Liraglutide use and evaluation of pancreatic outcomes in a US commercially insured population.

AIMS: Both acute pancreatitis (AP) and pancreatic cancer (PC) have been areas of focus for studies of incretin drugs. This 5-year prospective cohort study aimed to quantify possible associations between liraglutide and risk of AP and PC as compared to other antidiabetic drugs (ADs). MATERIALS AND METHODS: Patients initiating liraglutide or other ADs who were enrolled in a US health plan (2010-2014) were included. Comparisons of AP and PC incidence rates were made between matched cohorts of liraglutide initiators and initiators of other ADs. Adjudicated AP cases and algorithm-based PC cases were identified. Propensity score-matched intention-to-treat (ITT) and time-on-drug (TOD) analyses were completed using Poisson regression. A latency analysis was performed for PC. RESULTS: Median follow-up was 405 days for AP cohorts (9995 liraglutide, 1:1 matched to all comparators) and 503 days for PC cohorts (35 163 liraglutide, 1:1 matched to all comparators). In the primary AP analysis, "current" use of liraglutide was not significantly associated with elevated risk across comparators (all comparators relative risk [RR] = 1.2; 95% confidence interval [CI], 0.6-2.3). ITT results were similar where, in the primary analysis, no RRs were significantly associated with PC (all comparators RR = 0.7; 95% CI, 0.3-1.4); latency and TOD analyses did not alter findings. There was no evidence of a dose-response effect. CONCLUSIONS: Liraglutide was not associated with an increased risk of AP or PC, although risk estimates were more variable for AP, and numbers of cases for both outcomes were limited because of the rarity of outcomes.

Dipeptidyl-peptidase-4 inhibitors and pancreatic cancer: a cohort study.

AIM: To compare pancreatic cancer incidence and diagnostic evaluation among patients initiating dipeptidyl-peptidase-4 (DPP-4) inhibitor treatment with those initiating sulfonylureas (SU) and thiazolidinediones (TZD). METHODS: Medicare claims data were examined in a new-user active-comparator cohort study. Patients >65 years with no prescriptions for DPP-4 inhibitors, SU or TZD at baseline were included if they had at least two claims for the same drug within 180 days. Using an as-treated approach and propensity score-adjusted Cox models, we estimated the hazard ratios (HRs) and 95% confidence intervals (CIs) for pancreatic cancer. Diagnostic evaluations were compared using risk ratios. RESULTS: In the DPP-4 inhibitor versus SU comparison, there were 18 179 patients who initiated treatment with DPP-4 inhibitors, of whom 26 developed pancreatic cancer (interquartile range follow-up 5-18 months). In the DPP-4 inhibitor versus TZD comparison there were 29 366 people initiating DPP-4 inhibitor treatment and 52 of these developed pancreatic cancer. The risk of pancreatic cancer with DPP-4 inhibitor treatment was lower relative to SU treatment (HR: 0.6, CI: 0.4-0.9) and similar to TZD treatment (HR: 1.0, 95% CI: 0.7-1.4). After the first 6 months of follow-up were excluded to reduce the potential for reverse causality, the results were not altered. The probability of diagnostic evaluation after commencing DPP-4 inhibitor treatment (79.3%) was similar to that for TZD (74.1%, risk ratio 1.06, 95% CI: 1.05-1.07) and SU (74.6%) (risk ratio 1.06, 95% CI: 1.05-1.07). The probability of diagnostic evaluation before the index date (date of initiating treatment) was ∼80% for all cohorts. CONCLUSION: Although the present study was limited by sample size and the observed duration of treatment in the USA, our well-controlled population-based study suggests there is no higher short-term pancreatic cancer risk with DPP-4 inhibitor treatment relative to SU or TZD treatment.

A prospective, claims-based assessment of the risk of pancreatitis and pancreatic cancer with liraglutide compared to other antidiabetic drugs.

AIM: We evaluated the relationship between liraglutide and acute pancreatitis or pancreatic cancer in an ongoing post-marketing safety assessment programme. METHODS: Initiators of liraglutide, exenatide, metformin, pioglitazone or groups containing initiators of dipeptidyl peptidase-4 inhibitors or sulfonylureas were identified in a US commercial health insurance claims database (1 February 2010 to 31 March 2013) and followed for a median of 15 months. We estimated incidence rates (IR/100 000 person-years), rate ratio (RR) and 95% confidence intervals (CI) of new insurance claims with diagnoses of primary inpatient acute pancreatitis or pancreatic cancer from Poisson regression models. RESULTS: The IR for acute pancreatitis for liraglutide was 187.5 compared with 154.4 for all non-glucagon-like peptide-1 (GLP-1)-based therapies (adjusted RR 1.10; CI 0.81-1.49). The IR for pancreatic cancer was 19.9 for liraglutide compared with 33.0 for all non-GLP-1-based therapies (adjusted RR 0.65; 95% CI 0.26-1.60). CONCLUSION: We did not observe excess risk of either outcome associated with liraglutide relative to individual or pooled comparator drugs.

Exenatide therapy and the risk of pancreatitis and pancreatic cancer in a privately insured population.

