Proton pump inhibitors and the risk of inflammatory bowel disease: population-based cohort study.

OBJECTIVE: To determine whether the use of proton pump inhibitors (PPIs) compared with the use of histamine-2 receptor antagonists (H2RAs) is associated with an increased risk of inflammatory bowel disease (IBD). DESIGN: Population-based cohort study designed to address the impact of protopathic bias. SETTING: General practices contributing data to the UK Clinical Practice Research Datalink GOLD. PARTICIPANTS: 1 498 416 initiators of PPIs and 322 474 initiators of H2RAs from 1 January 1990 to 31 December 2018, with follow-up until 31 December 2019. Patients were analysed according to the timing of the IBD diagnosis after treatment initiation (early vs late). MAIN OUTCOME MEASURES: Standardised morbidity ratio weighted Cox proportional hazards models were used to estimate marginal HRs and 95% CIs. In the early-event analysis, IBD diagnoses were assessed within the first 2 years of treatment initiation, an analysis subject to potential protopathic bias. In the late-event analysis, all exposures were lagged by 2 years to account for latency and minimise protopathic bias. RESULTS: In the early-event analysis, the use of PPIs was associated with an increased risk of IBD within the first 2 years of treatment initiation, compared with H2RAs (HR 1.39, 95% CI 1.14 to 1.69). In contrast, the use of PPIs was not associated with an increased risk of IBD in the late-event analysis (HR 1.05, 95% CI 0.90 to 1.22). The results remained consistent in several sensitivity analyses. CONCLUSIONS: Compared with H2RAs, PPIs were not associated with an increased risk of IBD, after accounting for protopathic bias.

Contemporary trends in the utilization of second-line pharmacological therapies for type 2 diabetes in the United States and the United Kingdom.

AIM: To examine trends of second-line glucose-lowering therapies among patients with type 2 diabetes (T2D) initiating first-line metformin in the United States and the United Kingdom, overall and by subgroups of cardiovascular disease (CVD) and calendar time. METHODS: Using the US Optum Clinformatics and the UK Clinical Practice Research Datalink, we identified adults with T2D who initiated first-line metformin or sulphonylurea monotherapy, separately, from 2013 to 2019. Within both cohorts, we identified patterns of second-line medications through June 2021. We stratified patterns by CVD and calendar time to investigate the impact of rapidly evolving treatment guidelines. RESULTS: We identified 148 511 and 169 316 patients initiating treatment with metformin monotherapy in the United States and the United Kingdom, respectively. Throughout the study period, sulphonylureas and dipeptidyl peptidase-4 inhibitors were the most frequently initiated second-line medications in the United States (43.4% and 18.2%, respectively) and the United Kingdom (42.5% and 35.8%, respectively). After 2018, sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists were more commonly used as second-line agents in the United States and the United Kingdom, although these agents were not preferentially prescribed among patients with CVD. Initiation of first-line sulphonylureas was much less common, and most sulphonylurea initiators had metformin added as the second-line agent. CONCLUSIONS: This international cohort study shows that sulphonylureas remain the most common second-line medications prescribed following metformin in both the United States and the United Kingdom. Despite recommendations, the use of newer glucose-lowering therapies with cardiovascular benefits remains low.

Proton pump inhibitors and risk of gastric cancer: population-based cohort study.

OBJECTIVE: To determine whether new users of proton pump inhibitors (PPIs) are at an increased risk of gastric cancer compared with new users of histamine-2 receptor antagonists (H2RAs). DESIGN: Using the UK Clinical Practice Research Datalink, we conducted a population-based cohort study using a new-user active comparator design. From 1 January 1990 to 30 April 2018, we identified 973 281 new users of PPIs and 193 306 new users of H2RAs. Cox proportional hazards models were fit to estimate HRs and 95% CIs of gastric cancer, and the number needed to harm was estimated using the Kaplan-Meier method. The models were weighted using standardised mortality ratio weights using calendar time-specific propensity scores. Secondary analyses assessed duration and dose-response associations. RESULTS: After a median follow-up of 5.0 years, the use of PPIs was associated with a 45% increased risk of gastric cancer compared with the use of H2RAs (HR 1.45, 95% CI 1.06 to 1.98). The number needed to harm was 2121 and 1191 for five and 10 years after treatment initiation, respectively. The HRs increased with cumulative duration, cumulative omeprazole equivalents and time since treatment initiation. The results were consistent across several sensitivity analyses. CONCLUSION: The findings of this large population-based cohort study indicate that the use of PPIs is associated with an increased risk of gastric cancer compared with the use of H2RAs, although the absolute risk remains low.

