exenatide and Pancreatitis

Several randomized trials with metabolic outcomes have reported that glucagon like peptide-1 receptor agonists (GLP-1 RA) could be associated with an increased risk of pancreatitis. The present meta-analysis aimed to examine this hypothesis.. An extensive Medline, Embase, and Cochrane Database search for "exenatide", "liraglutide", "albiglutide", "taspoglutide", "dulaglutide", "lixisenatide", and "semaglutide" was performed up to March 31st, 2013.. (i) randomized trials, (ii) duration ≥12 weeks; (iii) on type 2 diabetes; and (iv) comparison of GLP-1RA with placebo or active drugs. Mantel-Haenszel odds ratio with 95% confidence interval (MH-OR) was calculated for pancreatitis.. 80 eligible trials were identified. Of these, 39 had not disclosed their findings or did not report any information on pancreatitis. The remaining 41 trials enrolled 14,972 patients, with a total exposure of 14,333 patient × years (8353 and 5980 patient × years for GLP-1 receptor agonists and comparators, respectively). The overall risk of pancreatitis was not different between GLP-1RA and comparators (MH-OR: 1.01[0.37; 2.76]; p = 0.99).. The present meta-analysis does not suggest any increase in the risk of pancreatitis with the use of GLP-1RA. However, it should be recognized that the number of observed cases of incident pancreatitis is very small and the confidence intervals of risk estimates are wide.

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

Glucagon-like peptide 1 receptor (GLP-1R) agonists provide good glycemic control combined with low hypoglycemia risk and weight loss. Here, we summarize the recently published data for this therapy class, focusing on sustainability of action, use in combination with basal insulin, and the efficacy of longer acting agents currently in development. The safety profile of GLP-1R agonists is also examined.. GLP-1R agonists provide sustained efficacy and their combination with basal insulin is well tolerated, providing additional glycemic control and weight benefits compared with basal insulin alone. Data suggest that the convenience of longer acting agents may be at the expense of efficacy. Despite the initial concerns, most evidence indicates that GLP-1R agonists do not increase the risk of pancreatitis or thyroid cancer. However, the extremely low incidence of these events means further investigations are required before a causal link can be eliminated. Large-scale clinical trials investigating the long-term cardiovascular safety of this therapy class are ongoing and may also provide important insights into pancreatic and thyroid safety.. GLP-1R agonists offer sustained glycemic efficacy, weight loss benefits, and a low risk of hypoglycemia. The results of ongoing trials should help to clarify the safety of this therapy class.

Topics: Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Exenatide; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Hypoglycemia; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Insulin; Liraglutide; Male; Pancreatitis; Peptides; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Thyroid Neoplasms; Treatment Outcome; Venoms

Recent suggestions that glucagon-like peptide-1 (GLP-1)-based therapies could cause pancreatitis, and even pancreatic cancer, are based on:. The worrying histological changes are not reproduced in all studies and are unexpectedly variable with different GLP-1-based therapies.. Singh's findings that pancreatitis is doubled with GLP-1-based therapies could relate to their use in obese patients who are prone to pancreatitis risk factors--gallstones and hypertriglyceridaemia. The other observational studies do not find an association between GLP-1-based therapies and pancreatitis.. The increased reports of pancreatitis and pancreatic cancer are likely to be attributable to 'notoriety bias'.. Butler's findings for those on GLP-1-based therapies vs. those not, could have other explanations. Meanwhile: META ANALYSIS: Randomized control trials with GLP-1-based therapies do not find increased pancreatitis risk. Meta-analysis of 53 randomized controlled trials including 20 212 dipeptidyl peptidase-4 inhibitor-treated patients found a significantly reduced risk of major adverse cardiovascular events [odds ratio 0.689 (0.528-0.899), P = 0.006] for dipeptidyl peptidase-4 inhibitors compared with control subjects.. The evidence suggests that there is more than a possibility that some of the GLP-1 receptor agonists, and possibly also some dipeptidyl peptidase-4 inhibitors, may be associated with reduced cardiovascular events. Eight ongoing long-term cardiovascular randomized controlled trials will report from September 2013 onwards. These trials should resolve the issue of pancreatitis risk and substantiate the extent of benefit.. Whilst we should remain vigilant, currently the balance of evidence is strongly in support of GLP-1-based therapy, with benefits far outweighing potential risks.

Topics: Adverse Drug Reaction Reporting Systems; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Liraglutide; Male; Pancreatic Neoplasms; Pancreatitis; Patient Selection; Peptides; Randomized Controlled Trials as Topic; Receptors, Glucagon; Risk Assessment; Risk Factors; Venoms

Within recent years, glucagon-like peptide 1 receptor agonists (GLP-1-RA) have emerged as a new treatment option for type 2 diabetes. The GLP-1-RA are administered subcutaneously and differ substantially in pharmacokinetic profiles.. This review describes the pharmacokinetics and safety aspects of the currently available GLP-1 receptor agonists, liraglutide (based on the structure of native GLP-1), exenatide twice daily and exenatide once weekly (based on exendin-4) in relation to the kinetics and toxicology of native GLP-1. The review is based on electronic literature searches and legal documents in the form of assessment reports from the European Medicines Agency and the United States Food and Drug Administration.. GLP-1-based therapy combines several unique mechanisms of action and have the potential to gain widespread use in the fight against diabetes and obesity. The difference in chemical structure have strong implications for key pharmacokinetic parameters such as absorption and clearance, and eventually the safety and efficacy of the individual GLP-1-RA. The main safety concerns are pancreatitis and neoplasms, for which there are no identifiable differences in risk between the available agents. Antibody formation and injection site reactions are more frequent with the exendin-4-based compounds. The efficacy with regard to Hb(A1c) reduction is superior with the longer-acting agonists, whereas the shorter-acting GLP-1-RA seems to provide greater postprandial glucose control and lower tolerability as a possible consequence of less induction of tachyphylaxis. The future place of these agents will depend on the added safety and efficacy data in the several ongoing cardiovascular outcome trials.

