outcome; Weight Loss

Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors reduce weight and improve insulin sensitivity via different mechanisms.. The efficacy of once-weekly exenatide (EQW) and dapagliflozin (DAPA) alone and coadministered (EQW/DAPA), DAPA/extended-release (ER) metformin (DAPA/MET), and phentermine topiramate extended release (PHEN/TPM) on metabolic parameters, body composition, and sex hormones were examined in obese women with PCOS.. Nondiabetic women (n = 119; aged 18-45 years) with a body mass index (BMI) greater than 30 and less than 45 and polycystic ovary syndrome (National Institutes of Health criteria) were randomly assigned in a single-blinded fashion to EQW (2 mg weekly); DAPA (10 mg daily), EQW/DAPA (2 mg weekly/10 mg daily), DAPA (10 mg)/MET (2000 mg XR daily), or PHEN (7.5 mg)/TPM (46 mg ER daily) treatment for 24 weeks. Study visits at baseline and 24 weeks included weight, blood pressure (BP), waist (WC) measures, and body composition evaluated by dual-energy x-ray absorptiometry (DXA). Oral glucose tolerance tests were conducted to assess glycemia and mean blood glucose (MBG), and compute insulin sensitivity (SI) and secretion (IS) measures. Sex steroids, free androgen index (FAI), and lipid profiles were measured in the fasting sample.. EQW/DAPA and PHEN/TPM resulted in the most loss of weight and total body fat by DXA, and WC. Despite equivalent reductions in BMI and WC with PHEN/TPM, only EQW/DAPA and EQW resulted in significant improvements in MBG, SI, and IS. Reductions in fasting glucose, testosterone, FAI, and BP were seen with all drugs.. Dual therapy with EQW/DAPA was superior to either alone, DAPA/MET and PHEN/TPM in terms of clinical and metabolic benefits in this patient population.

Topics: Adolescent; Adult; Benzhydryl Compounds; Blood Glucose; Drug Therapy, Combination; Exenatide; Female; Glucose Tolerance Test; Glucosides; Humans; Hypoglycemic Agents; Metformin; Middle Aged; Obesity; Phentermine; Polycystic Ovary Syndrome; Prospective Studies; Single-Blind Method; Topiramate; Treatment Outcome; Weight Loss; Young Adult

Topics: Adolescent; Adult; Blood Glucose; Clozapine; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Female; Humans; Male; Middle Aged; Obesity; Pilot Projects; Schizophrenia; Weight Loss; Young Adult

To compare the efficacy and safety of adding the glucagon-like peptide-1 receptor agonist exenatide once weekly (QW) 2 mg or placebo among patients with type 2 diabetes who were inadequately controlled despite titrated insulin glargine (IG) ± metformin.. This multicentre, double-blind study (ClinicalTrials.gov identifier: NCT02229383) randomized (1:1) patients with persistent hyperglycaemia after an 8-week titration phase (glycated haemoglobin [HbA1c] 7.0%-10.5% [53-91 mmol/mol]) to exenatide QW or placebo. The primary endpoint was HbA1c change from baseline to week 28. Secondary endpoints included body weight, 2-hour postprandial glucose, and mean daily IG dose.. Of 464 randomized patients (mean: age, 58 years; HbA1c, 8.5% [69 mmol/mol]; diabetes duration, 11.3 years), 91% completed 28 weeks. Exenatide QW + IG vs placebo + IG significantly reduced HbA1c (least-squares mean difference, -0.73% [-8.0 mmol/mol]; 95% confidence interval, -0.93%, -0.53% [-10.2, -5.8 mmol/mol]; P < .001; final HbA1c, 7.55% [59 mmol/mol] and 8.24% [67 mmol/mol], respectively); body weight (-1.50 kg; -2.17, -0.84; P < .001); and 2-hour postprandial glucose (-1.52 mmol/L [-27.5 mg/dL]; -2.15, -0.90 [-38.7, -16.2]; P < .001). Significantly more exenatide QW + IG-treated patients vs placebo + IG-treated patients reached HbA1c <7.0% (<53 mmol/mol) (32.5% vs 7.4%; P < .001); daily IG dose increased by 2 and 4 units, respectively. Gastrointestinal and injection-site adverse events were more frequent with exenatide QW + IG (15.1% and 7.8%, respectively) than with placebo + IG (10.8% and 3.0%, respectively); hypoglycaemia incidence was similar between the exenatide QW + IG (29.7%) and placebo + IG (29.0%) groups, with no major hypoglycaemic events.. Among patients with inadequate glycaemic control, exenatide QW significantly improved glucose control and decreased body weight, without increased hypoglycaemia or unexpected safety findings.

Topics: Aged; Body Mass Index; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Drug Monitoring; Drug Therapy, Combination; Exenatide; Female; Follow-Up Studies; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin Glargine; Male; Middle Aged; Obesity; Weight Loss

Weight loss in response to the long-acting GLP-1 receptor (GLP1R) analog, liraglutide, is correlated with delay in gastric-emptying (GE). The aim of this pilot study was to assess whether specific genetic variants in GLP1R or TCF7L2 are associated with delayed GE and weight loss in obese patients treated with liraglutide or the short-acting GLP-1 agonist, exenatide.. We evaluated in obese individuals the associations of genetic variations of GLP1R (rs6923761) and TCF7L2 (rs7903146) on GE T. There was a significant correlation between changes in weight and GE T. The minor A allele of GLP1R (rs6923761) is associated with greater delay in GE T

Topics: Adult; Alleles; Double-Blind Method; Exenatide; Female; Gastric Emptying; Genetic Variation; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Obesity; Pharmacogenetics; Pilot Projects; Weight Loss

To assess the effect of baseline body mass index (BMI) and the occurrence of nausea and/or vomiting on weight loss induced by semalgutide, a once-weekly glucagon-like peptide 1 analogue for the treatment of type 2 diabetes. Semaglutide demonstrated superior reductions in HbA1c and superior weight loss (by 2.3-6.3 kg) versus different comparators across the SUSTAIN 1 to 5 trials; the contributing factors to weight loss are not established.. Subjects with inadequately controlled type 2 diabetes (drug-naïve or on background treatment) were randomized to subcutaneous semaglutide 0.5 mg (excluding SUSTAIN 3), 1.0 mg (all trials), or comparator (placebo, sitagliptin, exenatide extended release or insulin glargine). Subjects were subdivided by baseline BMI and reporting (yes/no) of any nausea and/or vomiting. Change from baseline in body weight was assessed within each trial and subgroup. A mediation analysis separated weight loss into direct or indirect (mediated by nausea or vomiting) effects.. Clinically relevant weight-loss differences were observed across all BMI subgroups, with a trend towards higher absolute weight loss with higher baseline BMI. Overall, 15.2% to 24.0% and 21.5% to 27.2% of subjects experienced nausea or vomiting with semaglutide 0.5 and 1.0 mg, respectively, versus 6.0% to 14.1% with comparators. Only 0.07 to 0.5 kg of the treatment difference between semaglutide and comparators was mediated by nausea or vomiting (indirect effects).. In SUSTAIN 1 to 5, semaglutide-induced weight loss was consistently greater versus comparators, regardless of baseline BMI. The contribution of nausea or vomiting to this weight loss was minor.

Topics: Adult; Aged; Body Mass Index; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Insulin Glargine; Male; Middle Aged; Nausea; Sitagliptin Phosphate; Treatment Outcome; Vomiting; Weight Loss

A commonly used therapeutic strategy for type 2 diabetes mellitus (DM) in humans involves the use of synthetic incretin hormone-based therapies including exenatide, a glucagon-like pepetide-1 hormone agonist. Glucagon-like pepetide-1 agonists can be used alone or as an ancillary therapy with other agents, including insulin and oral antihyperglycemics. Little is known about the role of these therapies for DM in cats. Therefore, the primary objective of this study was to evaluate the safety and efficacy of short-acting exenatide combined with insulin, as compared to placebo and insulin for the treatment of DM in cats. Treatment with exenatide was well tolerated; only 2 cats developed side effects requiring dose reduction. Two cats (25%) went into diabetic remission while receiving exenatide and insulin, whereas remission was not reported during placebo treatment. The average change in the daily exogenous insulin dose was significant (β = -0.56 U/kg, 95% confidence interval, -0.96 to -0.15, P = 0.007), and the dose of insulin administered was lower during exenatide treatment. The average weight loss experienced on exenatide was significantly higher than on placebo (β = 0.65 kg, 95% confidence interval, 0.09-1.21, P = 0.02). There was no significant difference in any of the hormone concentrations evaluated for cats on exenatide vs placebo treatments. Overall, the treatment of diabetic cats with insulin and a fixed dose of exenatide was found to be safe. The weight loss and decreased exogenous insulin requirement experienced with exenatide treatment could be a significant benefit for overweight diabetic cats and warrants further evaluation.

Topics: Animals; Blood Glucose; Cat Diseases; Cats; Cross-Over Studies; Diabetes Mellitus; Double-Blind Method; Drug Therapy, Combination; Exenatide; Female; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin Glargine; Male; Placebos; Random Allocation; Weight Loss

Dapagliflozin and exenatide reduce body weight by differing mechanisms. Dual therapy with these agents reduces body weight, adipose tissue volume, glycaemia and systolic blood pressure (SBP) over 24 weeks. Here, we examined these effects over 1 year in obese adults without diabetes.. Obese adults without diabetes (N = 50; aged 18-70 years; body mass index, 30-45 kg/m. Of the original 25 dapagliflozin + exenatide-treated and 25 placebo-treated participants, respectively, 21 (84%) and 17 (68%) entered the open-label period and 16 (64%) and 17 (68%) completed 52 weeks of treatment. At baseline, mean body weight was 104.6 kg, and 73.5% of participants had prediabetes (impaired fasting glucose or impaired glucose tolerance). Reductions with dapagliflozin + exenatide at 24 weeks were sustained at 52 weeks, respectively, for body weight (-4.5 and -5.7 kg), total adipose tissue volume (-3.8 and -5.3 L), proportion with prediabetes (34.8% and 35.3%), and SBP (-9.8 and -12.0 mm Hg). Effects on body weight, SBP and glycaemia at 52 weeks with placebo → dapagliflozin + exenatide were similar to those observed with continuation of dapagliflozin + exenatide. Nausea and injection-site reactions were more frequent with dapagliflozin + exenatide than with placebo and diminished over time. Safety and tolerability were similar to that in previous diabetes trials with these agents. No clear difference in adverse event-related withdrawals between placebo and active treatment periods was observed.. Dapagliflozin + exenatide dual therapy produced sustained reductions in body weight, prediabetes and SBP over 52 weeks and was well tolerated in obese adults without diabetes.

Topics: Adiposity; Anti-Obesity Agents; Benzhydryl Compounds; Body Mass Index; Cardiovascular Diseases; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Exenatide; Female; Follow-Up Studies; Ghrelin; Glucosides; Humans; Hypoglycemic Agents; Male; Membrane Transport Modulators; Middle Aged; Obesity; Peptides; Prediabetic State; Proof of Concept Study; Risk Factors; Sodium-Glucose Transport Proteins; Sweden; Venoms; Weight Loss

Bone morphogenetic protein 4 (BMP-4) has been proven to regulate white adipogensis. We aimed to demonstrate the correlation of BMP-4 with fat distribution and Exenatide treatment on it.. We enrolled 69 obese patients. Anthropometric and metabolic indexes were collected. Fat distribution was measured by dual-energy X-ray absorptiometry. BPM-4 levels were assessed using enzyme-link immunosorbent assay kit. 30 obese patients were treated with Exenatide twice a day. Change in body weight, metabolic-related indices and BPM-4 levels were evaluated after 18 weeks.. 1) The mean(±SD) BMP-4 levels were 763.98 ± 324.11 pg/ml in the obese. BPM-4 levels were significantly positively correlated with estimated visceral adipose tissue mass in all subjects and also in females (r = 0.377, r = 0.625, respectively,all P < 0.05). BPM-4 levels were also significantly positively correlated with body mass index, hip circumference and total fat% in females (r = 0.375,r = 0.429,r = 0.493,respectively, all P < 0.05). BPM-4 levels were negatively correlated with total cholesterol(TC) in all subjects and males also (r = -0.373,r = -0.332,respectively, all P < 0.05). BPM-4 levels were also significantly positively correlated with free triiodothyronine in males (r = 0.441, P < 0.05). 3) Multivariate analyses showed that TC was risk factor of BMP-4 concentration in males and Est.VAT Area was risk factor of BMP-4 levels in females. 4) BMP-4 levels were significantly higher in the obesity with slightly increased thyroid stimulating hormone(TSH) than the obesity without slightly increased TSH (902.08 ± 354.74 pg/ml vs. 720.24 ± 306.41 pg/ml, P < 0.05). 5) Exenatide treatment leads to a significant decreased in BMP-4 from 860.05 ± 352.65 pg/ml to 649.44 + 277.49 pg/ml independent of weight loss(P < 0.05).. BMP-4 levels were associated with the visceral adipose tissue and may play a certain role in fat distribution and subclinical hypothyroidism in obesity. Exenatide treatment reduced BMP-4 levels independent of weight loss.. Clinicaltrials.gov Identifier: NCT02118376 , Registered 16 April.

Topics: Absorptiometry, Photon; Adiposity; Adult; Body Mass Index; Bone Morphogenetic Protein 4; China; Cholesterol; Drug Monitoring; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Intra-Abdominal Fat; Male; Middle Aged; Obesity; Peptides; Reproducibility of Results; Sex Characteristics; Thyrotropin; Triiodothyronine; Venoms; Weight Loss

Weight loss remains one of the most important arms in obese patients with polycystic ovary syndrome (PCOS). Further studies are needed to identify the best treatment.. To evaluate the effects of exenatide (EXE) on reproductive and metabolic function in overweight/obese (OW/OB) PCOS.. This is a 24-week open-label prospective, randomized, clinical study.. This study randomized 176 OW/OB women diagnosed with PCOS to receive either EXE 10 μg BID (n = 88) or metformin (MET) 1000 mg BID (n = 88) for the first 12 weeks. Then all patients were treated with MET alone during the second 12 weeks. We observed metabolic parameters at 0 and 12 weeks, and then tracked the rate of pregnancy during the second 12 weeks.. After the first 12 weeks of intervention, compared with MET, subjects who received EXE had significantly decreased weight (4.29 ± 1.29 kg vs 2.28 ± 0.55 kg, P < .001) and total fat% (4.67 ± 0.09% vs 1.11 ± 0.32%, P < .001), improved the homeostasis model of assessment for insulin resistance (1.30 ± 0.58 vs 0.59 ± 0.12, P < .001) and increased the menstrual frequency ratio (0.62 ± 0.12 vs 0.37 ± 0.01, P < .001). During the second 12 weeks, the rate of natural pregnancy of EXE-treated patients was significantly higher than MET-treated patients (43.60% vs 18.70%, P < .05).. Short-term EXE therapy was linked to significant weight loss and central adiposity reduction, which may further explain the improvements in insulin resistance, inflammatory marker and menstrual cycle, which may contribute to increasing pregnancy rates in OW/OB women with PCOS.

Topics: Adolescent; Adult; Exenatide; Female; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Menstrual Cycle; Obesity; Overweight; Peptides; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Rate; Prospective Studies; Venoms; Weight Loss; Young Adult

To explore the effects of dual therapy with dapagliflozin and exenatide on body weight, body composition, glycaemic variables and systolic blood pressure (SBP) in obese adults without diabetes.. In this single-centre, double-blind trial, we randomized 50 obese adults without diabetes (aged 18-70 years; body mass index 30-45 kg/m. Of 25 dapagliflozin/exenatide- and 25 placebo-treated participants, 23 (92.0%) and 20 (80.0%) completed 24 weeks of treatment, respectively. At baseline, the mean participant age was 52 years, 61% were female, the mean body weight was 104.6 kg, and 73.5% of participants had prediabetes (impaired fasting glucose or impaired glucose tolerance). After 24 weeks, for dapagliflozin/exenatide versus placebo: the difference in body weight change was -4.13 kg (95% confidence interval -6.44, -1.81; P < .001), which was mostly attributable to adipose tissue reduction without lean tissue change; 36.0% versus 4.2% of participants achieved ≥5% body weight loss, respectively; and prediabetes was less frequent with active treatment (34.8% vs 85.0%, respectively; P < .01). The difference in SBP change for dapagliflozin/exenatide versus placebo was -6.7 mm Hg. As expected, nausea and injection-site reactions were more frequent with dapagliflozin/exenatide than with placebo. Only two and three participants, respectively, discontinued because of adverse events.. Compared with placebo, dapagliflozin/exenatide dual therapy reduced body weight, frequency of prediabetes and SBP over 24 weeks and was well tolerated in obese adults without diabetes.

Topics: Adipose Tissue; Adult; Aged; Benzhydryl Compounds; Blood Glucose; Blood Pressure; Body Composition; Body Weight; Double-Blind Method; Drug Therapy, Combination; Exenatide; Female; Glucose Intolerance; Glucosides; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Magnetic Resonance Imaging; Male; Middle Aged; Nausea; Obesity; Peptides; Prediabetic State; Treatment Outcome; Venoms; Weight Loss

Schizophrenia is associated with cardiovascular co-morbidity and a reduced life-expectancy of up to 20 years. Antipsychotics are dopamine D. Antipsychotic-treated, obese, non-diabetic, schizophrenia spectrum patients were randomized to double-blinded adjunctive treatment with once-weekly subcutaneous exenatide (n = 23) or placebo (n = 22) injections for 3 months. The primary outcome was loss of body weight after treatment and repeated measures analysis of variance was used as statistical analysis.. Between March 2013 and June 2015, 40 patients completed the trial. At baseline, mean body weight was 118.3 ± 16.0 kg in the exenatide group and 111.7 ± 18.0 kg in the placebo group, with no group differences ( P = .23). The exenatide and placebo groups experienced significant ( P = .004), however similar ( P = .98), weight losses of 2.24 ± 3.3 and 2.23 ± 4.4 kg, respectively, after 3 months of treatment.. Treatment with exenatide once-weekly did not promote weight loss in obese, antipsychotic-treated patients with schizophrenia compared to placebo. Our results could suggest that the body weight-lowering effect of GLP-1RAs involves dopaminergic signaling, but blockade of other receptor systems may also play a role. Nevertheless, anti-obesity regimens effective in the general population may not be readily implemented in antipsychotic-treated patients with schizophrenia.

