{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T12:57:07Z","timestamp":1792069027811,"version":"4.4.0"},"reference-count":26,"publisher":"American Medical Association (AMA)","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"<jats:sec>\n                    <jats:title>Importance<\/jats:title>\n                    <jats:p>Concerns have been raised that glucagon-like peptide-1 receptor agonists (GLP-1RA) may increase the risk of pancreatic cancer.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To investigate the association of GLP-1RA treatment with pancreatic cancer incidence over 9 years of follow-up.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design, Setting, and Participants<\/jats:title>\n                    <jats:p>In this population-based historical cohort study, adult patients (aged 21 to 89 years) with type 2 diabetes insured by Clalit Healthcare Services, the largest state-mandated health organization in Israel, were followed up from 2009, when GLP-1RA became available in Israel, until pancreatic cancer diagnosis, death, reaching age 90 years, or end of follow-up (December 2017). Data were analyzed from June 2022 to November 2023.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Exposures<\/jats:title>\n                    <jats:p>Treatment with GLP-1RA was compared with basal insulin.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Main Outcome and Measures<\/jats:title>\n                    <jats:p>Pancreatic cancer incidence was compared according to weighted cumulative exposures to GLP-1RA and to basal insulin in a Cox model implemented in discrete time, with time origin at 2 years after diabetes diagnosis, adjusting for confounding. In sensitivity analyses, propensity score\u2013matched pair new-user design and prevalent new-user design were used for the comparison. Because of risk for reverse-causation bias, results in the fifth to seventh year after medication were emphasized.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>During a cumulative follow-up of 3\u202f290\u202f439 person-years of 543\u202f595 adults with a mean (SD) age of 59.9 (12.8) years (277\u202f502 women [51%]) with incident diabetes, 1665 patients received pancreatic cancer diagnoses. In total, 33\u202f377 patients (6.1%) used GLP-1RA and 106\u202f849 (19.7%) used basal insulin. The estimated hazard ratio (HR) for pancreatic cancer associated with incremental use of 1 defined daily dose per day of GLP-1RA compared with basal insulin in the fifth to seventh year previously (all other characteristics, including age, sex, ethnic background, sociodemographic status, baseline body mass index, smoking history, history of pancreatitis, other glucose-lowering medications treatment history, and length of diabetes, being equal) was 0.50 (95% CI, 0.15-1.71). The new-user and prevalent new-user designs showed HRs from the fifth year onwards following initiation of GLP-1RA vs basal insulin of 0.52 (95 % CI, 0.19-1.41) and 0.75 (95 % CI, 0.37-1.53), respectively.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Relevance<\/jats:title>\n                    <jats:p>In this historical cohort study of adults with type 2 diabetes, no support for an increased pancreatic cancer incidence over 7 years following start of GLP-1RA treatment was found. However, monitoring for pancreatic cancer risk beyond 7 years following initiation of therapy is still required.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial Registration<\/jats:title>\n                    <jats:p>\n                      ClinicalTrials.gov Identifier:\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/classic.clinicaltrials.gov\/ct2\/history\/NCT02072902?V_2=View\">NCT02072902<\/jats:ext-link>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2023.50408","type":"journal-article","created":{"date-parts":[[2024,1,4]],"date-time":"2024-01-04T11:32:05Z","timestamp":1704367925000},"page":"e2350408","source":"Crossref","is-referenced-by-count":125,"title":["Glucagon-Like Peptide-1 Receptor Agonists and Pancreatic Cancer Risk in Patients With Type 2 Diabetes"],"prefix":"10.1001","volume":"7","author":[{"given":"Rachel","family":"Dankner","sequence":"first","affiliation":[{"name":"Public Health Research Center, Gertner Institute for Epidemiology and Health Policy Research, Sheba Medical Center, Ramat Gan, Israel"},{"name":"Department for Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Havi","family":"Murad","sequence":"additional","affiliation":[{"name":"Biostatistics and Biomathematics Unit, Gertner Institute for Epidemiology and Health Policy Research, Sheba Medical Center, Ramat Gan, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nirit","family":"Agay","sequence":"additional","affiliation":[{"name":"Public Health Research Center, Gertner Institute for