Topics: Animals; Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Liraglutide; Pancreatitis; Peptides; Tachyphylaxis; Venoms

The association between GLP-1 agonists, acute pancreatitis (AP), any cancer and thyroid cancer is discussed. This meta-analysis was aimed at evaluating the risk of those serious adverse events associated with GLP-1 agonists in patients with type 2 diabetes.. Medline, EMBASE, Cochrane Library and clinicaltrials.gov were searched in order to identify longitudinal studies evaluating exenatide or liraglutide use and reporting data on AP or cancer. Odds ratios (ORs) were pooled using a random-effects model. I(2) statistics assessed heterogeneity.. Twenty-five studies were included. Neither exenatide (OR 0.84 [95% CI 0.58-1.22], I(2) = 30%) nor liraglutide (OR 0.97 [95% CI 0.21-4.39], I(2) = 0%) were associated with an increased risk of AP, independent of baseline comparator. The pooled OR for cancer associated with exenatide was 0.86 (95% CI 0.29, 2.60, I(2) = 0%) and for liraglutide was 1.35 (95% CI 0.70, 2.59, I(2) = 0%). Liraglutide was not associated with an increased risk for thyroid cancer (OR 1.54 [95% CI 0.40-6.02], I(2) = 0%). For exenatide, no thyroid malignancies were reported.. Current available published evidence is insufficient to support an increased risk of AP or cancer associated with GLP-1 agonists. These rare and long-term adverse events deserve properly monitoring in future studies evaluating GLP-1 agonists.

Topics: Diabetes Mellitus, Type 2; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Liraglutide; Neoplasms; Pancreatitis; Peptides; Venoms

Although several classes of pharmacotherapy are available for type 2 diabetes, glycaemic control is often hampered by medication-related adverse effects and contraindications such as renal impairment. Glucagon-like peptide-1 (GLP-1) receptor agonists provide a new pharmacotherapeutic option based on the multiple glucose-lowering effects of the human hormone GLP-1. This mechanism of action not only provides therapeutic efficacy but also suggests that GLP-1 receptor agonists have distinct safety and tolerability concerns compared with other diabetes therapies. Stimulation of pancreatic insulin secretion by GLP-1 receptor agonists is glucose dependent, conferring a lesser risk of hypoglycaemia than that seen with sulfonylureas. Individual GLP-1 receptor agonists differ in their metabolism and excretion profiles, affecting the choice of agent for patients with renal impairment. As with other protein-based therapies, GLP-1 receptor agonists may induce the formation of antibodies that may attenuate therapeutic efficacy and affect safety. Conclusions on cardiovascular safety must await outcomes studies, but at present no signal of harm has been reported, and preclinical data and effects on risk markers suggest a potential for benefit. Current data on thyroid medullary cancer in humans and pancreatic malignancy in rodents do not suggest that there is any reason to restrict the clinical use of GLP-1 analogues in most people with diabetes. It is currently difficult to ascertain the possible contributory role of GLP-1 receptor agonists in increasing the risk of pancreatitis, and vigilance for signs and symptoms is prudent. Primary tolerability issues include transient gastrointestinal symptoms, common with GLP-1 receptor agonists, which can be reduced through dose titration.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug-Related Side Effects and Adverse Reactions; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemia; Incretins; Liraglutide; Nausea; Pancreatitis; Peptides; Randomized Controlled Trials as Topic; Receptors, Glucagon; Thyroid Gland; Venoms; Vomiting

To assess the risk of acute pancreatitis during treatment with glucagon-like peptide 1 receptor agonist dulaglutide, placebo, and active comparators across phase 2/3 dulaglutide trials.. A total of 6,005 patients with type 2 diabetes participated (dulaglutide group. The exposure-adjusted incidence rate of acute pancreatitis in dulaglutide-treated patients was similar to the rates with placebo, with few reported cases during the entire program.

Topics: Acute Disease; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Insulin Glargine; Male; Metformin; Middle Aged; Pancreatitis; Peptides; Recombinant Fusion Proteins; Sitagliptin Phosphate; Venoms

The amount of immortal time bias in studies with nonfatal outcomes is unclear. To quantify the magnitude of bias from mishandling of immortal person-time in studies of nonfatal outcomes.. We derived formulas for quantifying bias from misclassified or excluded immortal person-time in settings with nonfatal outcomes, assuming a constant rate of outcome. In the situation of misclassified or excluded immortal person-time, the quantification includes the immortal time and corresponding events mistakenly attributed to the exposed group (misclassified) or excluded from study (excluded) that must be attributed to the comparison group.. With misclassified immortal person-time, the magnitude of bias varies according to the incidence rate ratio of immortal time and comparison group as well as the rate ratio of immortal time and exposed group: toward null for both ratios less than 1, no bias for both ratios equal to 1, away from null for both ratios greater than 1. For one ratio less than 1 and the other greater than 1, the direction and magnitude of bias can be obtained from the formula provided. With excluded immortal person-time, the magnitude of bias is associated with the incidence rate ratio of immortal time and comparison group: toward null for the ratio less than 1, no bias for the ratio equal to 1, and away from null for the ratio greater than 1.. Bias due to immortal person-time in studies with nonfatal outcomes can vary widely and can be quantified under assumptions that apply to many studies.

Topics: Bias; Epidemiologic Research Design; Exenatide; Follow-Up Studies; Humans; Hypoglycemic Agents; Mortality; Pancreatitis; Peptides; Retrospective Studies; Time Factors; Treatment Outcome; Venoms

We investigated factors affecting the timing of signal detection by comparing variations in reporting time of known and unknown ADRs after initial drug release in the USA. Data on adverse event reactions (AERs) submitted to U.S. FDA was used. Six ADRs associated with 6 drugs (rosuvastatin, aripiprazole, teriparatide, telithromycin, exenatide, varenicline) were investigated: Changes in the proportional reporting ratio, reporting odds ratio, and information component as indexes of signal detection were followed every 3 months after each drugs release, and the time for detection of signals was investigated. The time for the detection of signal to be detected after drug release in the USA was 2-10 months for known ADRs and 19-44 months for unknown ones. The median lag time for known and unknown ADRs was 99.0-122.5 days and 185.5-306.0 days, respectively. When the FDA released advisory information on rare but potentially serious health risks of an unknown ADR, the time lag to report from the onset of ADRs to the FDA was shorter. This study suggested that one factor affecting signal detection time is whether an ADR was known or unknown at release.