Topics: Absorptiometry, Photon; Adult; Antipsychotic Agents; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Body Composition; Body Weight; Double-Blind Method; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Incretins; Male; Middle Aged; Obesity; Peptides; Schizophrenia; Treatment Outcome; Venoms; Waist Circumference; Waist-Hip Ratio; Weight Loss; Young Adult

To characterize gastrointestinal adverse events (AEs) with different glucagon-like peptide-1 receptor agonists (GLP-1RAs).. Two retrospective intention-to-treat analyses of 6-month patient-level data were conducted. Data from three studies comparing exenatide once weekly (n = 617) with exenatide twice daily (n = 606) were pooled, and one (DURATION-6) comparing exenatide once weekly (n = 461) with liraglutide (n = 450) was analysed separately. Patient-reported gastrointestinal AEs were classified as upper or lower, AE incidences and timing were determined, subgroups were analysed, and associations of gastrointestinal AEs with efficacy were examined.. Nausea was the most common gastrointestinal AE for all treatments. Fewer exenatide once-weekly-treated vs exenatide twice-daily- or liraglutide-treated patients reported gastrointestinal AEs (34% vs 45% and 25% vs 41%, respectively; both P  < .0001). Fewer exenatide once-weekly-treated patients reported upper plus lower events than liraglutide-treated patients ( P  < .001); the difference between exenatide once weekly and twice daily was not significant. Within each group, more women than men reported gastrointestinal AEs. Events occurrred early and were predominantly mild. Glycated haemoglobin reductions were similar for patients with or without gastrointestinal AEs. Weight loss was greater for patients with gastrointestinal AEs with exenatide once weekly and exenatide twice daily ( P  < .05); no difference was observed in DURATION-6.. Gastrointestinal AEs were less frequent with exenatide once weekly vs exenatide twice daily or liraglutide, and combined upper and lower events occurred less often. Gastrointestinal AEs were typically mild and occurred early. Gastrointestinal AEs did not affect glycaemic control but may be associated with greater weight loss.

Topics: Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Female; Gastrointestinal Diseases; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Incidence; Incretins; Intention to Treat Analysis; Liraglutide; Male; Nausea; Patient Dropouts; Peptides; Retrospective Studies; Self Report; Severity of Illness Index; Sex Factors; Venoms; Weight Loss

In two previous, separate clinical trials, we demonstrated significant reductions in body mass index (BMI) with exenatide in adolescents with severe obesity. In the present study, we pooled data from these near identical trials to evaluate factors that may predict BMI reduction at 3 months. Data from 32 patients (mean age 14.3 ± 2.2 years; 69% female; mean BMI 39.8 ± 5.8 kg m(-2)) were included. Exenatide treatment consisted of 5 mcg twice daily for 1 month, followed by an increase to 10 mcg twice daily for 2 additional months. Predictor variables included baseline BMI, BMI percent change at 1 month, incidence of nausea or vomiting and baseline appetite and satiety measures. Treatment effects of percent change in BMI from baseline were estimated within predictor subgroups using generalized estimating equations with exchangeable working correlation and robust variance estimation for confidence intervals and P-values to account for paired observations. The pooled data treatment effect on absolute BMI at 3 months was -3.42% (95% confidence interval: -5.41%, -1.42%) compared to placebo. Within treated participants, appetite at baseline (treatment effect in high [-4.28%] vs. low [1.02%], P = 0.028) and sex (treatment effect in female [-4.78%] vs. male [0.76%], P = 0.007) were significant predictors of change in BMI at 3 months. Baseline BMI, BMI percent change at 1 month, age, incidence of nausea, vomiting, or other gastrointestinal symptoms and satiety scores did not predict 3-month responses. Sex and measures of appetite may serve as useful predictors of glucagon-like peptide-1 receptor agonist treatment response among adolescents with severe obesity.

Topics: Adolescent; Body Mass Index; Child; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Male; Obesity, Morbid; Peptides; Treatment Outcome; Venoms; Weight Loss; Young Adult

To investigate the effect of exenatide treatment on serum ghrelin levels in obese female patients with type 2 diabetes mellitus.. Fourteen female patients with type 2 diabetes mellitus being treated with metformin and exenatide were enrolled. A mixed meal test was applied to the patients while continuing with their daily medications. Blood samples were taken before and at 60, 120, and 180 minutes following mixed meal test to measure serum total ghrelin, glucose, and insulin levels. The following week, exenatide treatment of the patients was paused for 24 hours and the same experimental procedures were repeated.. Serum ghrelin levels were suppressed significantly at 180 minutes with exenatide treatment compared with baseline (294.4 ± 57.5 versus 234.5 ± 59.4 pg/mL) (p < 0.001). Serum ghrelin levels at 180 minutes were statistically different when percentage change in serum ghrelin levels after mixed meal tests with and without exenatide usage were compared (p = 0.001). Estimated total area under the curve values for serum ghrelin concentrations was also significantly lower with exenatide compared with omitted treatment (p = 0.035).. These results suggest that the effect of exenatide on weight loss may be related with the suppression of serum ghrelin levels, which is an orexigenic peptide.

Topics: Adult; Biomarkers; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Down-Regulation; Drug Therapy, Combination; Eating; Exenatide; Female; Ghrelin; Humans; Hypoglycemic Agents; Incretins; Metformin; Middle Aged; Obesity; Peptides; Postprandial Period; Prospective Studies; Time Factors; Treatment Outcome; Venoms; Weight Loss

To test our hypothesis that initiating therapy with a combination of agents known to improve insulin secretion and insulin sensitivity in subjects with new-onset diabetes would produce greater, more durable reduction in glycated haemoglobin (HbA1c) levels, while avoiding hypoglycaemia and weight gain, compared with sequential addition of agents that lower plasma glucose but do not correct established pathophysiological abnormalities.. Drug-naïve, recently diagnosed subjects with type 2 diabetes mellitus (T2DM) were randomized in an open-fashion design in a single-centre study to metformin/pioglitazone/exenatide (triple therapy; n = 106) or an escalating dose of metformin followed by sequential addition of sulfonylurea and glargine insulin (conventional therapy; n = 115) to maintain HbA1c levels at <6.5% for 2 years.. Participants receiving triple therapy experienced a significantly greater reduction in HbA1c level than those receiving conventional therapy (5.95 vs. 6.50%; p < 0.001). Despite lower HbA1c values, participants receiving triple therapy experienced a 7.5-fold lower rate of hypoglycaemia compared with participants receiving conventional therapy. Participants receiving triple therapy experienced a mean weight loss of 1.2 kg versus a mean weight gain of 4.1 kg (p < 0.01) in those receiving conventional therapy.. The results of this exploratory study show that combination therapy with metformin/pioglitazone/exenatide in patients with newly diagnosed T2DM is more effective and results in fewer hypoglycaemic events than sequential add-on therapy with metformin, sulfonylurea and then basal insulin.

Topics: Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Resistance; Male; Metformin; Middle Aged; Peptides; Pioglitazone; Thiazolidinediones; Venoms; Weight Gain; Weight Loss

Bariatric surgery constitutes the most effective treatment for severely obese type 2 diabetic patients. Exenatide is a glucagon-like peptide 1 receptor agonist that can improve glycemic control and cause weight loss in patients with type 2 diabetes. Clinical experience with exenatide in obese patients with type 2 diabetes waiting for bariatric surgery has not been reported. The aim of the study was to evaluate, in clinical practice, weight and metabolic effects of exenatide (after 3 and 6 months) in patients with type 2 diabetes and obesity waiting for bariatric surgery.. A total of 100 diabetic adult subjects with a BMI ≥ 35 kg/m(2) were included. Primary endpoints were changes in weight and HbA1c after 6 months of treatment. Secondary endpoints were changes from baseline of a variety of clinical measures (triglycerides levels, blood pressure, and waist circumference). Data were analyzed at 3 and 6 months of follow-up.. Treatment for 6 months with exenatide decreased significantly body weight (-12.5 kg) and waist circumference (-13 cm). Twenty percent of patients reduced their BMI under 35 kg/m(2) and significantly improved their metabolic profile (HbA1c <7 %). Significant and maintained decreases in HbA1c of 1 % were observed in the 3 and 6 months cohorts. Triglycerides levels and blood pressure also decreased from baseline to the end of the study. Treatment was discontinued in 19 % of patients mainly due to drug inefficacy (6 %) or adverse events (4 %).. Exenatide twice daily (BID) leads to early, robust, and significant weight loss in a subset of patients with diabetes and severe obesity before bariatric surgery. Clinical trials are needed to confirm the benefits of GLP-1 agonists in type 2 diabetic obese patients or high-risk super-obese patients waiting for bariatric surgery.

Topics: Adult; Bariatric Surgery; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Male; Middle Aged; Obesity, Morbid; Peptides; Prospective Studies; Treatment Outcome; Venoms; Waist Circumference; Weight Loss

Overweight or obesity contributes to the development of type 2 diabetes mellitus (T2DM) and increases cardiovascular risk. Exenatide, a glucagon-like peptide-1 receptor agonist, significantly reduces glycated hemoglobin (A1C) and body weight and improves cardiovascular risk markers in patients with T2DM. As weight loss alone has been shown to reduce A1C and cardiovascular risk markers, this analysis explored whether weight loss contributed importantly to clinical responses to exenatide once weekly.. A pooled analysis from eight studies of exenatide once weekly was conducted. Patients were distributed into quartiles from greatest weight loss (Quartile 1) to least loss or gain (Quartile 4). Parameters evaluated for each quartile included A1C, fasting plasma glucose (FPG), blood pressure (BP), heart rate, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides, and the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST).. The median changes from baseline in body weight in Quartiles 1-4 were -6.0, -3.0, -1.0, and +1.0 kg, respectively. All quartiles had reductions in A1C (median changes -1.6, -1.4, -1.1, and -1.2%, respectively) and FPG (-41, -40, -31, and -25 mg/dL, respectively), with the greatest decreases in Quartiles 1 and 2. Most cardiovascular risk markers (except diastolic BP) and liver enzymes improved in Quartiles 1 through 3 and were relatively unchanged in Quartile 4. Higher rates of gastrointestinal adverse events and hypoglycemia were observed in Quartile 1 compared with Quartiles 2 through 4.. Exenatide once weekly improved glycemic parameters independent of weight change, although the magnitude of improvement increased with increasing weight loss. The greatest trend of improvement in glycemic parameters, cardiovascular risk factors including systolic BP, LDL-C, total cholesterol, and triglycerides, and in liver enzymes, was seen in the patient quartiles with the greatest reductions in body weight.

Topics: Aged; Biomarkers; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Female; Humans; Hypoglycemic Agents; Male; Middle Aged; Peptides; Risk Factors; Venoms; Weight Loss

In a 30 week, double-blind, randomized, controlled Phase 3 study in patients with type 2 diabetes mellitus, the addition of fixed-dose exenatide twice daily (BID) to titrated insulin glargine resulted in significant glycated hemoglobin (HbA(1c)) lowering and weight loss without increased hypoglycemia risk versus titrated insulin glargine alone. Because individualized insulin titration contributed to these results, this post-hoc analysis examined the results in the context of the degree of insulin titration that occurred.. Subjects on pre-existing insulin glargine (with or without oral antidiabetes agents) were randomized to placebo (n = 123) or exenatide BID (n = 138; 5 µg for 4 weeks, then 10 µg ongoing). Insulin glargine was titrated in both arms per the Treat-to-Target algorithm. Tertiles (T1, T2, T3) were based on change in insulin dose from baseline to endpoint. Change in HbA(1c), hypoglycemia risk, and weight gain were assessed per insulin dose tertile.. The population comprised adult patients (mean age = 59 y) with type 2 diabetes and an HbA(1c) level between 7.0% and 10.5% (mean HbA(1c) = 8.4%). Insulin titration ranged from modest reductions in T1 to substantial increases in T3. Greater improvements in HbA1c were demonstrated with exenatide BID versus placebo in all tertiles (statistically significant in T2 and T3). With exenatide BID, more subjects achieved HbA(1c) <7.0% vs. placebo: T1, 44% vs. 29% (P = not significant); T2, 65% vs. 26%; T3, 54% vs. 29% (P < 0.05 for T2 and T3). Incidence of hypoglycemia was numerically lower with exenatide BID in all tertiles. Adjunctive exenatide BID was associated with statistically significantly greater weight loss (T1, T2) or mitigation of weight gain (T3) compared with placebo. Rates of nausea (42% vs. 8%), diarrhea (18% vs. 7%), and vomiting (18% vs. 4%) were higher with exenatide BID than with placebo and did not vary by tertile.. Addition of fixed-dose exenatide BID to optimized insulin glargine, regardless of the extent of insulin titration, significantly improved glycemia without increasing hypoglycemia risk, while mitigating insulin-induced weight gain in this post-hoc analysis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Male; Middle Aged; Peptides; Titrimetry; Treatment Outcome; Venoms; Weight Loss; Young Adult

The purpose of this study was to evaluate the advantages of exenatide treatment on obesity and non-alcoholic fatty liver disease (NAFLD) with elevated liver enzymes in patients with type 2 diabetes (T2D).. A total of 60 newly diagnosed patients with obesity, NAFLD with elevated liver enzymes and T2D were included in the study. The patients were randomly divided into two groups. The exenatide treatment group (n = 30) were treated with exenatide and insulin glargine, and the intensive insulin therapy group (n = 30) were treated with insulin aspart and insulin glargine for 12 weeks. Selected clinical characteristics were determined, and ultrasonography was performed at both baseline and 12 weeks following treatment.. At baseline, the clinical characteristics were matched between the two groups. After 12 weeks, fasting blood glucose (FBG), postprandial blood glucose (PBG), glycosylated haemoglobin (HbA1c), total cholesterol (TC), triglyceride (TG) and total bilirubin levels were significantly decreased in the two groups (p < 0.001). Body weight and waist circumference were significantly decreased in the exenatide group but increased in the intensive insulin group (p < 0.001). The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and γ-glutamyl transpeptidase (γGGT) in the exenatide group were significantly lower than in the intensive insulin group (p < 0.001). The mean body weight change correlated with the levels of ALT, AST and γGGT change (ALT, r = 0.761; AST, r = 0.733; γGGT, r = 0.752; p < 0.001). Moreover, the reversal rate of fatty liver was significantly higher in the exenatide group (93.3%) than the intensive insulin group (66.7%) (p < 0.01).. Exenatide has a better hepatic-protective effect than intensive insulin therapy and perhaps represents a unique option for adjunctive therapy for patients with obesity, non-alcoholic fatty liver disease with elevated liver enzymes and T2D.

Topics: Adult; Biomarkers; Body Mass Index; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diet, Diabetic; Drug Therapy, Combination; Exenatide; Exercise; Female; Glycated Hemoglobin; Hepatic Insufficiency; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Liver; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Obesity; Peptides; Ultrasonography; Venoms; Waist Circumference; Weight Loss

BACKGROUND. There is increasing interest in methods to more rapidly and cost-efficiently investigate drugs that are approved for clinical use in the treatment of another condition. Exenatide is a type 2 diabetes treatment that has been shown to have neuroprotective/neurorestorative properties in preclinical models of neurodegeneration. METHODS. As a proof of concept, using a single-blind trial design, we evaluated the progress of 45 patients with moderate Parkinson's disease (PD), randomly assigned to receive subcutaneous exenatide injection for 12 months or to act as controls. Their PD was compared after overnight withdrawal of conventional PD medication using blinded video assessment of the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), together with several nonmotor tests, at baseline, 6 months, and 12 months and after a further 2-month washout period (14 months). RESULTS. Exenatide was well tolerated, although weight loss was common and l-dopa dose failures occurred in a single patient. Single-blinded rating of the exenatide group suggested clinically relevant improvements in PD across motor and cognitive measures compared with the control group. Exenatide-treated patients had a mean improvement at 12 months on the MDS-UPDRS of 2.7 points, compared with mean decline of 2.2 points in control patients (P = 0.037). CONCLUSION. These results demonstrate a potential cost-efficient approach through which preliminary clinical data of possible biological effects are obtainable, prior to undertaking the major investment required for double-blind trials of a potential disease-modifying drug in PD.. Clinicaltrials.gov NCT01174810.. Cure Parkinson's Trust.

Topics: Aged; Antiparkinson Agents; Constipation; Disease Progression; Drug Repositioning; Exenatide; Female; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Male; Middle Aged; Motor Activity; Off-Label Use; Parkinson Disease; Peptides; Venoms; Weight Loss

We report the discovery and translational therapeutic efficacy of a peptide with potent, balanced co-agonism at both of the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This unimolecular dual incretin is derived from an intermixed sequence of GLP-1 and GIP, and demonstrated enhanced antihyperglycemic and insulinotropic efficacy relative to selective GLP-1 agonists. Notably, this superior efficacy translated across rodent models of obesity and diabetes, including db/db mice and ZDF rats, to primates (cynomolgus monkeys and humans). Furthermore, this co-agonist exhibited synergism in reducing fat mass in obese rodents, whereas a selective GIP agonist demonstrated negligible weight-lowering efficacy. The unimolecular dual incretins corrected two causal mechanisms of diabesity, adiposity-induced insulin resistance and pancreatic insulin deficiency, more effectively than did selective mono-agonists. The duration of action of the unimolecular dual incretins was refined through site-specific lipidation or PEGylation to support less frequent administration. These peptides provide comparable pharmacology to the native peptides and enhanced efficacy relative to similarly modified selective GLP-1 agonists. The pharmacokinetic enhancement lessened peak drug exposure and, in combination with less dependence on GLP-1-mediated pharmacology, avoided the adverse gastrointestinal effects that typify selective GLP-1-based agonists. This discovery and validation of a balanced and high-potency dual incretin agonist enables a more physiological approach to management of diseases associated with impaired glucose tolerance.

Topics: Acylation; Adolescent; Adult; Aged; Animals; Diabetes Mellitus, Type 2; Exenatide; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Haplorhini; Humans; Hyperglycemia; Incretins; Insulin; Liraglutide; Male; Mice; Middle Aged; Peptides; Rats; Receptors, Gastrointestinal Hormone; Receptors, Glucagon; Rodentia; Treatment Outcome; Venoms; Weight Loss; Young Adult

We investigated the relationship between weight change and related factors in subjects with type 2 diabetes mellitus (T2DM) treated with liraglutide versus comparator diabetes therapies.. Twenty-six-week data from seven phase 3, randomized trials in the liraglutide T2DM development programme were analysed by trial and treatment group: liraglutide (1.2 and 1.8 mg), active comparator and placebo. Outcome measures included proportions of subjects in various weight change categories and their percentage weight change from baseline; impact of body mass index (BMI) and gastrointestinal (GI) adverse events (AEs) on weight change and correlation of weight change with change in glycosylated haemoglobin (HbA1c).. A number of subjects experienced >5% weight loss during the trials (24.4% liraglutide 1.8 mg and 17.7% liraglutide 1.2 mg; 17.7% exenatide, 10.0% sitagliptin, 3.6-7.0% sulphonylurea, 2.6% thiazolidinedione and 2.6% glargine; 9.9% placebo). More weight loss was seen with liraglutide 1.2 and 1.8 mg than with active comparators except exenatide. Across trials, higher initial BMI was associated with slightly greater weight loss with liraglutide. Mean weight loss increased slightly the longer GI AEs persisted. Although HbA1c reduction was slightly larger in higher weight loss categories across treatments (including placebo), sample sizes were small and no clear correlation could be determined. Liraglutide-treated subjects experienced additional HbA1c reduction beyond that which appeared weight induced; thus, not all HbA1c-lowering effect appears weight mediated.. The majority of liraglutide-treated T2DM subjects experienced weight loss in this analysis. Weight loss was greater and occurred more in glucagon-like peptide-1 receptor agonist-treated subjects than in active comparator-treated subjects.

