OBJECTIVE Concerns have been raised about a possible increased risk of pancreatic cancer associated with incretin-based therapies. We examined the risk of pancreatic cancer among patients with diabetes prescribed incretin drugs.

RESEARCH DESIGN AND METHODS With the use of public health insurance databases of Belgium and the Lombardy Region, Italy, we created two retrospective cohorts that included adult patients who were first prescribed an incretin drug or another noninsulin antidiabetic drug (NIAD) from 1 July 2008 to 31 December 2013 in Belgium and from 1 January 2008 to 31 December 2012 in the Lombardy Region. The risk of pancreatic cancer was evaluated by multivariate-adjusted Cox models that included time-dependent variables. Adjusted hazard ratios (aHRs) from Belgium and Italy were pooled by using fixed-effects meta-analyses.

RESULTS The cohorts included 525,733 patients with diabetes treated with NIADs and 33,292 with incretin drugs. Results in both cohorts were similar. Eighty-five and 1,589 subjects who developed pancreatic cancer were registered among the incretin and NIAD new users, respectively, which represented an aHR of pancreatic cancer of 2.14 (95% CI 1.71–2.67) among those prescribed an incretin compared with an NIAD. The aHR with a drug use lag exposure of 6 months was 1.69 (1.24–2.32). The aHR decreased from 3.35 (2.32–4.84) in the first 3 months after the first incretin prescription to 2.12 (1.22–3.66) in months 3–5.9, 1.95 (1.20–3.16) in months 6–11.9, and 1.69 (1.12–2.55) after 12 months. Among those prescribed an NIAD, pancreatic cancer occurred mostly within the year after the first prescription. The risk of pancreatic cancer among patients subsequently prescribed insulin was 6.89 (6.05–7.85).

CONCLUSIONS The recent prescription of incretin therapy is associated with an increased risk of pancreatic cancer. The reason for such an increase is likely the consequence of an occult pancreatic cancer that provokes or aggravates diabetes. Studies are warranted for assessing the risk of pancreatic cancer associated with long-term use of incretin drugs.

目的已经提出了与基于肠降血糖素的疗法相关的胰腺癌风险可能增加的担忧。我们检查了糖尿病患者服用降钙素药物后发生胰腺癌的风险。

研究设计和方法利用比利时和意大利伦巴第大区的公共健康保险数据库，我们创建了两个回顾性队列，其中包括从2008年7月1日至2013年12月31日在比利时以及2008年1月1日至2012年12月31日在伦巴第大区。胰腺癌的风险通过多变量调整的Cox模型进行评估，该模型包括时间依赖性变量。使用固定效应荟萃分析汇总了来自比利时和意大利的调整后的危险比（aHR）。

结果该队列包括525733例接受NIAD治疗的糖尿病患者和33292例接受降钙素药物治疗的患者。两个队列的结果相似。在肠降血糖素和NIAD的新用户中分别登记了发生胰腺癌的85名受试者和1,589名受试者，这意味着与NIAD相比，开具降钙素的胰腺癌的aHR为2.14（95％CI 1.71–2.67）。药物使用滞后时间为6个月的aHR为1.69（1.24–2.32）。aHR从首次口服降压药后的头3个月的3.35（2.32-4.84）下降到3–5.9个月的2.12（1.22–3.66），6–11.9个月的1.95（1.20–3.16）和1.69（1.12–2） 2.55）12个月后。在开具NIAD的处方药中，胰腺癌多发生在首次开处方后的一年内。

结论最近肠降血糖素治疗的处方与胰腺癌的风险增加有关。这种增加的原因很可能是诱发或加重糖尿病的隐匿性胰腺癌的结果。有必要进行研究以评估与长期使用肠降血糖素药物有关的胰腺癌的风险。