Topics: Adverse Drug Reaction Reporting Systems; Aripiprazole; Chemical and Drug Induced Liver Injury; Data Mining; Databases, Factual; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Exenatide; Humans; Hypercalcemia; Ketolides; Pancreatitis; Peptides; Rhabdomyolysis; Rosuvastatin Calcium; Suicide; Teriparatide; Time Factors; United States; United States Food and Drug Administration; Varenicline; Venoms

Glucagon Like Peptide-1 (GLP-1) drugs are currently used to treat type-2 diabetes. Safety concerns for increased risk of pancreatitis and pancreatic ductal metaplasia have accompanied these drugs. High fat diet (HFD) is a type-2 diabetes risk factor that may affect the response to GLP-1 drug treatment. The objective of the present study was to investigate the effects of diet and GLP-1 based drugs on the exocrine pancreas in mice. Experiments were designed in a mouse model of insulin resistance created by feeding a HFD or standard diet (STD) for 6weeks. The GLP-1 drugs, sitagliptin (SIT) and exenatide (EXE) were administered once daily for additional 6weeks in both mice fed HFD or STD. The results showed that body weight, blood glucose levels, and serum levels of pro-inflammatory cytokines (TNFα, IL-1β, and KC) were significantly greater in HFD mice than in STD mice regardless of GLP-1 drug treatment. The semi-quantitative grading showed that pancreatic changes were significantly greater in EXE and SIT-treated mice compared to control and that HFD exacerbated spontaneous exocrine pancreatic changes seen in saline-treated mice on a standard diet. Exocrine pancreatic changes identified in this study included acinar cell injury (hypertrophy, autophagy, apoptosis, necrosis, and atrophy), vascular injury, interstitial edema and inflammation, fat necrosis, and duct changes. These findings support HFD as a risk factor to increased susceptibility/severity for acute pancreatitis and indicate that GLP-1 drugs cause pancreatic injury that can be exacerbated in a HFD environment.

Topics: Acute Disease; Animals; Apoptosis; Atrophy; Diet, High-Fat; Exenatide; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Male; Mice; Mice, Inbred C57BL; Necrosis; Pancreas; Pancreatitis; Peptides; Pyrazines; Receptors, Glucagon; Sitagliptin Phosphate; Triazoles; Venoms

Previous studies have suggested a link between glucagon-like peptide 1 (GLP-1)-based therapies and acute pancreatitis, while other studies have found no association. Because differences in diabetes severity may confound this relationship, a self-controlled case series (SCCS) analysis has been suggested as a means to control for individual-level confounding.. We evaluated the relationship between GLP-1-based therapies and pancreatitis by SCCS method using a large observational database. We calculated the incidence density ratio of pancreatitis for exposure versus non-exposure to each drug. To examine the robustness of our findings, we performed sensitivity analyses by varying risk windows, using two pancreatitis definitions and including incident pancreatitis or all occurrences.. From dispensing data on 1.2 million patients, we found 7992 sitagliptin-exposed patients and 3552 exenatide-exposed patients between 2004 and 2009. Using an ICD9/CPT-based case definition of pancreatitis, we identified 207 sitagliptin and 82 exenatide cases. Augmenting this definition with laboratory criteria increased our cohort to 245 sitagliptin and 96 exenatide cases. For sitagliptin and exenatide cases, respectively, the mean duration of observation was 5.2 and 5.5 years, and the mean duration of drug exposure was 0.7 and 0.5 years. For all analyses (including different pancreatitis definitions, risk periods, and incident or recurrent events), the incidence density ratios for development of pancreatitis during exposure versus non-exposure ranged from 0.68 to 1.46, with all having 95% confidence intervals containing 1.. We found no association between the use of GLP-1-based therapies and pancreatitis using SCCS analysis in a large observational database.

Topics: Adult; Aged; Cohort Studies; Databases, Factual; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Male; Middle Aged; Pancreatitis; Peptides; Pyrazines; Risk Factors; Sitagliptin Phosphate; Triazoles; Venoms; Young Adult

Glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP4) inhibitors improve glucose tolerance by still incompletely understood mechanisms. Each class of antihyperglycemic drugs has also been proposed to increase pancreatitis risk. Here, we compare systematically the effects of two widely-used GLP-1 analogues, liraglutide and exendin-4, and the DPP4 inhibitor, sitagliptin, in the mouse.. C57BL6 mice were maintained for 131 days on a normal diet (ND) or a diet comprising 60% fat (HFD) before measurements of fasting blood glucose and insulin, and intraperitoneal glucose tolerance. Beta- and alpha- cell volume, and Reg3b immunoreactivity, were measured by immunohistochemical analysis of pancreatic slices.. Whereas liraglutide (200 µg/kg) and exendin-4 (10 µg/kg) treatment reduced body weight and/or improved glucose tolerance, sitagliptin (10 mg/kg) was without effect on either parameter. Liraglutide caused a sharp reduction in beta-cell mass in both ND and HFD mice, whereas exendin-4 exerted no effect. By contrast, sitagliptin unmasked an action of high fat diet to increase beta-cell mass. Reg3B positive area was augmented by all three agents in normal chow-fed mice, whilst sitagliptin and exendin-4, but not liraglutide, affected this parameter in HFD animals. Correspondingly sitagliptin, but not the GLP-1 analogues, increased circulating amylase levels in ND and HFD mice.. Liraglutide improves glucose tolerance in the mouse whilst exerting relatively modest effects on pancreatitis risk. Conversely, exendin-4 and sitagliptin, at doses which exert, respectively, minor or no effects on metabolic parameters, lead to signs of pancreatitis.

Topics: Animals; Blood Glucose; Body Weight; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Liraglutide; Male; Mice; Mice, Inbred C57BL; Pancreas; Pancreatitis; Peptides; Sitagliptin Phosphate; Venoms

As the incidence of acute pancreatitis continues to rise, establishing the etiology in order to prevent recurrence is important. Although the etiology of acute pancreatitis is not difficult in the majority of patients, almost a quarter of patients are initially labeled as having idiopathic acute pancreatitis. When confronted with a patient with acute pancreatitis and no clear etiology defined as an absence alcoholism, gallstones (ultrasound and/or MRI), a normal triglyceride level, and absence of tumor, it often appears reasonable to consider a drug as the cause of acute pancreatitis. Over 100 drugs have been implicated by case reports as causing acute pancreatitis. While some of these case reports are well written, many case reports represent poorly written experiences of the clinician simply implicating a drug without a careful evaluation. Over-reliance on case reports while ignoring randomized clinical trials and large pharmacoepidemiologic surveys has led to confusion about drug induced acute pancreatitis. This review will explain that drug induced acute pancreatitis does occur, but it is rare, and over diagnosis leads to misconceptions about the disease resulting in inappropriate patient care, increased litigation and a failure to address the true entity: idiopathic acute pancreatitis.