BACKGROUND: Postmarketing reports have linked exenatide use with acute pancreatitis and pancreatic cancer, but a definitive relationship has yet to be established. SUBJECTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Recombinant human bone morphogenetic protein-2 and pancreatic cancer: a retrospective cohort study.

PURPOSE: To assess whether use of recombinant human bone morphogenetic protein-2 (rhBMP-2) during lumbar spinal fusion surgery affects subsequent risk of pancreatic cancer. METHODS: Using US Medicare claims data, we performed a retrospective cohort study of patients who underwent lumbar spinal fusion surgery between October 2003 and December 2005. The study population, all >66 years, was identified from procedure codes for lumbar fusion. Claims for a bone morphogenetic protein (BMP) served as a proxy for rhBMP-2 exposure (another BMP product shared the same code). Pancreatic cancer was identified from claims indicating this diagnosis and cancer-specific therapy. We used Cox proportional hazard regression to estimate hazard ratios (HRs) and 95%CIs. RESULTS: Of the 93,654 patients in the study, the mean age was 75 years, and 16.5% had claims for BMP. During a mean 1.4 years of follow-up, 91 patients were diagnosed with pancreatic cancer (eight in the BMP- and 83 in the non-BMP cohort). Consistent with previous research, pancreatic cancer was associated with older age, male gender, black race, and diabetes mellitus. Compared to those who did not receive BMP, patients exposed to BMP were not at increased risk of pancreatic cancer (adjusted HR=0.70, 95%CI: 0.34-1.45). A chart review substudy validated the exposure measure; 52/55 patients with claims for BMP received rhBMP-2. CONCLUSIONS: In this large study of elderly patients who underwent lumbar fusion surgery, exposure to BMP was not associated with an increased risk of pancreatic cancer.

Bayesian derivation of an oral cancer slope factor distribution for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

The tobacco-specific nitrosamine (TSNA) 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is classified by the International Agency for Research on Cancer as a Group 1 carcinogen. Cancer risk assessment in humans exposed to TSNAs largely relies on potency values estimated from animal studies, but available cancer potency values for NNK derived from such studies are conflicting. In this analysis, oral cancer slope factors (CSFo) for NNK were derived according to U.S. Environmental Protection Agency guidelines. An animal study in which rats were exposed to NNK in drinking water was selected as the key study. The multistage-cancer model was fit to the tumor incidence data to determine a point of departure for low dose linear extrapolation, using a benchmark response of 10%. CSFo distributions were then computed using Bayesian methods and Monte Carlo simulation. The resultant CSFo point estimate (BMR/BMDL(10)) was 19.2 (mg/kg day)(-1) based on lung tumor data and 12.2 (mg/kg day)(-1) based on pancreatic tumors. The 95th percentiles of the CSFo distributions were 27.3 and 19.3 (mg/kg day)(-1) based on lung and pancreatic tumors, respectively. The approach using Bayesian methods better accounts for the uncertainty inherent in the values generated using input assumptions and provides for a more robust probabilistic dose-response assessment.

An assessment of the carcinogenic potential of shea oleine in the rat.

Shea oleine, an oil fraction derived from the nut of the tree Butyrospermum parkii, is used as a frying oil. As part of a series of studies, this investigation examined the carcinogenic potential of 15% (w/w) shea oleine in comparison with 15% (w/w) sheanut oil, and palm oil following dietary administration to rats over 104 weeks. The assessment comprised an evaluation of mortality, clinical signs, body weight, food intake, clinical pathology, organ weights and macroscopic and histopathological examination plus tumour type and incidence evaluation. Results showed that shea oleine produced no adverse effects and no evidence of tumorigenic potential compared to other commercially available sheanut and palm oils in the rat. Notable differences were confined to reduced body weight gain and food intake, reduced cholesterol and increased alkaline phosphatase levels, reduced heart weight and an increased incidence of pulmonary lipidosis with shea oleine diets. The latter effect may reflect a naturally lower incidence of this finding with palm oil diets. Tumour findings, specific to shea oleine diets, were restricted to an increase in the number of hepatomas for females, pancreatic exocrine adenomas for males and skin keratoacanthomas for males fed shea oleine diets. The increase in the incidence of hepatomas with treatment was thought to be related to the high fat content of the diets. The incidence of these tumour findings was similar to that given in published data for the Wistar rat, or the 'in house' values for tumour incidence in rats fed high-fat diets. In conclusion, none of the findings in this study were considered to be adverse effects. In comparison with other commercially available edible oils, shea oleine showed no tumorigenic potential following dietary administration at 7.5 g/kg/day in the rat.

Mutagenic activation of N-nitrosobis(2-oxopropyl)amine by pancreatic juice and assessment of its ductal tumorigenicity following intraductal administration in dogs.