Proton pump inhibitors and risk of colorectal cancer.

OBJECTIVE: To determine whether proton pump inhibitors (PPIs) are associated with an increased risk of colorectal cancer, compared with histamine-2 receptor antagonists (H2RAs). DESIGN: The United Kingdom Clinical Practice Research Datalink was used to identify initiators of PPIs and H2RA from 1990 to 2018, with follow-up until 2019. Cox proportional hazards models were fit to estimate marginal HRs and 95% CIs of colorectal cancer. The models were weighted using standardised mortality ratio weights using calendar time-specific propensity scores. Prespecified secondary analyses assessed associations with cumulative duration, cumulative dose and time since treatment initiation. The number needed to harm was calculated at five and 10 years of follow-up. RESULTS: The cohort included 1 293 749 and 292 387 initiators of PPIs and H2RAs, respectively, followed for a median duration of 4.9 years. While the use of PPIs was not associated with an overall increased risk of colorectal cancer (HR: 1.02, 95% CI 0.92 to 1.14), HRs increased with cumulative duration of PPI use (<2 years, HR: 0.93, 95% CI 0.83 to 1.04; 2-4 years, HR: 1.45, 95% CI 1.28 to 1.60; ≥4 years, HR: 1.60, 95% CI 1.42 to 1.80). Similar patterns were observed with cumulative dose and time since treatment initiation. The number needed to harm was 5343 and 792 for five and 10 years of follow-up, respectively. CONCLUSION: While any use of PPIs was not associated with an increased risk of colorectal cancer compared with H2RAs, prolonged use may be associated with a modest increased risk of this malignancy.

Incretin-based Drugs and the Incidence of Colorectal Cancer in Patients with Type 2 Diabetes.

BACKGROUND: Evidence on the safety of the incretin-based drugs (glucagon-like peptide-1 [GLP-1] analogues and dipeptidyl peptidase-4 [DPP-4] inhibitors) with respect to colorectal cancer is contradictory. The objective of this study was to determine whether use of incretin-based drugs is associated with risk of incident colorectal cancer in patients with type 2 diabetes. METHODS: Using data from the UK Clinical Practice Research Datalink, we identified a cohort of 112,040 patients newly treated with antidiabetic drugs between 1 January 2007 and 31 March 2015. We modeled use of GLP-1 analogues and DPP-4 inhibitors as time-varying variables and compared them with use of sulfonylureas. We lagged exposures by 1 year for latency and to reduce reverse causality and detection bias. We used time-dependent Cox proportional hazards models to estimate hazard ratios with 95% confidence intervals of incident colorectal cancer associated with the use of GLP-1 analogues and DPP-4 inhibitors overall, by cumulative duration of use and by time since initiation. RESULTS: During 388,619 person-years of follow-up, there were 733 incident colorectal cancer events (incidence rate: 1.9 per 1,000 person-years). Use of GLP-1 analogues was not associated with colorectal cancer incidence (hazard ratio: 1.0; 95% confidence interval = 0.7, 1.6), nor was use of DPP-4 inhibitors (hazard ratio: 1.2; 95% confidence interval = 1.0, 1.5). There was no evidence of a duration-response relation for either drug. CONCLUSIONS: The results of this large population-based study indicate that use of incretin-based drugs is not associated with colorectal cancer incidence among patients with type 2 diabetes.

Use of Dipeptidyl Peptidase-4 Inhibitors and New-onset Rheumatoid Arthritis in Patients with Type 2 Diabetes.