Topics: Acute Disease; Adverse Drug Reaction Reporting Systems; Animals; Diagnostic Errors; Exenatide; Humans; Hypoglycemic Agents; Incretins; Pancreatitis; Peptides; Predictive Value of Tests; Prognosis; Risk Assessment; Risk Factors; United States; United States Food and Drug Administration; Venoms

Acute pancreatitis has significant morbidity and mortality. Previous studies have raised the possibility that glucagonlike peptide 1 (GLP-1)-based therapies, including a GLP-1 mimetic (exenatide) and a dipeptidyl peptidase 4 inhibitor (sitagliptin phosphate), may increase the risk of acute pancreatitis.. To test whether GLP-1-based therapies such as exenatide and sitagliptin are associated with an increased risk of acute pancreatitis. We used conditional logistic regression to analyze the data.. Population-based case-control study.. A large administrative database in the United States from February 1, 2005, through December 31, 2008.. Adults with type 2 diabetes mellitus aged 18 to 64 years. We identified 1269 hospitalized cases with acute pancreatitis using a validated algorithm and 1269 control subjects matched for age category, sex, enrollment pattern, and diabetes complications.. Hospitalization for acute pancreatitis.. The mean age of included individuals was 52 years, and 57.45% were male. Cases were significantly more likely than controls to have hypertriglyceridemia (12.92% vs 8.35%), alcohol use (3.23% vs 0.24%), gallstones (9.06% vs 1.34), tobacco abuse (16.39% vs 5.52%), obesity (19.62% vs 9.77%), biliary and pancreatic cancer (2.84% vs 0%), cystic fibrosis (0.79% vs 0%), and any neoplasm (29.94% vs 18.05%). After adjusting for available confounders and metformin hydrochloride use, current use of GLP-1-based therapies within 30 days (adjusted odds ratio, 2.24 [95% CI, 1.36-3.68]) and recent use past 30 days and less than 2 years (2.01 [1.37-3.18]) were associated with significantly increased odds of acute pancreatitis relative to the odds in nonusers.. In this administrative database study of US adults with type 2 diabetes mellitus, treatment with the GLP-1-based therapies sitagliptin and exenatide was associated with increased odds of hospitalization for acute pancreatitis.

Topics: Acute Disease; Adolescent; Adult; Case-Control Studies; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Female; Glucagon-Like Peptide 1; Hospitalization; Humans; Logistic Models; Male; Middle Aged; Pancreatitis; Peptides; Pyrazines; Risk Factors; Sitagliptin Phosphate; Triazoles; Venoms

Topics: Acute Disease; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Metaphor; Pancreatitis; Peptides; Pyrazines; Sitagliptin Phosphate; Treatment Outcome; Triazoles; Venoms

Topics: Acute Disease; Animals; Diabetes Mellitus, Type 2; Evidence-Based Medicine; Exenatide; Humans; Hypoglycemic Agents; Pancreatitis; Peptides; Pyrazines; Risk Assessment; Risk Factors; Sitagliptin Phosphate; Triazoles; Venoms

Topics: Diabetes Mellitus, Type 2; Exenatide; Humans; Hypoglycemic Agents; Incretins; Pancreatitis; Peptides; Pyrazines; Sitagliptin Phosphate; Triazoles; Venoms

A recent autopsy analysis asserted that incretin drugs have the potential of increasing the risk for pancreatic cancer and for pancreatic neuroendocrine tumors. We examined the Network for Pancreatic Organ Donors with Diabetes (nPOD) database from which that analysis was derived. Our findings raise important questions about the comparability of the two groups of diabetes patients used for the analysis. Our review of the data available on the nPOD Web site and our reading of the earlier article lead us to the conclusion that the data, and the implications of the data, as expressed by the authors of the autopsy analysis are vastly overstated and are a misrepresentation of the information available.

Topics: Adolescent; Adult; Aged; Databases, Factual; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hyperplasia; Hypoglycemic Agents; Incretins; Male; Middle Aged; Models, Statistical; Pancreas; Pancreatitis; Peptides; Pyrazines; Receptors, Glucagon; Sitagliptin Phosphate; Tissue Banks; Triazoles; Venoms; Young Adult

To estimate the association between exenatide BID use and acute pancreatitis across two claims-based studies.. We pooled two cohort studies within separate commercial health insurance databases. We included initiators of exenatide BID and all other antihyperglycemic drugs without prior pancreatitis from 2005-2008. Poisson regression models provided rate ratios (RRs) and 95% confidence intervals (CIs) of the association of exenatide BID with acute pancreatitis adjusted for quintiles of propensity scores.. Primary inpatient diagnoses of acute pancreatitis with correction for misclassification via a validation sub-study.. There were 49,956 initiators of exenatide BID and 692,333 initiators of other antihyperglycemic drugs. Patients in the two studies were similar on many demographic and clinical characteristics. Exenatide BID initiators had a higher prevalence of diagnoses consistent with diabetes complications (e.g. peripheral neuropathy) and cardiovascular risk factors (e.g. hypertension). In both studies, current exenatide BID use was not associated with uncorrected outcomes of acute pancreatitis (pooled RR 1.0; CI 0.8-1.3). PPV correction resulted in a slightly higher point estimate for current use (pooled RR 1.3; CI 1.0-1.7) and past use (pooled RR 1.6; 95% CI 1.2-2.1).. These data are consistent with little or no higher risk of acute pancreatitis associated with current exenatide BID use relative to nonuse. Although previous work identified non-causal mechanisms, an increased incidence of acute pancreatitis following cessation of treatment remains a possibility. Bias due to residual confounding or outcome misclassification may remain, and should be considered a potential explanation for these findings.

Topics: Acute Disease; Databases, Factual; Exenatide; Female; Humans; Hypoglycemic Agents; Male; Pancreatitis; Peptides; Retrospective Studies; Risk Factors; Venoms

The potential association of glucagon-like peptide receptor agonists (GLP-1RAs) with the development of pancreatitis or pancreatic malignancies in patients with diabetes has been suggested. This study evaluated the long-term effects of the GLP-1RA exenatide on pancreatic exocrine structure and function in the Zucker diabetic fatty (ZDF) rat model of type 2 diabetes.. Rats received subcutaneous twice-daily injections of 0 (control), 6, 40 and 250 µg/kg/day exenatide for 3 months. Clinical signs, body and pancreas weight, food consumption, HbA1c, fasting serum amylase, lipase, glucose and insulin concentrations were evaluated during treatment and after a 28-day off-drug period to assess the reversibility of any observed effects. Morphometric analysis of pancreatic ductal cell proliferation and apoptosis were performed.. Plasma exenatide concentrations were several-fold higher than therapeutic levels observed in humans. No exenatide-related effects were observed on clinical signs, lipase concentration, pancreatic weight, pancreatic histology, ductal cell proliferation or apoptosis. Exenatide improved animal survival, physical condition, glucose concentrations and HbA1c, decreased food intake, and increased serum insulin concentration. Total amylase concentrations, although within normal ranges, were slightly higher in exenatide-treated rats; following the off-drug period, total amylase concentrations were comparable in treated and untreated rats. Exenatide-related minimal-to-moderate islet hypertrophy was observed at doses ≥6 µg/kg/day, with dose-related increases in incidence and degree. These changes were still present after the off-drug period.. Chronic administration of exenatide in ZDF rats resulted in the expected metabolic benefits and improved animal survival, with no adverse effects noted on pancreatic exocrine structure and function.