Topics: Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Liraglutide; Male; Middle Aged; Peptides; Pyrazines; Sitagliptin Phosphate; Sulfonylurea Compounds; Thiazolidinediones; Triazoles; Venoms; Weight Loss

To investigate the effect of treatment with the glucagon-like peptide 1 receptor agonist exenatide on weight loss and metabolic parameters in obese nondiabetic women.. Forty-one obese women (aged 48 ± 11 years and BMI 33.1 ± 4.1 kg/m(2)) participated in a 35-week randomized, double-blind, placebo-controlled, crossover study, including two 16-week treatment periods separated by a 3-week washout period. There was no lifestyle intervention. The primary outcome was change in body weight.. Subjects treated with exenatide lost an average of 2.49 ± 0.66 kg compared with a 0.43 ± 0.63 kg weight gain during placebo treatment. Weight loss with exenatide treatment was noted at 2 weeks. The degree of weight loss could be stratified. A total of 30% of subjects were high responders who lost ≥5% body weight (-7.96 ± 0.52%), 39% were moderate responders who lost <5% body weight (-2.43 ± 0.45%), and 31% were nonresponders who gained weight (1.93 ± 0.53%). Waist circumference also decreased significantly with exenatide treatment. Subjects experienced more nausea during exenatide treatment compared with placebo, but the severity decreased over time and did not correlate with weight loss.. Short-term exenatide treatment was associated with modest weight loss and decreased waist circumference in a cohort of obese nondiabetic women. A subset of individuals demonstrated robust weight loss that was detected very early in the course of treatment.

Topics: Adult; Cross-Over Studies; Double-Blind Method; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Middle Aged; Nausea; Obesity; Peptides; Receptors, Glucagon; Venoms; Waist Circumference; Weight Loss

The objective of this pilot study was to evaluate the effects of exenatide on BMI (primary endpoint) and cardiometabolic risk factors in nondiabetic youth with extreme obesity. Twelve children and adolescents (age 9-16 years old) with extreme obesity (BMI ≥1.2 times the 95th percentile or BMI ≥35 kg/m(2)) were enrolled in a 6-month, randomized, open-label, crossover, clinical trial consisting of two, 3-month phases: (i) a control phase of lifestyle modification and (ii) a drug phase of lifestyle modification plus exenatide. Participants were equally randomized to phase-order (i.e., starting with control or drug therapy) then crossed-over to the other treatment. BMI, body fat percentage, blood pressure, lipids, oral glucose tolerance tests (OGTT), adipokines, plasma biomarkers of endothelial activation, and endothelial function were assessed at baseline, 3-, and 6-months. The mean change over each 3-month phase was compared between treatments. Compared to control, exenatide significantly reduced BMI (-1.7 kg/m(2), 95% confidence interval (CI) (-3.0, -0.4), P = 0.01), body weight (-3.9 kg, 95% CI (-7.11, -0.69), P = 0.02), and fasting insulin (-7.5 mU/l, 95% CI (-13.71, -1.37), P = 0.02). Significant improvements were observed for OGTT-derived insulin sensitivity (P = 0.02) and β-cell function (P = 0.03). Compliance with the injection regimen was excellent (≥94%) and exenatide was generally well-tolerated (the most common adverse event was mild nausea in 36%). These preliminary data suggest that exenatide should be evaluated in larger, well-controlled trials for its ability to reduce BMI and improve cardiometabolic risk factors in youth with extreme obesity.

Topics: Adolescent; Blood Pressure; Body Mass Index; Body Weight; Cardiovascular Diseases; Child; Cross-Over Studies; Diabetes Mellitus, Type 2; Exenatide; Female; Glucose Tolerance Test; Humans; Injections, Subcutaneous; Male; Minnesota; Obesity, Morbid; Peptides; Pilot Projects; Risk Factors; Risk Reduction Behavior; Time Factors; Treatment Outcome; Venoms; Weight Loss

Exenatide is an analogue of GLP1 designed to improve the glycemic control in patients with obesity and type 2 diabetes. It may control other metabolic processes as well. We aimed to evaluate whether exenatide helps to achieve metabolic control goals in patients with obesity and type 2 diabetes (T2DM) after 24 weeks of treatment.. Open clinical trial in 102 obese patients, with age between 19-77 years (mean [ED] 53,2 [1,1] years), T2DM with mean evolution of 4,88 [0,5] years (range 1 to 20 years) with oral antidiabetic treatment.. There was a reduction of 19.7±7.1mg/dl in the fasting glucose average and of 0.33±0.17% in glycated hemoglobin (HbA(1c)). These last values were higher (2.12±0.53%) in patients with bad control prior to treatment (HbA(1c)>8.5%). The desirable threshold of HbA(1c)<7% was fulfilled by 14% more treated than control patients (43.6 vs. 57.9, P<.05). Reductions of 4.4±0.8kg average weight and of 1.7±0.3kg/m(2) body mass index were recorded. Although there was not a significant reduction in the overall lipid profile, a decrease of 4.9±5.1mg/dl total cholesterol, 3.2±4.3mg/dl LDL-C, 8.6±5.6mg/dl noHDL-C and 2.5±1, 4mg/dl HDL-C was observed. Patients outside target (LDL>100 and/or triglycerides>150mg/dl) showed significant differences in their concentrations of LDL-C and triglycerides. With respect to blood pressure (BP), significant differences were observed in diastolic BP (-18.9±5.7mmHg) but not in systolic BP (P<.05).. Exenatide is an effective drug not only for glycemic control but also for the overall metabolic control of HbA(1c), lipid profile, BP and body weight.

Topics: Adult; Aged; Anti-Obesity Agents; Antihypertensive Agents; Blood Glucose; Combined Modality Therapy; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Female; Gastric Emptying; Glycated Hemoglobin; Humans; Hypertension; Hypoglycemic Agents; Lipids; Male; Metformin; Middle Aged; Nausea; Obesity; Peptides; Satiety Response; Treatment Outcome; Venoms; Vomiting; Weight Loss; Young Adult

To determine variables associated with glycemic and body weight responses when adding exenatide to basal insulin-treated type 2 diabetes.. Exploratory subgroup analyses based on baseline A1C, disease duration, and BMI of a 30-week study comparing exenatide twice daily to placebo, added to optimized insulin glargine (intent-to-treat analysis: 137 exenatide; 122 placebo).. Exenatide participants had greater A1C reductions compared with optimized insulin glargine alone, irrespective of baseline A1C (P < 0.001). Exenatide participants with longer diabetes duration and those with lower BMI had greater A1C reductions (P < 0.01). Exenatide participants lost more weight, regardless of baseline A1C or BMI (P < 0.05). Exenatide participants with longer diabetes duration lost the most weight (P < 0.001).. Exenatide added to optimized basal insulin was associated with improved glycemic control and weight loss, irrespective of baseline A1C, diabetes duration, and BMI. Changes were evident in modestly obese patients and in those with longer diabetes duration.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Exenatide; Humans; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Long-Acting; Peptides; Venoms; Weight Loss

Treatment of patients with type 2 diabetes with glucagon-like peptide-1 (GLP-1) receptor agonist exenatide has showed improvements in glycaemic control coupled with weight loss and lowered blood pressure (BP). We examined the synergy between improved glycaemia and weight loss on BP reduction in patients treated with either exenatide twice daily (BID) or once weekly (QW).. Combining data from three controlled trials, 686 (53% male) patients [baseline mean ± SD: age 55 ± 10 years, weight 95 ± 20 kg, systolic blood pressure (SBP)/diastolic blood pressure (DBP) 130/79 ± 15/9 mmHg, HbA(1c) 8.3 ± 1.1%] treated with exenatide QW (n = 541) or BID (n = 145) were observed over 26 weeks. Using weighted means (WMs) of the longitudinal measures of HbA(1c) and weight, patients were subdivided into four groups at each visit by glycaemic and weight responses; patients who failed to reduce both HbA(1c) and weight below WMs became the reference group (R). The other three groups corresponded to patients with HbA(1c) reduction (A), weight reduction (W) and both HbA(1c) and weight reduction (AW).. Compared with R, patients in AW, A and W groups had a significantly higher likelihood of improving SBP <130 mmHg by 88, 30 and 61%, respectively. Compared with R, patients in AW, A and W had 63, 13 and 45% higher likelihood of improving DBP <80 mmHg.. Although the mechanism of BP-lowering effect of exenatide is not established, it appears that the short-term dynamics of BP is related to concomitant effects on glycaemia and body weight. These data offer a preliminary insight into the possible cardiometabolic effects of GLP-1 receptor agonism.

Topics: Aged; Blood Pressure; Diabetes Mellitus, Type 2; Double-Blind Method; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Longitudinal Studies; Male; Middle Aged; Peptides; Venoms; Weight Loss

To quantify how much exenatide added to metformin improves β-cell function, and to evaluate the impact on glycaemic control, insulin resistance and inflammation compared with metformin alone.. A total of 174 patients with Type 2 diabetes with poor glycaemic control were instructed to take metformin for 8 ± 2 months, then they were randomly assigned to exenatide (5 μg twice a day for the first 4 weeks and forced titration to 10 μg twice a day thereafter) or placebo for 12 months. At 12 months we evaluated anthropometric measurements, glycaemic control, insulin resistance and β-cell function variables, glucagon, adiponectin, high sensitivity-C reactive protein and tumour necrosis factor-α. Before and after 12 months, patients underwent a combined euglycaemic hyperinsulinaemic and hyperglycaemic clamp, with subsequent arginine stimulation.. Exenatide + metformin gave a greater decrease in body weight, glycaemic control, fasting plasma proinsulin and insulin and their ratio, homeostasis model assessment for insulin resistance (HOMA-IR), and glucagon values and a greater increase in C-peptide levels, homeostasis model assessment β-cell function index (HOMA-β) and adiponectin compared with placebo + metformin. Exenatide + metformin decreased waist and hip circumference, and reduced concentrations of high sensitivity-C reactive protein and tumour necrosis factor-α. Exenatide + metformin gave a greater increase in M value (+34%), and disposition index (+55%) compared with placebo + metformin; first (+21%) and second phase (+34%) C-peptide response to glucose and C-peptide response to arginine (+25%) were also improved by exenatide + metformin treatment, but not by placebo + metformin.. Exenatide is effective not only on glycaemic control, but also in protecting β-cells and in reducing inflammation.

Topics: Adiponectin; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Exenatide; Fasting; Female; Glucose Clamp Technique; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin-Secreting Cells; Italy; Male; Metformin; Middle Aged; Peptides; Treatment Outcome; Tumor Necrosis Factor-alpha; Venoms; Weight Loss

Exenatide is a medication similar in structure and effect to native glucagon-like peptide-1, an incretin hormone with glucose-lowering properties. The aim of the study was to measure the change in total energy expenditure (TEE) and body composition during exenatide administration and by deduction the relative contributions of energy expenditure and energy intake to exenatide-induced weight loss. Forty-five obese (body mass index, 30-40 kg·m⁻²) subjects were identified. After exclusion criteria application, 28 subjects entered into the study and 18 subjects (12 female, 6 male) completed the study, which consisted of 6 visits over 14 weeks and injection of exenatide for an average of 84 ± 5 days. Respiratory gas analysis and doubly labeled water measurements were performed before initiation of exenatide and after approximately 3 months of exenatide administration. The average weight loss from the beginning of injection period to the end of the study in completed subjects was 2.0 ± 2.8 kg (p = 0.01). Fat mass declined by 1.3 ± 1.8 kg (p = 0.01) while the fat-free mass trended downward but was not significant (0.8 ± 2.2 kg, p = 0.14). There was no change in weight-adjusted TEE (p = 0.20), resting metabolic rate (p = 0.51), or physical activity energy expenditure (p = 0.38) and no change in the unadjusted thermic effect of a meal (p = 0.37). The significant weight loss because of exenatide administration was thus the result of decreasing energy intake. In obese nondiabetic subjects, exenatide administration did not increase TEE and by deduction the significant weight loss and loss of fat mass was due to decreased energy intake.

Topics: Adipose Tissue; Adult; Algorithms; Anti-Obesity Agents; Body Composition; Body Mass Index; Energy Intake; Energy Metabolism; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Male; Middle Aged; Obesity; Patient Dropouts; Peptides; Venoms; Weight Loss

Incretin-based therapies provide additional options for treating type 2 diabetes. We aimed to evaluate the efficacy and tolerability of exenatide monotherapy in obese patients with type 2 diabetes.. A 26-week, metformin controlled, parallel-group study was conducted among antidiabetic drug-naive obese patients aged > 18 years, and with type 2 diabetes. Participating patients were randomly assigned to receive exenatide or metformin treatments.. Fifty-nine patients (age (50.5 ± 8.6) years, body mass index (BMI) (30.2 ± 1.6) kg/m(2), and hemoglobin A1C (HbA(1C) (8.2 ± 1.2)%) were enrolled in the study. Glucose control and weight reduction improved in both groups receiving treatment. HbA(1C) and oral glucose tolerance test (OGTT) 2 hour glycemia reduction with exenatide was superior to that obtained with metformin ((-2.10 ± 1.79)% vs. (-1.66 ± 1.38)%, (-5.11 ± 2.68) mmol/L vs. (-2.80 ± 2.70) mmol/L, P < 0.05). Fast plasma glucose (FPG) reduction was not significantly different between the two groups ((-1.8 ± 2.0) mmol/L vs. (-1.6 ± 1.7) mmol/L, P > 0.05). Patients treated with exenatide achieved HbA(1C) of < 7% (97% of patients) and < 6.5% (79%) at end-point, vs. 93% and 73% with metformin (P > 0.05). Greater weight reduction was also achieved with exenatide ((-5.80 ± 3.66) kg) than with metformin ((-3.81 ± 1.38) kg, P < 0.01). Homeostasis model assessment of beta-cell function (HOMA-B) was not significantly increased, but the insulinogenic index and HOMA for insulin sensitivity (HOMA-S) were greatly improved in the exenatide group (P < 0.05). Nausea was the most common adverse effect in exenatide treatment (30% vs. 8%; P < 0.05), but most cases were of mild to moderate intensity. One case in the exenatide group was withdrawn early because of severe nausea. Hypoglycemia events were often observed during the first 4 weeks, with 12% of patients in the exenatide and 3.2% in metformin groups, respectively (P < 0.05). No incidents of severe hypoglycemia were reported.. Exenatide demonstrated more beneficial effects on HbA(1C), weight reduction and insulin resistance during 26 weeks of treatment, but there were more hypoglycemic events and mild-to-moderate nausea compared with metformin. These results suggested that exenatide monotherapy may provide a viable treatment option in newly developed type 2 diabetes.

Topics: Adult; Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Resistance; Male; Metformin; Middle Aged; Nausea; Obesity; Peptides; Venoms; Weight Loss

We wanted to understand the effects of once-weekly vs. twice-daily glucagon-like peptide-1 receptor agonism for treatment of patients with type 2 diabetes.. The objective of the study was to compare effects of exenatide once weekly (ExQW) and exenatide twice daily (ExBID) on glycemic control, body weight, and safety.. This was a 24-wk, randomized, open-label, comparator-controlled study.. The study was conducted at 43 sites in the United States.. The study population was 252 intent-to-treat patients with type 2 diabetes [baseline (mean ± SD): glycosylated hemoglobin (HbA1c) 8.4 ± 1.2%, fasting plasma glucose 171 ± 47 mg/dl, weight 96 ± 20 kg] that were drug naïve (19%) or previously treated with one (47%) or multiple (35%) oral antidiabetic medications.. Interventions included ExQW 2 mg for 24 wk or ExBID 5 μg for 4 wk followed by ExBID 10 μg for 20 wk.. The change in HbA1c from baseline to wk 24 was measured.. At 24 wk, ExQW produced significantly greater changes from baseline (least squares mean ± SE) vs. ExBID in HbA1c (-1.6 ± 0.1% vs. -0.9 ± 0.1%; P < 0.0001) and fasting plasma glucose (-35 ± 5 mg/dl vs. -12 ± 5 mg/dl; P = 0.0008). Similar reductions in mean body weight from baseline to wk 24 were observed in both groups (-2.3 ± 0.4 kg and -1.4 ± 0.4 kg). Both treatments were generally well tolerated. Transient and predominantly mild to moderate nausea, the most frequent adverse event, was less common with ExQW (14%) than with ExBID (35%). Injection-site reactions were infrequent, but more common with ExQW. No major hypoglycemia occurred.. Continuous glucagon-like peptide-1 receptor agonism with ExQW resulted in superior glycemic control, with less nausea, compared with ExBID in patients with type 2 diabetes. Both groups lost weight.

