Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Abrahami D

PROVIDER: S-EPMC6278586 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Abrahami Devin D Douros Antonios A Yin Hui H Yu Oriana Hy OH Faillie Jean-Luc JL Montastruc François F Platt Robert W RW Bouganim Nathaniel N Azoulay Laurent L

BMJ (Clinical research ed.) 20181205

<h4>Objective</h4>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.<h4>Design</h4>Population based cohort study.<h4>Setting</h4>General practices contributing data to the UK Clinical Practice Research Datalink.<h4>Participants</h4>154 162 adults newly treated with antidiabetic drugs between 1 January 2007 and 31 March 2017, followed ...[more]

PMID: 30518618

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Project description:Aims/hypothesisConcerns have been raised regarding a potential association of use of the incretin-based drugs dipeptidyl peptidase 4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP-1)-receptor agonists with risk of cholangiocarcinoma. We examined this association in nationwide data from three countries.MethodsWe used data from nationwide registers in Sweden, Denmark and Norway, 2007-2018, to conduct two cohort studies, one for DPP4 inhibitors and one for GLP-1-receptor agonists, to investigate the risk of incident cholangiocarcinoma compared with an active-comparator drug class (sulfonylureas). The cohorts included patients initiating treatment episodes with DPP4 inhibitors vs sulfonylureas, and GLP-1-receptor agonists vs sulfonylureas. We used Cox regression models, adjusted for potential confounders, to estimate hazard ratios from day 366 after treatment initiation to account for cancer latency.ResultsThe main analyses of DPP4 inhibitors included 1,414,144 person-years of follow-up from 222,577 patients receiving DPP4 inhibitors (median [IQR] follow-up time, 4.5 [2.6-7.0] years) and 123,908 patients receiving sulfonylureas (median [IQR] follow-up time, 5.1 [2.9-7.8] years) during which 350 cholangiocarcinoma events occurred. Use of DPP4 inhibitors, compared with sulfonylureas, was not associated with a statistically significant increase in risk of cholangiocarcinoma (incidence rate 26 vs 23 per 100,000 person-years; adjusted HR, 1.15 [95% CI 0.90, 1.46]; absolute rate difference 3 [95% CI -3, 10] events per 100,000 person-years). The main analyses of GLP-1-receptor agonists included 1,036,587 person-years of follow-up from 96,813 patients receiving GLP-1-receptor agonists (median [IQR] follow-up time, 4.4 [2.4-6.9] years) and 142,578 patients receiving sulfonylureas (median [IQR] follow-up time, 5.5 [3.2-8.1] years) during which 249 cholangiocarcinoma events occurred. Use of GLP-1-receptor agonists was not associated with a statistically significant increase in risk of cholangiocarcinoma (incidence rate 26 vs 23 per 100,000 person-years; adjusted HR, 1.25 [95% CI 0.89, 1.76]; absolute rate difference 3 [95% CI -5, 13] events per 100,000 patient-years).Conclusions/interpretationIn this analysis using nationwide data from three countries, use of DPP4 inhibitors and GLP-1-receptor agonists, compared with sulfonylureas, was not associated with a significantly increased risk of cholangiocarcinoma.

Project description:Type 2 diabetes in East Asians is characterized primarily by β-cell dysfunction, and with less adiposity and less insulin resistance compared with that in Caucasians. Such pathophysiological differences can determine the appropriate therapeutics for the disease. Incretins, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, are secreted in response to meal ingestion, and enhance insulin secretion glucose-dependently. Incretin-based drugs, dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 receptor agonists, that ameliorate β-cell dysfunction with limited hypoglycemia risk are now widely used in type 2 diabetes management. Recent meta-analyses of clinical trials on DPP-4i and glucagon-like peptide-1 receptor agonists found that the drugs were more effective in Asians, most likely because of amelioration of β-cell dysfunction. In addition, we found increased glycated hemoglobin-lowering effects of DPP-4i to be associated with intake of fish in type 2 diabetes, which suggests that dietary customs of East Asians might also underlie the greater efficacy of DPP-4i. Despite the limited risk, cases of severe hypoglycemia were reported for DPP-4i/sulfonylureas combinations. Importantly, hypoglycemia was more frequent in patients also receiving glibenclamide or glimepiride, which activate exchange protein directly activated by cyclic adenosine monophosphate 2, a critical mediator of incretin signaling, and was less frequent in patients receiving gliclazide, which does not activate exchange protein directly activated by cyclic adenosine monophosphate 2. Prevention of insulin-associated hypoglycemia by DPP-4i has gained attention with regard to the enhancement of hypoglycemia-induced glucagon secretion by insulinotropic polypeptide, but remains to be investigated in East Asians. Despite the safety issues, which are paramount and must be carefully monitored, the incretin-based drugs could have potential as a first choice therapy in East Asian type 2 diabetes patients.