Topics: Amylases; Animals; Apoptosis; Biomarkers; Blood Glucose; Body Weight; Cell Proliferation; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Eating; Exenatide; Fasting; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Hypoglycemic Agents; Injections, Subcutaneous; Lipase; Male; Organ Size; Pancreas; Pancreatitis; Peptides; Rats; Rats, Zucker; Receptors, Glucagon; Venoms

Pancreatic duct glands (PDGs) have been hypothesized to give rise to pancreatic intraepithelial neoplasia (PanIN). Treatment with the glucagon-like peptide (GLP)-1 analog, exendin-4, for 12 weeks induced the expansion of PDGs with mucinous metaplasia and columnar cell atypia resembling low-grade PanIN in rats. In the pancreata of Pdx1-Cre; LSL-Kras(G12D) mice, exendin-4 led to acceleration of the disruption of exocrine architecture and chronic pancreatitis with mucinous metaplasia and increased formation of murine PanIN lesions. PDGs and PanIN lesions in rodent and human pancreata express the GLP-1 receptor. Exendin-4 induced proproliferative signaling pathways in human pancreatic duct cells, cAMP-protein kinase A and mitogen-activated protein kinase phosphorylation of cAMP-responsive element-binding protein, and increased cyclin D1 expression. These GLP-1 effects were more pronounced in the presence of an activating mutation of Kras and were inhibited by metformin. These data reveal that GLP-1 mimetic therapy may induce focal proliferation in the exocrine pancreas and, in the context of exocrine dysplasia, may accelerate formation of neoplastic PanIN lesions and exacerbate chronic pancreatitis.

Topics: Animals; Exenatide; Glucagon-Like Peptide-1 Receptor; Homeodomain Proteins; Humans; Hypoglycemic Agents; Male; Metformin; Mice; Mutation; Pancreatic Ducts; Pancreatitis; Peptides; Proto-Oncogene Proteins p21(ras); Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Trans-Activators; Venoms

Previously, a retrospective cohort study found no increased risk of acute pancreatitis with current or recent use of exenatide twice daily compared with use of other anti-diabetic drugs. This follow-up study investigated incident acute pancreatitis, with the use of a different data source and analytic method, in patients exposed to exenatide twice daily compared with patients exposed to other anti-diabetic medications.. A large US health insurance claims database was used. Eligible patients had ≥ 9 months continuous enrollment without a claim for pancreatitis and a claim for a new anti-diabetic medication on or after 1 June 2005 to 31 March 2009. Cases of acute pancreatitis were defined as hospitalized patients with an Internation Classification of Disease 9 code of 577.0 in the primary position. A discrete time survival model was used to evaluate the relationship between exenatide twice daily and acute pancreatitis.. Of 482,034 eligible patients, 24,237 initiated exenatide twice daily and 457,797 initiated another anti-diabetic medication. Initiators of exenatide twice daily had more severe diabetes compared with initiators of other anti-diabetic medications. After adjustments for propensity score, insulin and use of medication potentially associated with acute pancreatitis, the odds ratio with exenatide twice daily exposure was 0.95 (95% CI 0.65-1.38). A secondary analysis that examined current, recent and past medication exposure found no increased risk of acute pancreatitis with exenatide twice daily, regardless of exposure category.. This study indicates that exposure to exenatide twice daily was not associated with an increased risk of acute pancreatitis compared with exposure to other anti-diabetic medications. These results should be interpreted in light of potential residual confounding and unknown biases.

Topics: Acute Disease; Adolescent; Adult; Aged; Child; Child, Preschool; Diabetes Mellitus, Type 2; Drug Administration Schedule; Exenatide; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Infant; Infant, Newborn; Insurance, Health; International Classification of Diseases; Male; Middle Aged; Pancreatitis; Peptides; Retrospective Studies; Risk; United States; Venoms; Young Adult

Topics: Animals; Exenatide; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Male; Pancreas; Pancreatic Ducts; Pancreatitis; Peptides; Proto-Oncogene Proteins p21(ras); Receptors, Glucagon; Venoms

Topics: Animals; Exenatide; Female; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Liraglutide; Male; Pancreas; Pancreatic Ducts; Pancreatitis; Peptides; Proto-Oncogene Proteins p21(ras); Receptors, Glucagon; Venoms

A possible association between glucagon-like peptide-1 (GLP-1) analogs and incidences of pancreatitis has been suggested based on clinical studies. In male and female diabetic Zucker diabetic fatty (ZDF) rats, we investigated the effects of continuous administration of liraglutide and exenatide on biochemical [lipase, pancreatic amylase (P-amylase)] and histopathological markers of pancreatitis. Male and female ZDF rats were dosed for 13 wk with liraglutide (0.4 or 1.0 mg·kg(-1)·day(-1) sc once daily) or exenatide (0.25 mg·kg(-1)·day(-1) sc, Alzet osmotic minipumps). P-amylase and lipase plasma activity were measured, and an extended histopathological and stereological (specific cell mass and proliferation rate) evaluation of the exocrine and the endocrine pancreas was performed. Expectedly, liraglutide and exenatide lowered blood glucose and Hb A(1c) in male and female ZDF rats, whereas β-cell mass and proliferation rate were increased with greatly improved blood glucose control. Whereas neither analog affected lipase activity, small increases in P-amylase activity were observed in animals treated with liraglutide and exenatide. However, concurrent or permanent increases in lipase and P-amylase activity were never observed. Triglycerides were lowered by both GLP-1 analogs. The qualitative histopathological findings did not reveal adverse effects of liraglutide. The findings were mainly minimal in severity and focal in distribution. Similarly, the quantitative stereological analyses revealed no effects of liraglutide or exenatide on overall pancreas weight or exocrine and duct cell mass or proliferation. The present study demonstrates that, in overtly diabetic male and female ZDF rats, prolonged exposure to GLP-1 receptor agonists does not affect biochemical or histopathological markers of pancreatitis, and whereas both exenatide and liraglutide increase β-cell mass, they have no effect on the exocrine pancreas. However, clinical outcome studies and studies using primate tissues and/or studies in nonhuman primates are needed to further assess human risk.