Topics: Adolescent; Adult; Aged; Blood Glucose; Blood Pressure; Body Weight; Chromatography, High Pressure Liquid; Combined Modality Therapy; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Exenatide; Exercise Therapy; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Peptides; Risk Factors; Venoms; Weight Loss; Young Adult

Exenatide, a synthetic GLP-1 analogue, is a new antidiabetic agent from the group ofincretine mimetics coming into the daily clinical practice. In our study we evaluated the effect of 6-months treatment with exenatide on diabetes compensation, anthropometric and biochemical parameters in the patients with poorly controlled type 2 diabetes mellitus and obesity.. We included 18 patients with poorly controlled diabetes (mean HbA1c 8.5 +/- 0.3%) treated with diet and peroral antidiabetic agents (4 patients were treated with insulin in the past). Exenatide was administered via subcutaneous injection twice daily for 6 months. Patients were examined after 1 month, when the dose ofexenatide was increased from 5 microg twice daily to 10 microg twice daily and after 3 and 6 months. We evaluated the diabetes compensation, biochemical parameters, body weight changes and side effects ofexenatide.. 6-months exenatide treatment significant decreased body weight (baseline vs 6 month treatment 107.3 +/- 4.4 kg vs 103.7 +/- 4.6 kg, p = 0.02), BMI (36.7 +/- 1.2 kg/m2 vs 35.3 +/- 1.3 kg/m2, p = 0.01) a HbA1c (8.5 +/- 0.3% vs 7.4 +/- 0.4%, p = 0.04) and increased HDL-cholesterol (0.92 +/- 0.1 mmol/l vs 0.98 +/- 0.1 mmol/l, p = 0.02). Fasting glycemia tended to decline at the end of the study, but the difference did not reach the statistical significance. The area under the curve of glycemia levels after the standardized breakfast in the subgroup of 8 patients after the 6-months exenatide treatment was significantly lower when compared to baseline values (2,908 +/- 148 vs 2,093 +/- 194, p = 0.03). Concentrations of total and LDL-cholesterol and triglycerides did not change significantly. The most frequent side effects of exenatide treatments were transient anorexia and nausea (38.5%), dyspepsia and functional gastrointestinal discomfort (38.5%) and various neuropsychical symptoms (nervosity and insomnia - 30.8%). Most of the side effects disappeared during the treatment, none of these side effects was a reason for discontinuation of a treatment. 3 minor hypoglycemic episodes occured in patients simultaneously treated with derivates of sulfonylurea, but no serious hypoglycemia occured during the entire study.. Exenatide treatment in obese patients with poor diabetes control was accompanied by statistically significant decrease of body weight, improvement of diabetes control and increase in HDL-cholesterol.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipids; Male; Middle Aged; Peptides; Venoms; Weight Loss

In the Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) study, the safety and efficacy of 30 weeks of treatment with the glucagon-like peptide-1 receptor agonist exenatide once weekly (exenatide QW; 2 mg) was compared with exenatide BID in 295 patients with type 2 diabetes. We now report the safety and efficacy of exenatide QW in 1) patients who continued treatment for an additional 22 weeks (52 weeks total) and 2) patients who switched from exenatide BID to exenatide QW after 30 weeks.. In this randomized, multicenter, comparator-controlled, open-label trial, 258 patients entered the 22-week open-ended assessment phase (n = 128 QW-only; n = 130 BID-->QW). A1C, fasting plasma glucose (FPG), body weight, blood pressure, fasting lipids, safety, and tolerability were assessed.. Patients continuing exenatide QW maintained A1C improvements through 52 weeks (least squares mean -2.0% [95% CI -2.1 to -1.8%]). Patients switching from exenatide BID to exenatide QW achieved further A1C improvements; both groups exhibited the same A1C reduction and mean A1C (6.6%) at week 52. At week 52, 71 and 54% of all patients achieved A1C <7.0% and 40 mg/dl, and body weight was reduced by >4 kg after 52 weeks. Nausea occurred less frequently in this assessment period and was predominantly mild. No major hypoglycemia was observed.. Exenatide QW elicited sustained improvements in glycemic control and body weight through 52 weeks of treatment. Patients switching to exenatide QW experienced further improvements in A1C and FPG, with sustained weight loss.

Topics: Blood Glucose; Blood Pressure; Exenatide; Humans; Hypoglycemic Agents; Lipids; Peptides; Venoms; Weight Loss

Unlike most antihyperglycaemic drugs, glucagon-like peptide-1 (GLP-1) receptor agonists have a glucose-dependent action and promote weight loss. We compared the efficacy and safety of liraglutide, a human GLP-1 analogue, with exenatide, an exendin-based GLP-1 receptor agonist.. Adults with inadequately controlled type 2 diabetes on maximally tolerated doses of metformin, sulphonylurea, or both, were stratified by previous oral antidiabetic therapy and randomly assigned to receive additional liraglutide 1.8 mg once a day (n=233) or exenatide 10 microg twice a day (n=231) in a 26-week open-label, parallel-group, multinational (15 countries) study. The primary outcome was change in glycosylated haemoglobin (HbA(1c)). Efficacy analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00518882.. Mean baseline HbA(1c) for the study population was 8.2%. Liraglutide reduced mean HbA(1c) significantly more than did exenatide (-1.12% [SE 0.08] vs -0.79% [0.08]; estimated treatment difference -0.33; 95% CI -0.47 to -0.18; p<0.0001) and more patients achieved a HbA(1c) value of less than 7% (54%vs 43%, respectively; odds ratio 2.02; 95% CI 1.31 to 3.11; p=0.0015). Liraglutide reduced mean fasting plasma glucose more than did exenatide (-1.61 mmol/L [SE 0.20] vs -0.60 mmol/L [0.20]; estimated treatment difference -1.01 mmol/L; 95% CI -1.37 to -0.65; p<0.0001) but postprandial glucose control was less effective after breakfast and dinner. Both drugs promoted similar weight losses (liraglutide -3.24 kg vs exenatide -2.87 kg). Both drugs were well tolerated, but nausea was less persistent (estimated treatment rate ratio 0.448, p<0.0001) and minor hypoglycaemia less frequent with liraglutide than with exenatide (1.93 vs 2.60 events per patient per year; rate ratio 0.55; 95% CI 0.34 to 0.88; p=0.0131; 25.5%vs 33.6% had minor hypoglycaemia). Two patients taking both exenatide and a sulphonylurea had a major hypoglycaemic episode.. Liraglutide once a day provided significantly greater improvements in glycaemic control than did exenatide twice a day, and was generally better tolerated. The results suggest that liraglutide might be a treatment option for type 2 diabetes, especially when weight loss and risk of hypoglycaemia are major considerations.. Novo Nordisk A/S.

Topics: Analysis of Variance; Blood Glucose; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Exenatide; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Injections, Subcutaneous; Linear Models; Liraglutide; Logistic Models; Male; Middle Aged; Nausea; Peptides; Treatment Outcome; Venoms; Weight Loss

In two previously reported multi-center, randomized, open-label, comparator (insulin) controlled trials in patients with type 2 diabetes sub-optimally controlled with metformin and a sulfonylurea, treatment with exenatide and insulin analogue therapy produced similar reductions in glycosylated hemoglobin A(1c) (A1C). However, treatment with exenatide was associated with a reduction in body weight while insulin analogue therapy was associated with weight gain. This analysis further characterizes the relative impact of commonly employed insulin analogues versus exenatide on weight change over a 6-month period.. In this pooled post-hoc analysis of two trials, 1047 subjects with diabetes were compared regarding the relative impact of an adjunctive treatment - an insulin analogue (glargine or biphasic insulin aspart) or exenatide (5 mug twice daily for 4 weeks, 10 mug thereafter) - on body weight.. While exenatide treatment provided similarly effective glycemic control compared with insulin analogue therapy, it was also associated with weight reduction in the majority of subjects (73.3%, averaging 3 kg decrease by endpoint), with approximately 22% achieving > or =5% weight loss, and 3.2% of subjects achieving > or =10% weight loss. In contrast, by the end of the study most insulin-treated subjects (75.9%) had gained weight (mean 3 kg). Only 2% of insulin-treated subjects achieved > or =5% weight loss, and 0.2% of subjects achieved > or =10% weight loss.. These findings support the use of exenatide as a treatment option in insulin-naïve subjects with type 2 diabetes and who are overweight and sub-optimally controlled by metformin and sulfonylurea. However, these results should be interpreted with caution given the exploratory nature of this post-hoc analysis.

Topics: Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Glycemic Index; Humans; Hypoglycemic Agents; Insulin; Life Style; Male; Metformin; Middle Aged; Peptides; Sulfonylurea Compounds; Venoms; Weight Gain; Weight Loss

In patients with type 2 diabetes, exenatide reduces A1C, postprandial and fasting glucose, and weight. In this study we investigated the effects of continuous exenatide administration from a long-acting release (LAR) formulation.. In this randomized, placebo-controlled phase 2 study, exenatide LAR (0.8 or 2.0 mg) was administered subcutaneously once weekly for 15 weeks to subjects with type 2 diabetes (n = 45) suboptimally controlled with metformin (60%) and/or diet and exercise (40%): 40% female, A1C (mean +/- SD) 8.5 +/- 1.2%, fasting plasma glucose 9.9 +/- 2.3 mmol/l, weight 106 +/- 20 kg, and diabetes duration 5 +/- 4 years.. From baseline to week 15, exenatide LAR reduced mean +/- SE A1C by -1.4 +/- 0.3% (0.8 mg) and -1.7 +/- 0.3% (2.0 mg), compared with +0.4 +/- 0.3% with placebo LAR (P < 0.0001 for both). A1C of < or =7% was achieved by 36 and 86% of subjects receiving 0.8 and 2.0 mg exenatide LAR, respectively, compared with 0% of subjects receiving placebo LAR. Fasting plasma glucose was reduced by -2.4 +/- 0.9 mmol/l (0.8 mg) and -2.2 +/- 0.5 mmol/l (2.0 mg) compared with +1.0 +/- 0.7 mmol/l with placebo LAR (P < 0.001 for both). Exenatide LAR reduced self-monitored postprandial hyperglycemia. Subjects receiving 2.0 mg exenatide LAR had body weight reductions (-3.8 +/- 1.4 kg) (P < 0.05), whereas body weight was unchanged with both placebo LAR and the 0.8-mg dose. Mild nausea was the most frequent adverse event. No subjects treated with exenatide LAR withdrew from the study.. Exenatide LAR offers the potential of 24-h glycemic control and weight reduction with a novel once-weekly treatment for type 2 diabetes.

Topics: Adult; Aged; Blood Glucose; Blood Glucose Self-Monitoring; Body Weight; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Exenatide; Humans; Hypoglycemic Agents; Middle Aged; Peptides; Venoms; Weight Loss

Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes mellitus (T2DM), reduced glycosylated hemoglobin (HbA(1c)) and weight in 30-week placebo-controlled trials. Some patients were followed up in open-label extensions to provide 'real-world' exenatide clinical experience.. The purpose of this study was to examine the metabolic effects of 2 years of exenatide treatment in patients with T2DM.. For this interim analysis, data were pooled from patients who completed 1 of three 30-week, multicenter, double-blind, placebo-controlled trials and their open-label extensions. In the initial trials, subjects were randomized to BID 5-microg exenatide, 10-microg exenatide, or placebo for 30 weeks. All subjects who enrolled in the extension phase then received 5-pg exenatide BID for 4 weeks, followed by open-label treatment with 10-pg exenatide BID. Subjects continued their existing metformin and/or sulfonylurea regimens. Analyses were conducted on data from all subjects who had the opportunity to achieve 2 years of exenatide exposure, irrespective of their treatment arm in the 30-week placebo-controlled trials.. A total of 974 patients entered the open-label, extension phase of the trial. Two hundred eighty-three subjects (mean [SD] age, 57 [10] years; mean [SD] weight, 100[19] kg; sex, 63% male; mean [SD] body mass index, 34 [6] kg/m(2); mean [SD] HbA(1c), 8.3% [1.0%]) completed 2 years of exenatide treatment. Reductions in mean (SE) HbA(1c) from baseline to week 30 (-0.9% [0.1%]) were sustained through 2 years (-1.1% [0.1%]; P < 0.05 vs baseline), with 50% of the population achieving HbA(1c) < or = 7%. At week 30, exenatide was associated with a significant reduction in mean (SD) body weight from baseline (-2.1 [0.2] kg), with progressive reductions after 2 years (-4.7 [0.3] kg; P < 0.001 vs baseline). Patients with normal baseline alanine aminotransferase (ALT) (132/283 [47%]; normal: female < or =19 IU/L; male < or =30 IU/L) had no significant ALT change. However, patients with elevated ALT at baseline (151/283 [53%]) had a mean (SEM) reduction of ALT (-11 [1] IU/L from baseline 38 [1] IU/1; P < 0.05) and 39% achieved normal ALT by week 104. Patients with elevated ALT at baseline lost significantly more weight than patients with normal ALT at baseline (P = 0.04). However, weight change was minimally correlated with baseline ALT (r = -0.09) or ALT change (r = 0.31). Also, homeostasis model assessment of the beta-cell function (HOMA-B), blood pressure, and aspartate aminotransferase (AST) all improved. The most frequently reported adverse event was mild-to-moderate nausea.. In these patients with T2DM, adjunctive exenatide treatment for 2 years was generally well tolerated and resulted in a sustained reduction of HbA(1c), progressive reduction in weight, and improvements in HOMA-B, blood pressure, and the hepatic injury biomarkers, AST and ALT.

Topics: Aged; Alanine Transaminase; Aspartate Aminotransferases; Biomarkers; Blood Pressure; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Exenatide; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin-Secreting Cells; Liver Function Tests; Male; Metformin; Middle Aged; Obesity; Peptides; Sulfonylurea Compounds; Venoms; Weight Loss

Exenatide therapy is effective in combination with metformin or sulfonylureas for treating type 2 diabetes. Thiazolidinediones (TZDs) also are commonly used, but the efficacy of exenatide with a TZD has not been reported.. To compare the effects of exenatide versus placebo on glycemic control.. Placebo run-in, randomized, double-blind, placebo-controlled trial conducted from May 2004 to August 2005.. 49 sites in Canada, Spain, and the United States.. 233 (exenatide group, n = 121; placebo group, n = 112) patients with type 2 diabetes that was suboptimally controlled with TZD treatment (with or without metformin). Mean (+/-SE) baseline glycated hemoglobin A1c level was 7.9% +/- 0.1%.. Subcutaneous abdominal injections of 10 microg of exenatide or placebo twice daily, added to a TZD (with or without metformin) for 16 weeks.. The primary outcome was change from baseline in hemoglobin A1c level. Other outcomes were fasting serum glucose level, body weight, self-monitored blood glucose level, and any adverse events.. Exenatide treatment reduced hemoglobin A(1c) level (mean difference, -0.98% [95% CI, -1.21% to -0.74%]), serum fasting glucose level (mean difference, -1.69 mmol/L [-30.5 mg/dL] [CI, -2.22 to -1.17 mmol/L {-40.0 to -21.1 mg/dL}]), and body weight (mean difference, -1.51 kg [CI, -2.15 to -0.88 kg]). Sixteen percent of patients in the exenatide group and 2% of patients in the placebo group discontinued treatment because of adverse events. In the exenatide group, 40% (n = 48) of patients experienced nausea (mostly mild [n = 21] or moderate [n = 19]), 13% experienced vomiting, and 11% experienced hypoglycemia. In the placebo group, 15% of patients experienced nausea, 1% experienced vomiting, and 7% experienced hypoglycemia.. Combinations with TZDs and sulfonylureas were not tested. Trial duration was relatively short. Only 71% and 86% of patients in the exenatide and placebo groups, respectively, completed the study.. Exenatide therapy improved glycemic control, reduced body weight, and caused gastrointestinal symptoms more than placebo in patients with type 2 diabetes that was suboptimally controlled with TZD therapy. ClinicalTrials.gov registration number: NCT00099320. For more information on exenatide click here.

Topics: Adult; Aged; Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Injections, Subcutaneous; Insulin-Secreting Cells; Male; Metformin; Middle Aged; Nausea; Peptides; Thiazolidinediones; Venoms; Vomiting; Weight Loss

The ability of the incretin mimetic exenatide to improve glycaemic control and reduce body weight was assessed over 82 weeks in patients with type 2 diabetes failing to achieve glycaemic control with maximally effective doses of metformin.. In this interim 82-week analysis, 150 (total cohort) of an eligible population of 183 patients opted to continue exenatide treatment in an uncontrolled open-label extension of a 30-week double-blind, placebo-controlled trial. Of these, 92 patients (completer cohort) achieved 82 weeks of exenatide therapy. Patients continued metformin throughout the study.. At the end of the placebo-controlled trial, exenatide resulted in an haemoglobin A1c (HbA1c) reduction from baseline of -1.0 +/- 0.1% (mean +/- SE) (exenatide treatment arms), with durable HbA1c reductions after 82 weeks of -1.3 +/- 0.1%. The percent of patients who achieved HbA1c < or = 7% at weeks 30 and 82 was 46 and 59% respectively. After 30 weeks, exenatide caused a reduction in weight from baseline of -3.0 +/- 0.6 kg, with a progressive reduction in weight of -5.3 +/- 0.8 kg after 82 weeks. In addition, exenatide treatment produced clinically significant improvements in cardiovascular risk factors after 82 weeks. The most frequent adverse event after 30 and 82 weeks of exenatide was nausea, which was generally of mild-or-moderate intensity. It decreased in incidence after initiation in the controlled trial and the uncontrolled open-label extension. Hypoglycaemia was rare, with no severe events.. Exenatide was generally well tolerated, producing a durable reduction in HbA1c and a progressive reduction in weight over 82 weeks in patients with type 2 diabetes failing to achieve glycaemic control with metformin.

Topics: Adult; Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipids; Male; Metformin; Middle Aged; Overweight; Peptides; Risk Factors; Venoms; Weight Loss

Exenatide, an incretin mimetic for the adjunct treatment of type 2 diabetes (DM2), reduced A1C and weight in 30-week placebo-controlled trials. This analysis examined the effects of exenatide on glycaemic control and weight over an 82-week period in patients with DM2 unable to achieve adequate glycaemic control with sulphonylurea (SU) and/or metformin (MET).. This interim analysis is of 314 patients who received exenatide in the 30-week placebo-controlled trials and subsequently in 52 weeks of open-label uncontrolled extension studies for 82 weeks of exenatide in total. Patients continued their SU and/or MET regimens throughout.. Patients completed 82 weeks of exenatide treatment [n = 314, 63% M, age 56 +/- 10 years, weight 99 +/- 21 kg, body mass index 34 +/- 6 kg/m2, A1C 8.3 +/- 1.0% (mean +/- SD)]. Reduction in A1C from baseline to week 30 [-0.9 +/- 0.1% (mean +/- SE)] was sustained to week 82 (-1.1 +/- 0.1%), with 48% of patients achieving A1C < or = 7% at week 82. At week 30, exenatide reduced body weight (a secondary endpoint) from baseline (-2.1 +/- 0.2 kg), with progressive reduction at week 82 (-4.4 +/- 0.3 kg). Similar results were observed for the intent-to-treat population (n = 551), with reductions in A1C and weight at week 82 of -0.8 +/- 0.1% and -3.5 +/- 0.2 kg respectively. The 82-week completer cohort showed statistically significant improvement in some cardiovascular risk factors. The most frequent adverse events were generally mild-to-moderate nausea and hypoglycaemia.. In summary, 82 weeks of adjunctive exenatide treatment in patients with DM2 treated with SU and/or MET resulted in sustained reduction in A1C and progressive reduction in weight, as well as improvement in some cardiovascular risk factors.