Project description:OBJECTIVE:To determine whether the use of incretin based drugs compared with sulfonylureas is associated with an increased risk of incident pancreatic cancer in people with type 2 diabetes. DESIGN:Population based cohort. SETTING:Large, international, multicentre study combining the health records from six participating sites in Canada, the United States, and the United Kingdom. PARTICIPANTS:A cohort of 972,384 patients initiating antidiabetic drugs between 1 January 2007 and 30 June 2013, with follow-up until 30 June 2014. MAIN OUTCOME MEASURES:Within each cohort we conducted nested case-control analyses, where incident cases of pancreatic cancer were matched with up to 20 controls on sex, age, cohort entry date, duration of treated diabetes, and duration of follow-up. Hazard ratios and 95% confidence intervals for incident pancreatic cancer were estimated, comparing use of incretin based drugs with use of sulfonylureas, with drug use lagged by one year for latency purposes. Secondary analyses assessed whether the risk varied by class (dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists) or by duration of use (cumulative duration of use and time since treatment initiation). Site specific hazard ratios were pooled using random effects models. RESULTS:During 2,024,441 person years of follow-up (median follow-up ranging from 1.3 to 2.8 years; maximum 8 years), 1221 patients were newly diagnosed as having pancreatic cancer (incidence rate 0.60 per 1000 person years). Compared with sulfonylureas, incretin based drugs were not associated with an increased risk of pancreatic cancer (pooled adjusted hazard ratio 1.02, 95% confidence interval 0.84 to 1.23). Similarly, the risk did not vary by class and evidence of a duration-response relation was lacking. CONCLUSIONS:In this large, population based study the use of incretin based drugs was not associated with an increased risk of pancreatic cancer compared with sulfonylureas. Although this potential adverse drug reaction will need to be monitored long term owing to the latency of the cancer, these findings provide some reassurance on the safety of incretin based drugs.

Project description:BackgroundCurrent evidence of the association between the use of sulfonylurea and cancer risk is highly conflicting and little evidence of this association is from the mainland Chinese population. This study aimed to evaluate the potential effects of sulfonylurea use on cancer risk among patients with type 2 diabetes mellitus (T2DM).MethodsA retrospective cohort study of T2DM patients who were new users of sulfonylurea or metformin was conducted using the Yinzhou Regional Health Care Database. A marginal structural Cox model was used to estimate the hazard ratio (HR) of cancer associated with the use of sulfonylurea compared with metformin, with time-varying confounders controlled by inverse probability weighting. Secondary analyses using different glucose-lowering drugs (GLDs) as comparator and sensitivity analyses for potential bias due to latency period, model misspecification, missing data, analyses strategy (intention-to-treat and per-protocol), and diagnosis validation were performed to examine the robustness of the results.ResultsAfter fully controlling for time-varying confounding, baseline confounding, and competing risk, the use of sulfonylurea was not associated with the risk of any cancer (HR 1.09; 95% CI, 0.93-1.27), compared with the use of metformin. In the secondary analyses, compared with α - glucosidase inhibitors, thiazolidinediones, glinides, other GLDs except sulfonylure and insulin, and T2DM patients not treated with sulfonylureas, the HRs of the association between sulfonylurea use and cancer risk were 0.92 (95% CI; 0.78-1.08), 0.89 (95% CI; 0.66-1.19), 0.85 (95% CI; 0.71-1.02), 1.04 (95% CI; 0.89-1.22), and 1.07 (95% CI; 0.99-1.16), respectively. The results of analyses for various subgroups, risk of site-specific cancers, cumulative duration, dose-response relationship, and sensitivity analyses of different latency periods and missing data were generally consistent with the findings of the primary analyses.ConclusionNo association between sulfonylurea use and cancer risk was found in this study after properly controlling biases due to time-varying confounders and other sources. Further studies on the association between sulfonylurea use and the risk of cancer by using data from a Chinese population with higher representativeness are needed.

Project description:OBJECTIVE:To assess whether adding or switching to sulfonylureas is associated with an increased risk of myocardial infarction, ischaemic stroke, cardiovascular death, all cause mortality, and severe hypoglycaemia, compared with remaining on metformin monotherapy in patients with type 2 diabetes. DESIGN:Population based cohort study. SETTING:General practices contributing data to the UK Clinical Practice Research Datalink. PARTICIPANTS:Patients with type 2 diabetes initiating metformin monotherapy between 1998 and 2013. MAIN OUTCOME MEASURES:Using the prevalent new-user cohort design we matched 1:1 patients adding or switching to sulfonylureas with those remaining on metformin monotherapy on high-dimensional propensity score, haemoglobin A1c, and number of previous metformin prescriptions. The two groups were compared using Cox proportional hazards models to estimate adjusted hazard ratios and 95% confidence intervals for the study outcomes. RESULTS:Among 77?138 metformin initiators, 25?699 added or switched to sulfonylureas during the study period. During a mean follow-up of 1.1 years, sulfonylureas were associated with an increased risk of myocardial infarction (incidence rate 7.8 v 6.2 per 1000 person years, hazard ratio 1.26, 95% confidence interval 1.01 to 1.56), all cause mortality (27.3 v 21.5, 1.28, 1.15 to 1.44), and severe hypoglycaemia (5.5 v 0.7, 7.60, 4.64 to 12.44) compared with continuing metformin monotherapy. There was a trend towards increased risks of ischaemic stroke (6.7 v 5.5, 1.24, 0.99 to 1.56) and cardiovascular death (9.4 v 8.1, 1.18, 0.98 to 1.43). Compared with adding sulfonylureas, switching to sulfonylureas was associated with an increased risk of myocardial infarction (hazard ratio 1.51, 95% confidence interval, 1.03 to 2.24) and all-cause mortality (1.23, 1.00 to 1.50). No differences were observed for ischaemic stroke, cardiovascular death, or severe hypoglycaemia. CONCLUSIONS:Sulfonylureas as second line drugs are associated with an increased risk of myocardial infarction, all cause mortality, and severe hypoglycaemia, compared with remaining on metformin monotherapy. Continuing metformin when introducing sulfonylureas appears to be safer than switching.

Dataset Information

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

Objective

Design

Setting

Participants

Main outcome measures

Results

Conclusion

Publications

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

Similar Datasets

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