Topics: Animals; Blood Glucose; Cell Proliferation; Exenatide; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Hypoglycemic Agents; Lipase; Liraglutide; Male; Pancreas; Pancreatic alpha-Amylases; Pancreatitis; Peptides; Rats; Rats, Zucker; Venoms

Postmarketing reports have linked exenatide use with acute pancreatitis and pancreatic cancer, but a definitive relationship has yet to be established.. We conducted a retrospective cohort analysis of patients with type 2 diabetes with employer-provided health insurance from 2007 to 2009. Multivariate models estimated the association between exenatide use and acute pancreatitis and pancreatic cancer. We required at least 1 year of exenatide exposure in the pancreatic cancer analysis. Sensitivity analyses were conducted that quasirandomized exenatide use based on patient out-of-pocket costs.. Among 268,561 patients included in the acute pancreatitis analysis, only 2.6% used exenatide. Hospitalization for acute pancreatitis was rare (0.247% of patients). In unadjusted and adjusted analyses, patients who did not use exenatide were more likely to be hospitalized for acute pancreatitis (0.249% vs. 0.196% in unadjusted analysis), but the difference was not statistically significant in either analysis (P = 0.22 and P = 0.70, respectively). Among 209,306 patients in the pancreatic cancer analysis, 0.070% were diagnosed with pancreatic cancer, and 0.88% had at least 1 year of continuous exenatide exposure prior to the diagnosis. Those with exenatide exposure had higher rates of pancreatic cancer compared with those without (0.081% vs. 0.070% in unadjusted analysis). In both unadjusted and adjusted analyses, the difference was not statistically significant (P = 0.80 and P = 0.46, respectively). In sensitivity analyses, results were similar.. We found no association between exenatide use and either hospitalization for acute pancreatitis or pancreatic cancer in a large sample of privately insured U.S. patients.

Topics: Diabetes Mellitus, Type 2; Exenatide; Female; Hospitalization; Humans; Hypoglycemic Agents; Incidence; Insurance, Health; Logistic Models; Male; Middle Aged; Multivariate Analysis; Pancreatic Neoplasms; Pancreatitis; Peptides; Retrospective Studies; Risk Assessment; United States; Venoms

Reports of acute pancreatitis associated with exenatide treatment prompted this study to estimate the association between acute pancreatitis and exenatide use relative to other antihyperglycaemic drugs.. This cohort study included patients without claims for prior pancreatic disease who initiated exenatide or other antihyperglycaemic drugs between June 2005 and December 2007. Acute pancreatitis was identified with diagnosis codes and confirmed through review of blinded medical records. Poisson regression models provided estimates of rate ratios (RRs) and 95% confidence intervals (CIs) comparing the rate of acute pancreatitis during periods of current (days supplied + 31 days), recent (current definition + 31 days) and past use (≥32 days beyond current definition) of exenatide relative to other antihyperglycaemic drugs, adjusted for propensity scores. A prespecified nested case-control analysis provided RR estimates adjusted for patient characteristics abstracted from medical records.. Initiators of exenatide (N = 25719) had more baseline claims for obesity and concomitant diabetes drugs than comparators (N = 234536). There were 40 confirmed cases of acute pancreatitis in the exenatide cohort and 254 among other antihyperglycaemic drug initiators. Compared to other antihyperglycaemic drugs, the propensity score-adjusted RR for exenatide was 0.5 (95% CI 0.2-0.9) for current use, 1.1 (95% CI 0.4-3.2) for recent use and 2.8 (95% CI 1.6-4.7) for past use. The case-control analysis resulted in a RR of 0.2 for current use (95% CI 0.0-1.4) and 0.1 for recent use (95% CI 0.0-1.3), but an attenuated RR in the past use association (RR 1.1; 95% CI 0.1-11.0).. Exenatide use was not associated with an increased risk of acute pancreatitis.

Topics: Acute Disease; Adolescent; Adult; Aged; Child; Child, Preschool; Cohort Studies; Databases, Factual; Diabetes Mellitus, Type 2; Exenatide; Female; Humans; Hypoglycemic Agents; Infant; Infant, Newborn; Male; Middle Aged; Pancreatitis; Peptides; Risk Assessment; Risk Factors; Venoms; Young Adult

Glucagon-like peptide-1-based therapy is gaining widespread use for type 2 diabetes, although there are concerns about risks for pancreatitis and pancreatic and thyroid cancers. There are also concerns that dipeptidyl peptidase-4 inhibitors could cause cancer, given their effects on immune function.. We examined the US Food and Drug Administration's database of reported adverse events for those associated with the dipeptidyl peptidase-4 inhibitor sitagliptin and the glucagon-like peptide-1 mimetic exenatide, from 2004-2009; data on adverse events associated with 4 other medications were compared as controls. The primary outcomes measures were rates of reported pancreatitis, pancreatic and thyroid cancer, and all cancers associated with sitagliptin or exenatide, compared with other therapies.. Use of sitagliptin or exenatide increased the odds ratio for reported pancreatitis 6-fold as compared with other therapies (P<2×10(-16)). Pancreatic cancer was more commonly reported among patients who took sitagliptin or exenatide as compared with other therapies (P<.008, P<9×10(-5)). All other cancers occurred similarly among patients who took sitagliptin compared with other therapies (P=.20).. These data are consistent with case reports and animal studies indicating an increased risk for pancreatitis with glucagon-like peptide-1-based therapy. The findings also raise caution about the potential long-term actions of these drugs to promote pancreatic cancer.

Topics: Adverse Drug Reaction Reporting Systems; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Odds Ratio; Pancreatic Neoplasms; Pancreatitis; Peptides; Pyrazines; Receptors, Glucagon; Risk Assessment; Risk Factors; Sitagliptin Phosphate; Thyroid Neoplasms; Triazoles; United States; United States Food and Drug Administration; Venoms

Topics: Diabetes Mellitus, Type 2; Drug Industry; Editorial Policies; Exenatide; Humans; Hypoglycemic Agents; Incretins; Pancreatitis; Peptides; Periodicals as Topic; Pyrazines; Sitagliptin Phosphate; Triazoles; Venoms

To report what is, to our knowledge, the first postmarketing case of acute pancreatitis associated with liraglutide.. A 60-year-old female with type 2 diabetes presented with a 16-hour history of mid-epigastric pain 3 weeks after treatment was changed from exenatide 10 μg twice daily, which she had taken for 4 years, to liraglutide 1.8 mg daily. Her serum lipase level was elevated (478 units/L) at admission, and other laboratory values were within normal limits. Liraglutide was discontinued at admission. Standard therapy for pancreatitis resulted in symptom resolution and a significant decrease in serum lipase (131 units/L) by hospital day 4; she was discharged on hospital day 5.. Based on the Naranjo scale, this case represents a probable adverse drug reaction. Eight cases of pancreatitis were observed in liraglutide-treated patients in premarketing clinical trials. Extensive literature describing exenatide-related pancreatitis and premarketing reports of liraglutide-related pancreatitis, along with the temporal relationship between the initiation of liraglutide and the onset of this patient's symptoms, suggest that the episode of pancreatitis was induced by liraglutide.. Liraglutide should be used cautiously in patients with a history of pancreatitis, and clinicians should have a high index of suspicion for this rare, but potentially serious, adverse effect.