Topics: Adolescent; Adult; Aged; Blood Glucose; Blood Pressure; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Double-Blind Method; Drug Therapy, Combination; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipids; Male; Metformin; Middle Aged; Overweight; Peptides; Risk Factors; Sulfonylurea Compounds; Venoms; Weight Loss

Exenatide is the first of a new class of agents known as incretin mimetics that are in development for the treatment of type 2 diabetes. Exenatide has been shown to reduce fasting and postprandial glucose in patients with type 2 diabetes, as well as provide sustained reductions in hemoglobin A 1c (HbA 1c). This study was designed to assess the dose dependencies of the glucoregulatory effects and tolerability of exenatide when added to diet and exercise or metformin monotherapy in patients with type 2 diabetes.. In this randomized, triple-blinded, placebo-controlled Phase 2 clinical trial, 156 patients were randomized to placebo or exenatide at 2.5, 5.0, 7.5, or 10.0 microg administered b.i.d. for 28 days.. After 28 days of therapy, exenatide was associated with significant (P < 0.0001, linear contrast testing), dose-dependent reductions in HbA 1c (0.1 +/- 0.1%, -0.3 +/- 0.1%, -0.4 +/- 0.1%, +/-0.5 +/- 0.0%, and -0.5 +/- 0.1% for placebo and 2.5, 5.0, 7.5, and 10.0 microg b.i.d. exenatide, respectively) and significant (P = 0.0006, linear contrast testing) reductions in fasting plasma glucose (+6.8 +/- 4.1, -20.1 +/- 5.2, -21.2 +/- 3.9, -17.7 +/- 4.8, and -17.3 +/- 4.4 mg/dL for placebo and 2.5, 5.0, 7.5, and 10.0 microg b.i.d. exenatide, respectively) by Day 28. These reductions were similar for patients treated with diet/exercise and those treated with metformin. In addition, patients receiving exenatide exhibited dose-dependent reductions in body weight (0.0 +/- 0.3, -0.7 +/- 0.3, -0.7 +/- 0.2, -1.4 +/- 0.3, and -1.8 +/- 0.3 kg for placebo and 2.5, 5.0, 7.5, and 10.0 microg b.i.d. exenatide, respectively; P < 0.01 for 7.5 and 10.0 microg b.i.d. exenatide doses compared with placebo) at Day 28. The most common adverse event was mild-to-moderate nausea that was dose-dependent (seven of 123 patients randomized to exenatide withdrew from the study because of gastrointestinal effects).. Exenatide dose-dependently improved glycemic control and reduced body weight over 28 days in patients with type 2 diabetes treated with diet/exercise or metformin.

Topics: Blood Glucose; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Peptides; Placebos; Racial Groups; Research Design; Venoms; Weight Loss

This study evaluated the ability of the incretin mimetic exenatide (exendin-4) to improve glycemic control in patients with type 2 diabetes failing maximally effective doses of a sulfonylurea as monotherapy.. This was a triple-blind, placebo-controlled, 30-week study conducted at 101 sites in the U.S. After a 4-week, single-blind, placebo lead-in period, 377 subjects were randomized (60% men, age 55 +/- 11 years, BMI 33 +/- 6 kg/m(2), HbA(1c) 8.6 +/- 1.2% [+/-SD]) and began 4 weeks at 5 microg subcutaneous exenatide twice daily (before breakfast and dinner; arms A and B) or placebo. Subsequently, subjects in arm B were escalated to 10 microg b.i.d. exenatide. All subjects continued sulfonylurea therapy.. At week 30, HbA(1c) changes from baseline were -0.86 +/- 0.11, -0.46 +/- 0.12, and 0.12 +/- 0.09% (+/-SE) in the 10-microg, 5-microg, and placebo arms, respectively (adjusted P < 0.001). Of evaluable subjects with baseline HbA(1c) > 7% (n = 237), 41% (10 microg), 33% (5 microg), and 9% (placebo) achieved HbA(1c)

Topics: Adult; Aged; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Exenatide; Fasting; Female; Glycated Hemoglobin; Humans; Insulin; Male; Middle Aged; Peptides; Proinsulin; Retreatment; Sulfonylurea Compounds; Treatment Failure; Venoms; Weight Loss

Glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy in patients with type 2 diabetes and obesity leads to a significant reduction in serum thyrotropin (TSH) levels but it is unclear whether this is related to weight loss and improvement in sensitivity to thyroid hormones (TH).. We prospectively analysed clinical and biochemical data in patients with type 2 diabetes and obesity who were commenced on the GLP-1 RA exenatide and followed them for 12 months. We assessed the relationship between changes in body weight and serum TSH and resistance to TH indices.. Exenatide therapy reduces serum TSH levels and improves central sensitivity to TH action over 12 months via its effect on weight loss. The effectiveness of weight loss strategies, rather than TH replacement, should be investigated in individuals with obesity and mildly raised serum TSH levels.

Topics: Body Weight; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Male; Middle Aged; Obesity; Thyroid Hormones; Thyrotropin; Weight Loss

There is a closely relationship between the development and progression of nonalcoholic fatty liver disease (NAFLD) or metabolic associated fatty liver disease (MAFLD) and obesity and diabetes. NAFLD fibrosis scores should be routinely used to rule out patients with advanced fibrosis. High scores may help identify patients at higher risk of all causes andliverrelated morbidity and mortality. The aim of this study was to investigate the association between exenatide and fibrosis scores. The effect of exenatide treatment on fibrosis scores was evaluated in type 2 diabetes mellitus (DM) patients with MAFLD. Evaluation was made of 50 patients with type 2 DM and MAFLD. The NFS, FIB4 and APRI scores were calculated before and after 6 months of treatment. After 6 months of exenatide treatment, the NFS and APRI scores were determined to have decreased significantly. Exenatide was observed to control blood glucose, reduce body weight and improve fibrosis scores in MAFLD patients with type 2 diabetes.

Topics: Adult; Biomarkers; Blood Glucose; Decision Support Techniques; Diabetes Mellitus, Type 2; Exenatide; Female; Humans; Hypoglycemic Agents; Incretins; Liver; Liver Cirrhosis; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Predictive Value of Tests; Retrospective Studies; Time Factors; Treatment Outcome; Weight Loss

There is a critical unmet need for therapeutics to treat the epidemic of comorbidities associated with obesity and type 2 diabetes, ideally devoid of nausea/emesis. This study developed monomeric peptide agonists of glucagon-like peptide 1 receptor (GLP-1R) and neuropeptide Y2 receptor (Y2-R) based on exendin-4 (Ex-4) and PYY

Topics: Animals; Binding, Competitive; Blood Glucose; Exenatide; Glucagon-Like Peptide-1 Receptor; Glucose; Humans; Insulin Secretion; Islets of Langerhans; Male; Microsomes, Liver; Models, Molecular; Molecular Docking Simulation; Nausea; Peptide YY; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Shrews; Structure-Activity Relationship; Vomiting; Weight Loss

Glucagon-like peptide 1 (GLP-1) and PAS kinase (PASK) control glucose and energy homeostasis according to nutritional status. Thus, both glucose availability and GLP-1 lead to hepatic glycogen synthesis or degradation. We used a murine model to discover whether PASK mediates the effect of exendin-4 (GLP-1 analogue) in the adaptation of hepatic glycogen metabolism to nutritional status. The results indicate that both exendin-4 and fasting block the

Topics: Adaptation, Physiological; Animals; Exenatide; Fasting; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucokinase; Glucose; Glucose Transporter Type 2; Liver; Liver Glycogen; Male; Mice; Mice, Inbred C57BL; Nutritional Status; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Receptors, Cytoplasmic and Nuclear; Up-Regulation; Weight Loss

Ectopic lipid deposition is closely associated with type 2 diabetes (T2D). Accumulating evidence shows that GLP-1 receptor agonists (GLP-1 RAs) improve obesity and liver steatosis. However, it remains unknown whether and how they ameliorate lipid deposition in skeletal muscle. This study aimed to investigate the effect of exenatide (a GLP-1 RA) on intramyocellular lipid deposition in the skeletal muscle of T2D models and its dependence on weight loss.. Ob/ob mice and diet-induced obese (DIO) mice were treated with exenatide (24 nmol/kg), leptin (1 mg/kg), or saline control intraperitoneally once daily for 4 weeks. Phenotypic evaluations were performed during and after the intervention. PA-induced myoblast C2C12 cells were used as an in vitro model. The expression of key enzymes involved in lipid metabolism was assessed in the skeletal muscle of ob/ob mice and DIO mice.. In ob/ob mice, 4-week exenatide treatment did not improve the body weight and fat mass, but modestly ameliorated intramyocellular lipid deposition and lipid profiles. In DIO mice, it remarkably alleviated the body weight, lipid profiles, and intramyocellular lipid deposition. In the skeletal muscle of these two models, exenatide treatment activated the AMP-activated protein kinase (AMPK) signaling pathway, stimulated lipid oxidation enzymes, and upregulated the insulin signaling pathway. In vitro, exendin-4 activated the AMPK signaling pathway and stimulated lipid metabolism to improve lipid accumulation in palmitate-induced myoblast C2C12 cells.. Exenatide ameliorated intramyocellular lipid deposition without body weight reduction in ob/ob mice, but alleviated body weight and intramyocellular lipid deposition in DIO mice. The underlying mechanism included the activation of AMPK signaling pathway and improvement in insulin sensitivity, independent of weight loss in ob/ob mice.

Topics: AMP-Activated Protein Kinases; Animals; Body Weight; Cells, Cultured; Exenatide; Glucagon-Like Peptide-1 Receptor; Lipid Metabolism; Male; Mice; Mice, Obese; Signal Transduction; Weight Loss

Hypothalamic obesity (HO) in children after treatment for a tumor in the suprasellar region has severe implications. Previous studies have shown various effects of glucagon-like peptide-1 (GLP-1) receptor agonist in acquired HO, but in adults only. We present our experience of GLP-1 receptor agonist (exenatide) treatment during a 1-year period on body mass index (BMI) in children with acquired HO.. Children with severe weight gain after treatment for suprasellar tumor were given 2 mg exenatide weekly for a 12-month period. All had undergone previous dietary intervention. BMI standard deviation score (SDS), weight change, and adverse effects were assessed.. Five children with a mean age of 15.4 years (range 13-18) and a mean follow-up time of 8.4 years (mean age of 7.0 years at the time of brain tumor diagnosis) were treated with GLP-1 receptor agonist. After 1 year, BMI SDS or absolute weight had not changed significantly compared to the period without treatment (BMI SDS change +0.005, 95% CI -0.07 to 0.08, p = 0.89, and absolute weight change +1.5 kg, 95% CI -0.08 to 3.1, p = 0.061). Only 1 patient experienced weight loss after 1 year (-5.4 kg, BMI SDS -0.33). All patients experienced mild side effects, such as injection pain or nausea, and 2 patients stopped treatment upon their own request after 8 and 11 months, respectively.. In this small cohort, we found little effect of GLP-1 receptor agonist in the treatment for acquired HO. Future research should focus on the prevention of HO or, if prevention is not possible, on alternative, individualized interventions.

Topics: Adolescent; Body Mass Index; Body Weight; Child; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Hypothalamic Diseases; Obesity; Weight Loss

Topics: Blood Pressure; C-Reactive Protein; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Liraglutide; Models, Animal; Retrospective Studies; Weight Loss

The SUSTAIN 3 and 7 clinical trials compared the efficacy and safety of once-weekly semaglutide relative to exenatide extended-release (ER) and dulaglutide, respectively, in the treatment of patients with type 2 diabetes (T2D). The trials included a series of clinically relevant single and composite endpoints focused on improving glycemic control and reducing body weight, while avoiding hypoglycemia. The present study combined SUSTAIN 3 and 7 outcomes with short-term treatment costs to evaluate the relative cost of control of once-weekly semaglutide versus exenatide ER and dulaglutide.. Proportions of patients reaching three endpoints were taken from SUSTAIN 3 and 7 for comparisons with exenatide ER and dulaglutide, respectively. The endpoints investigated were HbA1c < 7.0%, HbA1c < 7.0% without hypoglycemia or weight gain, and a ≥ 1.0% HbA1c reduction with ≥ 5.0% weight loss. Annual per patient treatment costs were based on US wholesale acquisition costs from July 2018. Relative cost of control was calculated by plotting the ratio of the treatment costs and the ratio of the proportions of patients reaching each endpoint on the cost-efficacy plane.. Once-weekly semaglutide 0.5 mg and 1.0 mg were most effective at bringing patients to each of the three endpoints across both SUSTAIN trials. The efficacy-to-cost ratios for once-weekly semaglutide 0.5 mg and 1.0 mg were also superior to all comparators when assessing both the single endpoint of HbA1c < 7.0% and the two composite endpoints including weight loss and hypoglycemia.. The present study showed that once-weekly semaglutide 0.5 mg and 1.0 mg offer superior cost of control versus exenatide ER and dulaglutide in terms of achieving single and composite endpoints, based on an analysis of retrieved dropout data. Once-weekly semaglutide 0.5 mg and 1.0 mg would therefore represent good value for money in the USA, particularly in the attainment of multi-model T2D treatment goals.. Novo Nordisk A/S.

Topics: Body Weight; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Female; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Male; Middle Aged; Recombinant Fusion Proteins; Weight Loss

Obesity has been linked to an inflammation like state in the hypothalamus, mainly characterized by reactive gliosis (RG) of astrocytes and microglia. Here, using two diet models or pharmacological treatment, we assessed the effects of mild and drastic weight loss on RG, in the context of high-fat diet (HFD) induced obesity.. We subjected HFD-induced obese (DIO) male C57BL/6J mice to a weight loss intervention with a switch to standard chow, calorie restriction (CR), or treatment with the Glp1 receptor agonist Exendin-4 (EX4). The severity of RG was estimated by an ordinal scoring system based on fluorescence intensities of glial fibrillary acidic protein, ionized calcium-binding adapter molecule 1 positive (Iba1), cell numbers, and morphological characteristics.. In contrast to previous reports, DIO mice fed chronically with HFD showed no differences in microglial or astrocytic RG, compared to chow controls. Moreover, mild or profound weight loss had no impact on microglial RG. However, astrocyte RG was increased in CR and EX4 groups compared to chow fed animals and strongly correlated to body weight loss. Profound weight loss by either CR or EX4 was further linked to increased levels of circulating non-esterified free fatty acids.. Overall, our data demonstrate that in a chronically obese state, astrocyte and microglial RG is indifferent from that observed in age-matched chow controls. Nonetheless, profound acute weight loss can induce astrocyte RG in the hypothalamic arcuate nucleus, possibly due to increased circulating NEFAs. This suggests that astrocytes may sense acute changes to both the dietary environment and body weight.

Topics: Animals; Anti-Obesity Agents; Arcuate Nucleus of Hypothalamus; Astrocytes; Calcium-Binding Proteins; Caloric Restriction; Exenatide; Glial Fibrillary Acidic Protein; Gliosis; Male; Mice; Mice, Inbred C57BL; Microfilament Proteins; Obesity; Weight Loss

To investigate the chronic effects of twice-daily administration of stable apelin analogues, apelin-13 amide and pyroglutamyl (pGlu) apelin-13 amide, on metabolic variables in glucose-intolerant and insulin-resistant diet-induced obese mice fed a high-fat diet for 150 days.. Groups of mice received twice-daily (9 am and 5 pm) injections of saline vehicle, apelin-13 amide, (pGlu)apelin-13 amide or exendin-4(1-39) for 28 days (all at 25 nmol/kg). Energy intake, body weight, non-fasting blood glucose, plasma insulin, glucose tolerance, metabolic response to feeding and insulin sensitivity, together with pancreatic hormone content and biochemical variables such as lipids and total GLP-1 were monitored. Dual-energy X-ray absorptiometry analysis and indirect calorimetry were also performed.. Administration of apelin-13 amide, (pGlu)apelin-13 amide or exendin-4 significantly decreased body weight, food intake and blood glucose and increased plasma insulin compared with high-fat-fed saline-treated controls (P < .05 and P < .001), Additionally, all peptide-treated groups exhibited improved glucose tolerance (oral and intraperitoneal), metabolic responses to feeding and associated insulin secretion. (pGlu)apelin-13 amide also significantly improved glycated haemoglobin and insulin sensitivity after 28 days. Both (pGlu)apelin-13 amide and exendin-4 increased bone mineral content and decreased respiratory exchange ratio, whereas only (pGlu)apelin-13 amide increased energy expenditure. All treatment groups displayed reduced circulating triglycerides and increased glucagon-like peptide-1 concentrations, although only (pGlu)apelin-13 amide significantly reduced LDL cholesterol and total body fat, and increased pancreatic insulin content.. These data indicate the therapeutic potential of stable apelin-13 analogues, with effects equivalent to or better than those of exendin-4.

Topics: Adiposity; Amides; Animals; Anti-Obesity Agents; Diabetes Mellitus, Type 2; Diet, High-Fat; Drug Stability; Energy Intake; Energy Metabolism; Exenatide; Glucagon-Like Peptide-1 Receptor; Hyperglycemia; Hypoglycemic Agents; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Male; Mice; Obesity; Weight Loss

A retrospective cohort study was conducted in patients with type 2 diabetes in an electronic medical record database to compare real-world, 6-month glycated haemoglobin (HbA1c) and weight outcomes for exenatide once weekly with those for dulaglutide and albiglutide. The study included 2465 patients: exenatide once weekly, n = 2133; dulaglutide, n = 201; and albiglutide, n = 131. The overall mean (standard deviation [s.d.]) age was 60 (11) years and 54% were men; neither differed among the comparison groups. The mean (s.d.) baseline HbA1c was similar in the exenatide once-weekly (8.3 [1.7]%) and dulaglutide groups (8.5 [1.5]%; P = .165), but higher in the albiglutide group (8.7 [1.7]%; P < .001). The overall mean (s.d.) HbA1c change was -0.5 (1.5)% (P < .001) and this did not differ among the comparison groups in either adjusted or unadjusted analyses. The mean (s.d.) weight change was -1.4 (4.7) kg for exenatide once weekly and -1.6 (3.7) kg for albiglutide (P = .579), but was greater for dulaglutide, at -2.7 (5.7) kg (P = .001). Outcomes were similar in subsets of insulin-naive patients with baseline HbA1c ≥7.0% or ≥9.0%. All agents significantly reduced HbA1c at 6 months, with no significant differences among agents or according to baseline HbA1c in insulin-naive subgroups.

Topics: Adult; Aged; Body Mass Index; Cohort Studies; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Male; Middle Aged; Obesity; Recombinant Fusion Proteins; Retrospective Studies; Weight Loss

Topics: Exenatide; Female; Humans; Obesity; Overweight; Polycystic Ovary Syndrome; Pregnancy; Weight Loss

To evaluate in a real-world setting the effectiveness of exenatide once-weekly (ExQW) in patients with T2D and to determine predictors of glycaemic and weight response to this drug at 6 months.. Observational, retrospective, multicenter study in adult patients with T2D and BMI ≥30 kg/m. In a real-world setting, ExQW significantly decreased A1C, weight, blood pressure and lipids at 6 months. Our study identified higher baseline A1C as the sole independent predictor of glycaemic response to ExQW and higher BMI and previous DDP4i treatment as predictive factors of meaningful weight response.