BACKGROUND: Case reports have suggested a link between dipeptidyl peptidase-4 (DPP-4) inhibitors, antidiabetic drugs used as second- to third-line treatments, and incidence of rheumatoid arthritis. Because the DPP-4 enzyme is involved in several immunologic processes and possibly in the pathophysiology of rheumatoid arthritis, further research is warranted. This population-based study aimed to determine whether use of DPP-4 inhibitors is associated with incidence of rheumatoid arthritis. METHODS: Using the United Kingdom Clinical Practice Research Datalink, we conducted a cohort study among 144,603 patients with type 2 diabetes initiating antidiabetic drugs between 2007 and 2016. We estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for incident rheumatoid arthritis using time-dependent Cox proportional hazards models, comparing use of DPP-4 inhibitors with use of other antidiabetic drugs. We imposed a 6-month exposure lag period for latency and diagnostic delays. Secondary analyses included assessment of the duration-response relation and comparison with other second-line antidiabetic drugs, among others. RESULTS: During 567,169 person-years of follow-up, 464 patients were newly diagnosed with rheumatoid arthritis (crude incidence rate: 82 per 100,000/year). Compared with use of other antidiabetic drugs, use of DPP-4 inhibitors was not associated with an increased risk of rheumatoid arthritis (82 vs. 79 per 100,000/year; HR = 1.0; 95% CI = 0.8, 1.3), with no evidence of duration-response relation. The results did not change after using second-line antidiabetic drugs as the comparator group. CONCLUSIONS: In this large population-based study, use of DPP-4 inhibitors was not associated with an increased risk of incident rheumatoid arthritis.

Sodium-Glucose Cotransporter 2 Inhibitors and the Short-term Risk of Bladder Cancer: An International Multisite Cohort Study.

OBJECTIVE: To determine whether sodium-glucose cotransporter 2 (SGLT2) inhibitors, compared with glucagon-like peptide 1 receptor agonists (GLP-1RAs) or dipeptidyl peptidase 4 (DPP-4) inhibitors, are associated with an increased risk of early bladder cancer events. RESEARCH DESIGN AND METHODS: We conducted a multisite, population-based, new-user, active comparator cohort study using the U.K. Clinical Practice Research Datalink, Medicare fee-for-service, Optum's de-identifed Clinformatics Data Mart Database (CDM), and MarketScan Health databases from January 2013 through December 2020. We assembled two cohorts of adults with type 2 diabetes initiating 1) SGLT2 inhibitors or GLP-1RAs and 2) SGLT2 inhibitors or DPP-4 inhibitors. Cox proportional hazards models were fit to estimate hazard ratios (HRs) and 95% CIs of incident bladder cancer. The models were weighted using propensity score fine stratification. Site-specific HRs were pooled using random-effects models. RESULTS: SGLT2 inhibitor (n = 453,560) and GLP-1RA (n = 375,997) users had a median follow-up ranging from 1.5 to 2.2 years. Overall, SGLT2 inhibitors were not associated with an increased risk of bladder cancer compared with GLP-1RAs (HR 0.90, 95% CI 0.81-1.00). Similarly, when compared with DPP-4 inhibitors (n = 853,186), SGLT2 inhibitors (n = 347,059) were not associated with an increased risk of bladder cancer (HR 0.99, 95% CI 0.91-1.09) over a median follow-up ranging from 1.6 to 2.6 years. Results were consistent across sensitivity analyses. CONCLUSIONS: Contrary to previous randomized controlled trials, these findings indicate that the use of SGLT2 inhibitors is not associated with an increased risk of bladder cancer compared with GLP-1RAs or DPP-4 inhibitors. This should provide reassurance on the short-term effects of SGLT2 inhibitors on bladder cancer incidence.

Statins and lower mortality in rheumatic diseases: An effect of immortal time bias?

OBJECTIVE: Randomized controlled trials of the effectiveness of statins on rheumatic disease outcomes have shown limited or no benefit. On the other hand, observational studies have reported remarkable effectiveness of statins at reducing mortality in patients with rheumatic diseases. We evaluated these observational studies for the presence of immortal time bias, which tends to exaggerate the effectiveness of drugs by creating a survival advantage for exposed patients. METHODS: We searched PubMed for observational studies investigating the impact of statins in patients with common rheumatic diseases, including rheumatoid arthritis, osteoarthritis, lupus, ankylosing spondylitis, gout and systemic autoimmune diseases. Studies were included if estimates for all-cause mortality among statin users compared to non-users were reported. We evaluated each study for the presence of immortal time bias and estimated the impact of the bias on the published results. RESULTS: We found eight observational studies investigating the impact of statins on mortality among patients with rheumatic diseases. Four studies were affected by the classical variant of immortal time bias, while the others introduced immortal time into the comparator via random-calendar date assignment. The studies with the classical form of immortal time bias, which tends to exaggerate drug effectiveness, reported protective effects of statins on mortality ranging from 13% to 57% reductions. In contrast, immortal time bias through random-calendar date assignment, which tends to play down the effectiveness by introducing immortal time in the comparator, reported 16% to 37% reductions in mortality. CONCLUSION: Bias in observational studies may explain the discrepancy in findings with randomized controlled trials on the effectiveness of statins in patients with rheumatic diseases. Future observational studies will need to rely on incident and prevalent new-user designs that emulate randomized trials and avoid immortal time bias.