Topics: Acute Disease; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Lipase; Liraglutide; Middle Aged; Pancreatitis; Peptides; Venoms

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Pancreatic Neoplasms; Pancreatitis; Peptides; Pyrazines; Receptors, Glucagon; Risk Assessment; Risk Factors; Sitagliptin Phosphate; Thyroid Neoplasms; Triazoles; Uncertainty; Venoms

Topics: Exenatide; Humans; Hypoglycemic Agents; Pancreatic Neoplasms; Pancreatitis; Peptides; Pyrazines; Sitagliptin Phosphate; Triazoles; Venoms

The incretin system plays an important role in glucose homeostasis, largely through the actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Unlike GIP, the actions of GLP-1 are preserved in patients with type 2 diabetes mellitus, which has led to the development of injectable GLP-1 receptor (GLP-1R) agonists and oral dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1R agonists-which can be dosed to pharmacologic levels-act directly upon the GLP-1R. In contrast, DPP-4 inhibitors work indirectly by inhibiting the enzymatic inactivation of native GLP-1, resulting in a modest increase in endogenous GLP-1 levels. GLP-1R agonists generally lower the fasting and postprandial glucose levels more than DPP-4 inhibitors, resulting in a greater mean reduction in glycated hemoglobin level with GLP-1R agonists (0.4%-1.7%) compared with DPP-4 inhibitors (0.4%-1.0%). GLP-1R agonists also promote satiety and reduce total caloric intake, generally resulting in a mean weight loss of 1 to 4 kg over several months in most patients, whereas DPP-4 inhbitors are weight-neutral overall. GLP-1R agonists and DPP-4 inhibitors are generally safe and well tolerated. The glucose-dependent manner of stimulation of insulin release and inhibition of glucagon secretion by both GLP-1R agonists and DPP-4 inhibitors contribute to the low incidence of hypoglycemia. Although transient nausea occurs in 26% to 28% of patients treated with GLP-1R agonists but not DPP-4 inhibitors, this can be reduced by using a dose-escalation strategy. Other adverse events (AEs) associated with GLP-1R agonists include diarrhea, headache, and dizziness. The main AEs associated with DPP-4 inhibitors include upper respiratory tract infection, nasopharyngitis, and headache. Overall, compared with other therapies for type 2 diabetes mellitus with similar efficacy, incretin-based agents have low risk of hypoglycemia and weight gain. However, GLP-1R agonists demonstrate greater comparative efficacy and weight benefit than DPP-4 inhibitors.

Topics: Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Hypersensitivity; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Homeostasis; Humans; Hypoglycemic Agents; Incretins; Liraglutide; Pancreatitis; Peptides; Receptors, Glucagon; Venoms

Exendin-4 is a 39 amino acid agonist of the glucagon-like peptide receptor and has been approved for treatment of type 2 diabetes. Many reports describe an increased incidence of acute pancreatitis in humans treated with exendin-4 (exenatide). Previous studies have evaluated the effect of exendin-4 on beta cells and beta cell function. We evaluated the histological and biochemical effects of exendin-4 on the pancreas in rats.. We studied 20 Sprague-Dawley male rats, ten of which were treated with exendin-4 and ten of which were used as controls. The study period was 75 days. Serum and pancreatic tissue were removed for biochemical and histological study. Blood glucose, amylase, lipase, insulin and adipocytokines were compared between the two groups.. Animals treated with exendin-4 had more pancreatic acinar inflammation, more pyknotic nuclei and weighed significantly less than control rats. They also had higher serum lipase than control animals. Exendin-4 treatment was associated with lower insulin and leptin levels as well as lower HOMA values than in the untreated control group.. Although the use of exendin-4 in rats is associated with decreased weight gain, lower insulin resistance and lower leptin levels than in control animals, extended use of exendin-4 in rats leads to pancreatic acinar inflammation and pyknosis. This raises important concerns about the likelihood of inducing acute pancreatitis in humans receiving incretin mimetic therapy.

Topics: Adipokines; Alanine Transaminase; Amylases; Animals; Aspartate Aminotransferases; Blood Glucose; Body Weight; Exenatide; Humans; Hypoglycemic Agents; Insulin; Lipase; Male; Pancreas; Pancreatitis; Peptides; Rats; Rats, Sprague-Dawley; Venoms

Cases of acute pancreatitis have been reported in association with exenatide, sitagliptin, and type 2 diabetes without use of these medications. It remains unknown whether exenatide or sitagliptin increase the risk of acute pancreatitis.. A retrospective cohort study of a large medical and pharmacy claims database was performed. Data for 786,656 patients were analyzed. Cox proportional hazard models were built to compare the risk of acute pancreatitis between diabetic and nondiabetic subjects and between exenatide, sitagliptin, and control diabetes medication use.. Incidence of acute pancreatitis in the nondiabetic control group, diabetic control group, exenatide group, and sitagliptin group was 1.9, 5.6, 5.7, and 5.6 cases per 1,000 patient years, respectively. The risk of acute pancreatitis was significantly higher in the combined diabetic groups than in the nondiabetic control group (adjusted hazard ratio 2.1 [95% CI 1.7-2.5]). Risk of acute pancreatitis was similar in the exenatide versus diabetic control group (0.9 [0.6-1.5]) and sitagliptin versus diabetic control group (1.0 [0.7-1.3]).. Our study demonstrated increased incidence of acute pancreatitis in diabetic versus nondiabetic patients but did not find an association between the use of exenatide or sitagliptin and acute pancreatitis. The limitations of this observational claims-based analysis cannot exclude the possibility of an increased risk.