Topics: Adult; Aged; Blood Glucose; Blood Pressure; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Medication Adherence; Middle Aged; Peptides; Venoms; Weight Loss

Exenatide twice daily (EBID) and mealtime insulin are effective add-on therapies to basal insulin for type 2 diabetes patients in clinical trials. This study used electronic medical record (EMR) data to evaluate analogous real-world clinical responses.. Adult patients initiating EBID or mealtime insulin as add-on to basal insulin during January 2008-March 2013 were identified in a US EMR database. EBID patients were propensity score matched 1:1 to mealtime insulin patients. Cohorts were followed for 12 months before (baseline) and 6 months after the index. A1C, hypoglycemic events, change in weight, and other clinical measures were evaluated by A1C attainment level (<6.5, < 7, < 7.5, <8, <9%) and baseline A1C.. In total, 1249 EBID patients were matched to 1249 mealtime insulin patients. During follow-up, the percentage reaching A1C levels was similar for EBID vs mealtime insulin cohorts for all attainment levels (<7%: 27.8% vs 24.2%; < 9%: 79.7% vs 79.2%; p = NS). The percentage reaching A1C < 7% was similar for both cohorts with different baseline A1C. EBID patients had less hypoglycemia at all attainment levels (3.1% vs 11.1% [<6.5%]; 2.5% vs 4.7% [<9%]; all p < .03) and more weight loss (-9.0 vs -3.2 lb [<6.5%]; -3.4 vs +0.8 lb [<9%]; all p < .01).. EBID added to basal insulin was as effective in a real-world setting as mealtime insulin added to basal insulin in reducing A1C, with less weight gain and less hypoglycemia for a wide range of A1C attainment levels and baseline values.

Topics: Aged; Body Weight; Diabetes Mellitus, Type 2; Drug Administration Schedule; Electronic Health Records; Exenatide; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Male; Meals; Middle Aged; Retrospective Studies; Weight Loss

Topics: Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Weight Loss

Long-acting glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists (GLP-1RA), such as exendin-4 (Ex4), promote weight loss. On the basis of a newly discovered interaction between GLP-1 and oleoylethanolamide (OEA), we tested whether OEA enhances GLP-1RA-mediated anorectic signaling and weight loss. We analyzed the effect of GLP-1+OEA and Ex4+OEA on canonical GLP-1R signaling and other proteins/pathways that contribute to the hypophagic action of GLP-1RA (AMPK, Akt, mTOR, and glycolysis). We demonstrate that OEA enhances canonical GLP-1R signaling when combined with GLP-1 but not with Ex4. GLP-1 and Ex4 promote phosphorylation of mTOR pathway components, but OEA does not enhance this effect. OEA synergistically enhanced GLP-1- and Ex4-stimulated glycolysis but did not augment the hypophagic action of GLP-1 or Ex4 in lean or diet-induced obese (DIO) mice. However, the combination of Ex4+OEA promoted greater weight loss in DIO mice than Ex4 or OEA alone during a 7-day treatment. This was due in part to transient hypophagia and increased energy expenditure, phenotypes also observed in Ex4-treated DIO mice. Thus, OEA augments specific GLP-1RA-stimulated signaling but appears to work in parallel with Ex4 to promote weight loss in DIO mice. Elucidating cooperative mechanisms underlying Ex4+OEA-mediated weight loss could, therefore, be leveraged toward more effective obesity therapies.

Topics: AMP-Activated Protein Kinases; Animals; Anti-Obesity Agents; CHO Cells; Cricetulus; Diet, High-Fat; Disease Models, Animal; Drug Therapy, Combination; Endocannabinoids; Exenatide; Feeding Behavior; Glucagon-Like Peptide-1 Receptor; Glycolysis; Incretins; Male; Mice, Inbred C57BL; Obesity; Oleic Acids; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; Weight Loss

Glucagon-like peptide 1 (GLP-1) and serotonin play critical roles in energy balance regulation. Both systems are exploited clinically as antiobesity strategies. Surprisingly, whether they interact in order to regulate energy balance is poorly understood. Here we investigated mechanisms by which GLP-1 and serotonin interact at the level of the central nervous system. Serotonin depletion impaired the ability of exendin-4, a clinically used GLP-1 analog, to reduce body weight in rats, suggesting that serotonin is a critical mediator of the energy balance impact of GLP-1 receptor (GLP-1R) activation. Serotonin turnover and expression of 5-hydroxytryptamine (5-HT) 2A (5-HT

Topics: Aminopyridines; Animals; Anorexia; Appetite; Body Weight; Dorsal Raphe Nucleus; Exenatide; Feeding Behavior; Fenclonine; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Indoles; Liraglutide; Male; Peptides; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Serotonin; Serotonin Antagonists; Venoms; Weight Loss

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) added to insulin in type 2 diabetes patients have shown to lower body weight, improve glycaemic control and reduce total daily insulin dose in short term studies, although the individual response greatly varies.. To evaluate GLP-1 RA treatment on body weight, glycaemic control and total daily insulin dose in obese, insulin-using type 2 diabetes patients after 2 years follow-up in a real life setting and to explore a possible relation with eating behaviour.. The Martini Hospital and the University Medical Center in Groningen in the Netherlands.. Eligible patients were at least 18 years of age, were on insulin therapy and obese (BMI > 30 kg/m(2)), started GLP-1 RA treatment. At baseline eating behaviour was classified according to the validated Dutch Eating Behaviour Questionnaire. A 2 years follow-up was performed. Main outcome measures Body weight, HbA1c and total daily insulin dose.. 151 Patients started with exenatide or liraglutide. 120 patients completed the 2 years follow-up. From baseline to 2 years, body weight (mean ± SD) changed from 117.9 ± 22.1 to 107.9 ± 22.9 kg (P < 0.0001), HbA1c (median, IQR) changed from 7.9 (7.2-8.9) to 7.6 (6.9-8.3) % [63 (55-74) to 60 (52-67) mmol/mol] (P < 0.0001), total daily insulin dose changed from 90 (56-150) to 60 (0-100) Units/day (P < 0.0001). Weight change differed between eating behaviour groups (P < 0.001) in which external eating behaviour (n = 17) resulted in the smallest decline (-3.1 %) and restrained (n = 41) in the greatest (-10.3 %) in comparison with emotional (n = 37, -8.5 %) and indifferent (n = 25, -9.6 %) eating behaviours.. Two year of GLP-1 RA treatment resulted in a sustained reduction of weight, HbA1c and total daily insulin dose in obese, insulin-using type 2 diabetes patients in a real life setting. Largest weight loss was achieved in patients with a predominant restraint eating pattern while a predominant external eating pattern resulted in the smallest weight reduction.

Topics: Aged; Anti-Obesity Agents; Biomarkers; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Feeding Behavior; Female; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Incretins; Insulin; Liraglutide; Male; Middle Aged; Netherlands; Obesity; Peptides; Prospective Studies; Surveys and Questionnaires; Time Factors; Treatment Outcome; Venoms; Weight Loss

Topics: Adult; Clozapine; Diabetes Mellitus, Type 2; Exenatide; Humans; Male; Peptides; Schizophrenia; Venoms; Weight Loss

The aim of the work was to investigate whether continuation of treatment, side effects, and effect on weight loss of GLP-1 agonists in obese patients without diabetes are equally promising in daily clinical-practice-settings compared to controlled clinical trials. Obese patients without diabetes of our interdisciplinary obesity centre were treated off-label with GLP-1-agonists for different time periods. Application was started with low-dose and increased if side effects were tolerable. Monthly costs were € 125 for daily applications of 1.2 mg liraglutide or 10 μg exenatide twice daily. Data were obtained by telephone interviews about baseline characteristics, weight loss, sensation of satiation, duration of therapy, side effects, and reasons for discontinuation. Of 43 included cases (5 males, mean age 43±11 years, mean weight 107±24 kg, mean excess weight 35±21 kg) 7 were treated with exenatide and 36 with liraglutide. Excess weight loss in linear regression models was 6.7% per month (p <0.05) under control of age, sex, initial weight, and type of GLP-1 analogue treatment and did not significantly differ between liraglutide and exenatide. Overall, 58% of patients reported side effects mostly concerning the gastrointestinal tract. Surprisingly no patient reported vomiting. One patient developed a severe pancreatitis. At time of telephone interview only 30.2% were continuing treatment. Mean treatment duration was 2.98±2.71 months. Common reasons for discontinuation of treatment were no/little effect on weight loss (27.9%), intolerable side effects (20.9%), or financial reasons (14%). GLP-1 agonist treatment in obese patients without diabetes also correlates with significant weight loss in clinical practice. However, side effects and discontinuation of treatment are common. Therefore, long-term effect on weight loss might not be as promising as suggested by data from clinical trials.

Topics: Adult; Aged; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Liraglutide; Male; Medication Adherence; Middle Aged; Obesity; Off-Label Use; Peptides; Treatment Outcome; Venoms; Weight Loss; Young Adult

Metabolic syndrome (MetS) doubles the risk of adverse cardiovascular events. Glucagon-like peptide 1 (GLP-1) receptor agonists induce weight loss, increase insulin secretion, and improve glucose tolerance. Studies in healthy animals suggest cardioprotective properties of GLP-1 receptor agonists, perhaps partially mediated by improved sarco-endoplasmic reticulum Ca(2+) ATPase (SERCA) activity. We examined the acute effect of GLP-1 receptor agonists on coronary smooth muscle cells (CSM) enzymatically isolated from lean, healthy Ossabaw miniature swine. Intracellular Ca(2+) handling was interrogated with fura-2. The GLP-1 receptor agonist exenatide activated SERCA but did not alter other Ca(2+) transporters. Further, we tested the hypothesis that chronic, in vivo treatment with GLP-1 receptor agonist AC3174 would attenuate coronary artery disease (CAD) in swine with MetS. MetS was induced in 20 swine by 6 months' feeding of a hypercaloric, atherogenic diet. Swine were then randomized (n = 10/group) into placebo or AC3174 treatment groups and continued the diet for an additional 6 months. AC3174 treatment attenuated weight gain, increased insulin secretion, and improved glucose tolerance. Intravascular ultrasound and histology showed no effect of AC3174 on CAD. MetS abolished SERCA activation by GLP-1 receptor agonists. We conclude that MetS confers vascular resistance to GLP-1 receptor agonists, partially through impaired cellular signaling steps involving SERCA.

Topics: Animals; Blood Glucose; Calcium; Coronary Artery Disease; Coronary Vessels; Diet, Atherogenic; Exenatide; Glucagon-Like Peptide-1 Receptor; Insulin; Insulin Secretion; Metabolic Syndrome; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Peptides; Random Allocation; Receptors, Glucagon; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Swine; Ultrasonography; Venoms; Weight Loss

Several bariatric operations are currently used to treat obesity and obesity-related comorbidities. These vary in efficacy, but most are more effective than current pharmaceutical treatments. Roux-en-Y gastric bypass (RYGB) produces substantial body weight (BW) loss and enhanced glucose tolerance, and is associated with increased secretion of the gut hormone glucagon-like peptide 1 (GLP-1). Given the success of GLP-1-based agents in lowering blood glucose levels and BW, we hypothesized that an individual sensitivity to GLP-1 receptor agonism could predict metabolic benefits of surgeries associated with increased GLP-1 secretion. One hundred ninety-seven high-fat diet-induced obese male Long-Evans rats were monitored for BW loss during exendin-4 (Ex4) administration. Stable populations of responders and nonresponders were identified based on Ex4-induced BW loss and GLP-1-induced improvements in glucose tolerance. Subpopulations of Ex4 extreme responders and nonresponders underwent RYGB surgery. After RYGB, responders and nonresponders showed similar BW loss compared with sham, but nonresponders retained impaired glucose tolerance. These data indicate that the GLP-1 response tests may predict some but not all of the improvements observed after RYGB. These findings present an opportunity to optimize the use of bariatric surgery based on an improved understanding of GLP-1 biology and suggest an opportunity for a more personalized therapeutic approach to the metabolic syndrome.

Topics: Animals; Dietary Fats; Eating; Exenatide; Gastric Bypass; Gene Expression Regulation; Glucagon-Like Peptide-1 Receptor; Glucose Tolerance Test; Male; Obesity; Peptides; Rats; Rats, Long-Evans; Receptors, Glucagon; Venoms; Weight Loss

The effects of exenatide on glycemic control, lipid metabolism, blood pressure, and gastrointestinal symptoms were investigated in obese Japanese patients with type 2 diabetes mellitus. Twenty-six outpatients were enrolled and administered 5 μg of exenatide twice daily. If there was insufficient weight loss and/or insufficient improvement in glycemic control, the dose was increased to 10 μg twice daily. Follow-up was continued until the 12th week of administration. Hemoglobin A1c, glycoalbumin, fasting plasma glucose, body weight, fasting serum C-peptide, serum lipids, blood pressure, and pulse rate were measured before and after the observation period. In the initial phase of exenatide therapy, each patient received a diary to record gastrointestinal symptoms. During treatment with exenatide, hemoglobin A1c decreased significantly and serum C-peptide increased significantly. Body weight, low-density lipoprotein cholesterol, and systolic blood pressure decreased significantly. Nausea was the most frequent gastrointestinal symptom and occurred in 16 patients. Its onset was noted at a mean of 1.7 h after injection, the mean duration was 1.1 h, and it continued for a mean of 9.3 days after the initiation of administration. Patients with nausea showed a significant decrease in hemoglobin Alc, glycoalbumin, or body weight compared with those without nausea. These findings suggest that a more marked improvement in metabolic parameters by exenatide can be partly dependent on the manifestation of gastrointestinal symptoms.

Topics: Adult; Aged; Anti-Obesity Agents; Anticholesteremic Agents; Antihypertensive Agents; Body Mass Index; Diabetes Mellitus, Type 2; Exenatide; Female; Follow-Up Studies; Gastrointestinal Agents; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemic Agents; Injections, Subcutaneous; Japan; Male; Middle Aged; Nausea; Obesity; Peptides; Venoms; Weight Loss

Glucagon-like peptide-1 receptor agonists, a new class of anti-diabetic drugs, are widely used in the treatment of type 2 diabetes. However, the effect of glucagon-like peptide-1 receptor agonists on the treatment of preoperative weight loss in obese type 2 diabetic patients has not been reported.. A 38-year-old Taiwanese woman presented to our hospital with morbid obesity and type 2 diabetes mellitus. Bariatric surgery was recommended by a general surgery specialist. Weight loss before surgery was recommended to reduce the frequency of surgical complications. In addition to diet control with lifestyle modifications, pharmacological treatment with metformin and glucagon-like peptide-1 receptor agonists was administered. Fourteen months of treatment reduced her hemoglobin A1c level from 7.4 to 5.5% and reduced her body weight by 21.2 kg.. One year of diet control with lifestyle modifications and pharmacological treatment with glucagon-like peptide-1 receptor agonists and metformin markedly decreased hemoglobin A1c levels and resulted in effective and substantial weight loss in a morbidly obese patient with dysregulated diabetes during the preoperative period.

Topics: Adult; Bariatric Surgery; Combined Modality Therapy; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Metformin; Obesity, Morbid; Peptides; Preoperative Care; Receptors, Glucagon; Venoms; Weight Loss

To determine whether exenatide is effective in reducing weight and glycosylated hemoglobin level (HbA1c), and to investigate its efficacy in improving lipid profile, blood pressure, and creatinine levels in the Arab population.. This study was conducted at the Endocrine Unit, Dubai Hospital, Dubai, United Arab Emirates. We retrospectively collected data from patients with type 2 diabetes started on exenatide between November 2011 and February 2012. Data included demographics, clinical, laboratory results, and medications used. A general linear model adjusted by baseline characteristics (weight, HbA1C, age, use of statins, and duration of diabetes) was used to assess changes between baseline and end of trial in HbA1C, weight, low density lipoprotein cholesterol, total cholesterol, triglycerides, creatinine, and blood pressure.. After 6 months of treatment with exenatide, the HbA1c decreased by 0.47% (95% confidence level [CI]: -0.01 - 0.95) (p=0.055). Weight reduction was highly significant; 5.6 kg (95% CI: 3.34 - 7.85) (p<0.001). Those reductions remained significant after adjustment for confounding factors.. This study showed that weight reduction was highly significant with exenatide. The borderline significance in HbA1c reduction can be attributed to the small sample size. 

Topics: Adult; Arabs; Blood Pressure; Cholesterol, LDL; Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypoglycemic Agents; Male; Middle Aged; Obesity; Peptides; Retrospective Studies; Triglycerides; United Arab Emirates; Venoms; Weight Loss

A small number of studies have shown a significant reduction in HbA1c, weight and total daily insulin dose when a glucagon-like-peptide-1 (GLP-1) analogue was added in type 2 diabetes patients already on insulin treatment. Therefore, in a clinical setting, we investigated the effect of adding GLP-1 analogues in patients with type 2 diabetes already using insulin with respect to glycaemic control, body weight and insulin dose.. In this prospective hospital-based study, we included 125 patients suffering from type 2 diabetes, treated with insulin and with a body mass index ≥ 35 kg/m2, who had started on GLP-1 analogues (liraglutide/exenatide). HbA1c, body weight, daily insulin dose, and side effects were registered at baseline, and after three, six and 12 months.. HbA1c and weight decreased significantly at all the timepoints (p ≤ 0.001 compared with baseline; HbA1c: -5.5 mmol/mol (-0.5%) and weight: -14.3 kg after 12 months), with the largest decrease in the first three months. No significant correlation was found between weight loss and HbA1c reduction, and between duration of diabetes and both weight loss and HbA1c reduction. After six and 12 months, the total daily insulin dose decreased significantly (p < 0.001, -75.4 IU after 12 months). Moreover, 34% of the patients were able to stop using insulin therapy after 12 months.. By adding a GLP-1 analogue in obese patients with type 2 diabetes already on insulin therapy, a significant reduction of HbA1c levels and body weight, and a significant reduction in insulin dose or complete discontinuation of insulin can be achieved.

Topics: Adult; Aged; Body Mass Index; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Liraglutide; Male; Middle Aged; Obesity; Peptides; Prospective Studies; Venoms; Weight Loss; Young Adult

BIBYII STUDY OBJECTIVE: To obtain experience with longterm (24 months) exenatide treatment (Byetta) in patients with diabetes mellitus type 2 from a common clinical practice of diabetology departments in the Czech Republic. TYPE OF OBSERVATION: Observational study conducted by a randomly selected group of outpatient medical practitioners from 28 diabetology departments in the Czech Republic. OBSERVED AND ASSESSED POPULATION: From the original population of 465 patients, who underwent a minimum of three months Byetta treatment, 169 patients (36.6%) remained during the second prolonged observation after 18 months, and 76 patients completed 24 months of uninterrupted Byetta treatment. The following basic information about the patients was collected: year of birth, sex, age when diabetes mellitus (DM) manifested, height, maximum weight before diabetes and when DM manifested. The study recorded the following values in three- month intervals: weight, waistline, glycated haemoglobin (HbA1c), and DM treatment. The population of the prolonged observation comprised 50.3% women and 49.7 % men, and the average age at the time of DM2 manifestation was 48.0 (20- 73 years).. At the beginning of Byetta treatment, the average maximum BMI in the subpopulation observed for 24 months was 38.44; after 3, 6, 9, 12 and 24 months the following levels were measured, respectively: 36.79, 36.22, 35.91, 35.57 and 35.58. The original HbA1c level of 7.44% at the beginning of Byetta treatment decreased after 3, 6, 9, 12 and 24 months to 6.33, 5.98, 5.83, 5.86 and 5.93%.. Adding Byetta to the currently applied treatment of obese patients with diabetes mellitus type 2 over a period of 24 months has led to an improvement in HbA1c level by 1.51%, and BMI level was reduced by 2.37 after two years of Byetta treatment.