Trends in prescribing patterns of proton pump inhibitors surrounding new guidelines.

PURPOSE: The purpose of this study was to examine whether the latest National Institute for Health and Care Excellence proton pump inhibitor (PPI) guidelines changed physician prescribing patterns in clinical practice. METHODS: Using data from the United Kingdom Clinical Practice Research Datalink, we calculated monthly PPI prescribing rates in adults by dividing the number of PPI prescriptions by the number of patients in each calendar month. Using these rates, we conducted an interrupted time-series analysis to compare PPI prescription rates before (September 2010-August 2014) and after (September 2014-August 2018) guideline publication, estimating a slope and level change using segmented autoregression. RESULTS: In the preguideline period, monthly PPI prescription rate increased by 46.9 (95% confidence interval (CI): 40.8 to 53.0) prescriptions per 100,000 persons. Following guideline publication, there was no immediate change in the monthly PPI prescribing rate (137.6, 95% CI: -36.7 to 311.9 prescriptions per 100,000 persons), but there was a modest attenuation of the change in monthly rate (-23.9, 95% CI: -14.0 to -33.6 prescriptions per 100,000 persons). However, the predicted rates mirror the observed rates after guideline publication, suggesting limited changes. CONCLUSIONS: Despite efforts to minimize the overprescribing of PPIs, there was little meaningful change in clinical practice following the 2014 National Institute for Health and Care Excellence recommendations.

Use of Real-World Data to Emulate a Clinical Trial and Support Regulatory Decision Making: Assessing the Impact of Temporality, Comparator Choice, and Method of Adjustment.

External controls have been primarily used in the setting of single-arm trials of rare diseases; their use in common diseases has not been readily investigated, nor is there guidance on how to best select comparators. Thus, the objective of this study was to emulate a large cardiovascular outcome trial of type 2 diabetes to compare associations of effectiveness with different comparator groups to those reported in the trial. Using the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, we investigated six comparator groups using three calendar time periods (Early: 1999-2003; Later: 2004-2008, and Contemporaneous: 2009-2013) and two comparators (sulfonylureas and other second-to-third-line antidiabetic drugs). Hazard ratios (HRs) of the three-point composite cardiovascular outcome were estimated using four variations of the propensity score (adjustment, stratification, fine stratification, and matching) and compared with the LEADER trial (HR, 0.87; 95% confidence interval, 0.78-0.97). When comparing users of liraglutide with users of sulfonylureas, the HRs ranged from 0.57 to 1.03, with estimates in the early period most closely reflecting the LEADER trial (HR, 0.57-0.88). In contrast, the HRs ranged from 0.73 to 0.97 when comparing liraglutide users with users of any second-to-third-line antidiabetic drugs, although the later period generated estimates closest to the LEADER trial (HR, 0.77-0.84). Different methods of adjustment led to generally consistent HRs, aside from the fine stratification in the early period. This study highlights the complex interplay between comparator, temporality, and method of adjustment when selecting comparators using real-word data. These design choices must be considered in the design of trial emulation studies.

Defining Clinically Relevant Target Populations Using Real-World Data to Guide the Design of Representative Antidiabetic Drug Trials.