Topics: Diabetes Mellitus, Type 2; Exenatide; Female; Humans; Hypoglycemic Agents; Male; Middle Aged; Pancreatitis; Peptides; Proportional Hazards Models; Pyrazines; Retrospective Studies; Sitagliptin Phosphate; Triazoles; Venoms

The risk of developing pancreatitis is elevated in type 2 diabetes and obesity. Cases of pancreatitis have been reported in type 2 diabetes patients treated with GLP-1 (GLP-1R) receptor agonists. To examine whether the GLP-1R agonist exenatide potentially induces or modulates pancreatitis, the effect of exenatide was evaluated in normal or diabetic rodents. Normal and diabetic rats received a single exenatide dose (0.072, 0.24, and 0.72 nmol/kg) or vehicle. Diabetic ob/ob or HF-STZ mice were infused with exenatide (1.2 and 7.2 nmol·kg(-1)·day(-1)) or vehicle for 4 wk. Post-exenatide treatment, pancreatitis was induced with caerulein (CRN) or sodium taurocholate (ST), and changes in plasma amylase and lipase were measured. In ob/ob mice, plasma cytokines (IL-1β, IL-2, IL-6, MCP-1, IFNγ, and TNFα) and pancreatitis-associated genes were assessed. Pancreata were weighed and examined histologically. Exenatide treatment alone did not modify plasma amylase or lipase in any models tested. Exenatide attenuated CRN-induced release of amylase and lipase in normal rats and ob/ob mice but did not modify the response to ST infusion. Plasma cytokines and pancreatic weight were unaffected by exenatide. Exenatide upregulated Reg3b but not Il6, Ccl2, Nfkb1, or Vamp8 expression. Histological analysis revealed that the highest doses of exenatide decreased CRN- or ST-induced acute inflammation, vacuolation, and acinar single cell necrosis in mice and rats, respectively. Ductal cell proliferation rates were low and similar across all groups of ob/ob mice. In conclusion, exenatide did not modify plasma amylase and lipase concentrations in rodents without pancreatitis and improved chemically induced pancreatitis in normal and diabetic rodents.

Topics: Analysis of Variance; Animals; Area Under Curve; Cytokines; Diabetes Mellitus, Experimental; Exenatide; Hypoglycemic Agents; Mice; Pancreas; Pancreatitis; Peptides; Rats; Rats, Sprague-Dawley; Venoms

To estimate risk and relative risk (RR) of acute pancreatitis among patients using incretin-based diabetes therapies (exenatide or sitagliptin) compared to patients treated with agents with established safety profiles (metformin or glyburide).. The study population was derived from a large US commercial health insurance transaction database using an active drug safety surveillance system (i3 Aperio). This analysis is based on data from June 2005 through June 2008. Cohorts of exenatide and sitagliptin initiators were each matched to an equal number of metformin or glyburide (met/gly) initiators using propensity scores to reduce confounding in the comparison of outcomes during follow-up. Patients with claims suggesting pancreatic disease in the 6 months prior to cohort entry were excluded.. Claims for hospitalizations associated with a primary diagnosis of acute pancreatitis (ICD-9 577.0).. There were 27 996 exenatide initiators and 16 276 sitagliptin initiators and approximately equal numbers of matched comparators. During follow-up of up to 1 year, acute pancreatitis occurred among 0.13% of patients treated with exenatide and 0.12% of patients treated with sitagliptin. The risk of acute pancreatitis was comparable for initiators of exenatide (RR 1.0; 95% confidence interval (CI) 0.6-1.7) and sitagliptin (RR 1.0; 95% CI 0.5-2.0) relative to the comparison cohorts.. These data do not provide evidence for an association of acute pancreatitis among initiators of exenatide or sitagliptin compared to met/gly initiators. These results are limited by the data available in an administrative, healthcare database.

Topics: Adolescent; Adult; Databases, Factual; Exenatide; Female; Glyburide; Humans; Hypoglycemic Agents; Insurance, Health; Male; Metformin; Middle Aged; Pancreatitis; Peptides; Pyrazines; Risk Assessment; Safety; Sitagliptin Phosphate; Triazoles; United States; Venoms; Young Adult

Clinical reports link use of the glucagon-like peptide-1 receptor (GLP-1R) agonists exenatide and liraglutide to pancreatitis. However, whether these agents act on the exocrine pancreas is poorly understood.. We assessed whether the antidiabetic agents exendin (Ex)-4, liraglutide, the dipeptidyl peptidase-4 inhibitor sitagliptin, or the biguanide metformin were associated with changes in expression of genes associated with the development of experimental pancreatitis. The effects of Ex-4 when administered before or after the initiation of caerulein-induced experimental pancreatitis were determined. The importance of endogenous GLP-1R signaling for gene expression in the exocrine pancreas and the severity of pancreatitis was assessed in Glp1r(-/-) mice.. Acute administration of Ex-4 increased expression of egr-1 and c-fos in the exocrine pancreas. Administration of Ex-4 or liraglutide for 1 week increased pancreas weight and induced expression of mRNA transcripts encoding the anti-inflammatory proteins pancreatitis-associated protein (PAP) (RegIIIbeta) and RegIIIalpha. Chronic Ex-4 treatment of high-fat-fed mice increased expression of PAP and reduced pancreatic expression of mRNA transcripts encoding for the proinflammatory monocyte chemotactic protein-1, tumor necrosis factor-alpha, and signal transducer and activator of transcription-3. Sitagliptin and metformin did not significantly change pancreatic gene expression profiles. Ex-4 administered before or after caerulein did not modify the severity of experimental pancreatitis, and levels of pancreatic edema and serum amylase were comparable in caerulein-treated Glp1r(-/-) versus Glp1r(+/+) mice.. These findings demonstrate that GLP-1 receptor activation increases pancreatic mass and selectively modulates the expression of genes associated with pancreatitis. However, activation or genetic elimination of GLP-1R signaling does not modify the severity of experimental pancreatitis in mice.

Topics: Animals; Ceruletide; Dietary Fats; Disease Models, Animal; Early Growth Response Protein 1; Exenatide; Gene Expression; Genes, fos; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Liraglutide; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Pancreas, Exocrine; Pancreatitis; Pancreatitis-Associated Proteins; Peptides; Receptors, Glucagon; Severity of Illness Index; Signal Transduction; Venoms

Topics: Acute Disease; Adverse Drug Reaction Reporting Systems; Drug Labeling; Exenatide; Humans; Hypoglycemic Agents; Pancreatitis; Peptides; Risk Factors; United Kingdom; United States; United States Food and Drug Administration; Venoms

For a female, type 2 diabetic patient, with 4 years duration of diabetes, Exenatide (Byetta) was prescribed as glycaemic control was not satisfactory along with Glimepiride and Metformin. She had gastrointestinal disturbances, since the first day of the injection. From the eighth day she developed signs of acute pancreatitis which was confirmed with CT-Scan and biochemical investigations. Byetta was withdrawn, the patient was treated for acute pancreatitis and the symptoms subsided.

Topics: Acute Disease; Diabetes Mellitus, Type 2; Drug Interactions; Exenatide; Female; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Metformin; Middle Aged; Pancreatitis; Peptides; Sulfonylurea Compounds; Venoms

Topics: Adult; Aged; Animals; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Lizards; Male; Middle Aged; Pancreatitis; Peptides; Venoms

Topics: Abdominal Pain; Acute Disease; Aged; Diabetes Mellitus, Type 2; Exenatide; Humans; Hypoglycemic Agents; Male; Pancreatitis; Peptides; Venoms