Abstract：
UNASSIGNED: The existing evidence from pre- and post-marketing studies is conflicting on the risk of pancreatic events for anti-diabetic medications.
UNASSIGNED: A retrospective case/non-case study was conducted by using spontaneous reports on pancreatic events for anti-diabetic medications from the FDA Adverse Event Reporting System (FAERS) and VigiBase. Proportional Reporting Ratio (PRR), Reporting Odds Ratio (ROR), and Information Component (IC) were calculated by a disproportionality analysis. Furthermore, PubMed, Google Scholar, Scopus, and ClinicalTrials.gov were systematically searched for randomized controlled trials (RCTs) on anti-diabetic drugs with pancreatic outcomes.
UNASSIGNED: The FAERS data analysis found strong signals on incretin mimetics causing pancreatic events, with sitagliptin having the highest risk [PRR = 24.2, lower bound (LB) ROR = 24.4, IC025 = 4.4 for pancreatitis, and PRR = 15.4, LB ROR = 14.9, IC025 = 3.8 for pancreatic carcinoma]. Empagliflozin was the most pancreatitis-risk sodium-glucose co-transporter-2 inhibitor [PRR = 4.0, LB ROR = 3.5, IC025 = 1.8]. VigiBase reiterated these findings and identified some new signals for novel anti-diabetics. Meta-analysis revealed that the incidence of pancreatitis and pancreatic carcinoma with anti-diabetic medications was insignificant. However, compared to the placebo/active comparator, gliptins had a higher risk of acute pancreatitis (OR 1.44; 95% CI 1.03, 2.01; P = 0.03).
UNASSIGNED: Evidence from the post-marketing safety data analysis identified a strong association between incretin mimetics and pancreatic events. Fewer events in RCTs may justify insignificant meta-analysis results.
We conducted this research to identify the risk of pancreatitis and pancreatic carcinoma among anti-diabetic medications from pre-and post-marketing evidence available from clinical trials data and pharmacovigilance databases (FAERS, VigiBase). A disproportionality analysis of pharmacovigilance data was done to statistically check whether the selected drug-event pairs were frequently reported from the database (known as a ‘signal’). We performed further signal refinement analysis using OpenVigil 2.1 on the generated signals to check whether the signal sustains even after removing co-prescribed medications possessing the same risk. Also, conducted a systematic review of randomized controlled trials for evidence generation regarding the pancreatic safety of the medications. The findings from real-world data indicated that, among all anti-diabetics, incretin mimetics and sulfonylurea compounds produced signals for both pancreatitis and pancreatic carcinoma. Notable pancreatitis risk was also identified for newer anti-diabetics like SGLT-2 inhibitors. The findings from the meta-analysis of clinical trials indicated a 44% risk of DPP-4 inhibitors in causing acute pancreatitis and a 60% risk of GLP-1 agonists in elevating the lipase level, compared to placebo/active comparator. Thus, the study raises concerns over the risk of pancreatitis and pancreatic carcinoma among the users of anti-diabetic medications, especially incretin mimetics.
UNASSIGNED: A retrospective case/non-case study was conducted by using spontaneous reports on pancreatic events for anti-diabetic medications from the FDA Adverse Event Reporting System (FAERS) and VigiBase. Proportional Reporting Ratio (PRR), Reporting Odds Ratio (ROR), and Information Component (IC) were calculated by a disproportionality analysis. Furthermore, PubMed, Google Scholar, Scopus, and ClinicalTrials.gov were systematically searched for randomized controlled trials (RCTs) on anti-diabetic drugs with pancreatic outcomes.
UNASSIGNED: The FAERS data analysis found strong signals on incretin mimetics causing pancreatic events, with sitagliptin having the highest risk [PRR = 24.2, lower bound (LB) ROR = 24.4, IC025 = 4.4 for pancreatitis, and PRR = 15.4, LB ROR = 14.9, IC025 = 3.8 for pancreatic carcinoma]. Empagliflozin was the most pancreatitis-risk sodium-glucose co-transporter-2 inhibitor [PRR = 4.0, LB ROR = 3.5, IC025 = 1.8]. VigiBase reiterated these findings and identified some new signals for novel anti-diabetics. Meta-analysis revealed that the incidence of pancreatitis and pancreatic carcinoma with anti-diabetic medications was insignificant. However, compared to the placebo/active comparator, gliptins had a higher risk of acute pancreatitis (OR 1.44; 95% CI 1.03, 2.01; P = 0.03).
UNASSIGNED: Evidence from the post-marketing safety data analysis identified a strong association between incretin mimetics and pancreatic events. Fewer events in RCTs may justify insignificant meta-analysis results.
We conducted this research to identify the risk of pancreatitis and pancreatic carcinoma among anti-diabetic medications from pre-and post-marketing evidence available from clinical trials data and pharmacovigilance databases (FAERS, VigiBase). A disproportionality analysis of pharmacovigilance data was done to statistically check whether the selected drug-event pairs were frequently reported from the database (known as a ‘signal’). We performed further signal refinement analysis using OpenVigil 2.1 on the generated signals to check whether the signal sustains even after removing co-prescribed medications possessing the same risk. Also, conducted a systematic review of randomized controlled trials for evidence generation regarding the pancreatic safety of the medications. The findings from real-world data indicated that, among all anti-diabetics, incretin mimetics and sulfonylurea compounds produced signals for both pancreatitis and pancreatic carcinoma. Notable pancreatitis risk was also identified for newer anti-diabetics like SGLT-2 inhibitors. The findings from the meta-analysis of clinical trials indicated a 44% risk of DPP-4 inhibitors in causing acute pancreatitis and a 60% risk of GLP-1 agonists in elevating the lipase level, compared to placebo/active comparator. Thus, the study raises concerns over the risk of pancreatitis and pancreatic carcinoma among the users of anti-diabetic medications, especially incretin mimetics.