The US Food and Drug Administration is considering replacing cardiovascular outcome trials of antidiabetic drugs with trials that better represent patients with type 2 diabetes. However, designing such representative trials requires understanding the underlying target populations (i.e., populations intended to receive the drug in the real-world setting). Thus, we used the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial as a motivating example to illustrate how different target populations impact trial representativeness. Using the United Kingdom Clinical Practice Research Datalink, we identified three target populations: (i) all patients with type 2 diabetes; (ii) patients prescribed liraglutide; and (iii) patients who would have been eligible to receive liraglutide based on treatment stage (i.e., patients with poorly controlled diabetes eligible to receive a second-to-fifth line antidiabetic drug). We then examined the representativeness of the LEADER trial by applying its eligibility criteria to each target population. The target populations of patients with type 2 diabetes (n = 279,763), those prescribed liraglutide (n = 14,421), and those eligible to receive liraglutide based on the treatment stage (n = 85,610) differed substantially in terms of hemoglobin A1c, body mass index, prevalence of heart failure, and chronic kidney disease. Applying the LEADER trial eligibility criteria to these target populations resulted in the inclusion of 19.1%, 20.7%, and 34.8% patients, respectively. This study highlights how real-world data can be used to define different target populations. Explicitly defining these target populations can help in the design of future trials of antidiabetic drugs.

Trends in acid suppressant drug prescriptions in primary care in the UK: a population-based cross-sectional study.

OBJECTIVE: To examine proton pump inhibitor (PPI) and histamine-2 receptor antagonist (H2RA) prescribing patterns over a 29-year period by quantifying annual prevalence and prescribing intensity over time. DESIGN: Population-based cross-sectional study. SETTING: More than 700 general practices contributing data to the UK Clinical Practice Research Datalink (CPRD). PARTICIPANTS: Within a cohort of 14 242 329 patients registered in the CPRD, 3 027 383 patients were prescribed at least one PPI or H2RA from 1 January 1990 to 31 December 2018. PRIMARY AND SECONDARY OUTCOME MEASURES: Annual prescription rates were estimated by dividing the number of patients prescribed a PPI or H2RA by the total CPRD population. Change in prescribing intensity (number of prescriptions per year divided by person-years of follow-up) was calculated using negative binomial regression. RESULTS: From 1990 to 2018, 21.3% of the CPRD population was exposed to at least one acid suppressant drug. During that period, PPI prevalence increased from 0.2% to 14.2%, while H2RA prevalence remained low (range: 1.2%-3.4%). Yearly prescribing intensity to PPIs increased during the first 15 years of the study period but remained relatively constant for the remainder of the study period. In contrast, yearly prescribing intensity of H2RAs decreased from 1990 to 2009 but has begun to slightly increase over the past 5 years. CONCLUSIONS: While PPI prevalence has been increasing over time, its prescribing intensity has recently plateaued. Notwithstanding their efficacy, PPIs are associated with a number of adverse effects not attributed to H2RAs, whose prescribing intensity has begun to increase. Thus, H2RAs remain a valuable treatment option for individuals with gastric conditions.

The Association between Oral Anticoagulants and Cancer Incidence among Individuals with Nonvalvular Atrial Fibrillation.

OBJECTIVE: Existing evidence on the association between vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) and cancer is limited and contradictory. No observational studies have been conducted to simultaneously address the cancer safety of VKAs and DOACs. The objective of this study was to determine whether use of VKAs and DOACs, separately, when compared with nonuse, is associated with cancer overall and prespecified site-specific incidence. METHODS: Using the United Kingdom Clinical Practice Research Datalink, we identified patients newly diagnosed with nonvalvular atrial fibrillation (NVAF) between 2011 and 2017. Using a time-varying exposure definition, each person-day of follow-up was classified as use of (1) VKAs, (2) DOACs, (3) VKAs and DOACs (drug switchers), and (4) nonuse of anticoagulants (reference). We also conducted a head-to-head comparison of new users of DOACs versus VKAs using propensity score fine stratification weighting. Hazard ratios (HRs) with 95% confidence intervals (CIs) for cancer overall and prespecified subtypes were estimated using Cox proportional hazards models. RESULTS: Compared with nonuse, use of VKAs was not associated with cancer overall (HR: 1.05, 95% CI: 0.91-1.22) or cancer subtypes. Similarly, use of DOACs was not associated with cancer overall (HR: 1.13, 95% CI: 0.93-1.37), but an association was observed for colorectal cancer (HR: 1.73, 95% CI: 1.01-2.99), and pancreatic cancer generated an elevated, though nonsignificant HR (HR: 2.15, 95% CI: 0.72-6.44). Results were consistent in the head-to-head comparison. CONCLUSION: Use of oral anticoagulants is not associated with the incidence of cancer overall among patients with NVAF. Possible associations between DOACs and colorectal and pancreatic cancer warrant further study.

