Use of incretin-based drugs and risk of cholangiocarcinoma: Scandinavian cohort study,Diabetologia

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Use of incretin-based drugs and risk of cholangiocarcinoma: Scandinavian cohort study
Diabetologia ( IF 8.4 ) Pub Date : 2021-07-13 , DOI: 10.1007/s00125-021-05508-1
Peter Ueda ₁ , Viktor Wintzell ₁ , Mads Melbye _{2,

3,

4} , Björn Eliasson ₅ , Ann-Marie Svensson _{5,

6} , Stefan Franzén _{6,

7} , Soffia Gudbjörnsdottir _{5,

6} , Kristian Hveem _{8,

9} , Christian Jonasson _{8,

9,

10} , Henrik Svanström _{1,

2} , Björn Pasternak _{1,

2}

Affiliation

Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
The Swedish National Diabetes Register, Västra Götalandsregionen, Gothenburg, Sweden.
Health Metrics, Department of Public Health and Community Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Science, NTNU-Norwegian University of Science and Technology, Trondheim, Norway.
HUNT Research Center, Faculty of Medicine, NTNU-Norwegian University of Science and Technology, Levanger, Norway.
Division of Health Data and Digitalization, The Norwegian Institute of Public Health, Oslo, Norway.

Aims/hypothesis

Concerns 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.

Methods

We 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.

Results

The 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/interpretation

In 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.

Graphical abstract

中文翻译：

使用肠促胰岛素药物和胆管癌风险：斯堪的纳维亚队列研究

目标/假设

有人担心使用基于肠促胰岛素的药物二肽基肽酶 4 (DPP4) 抑制剂和胰高血糖素样肽-1 (GLP-1) 受体激动剂与胆管癌风险的潜在关联。我们在来自三个国家的全国性数据中检查了这种关联。

方法

我们使用瑞典、丹麦和挪威 2007-2018 年全国登记的数据进行两项队列研究，一项针对 DPP4 抑制剂，一项针对 GLP-1 受体激动剂，以调查与活性比较剂相比发生胆管癌的风险药物类（磺脲类）。队列包括使用 DPP4 抑制剂与磺脲类药物、GLP-1 受体激动剂与磺脲类药物开始治疗的患者。我们使用 Cox 回归模型（针对潜在混杂因素进行了调整）来估计治疗开始后第 366 天的风险比，以解释癌症潜伏期。

结果

DPP4 抑制剂的主要分析包括对 222,577 名接受 DPP4 抑制剂的患者（中位 [IQR] 随访时间，4.5 [2.6-7.0] 年）和 123,908 名接受磺脲类药物的患者（中位 [IQR] 遵循时间，5.1 [2.9–7.8] 年），在此期间发生了 350 起胆管癌事件。与磺脲类药物相比，使用 DPP4 抑制剂与胆管癌风险的统计学显着增加无关（发病率 26 对 23/100,000 人年；调整后的 HR，1.15 [95% CI 0.90, 1.46]；绝对率差异 3 [95% CI -3, 10] 每 100,000 人年事件）。GLP-1 受体激动剂的主要分析包括 96,813 名接受 GLP-1 受体激动剂的患者的 1,036,587 人年的随访（中位 [IQR] 随访时间，4.4 [2.4-6.9] 年）和 142，578 名接受磺脲类药物的患者（中位 [IQR] 随访时间，5.5 [3.2-8.1] 年），在此期间发生了 249 起胆管癌事件。使用 GLP-1 受体激动剂与胆管癌风险的统计学显着增加无关（发病率 26 对 23/100,000 人年；调整后的 HR，1.25 [95% CI 0.89, 1.76]；绝对率差异 3 [ 95% CI -5, 13] 事件每 100,000 患者年）。