exenatide and Diarrhea

GLP-1 receptor agonists (RAs) may cause nausea, vomiting or diarrhoea. The aim of this study was to assess the risk of adverse events (AEs) with GLP-1 RAs and their relation to dose, background medication and duration of action.. The PubMed database was searched and 32 clinical trials with GLP-1 RAs (phase 3) were selected. We performed a systematic analysis and compared the proportion of patients reporting nausea, vomiting or diarrhoea, for different doses and glucose-lowering background medications, and relative to a reference compound within the subclasses of short- (exenatide b.i.d.) and long-acting (liraglutide) GLP-1 RAs, calculating the relative risks ± 95% confidence intervals.. The risk of nausea was dose-dependent for long-acting (P = .0063) and across all GLP-1 RAs (P = .0017), and a similar trend was observed for vomiting (P = .23). Diarrhoea was dose-dependent (P = .031). Background treatment with metformin was associated with more nausea (P = .04) and vomiting (P = .0009). Compared to exenatide b.i.d., there was less nausea and diarrhoea with lixisenatide. Compared to liraglutide, there was a similar risk associated with dulaglutide, and less with exenatide q.w. and albiglutide. Long-acting GLP-1 RAs were associated with less nausea and vomiting, but with more diarrhoea than short-acting agents.. GLP-1 RAs are associated with gastrointestinal AEs that are related to dose and background medications (especially metformin) and may vary in a compound-specific manner. Long-acting agents are associated with less nausea and vomiting but with more diarrhoea.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Diarrhea; Drug Therapy, Combination; Exenatide; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Metformin; Nausea; Peptides; Venoms; Vomiting

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

Patient numbers in individual diabetes trials are often too limited to assess the effect of a treatment by different patient characteristics, and meta-analyses often do not include patient-level data. The purpose of this pooled analysis was to evaluate the efficacy and tolerability of exenatide once weekly (EQW) in patients with type 2 diabetes grouped into subpopulations by key demographic characteristics.. This post hoc analysis included data from patients who received EQW in seven randomised, controlled phase 3 trials that were 24-30 weeks in duration. Patients were classified into subpopulations on the basis of their baseline age (< 65 or ≥ 65 years), gender (male or female), race (White, Black, Asian, Hispanic), duration of diabetes (< 10 years, ≥ 10 years) and body mass index (BMI; < 25, ≥ 25 to < 30, ≥ 30 to < 35, ≥ 35 to < 40 or ≥ 40 kg/m(2)).. A total of 1719 patients were included in this analysis of patient subpopulations. All subpopulations experienced significant improvements from baseline in haemoglobin A1C, fasting glucose and body weight. Most subpopulations experienced significant improvements in blood pressure and lipid parameters. Overall, the most common AEs were hypoglycaemia (16.4% overall; 2.3% in patients not on concomitant sulfonylurea), nausea (14.7%), diarrhoea (10.9%) and nasopharyngitis (7.2%).. These results show that the treatment of type 2 diabetes with EQW for 24-30 weeks was associated with significant improvements in glycaemic control and body weight, irrespective of age, gender, race, duration of diabetes or BMI. The most common adverse events were gastrointestinal in nature.

Topics: Blood Glucose; Blood Pressure; Body Mass Index; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Diarrhea; Drug Administration Schedule; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Lipid Metabolism; Male; Middle Aged; Nasopharyngitis; Nausea; Peptides; Randomized Controlled Trials as Topic; Treatment Outcome; Venoms

We aimed to integrate evidence from all randomized controlled trials (RCTs) and assess the impact of different doses of exenatide or liraglutide on major gastrointestinal adverse events (GIAEs) in type 2 diabetes (T2DM).. RCTs evaluating different doses of exenatide and liraglutide against placebo or an active comparator with treatment duration ≥4 weeks were searched and reviewed. A total of 35, 32 and 28 RCTs met the selection criteria evaluated for nausea, vomiting, and diarrhea, respectively. Pairwise random-effects meta-analyses and mixed treatment comparisons (MTC) of all RCTs were performed.. All GLP-1 dose groups significantly increased the probability of nausea, vomiting and diarrhea relative to placebo and conventional treatment. MTC meta-analysis showed that there was 99.2% and 85.0% probability, respectively, that people with exenatide 10 μg twice daily (EX10BID) was more vulnerable to nausea and vomiting than those with other treatments. There was a 78.90% probability that liraglutide 1.2 mg once daily (LIR1.2) has a higher risk of diarrhea than other groups. A dose-dependent relationship of exenatide and liraglutide on GIAEs was observed.. Our MTC meta-analysis suggests that patients should be warned about these GIAEs in early stage of treatment by GLP-1s, especially by EX10BID and LIR1.2, to promote treatment compliance.