Epidemiology and Health Policy Research, Sheba Medical Center, Ramat Gan, Israel"},{"name":"Biostatistics and Biomathematics Unit, Gertner Institute for Epidemiology and Health Policy Research, Sheba Medical Center, Ramat Gan, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liraz","family":"Olmer","sequence":"additional","affiliation":[{"name":"Biostatistics and Biomathematics Unit, Gertner Institute for Epidemiology and Health Policy Research, Sheba Medical Center, Ramat Gan, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence S.","family":"Freedman","sequence":"additional","affiliation":[{"name":"Biostatistics and Biomathematics Unit, Gertner Institute for Epidemiology and Health Policy Research, Sheba Medical Center, Ramat Gan, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2024,1,4]]},"reference":[{"issue":"1","key":"zoi231470r1","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1053\/j.gastro.2011.02.018","article-title":"Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies.","volume":"141","author":"Elashoff","year":"2011","journal-title":"Gastroenterology"},{"issue":"7","key":"zoi231470r2","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1001\/jamainternmed.2013.2720","article-title":"Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study.","volume":"173","author":"Singh","year":"2013","journal-title":"JAMA Intern Med"},{"issue":"2","key":"zoi231470r4","doi-asserted-by":"publisher","first-page":"E253","DOI":"10.1152\/ajpendo.00182.2012","article-title":"The effects of 13 wk of liraglutide treatment on endocrine and exocrine pancreas in male and female ZDF rats: a quantitative and qualitative analysis revealing no evidence of drug-induced pancreatitis.","volume":"303","author":"Vrang","year":"2012","journal-title":"Am J Physiol Endocrinol Metab"},{"issue":"5","key":"zoi231470r5","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1111\/dom.2013.15.issue-5","article-title":"No evidence of drug-induced pancreatitis in rats treated with exenatide for 13 weeks.","volume":"15","author":"Tatarkiewicz","year":"2013","journal-title":"Diabetes Obes Metab"},{"issue":"11","key":"zoi231470r6","doi-asserted-by":"publisher","first-page":"1547","DOI":"10.1345\/aph.1Q789","article-title":"Pancreatitis: a potential complication of liraglutide?","volume":"46","author":"Franks","year":"2012","journal-title":"Ann Pharmacother"},{"issue":"6","key":"zoi231470r7","doi-asserted-by":"publisher","first-page":"906","DOI":"10.1111\/dom.2017.19.issue-6","article-title":"Glucagon-like peptide-1 receptor agonists and risk of acute pancreatitis in patients with type 2 diabetes.","volume":"19","author":"Storgaard","year":"2017","journal-title":"Diabetes Obes Metab"},{"issue":"2","key":"zoi231470r8","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/S2213-8587(17)30412-6","article-title":"Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis.","volume":"6","author":"Bethel","year":"2018","journal-title":"Lancet Diabetes Endocrinol"},{"key":"zoi231470r9","doi-asserted-by":"publisher","first-page":"i581","DOI":"10.1136\/bmj.i581","article-title":"Incretin based drugs and the risk of pancreatic cancer: international multicentre cohort study.","volume":"352","author":"Azoulay","year":"2016","journal-title":"BMJ"},{"issue":"3","key":"zoi231470r10","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1111\/dom.2016.18.issue-3","article-title":"Use of incretin agents and risk of pancreatic cancer: a population-based cohort study.","volume":"18","author":"Knapen","year":"2016","journal-title":"Diabetes Obes Metab"},{"issue":"9","key":"zoi231470r11","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1111\/dom.2017.19.issue-9","article-title":"Safety issues with glucagon-like peptide-1 receptor agonists (pancreatitis, pancreatic cancer and cholelithiasis): data from randomized controlled trials.","volume":"19","author":"Monami","year":"2017","journal-title":"Diabetes Obes Metab"},{"issue":"1","key":"zoi231470r12","doi-asserted-by":"publisher","first-page":"2375","DOI":"10.1038\/s41598-019-38956-2","article-title":"Glucagon-like peptide-1 receptor agonists and pancreatic cancer: a meta-analysis with trial sequential analysis.","volume":"9","author":"Pinto","year":"2019","journal-title":"Sci Rep"},{"issue":"2","key":"zoi231470r13","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1002\/pds.v32.2","article-title":"A systematic review and meta-analysis of observational studies of the association between the use of incretin-based therapies and the risk of pancreatic cancer.","volume":"32","author":"Hidayat","year":"2023","journal-title":"Pharmacoepidemiol Drug Saf"},{"key":"zoi231470r14","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.925377","article-title":"GLP-1 receptor agonist-associated tumor adverse events: a real-world