Topics: Adult; Aged; Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Peptides; Venoms; Weight Loss; Young Adult

BIBY STUDY OBJECTIVE: To obtain experience with exenatide treatment (Byetta) in patients with diabetes mellitus type 2 in a common clinical practice ofdiabetology departments. TYPE OF OBSERVATION: Observational study conducted by a randomly selected group of outpatient medical practitioners from 28 diabetology departments in the Czech Republic. OBSERVED AND ASSESSED POPULATION: 465 patients underwent at least three months of Byetta treatment; 347 persons (74.6% ofthe research population) stayed forthe extended observation of 6-12 months. Apart from the basic identification data (year of birth, sex, age when diabetes mellitus manifested, height, maximum patient weight before diabetes and when diabetes mellitus manifested), the following information was recorded in three-month intervals: weight, waistline, glycated haemoglobin (HbA(1c)), and diabetes mellitus treatment The population included 50.3% women and 49.7% men, and the average age at the time of diabetes manifestation was 48 (20-73 years). The period between the diabetes manifestation and the start of exenatide treatment was 8.3 years on average.. The average maximum BMI value before the detection of diabetes was 39.05 (+/- 6.73); at the time of the diabetes manifestation 37.88 (+/- 6.40); and at the start of Byetta treatment 39.01 (+/- 6.22). The BMI after three, six, and 12 months of treatment was as follows: 37.86 (+/- 6.12), 37.18 (+/- 6.0), and 36.60 (+/- 6.21); it decreased by > or = 0.5 in 83.3% patients who were under observation for 12 months. HbA(1c) value decreased in the first three months from 7.39% (+/- 1.57) to 6.41% (+/- 1.34), p < 0.0001. In the period of three-six months, the value decreased to 6.22% (+/- 1.34), and after 12 months, HbA(1c) was at 6.04 (+/- 1.20). An improvement in HbA(1c) value of 0.5-2.0% occurred after the first year in 49% of our research population. The waistline was measured on a regular basis in only 267 patients (58.9%). The average initial value of 120.7 cm was reduced within three months of the treatment to 118.3 cm, and within six and 12 months to 117.3 and 112.6 cm respectively.. Adding Byetta to the currently applied treatment of obese patients with diabetes mellitus type 2 led, in 66.8% of the population, to a statistically significant reduction in HbA(1c) levels in the first three-six months of the treatment; after 12 months of treatment, 25% of the population was still showing an improvement in HbA(1c) of > 2.0%. Of observed patients, 74.4% significantly reduced their BMI (by > 0.5) during the first three months; 39.6% of patients reduced their BMI in the period of three-six months.

Topics: Adult; Aged; Body Mass Index; Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Peptides; Venoms; Weight Loss; Young Adult

One developing strategy for obesity treatment has been to use combinations of differently acting pharmacotherapies to improve weight loss with fewer adverse effects. The purpose of this study was to determine whether the combination of naltrexone (Nal), an opioid antagonist acting on the reward system, and exendin-4 (Ex-4), a glucagon-like peptide 1 agonist acting on satiety signaling, would produce larger reductions in food intake than either alone in rats. Because the anorectic potencies of both compounds have been associated with nausea and malaise, the influence of these drug combinations on the acquisition of a conditioned taste aversion (CTA) was also determined.. In Experiment 1, the acute anorectic effects of Nal (0.32-3.2 mg kg(-1); intraperitoneally (i.p.)) and Ex-4 (1-10 μg kg(-1); i.p.) were assessed alone or in combination. Combinational doses were further investigated by the repeated daily administration of 1 mg kg(-1) Nal+3.2 μg kg(-1) Ex-4 for 4 days. In Experiment 2, both compounds alone or in combination were used as unconditioned stimuli in a series of CTA tests.. Nal and Ex-4, alone or in combination, suppressed food intake in a dose-dependent manner, and the interaction on food intake between Nal and Ex-4 was additive. In the CTA paradigm, Nal (1 mg kg(-1)) alone did not support acquisition, whereas a CTA was evident with doses of Ex-4 (1 or 3.2 μg kg(-1)). Combinations of Nal and Ex-4 also resulted in a more rapid and robust acquisition of a CTA.. Given that the Nal and Ex-4 combination produces additive effects on not only food intake reduction but also food aversion learning, this specific drug combination does not have the benefit of minimizing the adverse effects associated with each individual drug. These data suggest that it is necessary to evaluate both the positive and adverse effects at early stages of combinational drug development.

Topics: Animals; Appetite Depressants; Body Weight; Drug Interactions; Drug Therapy, Combination; Eating; Exenatide; Hypoglycemic Agents; Male; Naltrexone; Obesity; Peptides; Rats; Rats, Sprague-Dawley; Taste; Venoms; Weight Loss

The aim of this retrospective analysis was to assess the clinical effectiveness of exenatide in patients with type 2 diabetes in routine clinical practice.. Patients with type 2 diabetes mellitus and inadequate glycemic control were commenced on exenatide in an out-patient setting. Effects on Hba1c, weight and BMI at 3- and 6-month intervals were recorded by a retrospective review of medical records.. We examined a cross-section of 61 patients. The mean weight at treatment initiation was 114 kg and baseline Hba1c was 9.8% (84 mmol/mol). Mean reduction in Hba1c at 3 months was 0.8% (10 mmol/mol, P < 0.01) and mean reduction at 6 months was 0.5% (6 mmol/mol, P < 0.05). Mean weight loss at 3 months was 4.2 kg (P < 0.0001) and at 6 months was 6.6 kg (P < 0.0001). Seventeen patients were prescribed exenatide in addition to insulin, against current guidelines. This cohort of patients showed a greater mean reduction in weight (7.4 vs 6.2 kg) as compared to the group on exenatide without insulin, but mean Hba1c increased at 6 months by 0.35% (4 mmol/mol).. Adjunctive exenatide treatment in patients with suboptimally controlled type 2 diabetes on oral hypoglycaemic medications, achieved reductions in Hba1c and weight, in line with published studies. However, in patients already on insulin, favourable results can be achieved by the addition of exenatide by careful patient selection and follow-up.

Topics: Adult; Aged; Body Mass Index; Diabetes Mellitus, Type 2; Drug Evaluation; Drug Therapy, Combination; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Peptides; Retrospective Studies; Treatment Outcome; Venoms; Weight Loss

Previous studies with the novel once daily glucagon-like peptide-1 (GLP-1) analogue liraglutide and the GLP-1 receptor agonist exenatide have revealed profound insulinotrophic and antidiabetic effects, but also potent effects on gastric emptying (GE) and long-term and lasting reductions in body weight. In this study, we examined the acute and chronic effects of two different GLP-1 analogues with different pharmacokinetic profiles on GE, food intake and body weight.. On the basis of a series of dose-finding studies, the doses of exenatide and liraglutide with similar acute anorectic effects were identified. GE was assessed using a standard acetaminophen release assay. After the acute test, rats were dosed bi-daily for 14 days in which period food intake and body weight was monitored. On day 14, the GE rate was reassessed.. While both compounds exerted robust acute reductions in GE, the effect was markedly diminished following 14 days of dosing with liraglutide. In contrast, exenatide-treated rats still displayed a profound reduction in GE at the 14-day time-point. Both compounds exerted similar effects on body weight.. The data suggest that the 'gastric inhibitory' GLP-1 receptors in rats are subject to desensitization/tachyphylaxis but that this effect is dependent on full 24-h exposure as obtained by liraglutide. The body weight-lowering effects of GLP-1 receptor stimulation are not subject to desensitization. These data indicate that regulation of appetite signals in the brain, and not GE, is the main mechanism for liraglutide-induced weight loss.

Topics: Animals; Appetite Regulation; Eating; Exenatide; Gastric Emptying; Glucagon-Like Peptide 1; Hippocampus; Injections, Intravenous; Liraglutide; Male; Obesity; Peptides; Rats; Rats, Sprague-Dawley; Venoms; Weight Loss

Topics: Anti-Obesity Agents; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Overweight; Peptides; Receptors, Glucagon; Venoms; Weight Loss

This observational study evaluated the clinical effectiveness of exenatide BID (exenatide) vs. insulin glargine (glargine) in patients with type 2 diabetes mellitus in ambulatory clinical practice.. Retrospective analyses were conducted using an electronic medical record (EMR) database among adult patients with type 2 diabetes mellitus initiating exenatide or glargine between 1 November 2006 and 30 April 2009. The cohorts were propensity-score matched to control baseline demographics, clinical measures, health status and medication use. The changes from baseline to a 12-month follow-up period for A1C (primary outcome), weight, body mass index (BMI), blood pressure and lipid levels were compared between the matched cohorts using paired tests.. Propensity-score matching between the exenatide (n = 4494) and glargine (n = 5424) cohorts led to 2683 matched pairs with comparable characteristics, including age, gender and baseline clinical values. The exenatide cohort achieved a greater mean reduction in A1C (-0.6% vs. -0.4%, p < 0.01), weight (-2.6 kg vs. -0.2 kg, p < 0.01), BMI (-0.8 kg/m(2) vs. -0.04 kg/m(2) , p < 0.01) and systolic blood pressure (SBP) (-1.8 mmHg vs. -0.1 mmHg, p < 0.01) in the follow-up period. The changes in diastolic blood pressure and lipid levels were not significantly different between cohorts.. Compared to glargine, exenatide-treated patients experienced significant reductions in A1C, weight, BMI and SBP. Acknowledging the limitations of observational research, exenatide showed greater clinical effectiveness than glargine from a large EMR database in the ambulatory care setting.

Topics: Ambulatory Care; Blood Glucose; Body Mass Index; Body Weight; Cohort Studies; Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Glargine; Insulin, Long-Acting; Lipids; Male; Middle Aged; Peptides; Retrospective Studies; Treatment Outcome; Venoms; Weight Loss

Gastric bypass surgery and exenatide therapy represent two relatively new methods in treating morbid obesity and type 2 diabetes, although there are many differences between them. With the data supported from our hospital, we just want to investigate the differences between bypass surgery and exenatide injection and want to answer the question: Which one is the best? And Why?. Data from January 2009 to January 2010 were summarized for comparison at Shengjing hospital, including weight loss, plasma glucose and insulin changes, glycosylated hemoglobin, and the subjective scores of patients themselves. Plasma lipoprotein and serum ions were measured to evaluate the nutrition status.. Patients in the GB group received more weight loss and better glucose control compared with the EX group. At 6 months, feeding insulin level in the GB group was 18.1 ± 3.2 mU/L, which was much lower than that in the EX group (64.5 ± 13.2 mU/L, P < 0.01). The Hb1AC level in the GR group was 6.08 ± 0.56 %, much lower than that in the EX group (7.19 ± 0.72 %, P < 0.01). We did not find any statistical differences in lipoprotein, plasma ions, and subjective scores between the GB and EX groups.. Gastric bypass surgery is better in weight control and in the remission of insulin resistance compared with exenatide therapy. Both methods were safe and have no nutritional disorder in early stage, although the transferring in the GB group was higher than the EX group. The subjective scores from both groups declared that both methods could be accepted by patients.

Topics: Adult; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Eating; Exenatide; Fasting; Female; Gastric Bypass; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Lipoproteins; Male; Middle Aged; Obesity, Morbid; Peptides; Remission Induction; Treatment Outcome; Venoms; Weight Loss

Weight loss in obese humans produces a relative leptin deficiency, which is postulated to activate potent orexigenic and energy conservation mechanisms to restrict weight loss and promote weight regain. Here we determined whether leptin replacement alone or with GLP-1 receptor agonist exendin-4 attenuates weight regain or promotes greater weight loss in weight-reduced diet-induced obese (DIO) rats. Forty percent restriction in daily intake of a high-fat diet in DIO rats for 4 wk reduced body weight by 12%, body fat by 29%, and plasma leptin by 67% and normalized leptin sensitivity. When food restriction ended, body weight, body fat, and plasma leptin increased rapidly. Daily administration of leptin [3-h intraperitoneal (ip) infusions (4 nmol·kg(-1)·h(-1))] at onset and end of dark period for 3 wk did not attenuate hyperphagia and weight regain, nor did it affect mean daily meal sizes or meal numbers. Exendin-4 (50 pmol·kg(-1)·h(-1)) infusions during the same intervals prevented postrestriction hyperphagia and weight regain by normalizing meal size. Coadministration of leptin and exendin-4 did not reduce body weight more than exendin-4 alone. Instead, leptin began to attenuate the inhibitory effects of exendin-4 on food intake, meal size, and weight regain by the end of the second week of administration. Plasma leptin in rats receiving leptin was sevenfold greater than in rats receiving vehicle and 17-fold greater than in rats receiving exendin-4. Together, these results do not support the hypothesis that leptin replacement alone or with exendin-4 attenuates weight regain or promotes greater weight loss in weight-reduced DIO rats.

Topics: Animals; Body Composition; Body Fat Distribution; Body Weight; Caloric Restriction; Dose-Response Relationship, Drug; Eating; Exenatide; Glucagon-Like Peptide-1 Receptor; Hyperphagia; Leptin; Male; Obesity; Peptides; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Venoms; Weight Gain; Weight Loss

Hypothalamic obesity caused by damage of medial hypothalamic nuclei presents a therapeutic challenge. Glucagon-like peptide-1 agonist exenatide (synthetic version of exendin-4 (Ex4)), used for treatment of diabetes, causes weight loss via hindbrain signaling.. We tested Ex4 in an established rat model of medial hypothalamic lesions. Lesion and control animals were administered either daily intraperitoneal injections of 1 µg·kg(-1) Ex4 or saline for 9 days.. In our rat model, a significant difference in percent baseline food intake (lesion -20.8%, control -13.6%; p < 0.001) and percent change in body weight (lesion -4.9%/9 days, control -3.2%/9 days; p < 0.05) was observed during Ex4 treatment compared with saline.. Ex4 resulted in reduction of food intake and body weight. Follow-up studies are required to further elucidate its effects on energy homeostasis and to establish Ex4 as a potential drug for treatment of hypothalamic obesity.

Topics: Animals; Body Weight; Disease Models, Animal; Down-Regulation; Drug Evaluation, Preclinical; Energy Intake; Exenatide; Glucagon-Like Peptide 1; Hypoglycemic Agents; Hypothalamic Diseases; Male; Obesity; Peptides; Rats; Rats, Sprague-Dawley; Venoms; Weight Loss

The purpose of this study was to investigate the preferences of people with diabetes for liraglutide vs other glucose lowering drugs, based on outcomes of clinical trials.. Willingness to pay (WTP) for diabetes drug treatment was assessed by combining results from a recent WTP study with analysis of results from the Liraglutide Effect and Action in Diabetes (LEAD) programme. The LEAD programme included six randomised clinical trials with 3967 participants analysing efficacy and safety of liraglutide 1.2 mg (LEAD 1-6 trials), rosiglitazone (LEAD 1 trial), glimepiride (LEAD 2-3 trials), insulin glargine (LEAD 5 trial), and exenatide (LEAD 6 trial). The WTP survey used discrete choice experimental (DCE) methodology to evaluate the convenience and clinical effects of glucose lowering treatments.. People with type 2 diabetes were prepared to pay an extra €2.64/day for liraglutide compared with rosiglitazone, an extra €1.94/day compared with glimepiride, an extra €3.36/day compared with insulin glargine, and an extra €0.81/day compared with exenatide. Weight loss was the largest component of WTP for liraglutide compared with rosiglitazone, glimepiride, and insulin glargine. Differences in the administration of the two drugs was the largest component of WTP for liraglutide (once daily anytime) compared with exenatide (twice daily with meals). A limitation of the study was that it was based on six clinical trials where liraglutide was the test drug, but each trial had a different comparator, therefore the clinical effects of liraglutide were much better documented than the comparators.. WTP analyses of the clinical results from the LEAD programme suggested that participants with type 2 diabetes were willing to pay appreciably more for liraglutide than other glucose lowering treatments. This was driven by the relative advantage of weight loss compared with rosiglitazone, glimepiride, and insulin glargine, and administration frequency compared with exenatide.

Topics: Cost of Illness; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Disease Management; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin Glargine; Insulin, Long-Acting; Liraglutide; Peptides; Randomized Controlled Trials as Topic; Rosiglitazone; Sulfonylurea Compounds; Thiazolidinediones; Venoms; Weight Loss

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are effective for obese patients with type 2 diabetes mellitus (T2DM) because they concomitantly target obesity and dysglycaemia. Considering the high prevalence of non-alcoholic fatty liver disease (NAFLD) in patients with T2DM, we determined the impact of 6 months' GLP-1 RA therapy on intrahepatic lipid (IHL) in obese, T2DM patients with hepatic steatosis, and evaluated the inter-relationship between changes in IHL with those in glycosylated haemoglobin (HbA(1)c), body weight, and volume of abdominal visceral and subcutaneous adipose tissue (VAT and SAT). We prospectively studied 25 (12 male) patients, age 50±10 years, BMI 38.4±5.6 kg/m(2) (mean ± SD) with baseline IHL of 28.2% (16.5 to 43.1%) and HbA(1)c of 9.6% (7.9 to 10.7%) (median and interquartile range). Patients treated with metformin and sulphonylureas/DPP-IV inhibitors were given 6 months GLP-1 RA (exenatide, n = 19; liraglutide, n = 6). IHL was quantified by liver proton magnetic resonance spectroscopy ((1)H MRS) and VAT and SAT by whole body magnetic resonance imaging (MRI). Treatment was associated with mean weight loss of 5.0 kg (95% CI 3.5,6.5 kg), mean HbA(1c) reduction of 1·6% (17 mmol/mol) (0·8,2·4%) and a 42% relative reduction in IHL (-59.3, -16.5%). The relative reduction in IHL correlated with that in HbA(1)c (ρ = 0.49; p = 0.01) but was not significantly correlated with that in total body weight, VAT or SAT. The greatest IHL reduction occurred in individuals with highest pre-treatment levels. Mechanistic studies are needed to determine potential direct effects of GLP-1 RA on human liver lipid metabolism.