摘要：
上市前和上市后研究的现有证据在抗糖尿病药物的胰腺事件风险上存在矛盾。
使用来自FDA不良事件报告系统（FAERS）和VigiBase的抗糖尿病药物的胰腺事件自发报告，进行了回顾性病例/非病例研究。比例报告比率(PRR)，报告赔率比(ROR)，和信息成分(IC)是通过不成比例分析计算的。此外，PubMed,谷歌学者，Scopus,和ClinicalTrials.gov进行了系统的搜索，以寻找具有胰腺结局的抗糖尿病药物的随机对照试验（RCT）。
■FAERS数据分析发现肠促胰岛素模拟物引起胰腺事件的强烈信号，对于胰腺炎，西格列汀的风险最高[PRR=24.2，下限（LB）ROR=24.4，IC025=4.4，胰腺癌的PRR=15.4，LBROR=14.9，IC025=3.8]。Empagliflozin是胰腺炎风险最高的钠-葡萄糖协同转运蛋白2抑制剂[PRR=4.0,LBROR=3.5,IC025=1.8]。VigiBase重申了这些发现，并确定了一些新型抗糖尿病药物的新信号。Meta分析显示，使用抗糖尿病药物治疗胰腺炎和胰腺癌的发生率不明显。然而,与安慰剂/主动比较相比，格列汀类药物发生急性胰腺炎的风险较高(OR1.44;95%CI1.03,2.01;P=0.03)。
■上市后安全性数据分析的证据表明肠促胰岛素模拟物与胰腺事件之间存在很强的关联。RCT中的事件较少可能证明荟萃分析结果无关紧要。
我们进行了这项研究，以从临床试验数据和药物警戒数据库（FAERS，VigiBase)。对药物警戒数据进行不相称性分析，以统计方式检查所选药物-事件对是否经常从数据库中报告（称为“信号”）。我们使用OpenVigil2.1对生成的信号进行了进一步的信号细化分析，以检查即使在去除具有相同风险的共同处方药物后，信号是否仍持续。此外，对随机对照试验进行了系统评价,以获取有关药物胰腺安全性的证据.来自现实世界数据的发现表明，在所有抗糖尿病药物中，肠促胰岛素模拟物和磺酰脲化合物产生胰腺炎和胰腺癌的信号。对于较新的抗糖尿病药物如SGLT-2抑制剂也确定了显著的胰腺炎风险。临床试验的荟萃分析结果表明，DPP-4抑制剂引起急性胰腺炎的风险为44％，GLP-1激动剂升高脂肪酶水平的风险为60％。与安慰剂/主动比较相比。因此，这项研究引起了人们对使用抗糖尿病药物的人患胰腺炎和胰腺癌的风险的担忧，尤其是肠促胰岛素模拟物。
使用来自FDA不良事件报告系统（FAERS）和VigiBase的抗糖尿病药物的胰腺事件自发报告，进行了回顾性病例/非病例研究。比例报告比率(PRR)，报告赔率比(ROR)，和信息成分(IC)是通过不成比例分析计算的。此外，PubMed,谷歌学者，Scopus,和ClinicalTrials.gov进行了系统的搜索，以寻找具有胰腺结局的抗糖尿病药物的随机对照试验（RCT）。
■FAERS数据分析发现肠促胰岛素模拟物引起胰腺事件的强烈信号，对于胰腺炎，西格列汀的风险最高[PRR=24.2，下限（LB）ROR=24.4，IC025=4.4，胰腺癌的PRR=15.4，LBROR=14.9，IC025=3.8]。Empagliflozin是胰腺炎风险最高的钠-葡萄糖协同转运蛋白2抑制剂[PRR=4.0,LBROR=3.5,IC025=1.8]。VigiBase重申了这些发现，并确定了一些新型抗糖尿病药物的新信号。Meta分析显示，使用抗糖尿病药物治疗胰腺炎和胰腺癌的发生率不明显。然而,与安慰剂/主动比较相比，格列汀类药物发生急性胰腺炎的风险较高(OR1.44;95%CI1.03,2.01;P=0.03)。
■上市后安全性数据分析的证据表明肠促胰岛素模拟物与胰腺事件之间存在很强的关联。RCT中的事件较少可能证明荟萃分析结果无关紧要。
我们进行了这项研究，以从临床试验数据和药物警戒数据库（FAERS，VigiBase)。对药物警戒数据进行不相称性分析，以统计方式检查所选药物-事件对是否经常从数据库中报告（称为“信号”）。我们使用OpenVigil2.1对生成的信号进行了进一步的信号细化分析，以检查即使在去除具有相同风险的共同处方药物后，信号是否仍持续。此外，对随机对照试验进行了系统评价,以获取有关药物胰腺安全性的证据.来自现实世界数据的发现表明，在所有抗糖尿病药物中，肠促胰岛素模拟物和磺酰脲化合物产生胰腺炎和胰腺癌的信号。对于较新的抗糖尿病药物如SGLT-2抑制剂也确定了显著的胰腺炎风险。临床试验的荟萃分析结果表明，DPP-4抑制剂引起急性胰腺炎的风险为44％，GLP-1激动剂升高脂肪酶水平的风险为60％。与安慰剂/主动比较相比。因此，这项研究引起了人们对使用抗糖尿病药物的人患胰腺炎和胰腺癌的风险的担忧，尤其是肠促胰岛素模拟物。