Dipeptidyl peptidase-4 inhibitors and incidence of inflammatory bowel disease among patients with type 2 diabetes: population based cohort study.

OBJECTIVE: To assess whether the use of dipeptidyl peptidase-4 inhibitors is associated with the incidence of inflammatory bowel disease in patients with type 2 diabetes. DESIGN: Population based cohort study. SETTING: More than 700 general practices contributing data to the United Kingdom Clinical Practice Research Datalink. PARTICIPANTS: A cohort of 141 170 patients, at least 18 years of age, starting antidiabetic drugs between 1 January 2007 and 31 December 2016, with follow-up until 30 June 2017. MAIN OUTCOME MEASURES: Adjusted hazard ratios for incident inflammatory bowel disease associated with use of dipeptidyl peptidase-4 inhibitors overall, by cumulative duration of use, and by time since initiation, estimated using time dependent Cox proportional hazards models. Use of dipeptidyl peptidase-4 inhibitors was modelled as a time varying variable and compared with use of other antidiabetic drugs, with exposures lagged by six months to account for latency and diagnostic delays. RESULTS: During 552 413 person years of follow-up, 208 incident inflammatory bowel disease events occurred (crude incidence rate of 37.7 (95% confidence interval 32.7 to 43.1) per 100 000 person years). Overall, use of dipeptidyl peptidase-4 inhibitors was associated with an increased risk of inflammatory bowel disease (53.4 v 34.5 per 100 000 person years; hazard ratio 1.75, 95% confidence interval 1.22 to 2.49). Hazard ratios gradually increased with longer durations of use, reaching a peak after three to four years of use (hazard ratio 2.90, 1.31 to 6.41) and decreasing after more than four years of use (1.45, 0.44 to 4.76). A similar pattern was observed with time since starting dipeptidyl peptidase-4 inhibitors. These findings remained consistent in several sensitivity analyses. CONCLUSIONS: In this first population based study, the use of dipeptidyl peptidase-4 inhibitors was associated with an increased risk of inflammatory bowel disease. Although these findings need to be replicated, physicians should be aware of this possible association.

Incretin based drugs and risk of cholangiocarcinoma among patients with type 2 diabetes: population based cohort study.

OBJECTIVE: To determine whether use of dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists are associated with an increased risk of cholangiocarcinoma in adults with type 2 diabetes. DESIGN: Population based cohort study. SETTING: General practices contributing data to the UK Clinical Practice Research Datalink. PARTICIPANTS: 154 162 adults newly treated with antidiabetic drugs between 1 January 2007 and 31 March 2017, followed until 31 March 2018. MAIN OUTCOME MEASURES: Use of DPP-4 inhibitors and GLP-1 receptor agonists was modelled as a time varying variable and compared with use of other second or third line antidiabetic drugs. All exposures were lagged by one year to account for cancer latency and to minimise reverse causality. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals of incident cholangiocarcinoma associated with use of DPP-4 inhibitors and GLP-1 receptor agonists, separately. A post hoc pharmacovigilance analysis was conducted using the World Health Organization's global individual case safety report database, VigiBase, to estimate reporting odds ratios of cholangiocarcinoma. RESULTS: During 614 274 person years of follow-up, 105 incident cholangiocarcinoma events occurred (rate 17.1 per 100 000 person years). Use of DPP-4 inhibitors was associated with a 77% increased hazard of cholangiocarcinoma (hazard ratio 1.77, 95% confidence interval 1.04 to 3.01). Use of GLP-1 receptor agonists was associated with an increased hazard with a wide confidence interval (hazard ratio 1.97, 0.83 to 4.66). In the pharmacovigilance analysis, the use of DPP-4 inhibitors and GLP-1 receptor agonists were both associated with increased reporting odds ratios for cholangiocarcinoma, compared with use of sulfonylureas or thiazolidinediones (1.63, 1.00 to 2.66, 4.73, 2.95 to 7.58, respectively). CONCLUSION: Compared with use of other second or third line antidiabetic drugs, use of DPP-4 inhibitors, and possibly GLP-1 receptor agonists, might be associated with an increased risk of cholangiocarcinoma in adults with type 2 diabetes.