Topics: Diabetes Mellitus, Type 2; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Exenatide; Female; Gastrointestinal Diseases; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Male; Middle Aged; Nausea; Odds Ratio; Peptides; Randomized Controlled Trials as Topic; Receptors, Glucagon; Risk Assessment; Risk Factors; Time Factors; Venoms; Vomiting

Patients with irritable bowel syndrome (IBS) may experience postprandial symptom exacerbation. Nutrients stimulate intestinal release of glucagon-like peptide 1 (GLP-1), an incretin hormone with known gastrointestinal effects. However, prior to the postprandial rise in GLP-1, levels of the hunger hormone, ghrelin, peak. The aims of this study were to determine if ghrelin sensitizes colonic intrinsic and extrinsic neurons to the stimulatory actions of a GLP-1 receptor agonist, and if this differs in a rat model of IBS.. Calcium imaging of enteric neurons was compared between Sprague Dawley and Wistar Kyoto rats. Colonic contractile activity and vagal nerve recordings were also compared between strains.. Circulating GLP-1 concentrations differ between IBS subtypes. Mechanistically, we have provided evidence that calcium responses evoked by exendin-4, a GLP-1 receptor agonist, are potentiated by a ghrelin receptor (GHSR-1) agonist, in both submucosal and myenteric neurons. Although basal patterns of colonic contractility varied between Sprague Dawley and Wister Kyoto rats, the capacity of exendin-4 to alter smooth muscle function was modified by a GHSR-1 agonist in both strains. Gut-brain signaling via GLP-1-mediated activation of vagal afferents was also potentiated by the GHSR-1 agonist.. These findings support a temporal interaction between ghrelin and GLP-1, where the preprandial peak in ghrelin may temporarily sensitize colonic intrinsic and extrinsic neurons to the neurostimulatory actions of GLP-1. While the sensitizing effects of the GHSR-1 agonist were identified in both rat strains, in the rat model of IBS, underlying contractile activity was aberrant.

Topics: Animals; Colon; Constipation; Diarrhea; Electrophysiological Phenomena; Enteric Nervous System; Exenatide; Ghrelin; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Irritable Bowel Syndrome; Muscle Contraction; Muscle, Smooth; Neurons; Rats; Rats, Inbred WKY; Rats, Sprague-Dawley; Receptors, Ghrelin; Vagus Nerve

Type II diabetes mellitus (DM) is an increasingly prevalent cause of morbidity and mortality among U.S. adults, with increasing prevalence in emergency department (ED) visits. Multiple medications, such as exenatide, a glucagon-like peptide-1 agonist, have been developed in the past decade to combat this growing problem. This medication is well documented to cause gastrointestinal upset and skin nodules at the injection site. However, currently no documented cases exist regarding manipulation of injection nodules causing increased absorption or reports demonstrating an increase in adverse drug reactions.. We report an interesting case of an adult male patient who likely experienced increased systemic absorption of exenatide by manipulating an injection nodule, which ultimately resulted in nausea, retching, diarrhea, and a tachycardic heart rate of 130-140 beats/min. These symptoms are known side effects of exenatide. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Given the high frequency of DM patients presenting to the ED, emergency physicians should be familiar with diabetic maintenance medications and their adverse reactions. Treating these side effects and properly educating patients can alleviate discomfort, prevent future adverse reactions, and decrease return visits to the ED.

Topics: Chest Pain; Diabetes Mellitus, Type 2; Diarrhea; Emergency Service, Hospital; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Injection Site Reaction; Male; Middle Aged; Nausea; Tachycardia

Alterations in gut motility and visceral hypersensitivity are two major features of irritable bowel syndrome (IBS). The aim of this study was to investigate the roles of glucagon-like peptide-1 (GLP-1) in the pathogenesis of experimental IBS. Rat models of constipation-predominant IBS (IBS-C) and diarrhea-predominant IBS (IBS-D) were established. Fecal water content and behavioral responses to colorectal distention (CRD), using electromyography (EMG), were measured. The expression of glucagon-like peptide-1 receptor (GLP-1R) in the colon was detected by immunohistochemistry, and the serum concentration of GLP-1 was measured by ELISA assay. The movement of circular and longitudinal colonic muscle was detected using an organ bath recording technique. Compared to controls, the fecal water contents were lower in the IBS-C group, while they were higher in the IBS-D group (P<0.05). EMG response to CRD in the experimental IBS groups was increased compared with their respective controls (P<0.05). GLP-1R was localized in the mucosa layer, circular muscle and myenteric nerve plexus of the colon. Notably, the expression of GLP-1R in the IBS-C group was higher, but in the IBS-D group, it was lower compared with controls. The serum levels of GLP-1 in the IBS-C group were higher compared to those in the IBS-D group (P<0.05). In addition, administration of exogenous GLP-1 and exendin-4 inhibited colonic circular muscle contraction, particularly in the IBS-C group, while there was no significant effect on longitudinal muscle contraction. In conclusion, these results indicated that GLP-1 and GLP-1R are implicated in the pathogenesis of IBS-C and IBS-D.

Topics: Animals; Colon; Constipation; Diarrhea; Disease Models, Animal; Exenatide; Feces; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Irritable Bowel Syndrome; Male; Muscle Contraction; Peptides; Peristalsis; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Venoms; Water