study from 2004 to 2021 based on FAERS.","volume":"13","author":"Yang","year":"2022","journal-title":"Front Pharmacol"},{"issue":"1","key":"zoi231470r15","first-page":"23","article-title":"An assessment of the completeness and timeliness of the Israel National Cancer Registry.","volume":"23","author":"Moore","year":"2021","journal-title":"Isr Med Assoc J"},{"issue":"27","key":"zoi231470r16","doi-asserted-by":"publisher","first-page":"3437","DOI":"10.1002\/sim.v28:27","article-title":"Flexible modeling of the cumulative effects of time-dependent exposures on the hazard.","volume":"28","author":"Sylvestre","year":"2009","journal-title":"Stat Med"},{"issue":"10","key":"zoi231470r17","doi-asserted-by":"publisher","first-page":"1794","DOI":"10.1093\/aje\/kwz157","article-title":"Metformin treatment and cancer risk: cox regression analysis, with time-dependent covariates, of 320,000 persons with incident diabetes mellitus.","volume":"188","author":"Dankner","year":"2019","journal-title":"Am J Epidemiol"},{"issue":"5","key":"zoi231470r18","doi-asserted-by":"publisher","first-page":"M337","DOI":"10.1093\/gerona\/53A.5.M337","article-title":"Left-truncated data with age as time scale: an alternative for survival analysis in the elderly population.","volume":"53","author":"Lamarca","year":"1998","journal-title":"J Gerontol A Biol Sci Med Sci"},{"key":"zoi231470r19","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.jclinepi.2023.07.001","article-title":"Reverse causation biases weighted cumulative exposure model estimates, but can be investigated in sensitivity analyses.","volume":"161","author":"Agay","year":"2023","journal-title":"J Clin Epidemiol"},{"issue":"4","key":"zoi231470r20","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1002\/pds.v26.4","article-title":"Prevalent new-user cohort designs for comparative drug effect studies by time-conditional propensity scores.","volume":"26","author":"Suissa","year":"2017","journal-title":"Pharmacoepidemiol Drug Saf"},{"issue":"10","key":"zoi231470r21","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1016\/S2213-8587(19)30249-9","article-title":"Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials.","volume":"7","author":"Kristensen","year":"2019","journal-title":"Lancet Diabetes Endocrinol"},{"key":"zoi231470r22","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/j.canep.2018.10.010","article-title":"A historical cohort study on glycemic-control and cancer-risk among patients with diabetes.","volume":"57","author":"Dankner","year":"2018","journal-title":"Cancer Epidemiol"},{"issue":"5","key":"zoi231470r23","doi-asserted-by":"publisher","first-page":"2160","DOI":"10.1210\/jc.2013-1185","article-title":"Vitamin D levels for preventing acute coronary syndrome and mortality: evidence of a nonlinear association.","volume":"98","author":"Dror","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"key":"zoi231470r24","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1186\/1471-2458-11-609","article-title":"Assessing socioeconomic health care utilization inequity in Israel: impact of alternative approaches to morbidity adjustment.","volume":"11","author":"Shadmi","year":"2011","journal-title":"BMC Public Health"},{"issue":"15","key":"zoi231470r25","doi-asserted-by":"publisher","first-page":"1412","DOI":"10.1056\/NEJMoa2101765","article-title":"BNT162b2 mRNA COVID-19 vaccine in a nationwide mass vaccination setting.","volume":"384","author":"Dagan","year":"2021","journal-title":"N Engl J Med"},{"issue":"3","key":"zoi231470r26","doi-asserted-by":"publisher","first-page":"486","DOI":"10.2337\/dc15-1816","article-title":"Effect of long-acting insulin analogs on the risk of cancer: a systematic review of observational studies.","volume":"39","author":"Wu","year":"2016","journal-title":"Diabetes Care"},{"key":"zoi231470r3","unstructured":"US Food and Drug Administration. FDA Drug Safety Communication: FDA investigating reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas from incretin mimetic drugs for type 2 diabetes. 2016. Accessed November 29, 2023. https:\/\/www.fda.gov\/Drugs\/DrugSafety\/ ucm343187.htm"}],"container-title":["JAMA Network Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/articlepdf\/2813598\/dankner_2024_oi_231470_1703687274.71004.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,4]],"date-time":"2024-01-04T11:32:09Z","timestamp":1704367929000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/fullarticle\/2813598"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,4]]},"references-count":26,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2024,1,2]]}},"URL":"https:\/\/doi.org\/10.1001\/jamanetworkopen.2023.50408","relation":{},"ISSN":["2574-3805"],"issn-type":[{"value":"2574-3805","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,4]]}}}