Incretin based therapy and pancreatic cancer: Realising the reality

Table 1 Various incretin-based therapies

Class of drugs	Medications
GLP-1RA (oral/subcutaneous)	Subcutaneous-Exenatide, Albiglutide, Lixisenatide, Liraglutide, Semaglutide. Oral-Semaglutide
DPP-4I (oral)	Saxagliptin, Vildaglipitn, Sitagliptin, Aloglipitn, Linagliptin, Teneligliptin
Newer drugs/drugs in development	Tirzepatide (GLP1 + GIP co-agnoist)
	Cotadutide (GLP1 + glucagon co-agonist)
	Teduglutide (GLP-2 RA)
	Triple agnoists (GLP1 + Glucagon + GIP agnoists)

GLP-1RA: Glucagon like peptide receptor-1 receptor agonist; DPP-4I: Dipeptidyl peptidase-4 inhibitor; GIP: Gastric inhibitory peptide; GLP-2RA: Glucagon like peptide receptor-2 receptor agonist.

Table 2 Important observational studies which evaluated the relationship between incretin-based therapies and pancreatic carcinoma

Ref.	Study design	Population	Findings
Elashoff et al[6], 2011	Retrospective study (Control drugs-rosiglitazone, glinides, glipizide), 2004-09	Database-FDA AERS. Patients of T2DM on exenatide and sitagliptin. n = 1541 events (exenatide). n = 322 (sitagliptin). n = 691 (controls)	PC was more common among patients who took sitagliptin (2.7-fold) or exenatide (2.9-fold) as compared with other therapies
Montvida et al[34], 2019	Retrospective record-based study. 2005 onwards. Follow-up duration 2.27-4.3 yr	Centricity electronic medical record, United States. DPP-4i n = 50095. GLP-1 RA n = 12654. SU n = 110747. TZD n = 17597. Insulin n = 34805	Compared with DPP-4i, the GLP-1 RA group developed PC 3 yr later (95%CI: 0.84-5.16). No other significant differences were observed between groups
Nagel et al[35], 2016	Retrospective study (Control drugs-rosiglitazone, glinides, glipizide), 1968-2013	Database-FDA AERS. Patients of T2DM on sitagliptin, saxagliptin, linagliptin, and alogliptin. n = 156 PC patients	EB05 was 10.3 for sitagliptin, 7.1 for saxagliptin, 4.9 for linagliptin, and 1.4 for alogliptin, compared with all other agents
Azoulay et al[36], 2016	Nested case control analysis (control drug- sulfonylureas), 2007-2014. Follow-up 1.3-2.8 yr	Database-CNODES (Canada, United States, United Kingdom). n = 972384	Compared with SUs, incretin-based drugs were not associated with an increased risk of PC-pooled aHR 1.02 (95%CI: 0.84-1.23)
Tseng et al[37], 2017	Retrospective population-based cohort study, 1997-2010. Follow up-till occurrence of adverse pancreatic event	Database-The Taiwan National Health Insurance Research Database. n = 13171 incretin. n = 13171 non-incretins	PC occurred in 6 (0.05%) and 10 (0.08%) patients in the incretin and non- incretin cohort, respectively
Boniol et al[38], 2018	Retrospective cohort study, 2008-2013. Follow-up 1.8-2.3 yr	Public health insurance databases of Belgium, Lombardy (Italy). n = 33292 incretin. n = 525733 control	The aHR for PC was 2.14 (95%CI: 1.71–2.67) for incretin group compared with control

FDA AERS: Food and drug administration adverse event reporting system; T2DM: Type 2 diabetes mellitus; PC: Pancreatic carcinoma; EB05: Empirical Bayesian fifty centile; aHR: Adjusted hazard ratio; CI: Confidence interval; CNODES: Canadian network for observational drug effect studies; SU: Sulfonylurea; OHA: Oral hypoglycemic agent; RR: Risk ratio; TZD: Thiazolidinedione.

Table 3 Important systematic reviews and meta-analyses which evaluated the relationship between incretin-based therapies and pancreatic cancer

Ref.	Description	Findings
Alves et al[39], 2012	All studies (25 RCT/longitudinal observational) assessing the estimate of pancreatitis/PC in patients with T2DM using exenatide or liraglutide	For PC risk, the OR of exenatide was 0.86 (95%CI: 0.29-2.60) and liraglutide was 1.35 (95%CI: 0.70-2.59)
Chen et al[40], 2016	All RCTs reporting PC with use of incretin-based therapies compared with placebo or non-incretin anti-diabetic drugs in patients with T2DM	Overall, no increased risk of PC was detected in association with incretin-based treatment (RR = 0.7, 95%CI: 0.37–1.05). The incidence of PC was even lower among incretin-based groups than controls (RR = 0.50, 95%CI: 0.29–0.87) in trials with duration more than 104 wk
Zhang et al[41], 2017	6 prospective randomized controlled trials (EXAMINE, SAVOR-TIMI 53, TECOS, ELIXA, LEADER and SUSTAIN-6)-3 trials for DPP-4is and 3 trials for GLP-1 RAs	Incretin-based agents did not significantly affect PC-OR: 0.71 (95%CI: 0.45–1.11)
Pinto et al[42], 2019	12 RCTs with GLP-1 RAs as an intervention, from database inception till 2017	GLP-1 RAs did not increase the risk for pancreatic cancer when compared to other treatments-OR: 1.06 (95%CI: 0.67-1.67)
Abd El Aziz et al[43], 2020	Meta-analysis of cases of acute pancreatitis and PC as well as any malignant neoplasm reported in 11 CVOTs with GLP-1 RAs and DPP-4i	Neither GLP-1 RAs nor DPP-4is were associated with a significantly elevated or reduced risk of PC. For GLP-1 RA OR was 1.14 (95%CI: 0.77-1.7) and for DPP4i OR was 0.94 (95%CI: 0.52-1.68)

PC: Pancreatic cancer; RCT: Randomised controlled trial; T2DM: Type 2 diabetes mellitus; OR: Odds ratio; RR: Risk ratio; CVOT: Cardiovascular outcome trial; GLP-1 RA: Glucagon like peptide-1 receptor agonists; DPP-4i: Dipeptidyl Peptidase-4 inhibitors; OHA: Oral hypoglycemic agent.