Topics: Adiposity; Adult; Blood Glucose; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Exenatide; Fatty Liver; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Liraglutide; Liver; Male; Middle Aged; Obesity; Peptides; Prospective Studies; Venoms; Weight Loss

Significant weight loss following Roux-en-Y gastric bypass surgery (RYGB) in obese humans correlates with enhanced secretion of anorexigenic gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY(3-36) (PYY(3-36)). Our aim here was to identify a dosing strategy for intraperitoneal (IP) infusion of GLP-1 homologue exendin-4 alone and with PYY(3-36) that produces a sustained reduction in daily food intake and body weight in diet-induced obese (DIO) rats. We tested 12 exendin-4 strategies over 10 weeks. Exendin-4 infused during the first and last 3 h of the dark period at 15-20 pmol/h (0.15 nmol/kg/day) produced a sustained 24 ± 1% reduction in daily food intake for 17 days, and decreased body weight by 7%. In a separate group of DIO rats, none of seven dosing strategies combining exendin-4 and PYY(3-36) produced a similar reduction in daily food intake for >10 days. The subsequent decline in efficacies of exendin-4 alone and with PYY(3-36) on food intake and body weight in each experiment suggested possible receptor downregulation and tolerance to treatments. However, when treatments were discontinued for 1 day following losses in efficacies, daily food intake significantly increased. Together, these results demonstrate that (i) intermittent IP infusion of a low dose of exendin-4 can produce a relatively prolonged reduction in daily food intake and body weight in DIO rats, (ii) co-infusion of exendin-4 and PYY(3-36) does not further prolong this response, and (iii) activation of an orexigenic mechanism gradually occurs to counteract the inhibitory effects of exendin-4 alone and with PYY(3-36) on food intake and body weight.

Topics: Animals; Body Weight; Diet; Dose-Response Relationship, Drug; Drug Combinations; Drug Evaluation, Preclinical; Eating; Exenatide; Hypoglycemic Agents; Male; Obesity; Peptide Fragments; Peptide YY; Peptides; Rats; Rats, Sprague-Dawley; Venoms; Weight Loss

To assess the extent, safety, efficacy and tolerability of reported off-licence exenatide use through a nationwide audit.. The Association of British Clinical Diabetologists hosted a password-protected, online collection of anonymized data of exenatide use in real clinical practice. Three hundred and fifteen contributors from 126 centres across UK provided data on 6717 patients. HbA1c and weight changes, exenatide discontinuation, adverse events and treatment satisfaction were compared between non-insulin and insulin-treated patients.. Four thousand eight hundred and fifty-seven patients had baseline and follow-up treatment status with mean (±s.d.) baseline HbA1c 9.45 ± 1.69% and BMI 40.0 ± 8.2 kg/m(2) . Of the 4857 patients, 1921 (39.6%) used exenatide with insulin. Comparing patients who continued insulin with exenatide with non-insulin-treated patients, mean (±s.e.) latest HbA1c and weight reduction (median 26 weeks) were 0.51 ± 0.06 versus 0.94 ± 0.04% (p < 0.001) and 5.8 ± 0.2 versus 5.5 ± 0.1 kg (p = 0.278). Insulin-treated patients had higher rates of exenatide discontinuation (31.0 vs. 13.9%, p < 0.001), hypoglycaemia (8.9 vs. 6.1%, p < 0.001), gastrointestinal side effects (28.4 vs. 25.0%, p = 0.008) and treatment dissatisfaction (20.8 vs. 5.7%, p < 0.001). However, 34.2% of the patients continuing insulin still achieved HbA1c reduction ≥1%. There was significant insulin discontinuation, dose reduction and greater sulphonylurea discontinuation among insulin-treated patients.. Addition of exenatide to obese, insulin-treated patients can improve glycaemia and weight. Adverse events were statistically but probably not clinically significantly higher, but combination treatment was less well tolerated. Overall, exenatide was less effective in lowering HbA1c among insulin-treated patients, although significant number of insulin-treated patients still achieved significant HbA1c, weight and insulin reductions. Further research into identifying obese, insulin-treated patients who will tolerate and benefit from exenatide treatment is urgently needed.

Topics: Body Mass Index; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Medical Audit; Middle Aged; Obesity; Peptides; Treatment Outcome; United Kingdom; Venoms; Weight Loss

The glucagon-like-peptide-1 receptor (GLP-1R) agonists, liraglutide (Victoza) and the synthetic product of exendin-4 (Byetta), are approved for type II diabetes mellitus (T2DM) treatment and may be efficacious in obesity treatment as well, in part, due to the drugs' resistance to enzymatic degradation and prolonged half-life relative to endogenous GLP-1. To address the need to directly compare the food intake- and body weight-suppressive effects of these two GLP-1R ligands, acute and chronic dosing experiments were performed. Once-daily (q.d.) exendin-4 (0, 0.33, 1.5, and 3.0 µg/kg) and liraglutide (0, 50, 100, and 300 µg/kg, q.d.) both reduced the chow intake in nonobese rats in a dose-dependent fashion following either intraperitoneal (IP) or subcutaneous (SC) administration, whereas only liraglutide reduced 24 and 48 h body weight in nonobese, chow-maintained rats. Chow intake and body weight suppression by liraglutide were of greater magnitude and shorter latency following IP compared to SC delivery, whereas for exendin-4, the magnitude of intake-suppression was similar for IP and SC administration. The effects of chronic delivery (7 consecutive days; IP) of liraglutide (25 and 50 µg/kg; q.d.) and exendin-4 (3 µg/kg; q.d. and twice-daily (b.i.d.)) on food intake and body weight were also examined in diet-induced obese (DIO) rats. Liraglutide (50 µg/kg q.d.) and exendin-4 (3 µg/kg b.i.d.) were comparable in suppressing overall high fat/sucrose diet (HFS; 60% kcal from fat) intake. Both drugs regimens yielded marked weight loss over the 7-day period. The weight loss effect of liraglutide was achieved in the first 2 days and remained stable for the duration of the experiment; weight loss with exendin-4 appeared more linear over the 7-day period. In conclusion, administration of the GLP-1R ligands, exendin-4 (b.i.d.) and liraglutide (q.d.), lead to comparable and pronounced suppression of food intake and body weight in DIO rats, suggesting a potential role for these drugs as a clinical tool for obesity treatment.

Topics: Animals; Anti-Obesity Agents; Appetite Regulation; Dietary Fats; Dietary Sucrose; Dose-Response Relationship, Drug; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Injections, Intraperitoneal; Injections, Subcutaneous; Ligands; Liraglutide; Male; Obesity; Peptides; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Time Factors; Venoms; Weight Loss

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Exenatide; Humans; Hypoglycemic Agents; Peptides; Venoms; Weight Loss

The use of retroviral drugs in the treatment of infection by human immunodeficiency virus (HIV) is associated, especially for first generations, with side effects such as lipodystrophy, fatty liver and insulin resistance, which may trigger secondary diabetes or worsen existing diabetes. The use of Glucagon-Like Peptide-1 in obese patients with type 2 diabetes on HIV retroviral as an alternative to insulin therapy is not documented; we report the case of a 47-year-old treated with exenatide when insulin was discontinued. During the first year of treatment, exenatide, in combination with metformin and repaglinide, led to a weight loss of 14 kg and fat mass and waist circumference were respectively reduced from 31 to 25.5% and from 114 to 103 cm. Homeostatic model assessment (HOMA) was used to calculate β-cell secretion which increased from 50 to 78% and insulin sensitivity which increased from 28 to 51%, reflecting a decrease in HbA(1c) by 1.9%. Exenatide may be a new therapeutic option for HIV-infected type 2 diabetes patients undergoing retroviral therapy.

Topics: Adipose Tissue; Antiretroviral Therapy, Highly Active; Carbamates; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; HIV Infections; Humans; Hypoglycemic Agents; Insulin Resistance; Insulin-Secreting Cells; Male; Metformin; Middle Aged; Peptides; Piperidines; Venoms; Waist Circumference; Weight Loss

Exenatide use in type 2 diabetes is limited in routine clinical practice. We examined a cross-section of 90 patients. Mean weight and HBA(1c) were 114.9+/-20.6 kg, 10.3+/-2.1% at initiation; 108.0+/-15.3 kg (p<0.0001), 9.0+/-2.1% (p<0.001) at 3 months; 109.2+/-18.2 kg (p<0.0001), 9.5+/-2.3% (p=0.08) at 6 months. Exenatide appears effective in reducing HBA(1c) and weight.

Topics: Blood Glucose; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Peptides; Sulfonylurea Compounds; Treatment Outcome; Venoms; Weight Loss

Weight loss in patients with type 2 diabetes can improve glycemic control, lower blood pressure, and improve dyslipidemia. Glucagon-like peptide (GLP-1) receptor agonists are associated with weight loss and have potentially beneficial effects on cardiovascular risk biomarkers; however, there is limited information to indicate whether these effects remain outside of clinical trials.. Medical records from the General Electric Centricity research database were analyzed retrospectively to evaluate the relationship between weight loss and glycemic control and changes in blood pressure and lipids in patients with type 2 diabetes initiating therapy with exenatide, sitagliptin, or insulin. Baseline and follow-up (90-365 days after the index date) for weight, A1C, fasting blood glucose (FBG), blood pressure, triglycerides, and LDL, HDL, and total cholesterol were assessed.. A total of 6,280, 5,861, and 32,398 patients receiving exenatide, sitagliptin, or insulin, respectively, were included in the analysis. Exenatide-treated patients lost a mean +/- SD of 3.0 +/- 7.33 kg, sitagliptin-treated patients lost 1.1 +/- 5.39 kg, and insulin-treated patients gained 0.6 +/- 9.49 kg. There was a significant association between weight loss and a reduction in A1C and FBG with exenatide only and a reduction in blood pressure for all therapies. Weight loss was associated with some improvements in lipids, primarily in the GLP-1 receptor agonist group, with little association in the insulin group.. Weight reduction with GLP-1 receptor agonists was associated with a shift toward a more favorable cardiovascular risk profile. Outcome trials are needed to determine whether improvement in biomarkers translates into a reduction in cardiovascular events in patients with type 2 diabetes.

Topics: Aged; Blood Glucose; Cohort Studies; Diabetes Mellitus, Type 2; Exenatide; Female; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Multivariate Analysis; Peptides; Pyrazines; Sitagliptin Phosphate; Triazoles; Venoms; Weight Loss

Topics: Adamantane; Blood Pressure; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells; Lipids; Liraglutide; Male; Middle Aged; Peptides; Pyrazines; Sitagliptin Phosphate; Triazoles; Venoms; Weight Loss

The study objective was to analyze, in everyday practice, the long-term metabolic effects of exenatide (for 9 and 12 months) in patients with type 2 diabetes not responding to treatments with metformin and sulphonylurea at maximum dosages.. A total of 299 type 2 diabetics were recruited from 14 centres specializing in diabetes care across Belgium. Main study endpoints were changes in HbA(1c), weight and waist circumference, and tolerability and compliance. Two patient cohorts were analyzed for effectiveness, with data available at 9 (n=90) and 12 (n=94) months of follow-up.. Significant decreases in HbA(1c) of -1.3% and -1.6% were observed in the 9- and 12-month cohorts, respectively (P<0.001). The decrease in HbA(1c) was greater in patients with higher baseline levels (P<0.001), and the response was independent of baseline weight, body mass index (BMI), age, gender and diabetes duration. A progressive reduction of weight (4.9 kg) was also observed in the two cohorts at 9 and 12 months (P<0.001), with greater weight loss in patients with higher baseline BMI (P=0.046) and in female subjects (P=0.025). Waist circumference also decreased from baseline to endpoints. A correlation was observed between reduction in HbA(1c) and weight loss (P=0.019). Side effects, mainly of gastrointestinal origin, were reported in 33% (93/284 patients in the safety cohort). The rate of hypoglycaemia was 3.5%. Treatment was discontinued in 27% of patients (n=77) mainly due to drug inefficacy (53%, n=41) or adverse events (26%, n=20), or both (8%, n=6).. Exenatide leads to long-term improvement of glycaemic control as well as weight loss in a majority of patients not responding to combined oral drug therapy in real-world clinical practice. However, no baseline factors predictive of response could be identified. Exenatide can be considered an effective treatment option in such patients, including those with high baseline HbA(1c) and long duration of diabetes.

Topics: Aged; Body Mass Index; Diabetes Mellitus, Type 2; Exenatide; Female; Gastrointestinal Diseases; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Male; Middle Aged; Peptides; Retrospective Studies; Time Factors; Treatment Outcome; Venoms; Waist Circumference; Weight Loss

The overall safety profiles of GLP-1 agonists and DPP-4 inhibitors are favorable, with a low incidence of hypoglycemia. This attribute, along with their weight and cardiovascular benefits, particularly with the GLP-1 agonists, make them appropriate choices in our 3 patient cases. Ongoing safety investigations with GLP-1 agonists and DPP-4 inhibitors will provide further clarity to the complete safety profiles of these agents.

Topics: Adamantane; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin; Liraglutide; Male; Metformin; Middle Aged; Peptides; Pyrazines; Receptors, Glucagon; Risk; Sitagliptin Phosphate; Triazoles; Venoms; Weight Loss

A 54-year-old obese woman with poorly controlled type 2 diabetes was put on the maximum allowed doses of Metformin, Glimepiride and Rosiglitazone. When Exenatide was added, she lost 33 kg. She remained euglycemic for at least 7 months after the sequential discontinuation of Exenatide and the other oral agents.

Topics: Diabetes Mellitus, Type 2; Exenatide; Female; Humans; Metformin; Middle Aged; Obesity; Peptides; Remission Induction; Rosiglitazone; Sulfonylurea Compounds; Thiazolidinediones; Venoms; Weight Loss

Topics: Body Mass Index; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Exenatide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Peptides; Time Factors; Venoms; Weight Loss

Topics: Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Glucose; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Metformin; Peptides; Pyrazines; Sitagliptin Phosphate; Treatment Outcome; Triazoles; Venoms; Weight Loss

This is a retrospective analysis of medical records in 4 Belgian diabetes centres of 3 cohorts of patients with type 2 diabetes, with data available, respectively, after 3 months < or =163 patients exposed), 6 months (n=77) and 9 months (n=28) with exenatide therapy. This analysis mainly focuses on the 3 and 6 month cohorts. The mean HbA1 level at baseline averaged 9% and decreased by -1.3% and -1.4% at 3 and 6 months, respectively (-1.5% at 9 months). Neither the duration of diabetes nor initial body weight did influence the metabolic response. The decrease in HbA(1c) at 6 months was greater in patients with higher baseline HbA(1c):-0.5%, -1.4% and -2.4% for a baseline HbA(1c) level <8%, 8-10% and >10%, respectively. At 6 months, the composite criterion of a reduction of HbA(1c) by >1% or a final level <7% was reached by 69% of the cohort. Body weight decreased continuously over time, with a mean reduction of -2.1 kg at 3 months and -3.0 kg at 6 months (-4.9 kg at 9 months). The greater the baseline body weight, the greater the weight loss at final evaluation. Minor nausea and more rarely vomiting were observed, essentially during the first months of exenatide treatment. According to this observational study in routine practice, exenatide may be a valuable alternative to insulin for intensification of treatment of patients with type 2 diabetes after failure of oral drug combination, independently of baseline HbA(1c), body weight and duration of diabetes.

Topics: Belgium; Blood Glucose; Diabetes Mellitus, Type 2; Exenatide; Female; Humans; Hypoglycemic Agents; Male; Middle Aged; Peptides; Retrospective Studies; Venoms; Weight Loss

Topics: Adult; Aged; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Male; Metformin; Middle Aged; Nausea; Peptides; Thiazolidinediones; Venoms; Vomiting; Weight Loss

Topics: Diabetes Mellitus, Type 2; Exenatide; Humans; Hypoglycemic Agents; Obesity; Peptides; Venoms; Weight Loss

To evaluate the effect of exenatide on clinical parameters in obese patients with type 2 diabetes mellitus whose hyperglycemia is not adequately controlled despite treatment with oral hypoglycemic agents and insulin.. In this retrospective analysis, clinical progress of 52 obese patients with type 2 diabetes treated with exenatide, 5 mcg twice daily, in an outpatient setting was reviewed. Treatment initiation was between September and December 2005. Mean follow-up period was 26 weeks. Thirty-eight patients took exenatide regularly (Group A); 14 patients discontinued exenatide because of insurance, personal, or economic reasons (Group B). Measurements at baseline and at follow-up included body weight; blood pressure; and levels of hemoglobin A1c (HbA1c), high-sensitivity C-reactive protein (CRP), and plasma lipids. Insulin dosage requirements were assessed.. Mean body weight (+/- standard error of the mean) decreased by 6.46 +/- 0.8 kg (P<.001) in Group A and increased by 2.4 +/- 0.6 kg in Group B (P<001). In Group A, mean HbA1c decreased by 0.6 +/- 0.21% (P = .007), and the insulin dosage requirement decreased for rapid-acting and mixed insulins (P<.02). In Group A, means of the following parameters decreased: serum total cholesterol by 8.5 +/- 3.3% (P = .03), triglycerides by 26 +/- 7.6% (P = .01), systolic blood pressure by 9.2 +/- 3.3 mm Hg (P = .02), and high-sensitivity CRP by 34 +/- 14.3% (P = .05). These indices did not change in Group B.. Exenatide effectively treats obese patients with type 2 diabetes on insulin, leading to weight loss and reduction in levels of HbA1c, systolic blood pressure, triglycerides, and high-sensitivity CRP.

Topics: Blood Pressure; Body Weight; C-Reactive Protein; Cholesterol; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Male; Middle Aged; Obesity; Peptides; Retrospective Studies; Triglycerides; Venoms; Weight Loss

Topics: C-Peptide; Cross-Over Studies; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin-Secreting Cells; Insulin, Long-Acting; Metformin; Peptides; Randomized Controlled Trials as Topic; Risk Factors; Time Factors; Venoms; Weight Gain; Weight Loss

Topics: Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Metformin; Peptides; Sulfonylurea Compounds; Time Factors; Venoms; Weight Loss

Topics: Animals; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lizards; Peptides; Placebos; Time Factors; Venoms; Weight Loss

Exenatide has been shown to improve glycaemic control (over 30 weeks) in subjects with Type 2 diabetes. A recent extension study has shown that, in metformin-treated subjects with Type 2 diabetes, exenatide remained beneficial at 82 weeks. For those subjects who completed the study, in addition to the 1% fall in glycosylated haemoglobin (HbA1c) at 30 weeks, there was another 0.2% fall in HbA1c by 82 weeks. The weight loss achieved was a mean of 3 kg after 30 weeks, and this increased to 5.3 kg after 82 weeks in the completer cohort. In another extension study, continued benefit with exenatide was shown in subjects treated with metformin and/or sulfonylureas. For those subjects who completed the study, in addition to the 0.9% fall in HbA(1c) at 30 weeks, there was another 0.2% fall in HbA(1c) by 82 weeks. The weight loss achieved was a mean of 1.6 kg after 30 weeks, and this increased to 2.1 kg after 82 weeks in the completer cohort. The subjects taking exenatide with metformin had a greater weight loss (5.3 kg), compared with those treated with a sulfonylurea (3.9 kg) and those taking metformin and a sulfonylurea (4.1 kg). In conclusion, extension studies have confirmed that exenatide is an exciting new and useful medicine for Type 2 diabetes.

Topics: Diabetes Mellitus, Type 2; Exenatide; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Multicenter Studies as Topic; Peptides; Randomized Controlled Trials as Topic; Venoms; Weight Loss

Topics: Controlled Clinical Trials as Topic; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Islets of Langerhans; Metformin; Peptides; Placebos; Time Factors; Venoms; Weight Loss