CONCLUSION: The results suggest that systemic administration (s.c. and i.p.) of BOP induces liver damage due to BOP itself and/or its metabolites which might be formed in the liver and that interaction of BOP itself in the pancreatic duct with pancreatic juice plays an important role for pancreatic duct tumorigenicity. METHODS: Mutagenic activation and pancreatic duct tumorigenicity of N-nitrosobis (2-oxopropyl)amine (BOP) administered s.c., i.p., and i.d. were studied in dogs. RESULTS: Following i.p. administration of BOP, N-nitroso(2-hydroxypropyl) (2-oxopropyl)amine (HPOP) and N-nitrosobis(2-hydroxypropyl)amine (BHP), but not BOP, were detected in pancreatic juice, while following i.d. administration, only BOP was detected. The pancreatic juice of one dog that received 100 mg of BOP i.d. showed positive mutagenicity towards Salmonella typhimurium TA100, but the pancreatic juice of two dogs that received 100 mg of BOP i.p. was not mutagenic. BOP showed clear mutagenicity in the presence of pancreatic juice from untreated dogs, but the pancreatic juice could not activate HPOP and BHP to mutagens. BOP administered sc for 2 wk (total dose: 600 mg) induced clinical toxicity, nausea, vomiting, and loss of appetite at 10 wk. BOP administered i.p. for 4 mo (total dose: 2000 mg) induced liver damage at 6 mo, but no pancreatic injury. BOP administered i.d. for 6.5 or 12 mo (total dose: 2500 or 4700 mg, respectively) induced papillary hyperplasia and dysplasia of duct epithelial cells and ductal proliferation with fibrosis.

Dietary modulation of pancreatic carcinogenesis: calories and energy expenditure.

Physical activity (exercise) is a lifestyle factor that has received little attention with regard to its role in the etiology and/or prevention of cancer. These studies examined the effects of treadmill exercise on the early stages of pancreatic carcinogenesis initiated by azaserine in rats. Male Lewis rats were treated with azaserine at 2 weeks of age and weaned to experimental protocols at 3 weeks of age. Two experiments were undertaken; treadmill exercise began at 6 weeks of age (Experiment 1) or at 13 weeks of age (Experiment 2). Rats were exercised for 15-20 min/day and for 3-5 days/week. Treadmill speed and angle of incline were adjusted to afford a range of exercise intensities. The development of putative preneoplastic lesions of the pancreatic acinar cells (henceforth termed foci) was evaluated by quantitative stereological analysis using light microscopy. In Experiment 1, exercise resulted in a known paradoxical reduction in food intake by about 15% of the intake of the sedentary group fed ad libitum. The burden of azaserine-induced foci was decreased by approximately 37%, and this was attributed to the well known effects of reduced caloric intake in these young, rapidly growing rats. In Experiment 2, the higher intensity treadmill exercise group had an increased focal burden, compared to their sedentary pair-fed controls. Importantly, this enhancement occurred despite a reduction in food intake and body fat stores in this treadmill exercise group. These experiments demonstrate that exercise may suppress or promote carcinogenesis, depending upon the stage in the life cycle of the animal.

Ethylene oxide: an assessment of the epidemiological evidence on carcinogenicity.

Mortality from cancer among workers exposed to ethylene oxide (EtO) has been studied in 10 distinct cohorts that include about 29,800 workers and 2540 deaths. This paper presents a review and meta-analysis of these studies, primarily for leukaemia, non-Hodgkin's lymphoma, stomach cancer, pancreatic cancer, and cancer of the brain and nervous system. The magnitude and consistency of the standardised mortality ratios (SMRs) were evaluated for the individual and combined studies, as well as trends by intensity or frequency of exposure, by duration of exposure, and by latency (time since first exposure). Exposures to other workplace chemicals were examined as possible confounder variables. Three small studies by Hogstedt initially suggested an association between EtO and leukaemia, but in seven subsequent studies the SMRs for leukaemia have been much lower. For the combined studies the SMR = 1.06 (95% confidence interval (95% CI) 0.73-1.48). There was a slight suggestion of a trend by duration of exposure (p = 0.19) and a suggested increase with longer latency (p = 0.07), but there was no overall trend in risk of leukaemia by intensity or frequency of exposure; nor did a cumulative exposure analysis in the largest study indicate a quantitative association. There was also an indication that in two studies with increased risks the workers had been exposed to other potential carcinogens. For non-Hodgkin's lymphoma there was a suggestive risk overall (SMR = 1.35, 95% CI 0.93-1.90). Breakdowns by exposure intensity or frequency, exposure duration, or latency did not indicate an association, but a positive trend by cumulative exposure (p = 0.05) was seen in the largest study. There was a suggested increase in the overall SMR for stomach cancer (SMR = 1.28, 95% CI 0.98-1.65 (CI 0.73-2.26 when heterogeneity among the risk estimates was taken into account)), but analyses by intensity or duration of exposure or cumulative exposure did not support a causal association for stomach cancer. The overall SMRs and exposure-response analyses did not indicate a risk from EtO for pancreatic cancer (SMR = 0.98), brain and nervous system cancer (SMR = 0.89), or total cancer (SMR = 0.94). Although the current data do not provide consistent and convincing evidence that EtO causes leukaemia or non-Hodgkin's lymphoma, the issues are not resolved and await further studies of exposed populations.