Identifying Adverse Event Signals and Risk Analysis of Semaglutide Based on the FAERS Database
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摘要:
目的 依托美国食品药品监督管理局不良事件报告系统(adverse event reporting system,FAERS)数据库,挖掘司美格鲁肽治疗 2 型糖尿病时的不良事件(adverse event,AE)风险信号。 方法 综合运用报告比值法(reporting odds ratio,ROR)、比例报告比值比法(proportional reporting ratio,PRR)、多项伽马泊松分布缩减法((muti-item gamma poisson shrinker,MGPS)及贝叶斯可信区间递进神经网络法(bayesian confidence propagation neural network,BCPNN)四种算法挖掘数据,对FAERS数据库 2017 年第一季度至 2025 年第三季度收录的司美格鲁肽相关不良事件数据进行分析,评估各类风险信号的强度。 结果 共获得司美格鲁肽相关不良事件报告 14151 份,挖掘出阳性信号 178 个。明确AE发生时间的病例中,62.56%的不良事件发生在患者用药后30 d内,严重不良事件占总报告数的49.09%。阳性信号共涉及19个SOC,其中胃肠系统疾病,各类损伤、中毒及操作并发症两类报告量位居前列;恶心、食欲减退、呕吐为发生频次较高的不良事件。风险信号强度排名前三的依次为周期性呕吐综合征(ROR =540.67,95%CI:438.66~666.40)、胃排空障碍(ROR = 141.76,95%CI:133.00~151.10)、眼梗死(ROR = 63.31,95%CI:23.17~172.98)。此外,识别出37 项药品说明书中尚未收录的潜在不良事件信号,涵盖眼梗死(ROR=63.31,95%CI:23.17~172.98)和缺血性视神经病变(ROR=54.52,95%CI:45.50~65.33)、甲状腺髓样癌 (ROR =53.19,95%CI:29.84~94.81)等。结论 临床应用司美格鲁肽治疗2 型糖尿病时,应重点警惕胃肠道反应。针对本研究发现的潜在风险,应开展严格的用药前风险评估,强化用药监测与用药教育,从而最大限度保障患者用药安全。 Abstract:Objective To identify adverse event (AE) signals associated with semaglutide use in the treatment of type 2 diabetes mellitus based on the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database. Methods Four algorithms—reporting odds ratio (ROR), proportional reporting ratio (PRR), multi-item gamma Poisson shrinker (MGPS), and Bayesian confidence propagation neural network (BCPNN)—were used to mine the data. Semaglutide-related AE reports recorded in the FAERS database from the first quarter of 2017 through the third quarter of 2025 were analyzed to assess the strength of various risk signals. Results A total of 14, 151 semaglutide-related AE reports were identified, yielding 178 positive signals. Among cases with a documented time to onset, 62.56% of AEs occurred within 30 days after medication use. Serious AEs accounted for 49.09% of all reports. The positive signals involved 19 System Organ Classes (SOCs), with gastrointestinal disorders and injury, poisoning, and procedural complications accounting for the largest numbers of reports. Nausea, decreased appetite, and vomiting were the most frequently reported AEs. The three strongest risk signals were cyclic vomiting syndrome (ROR = 540.67, 95%CI: 438.66~666.40), gastric emptying disorder (ROR = 141.76, 95%CI: 133.00~151.10), ocular infarction (ROR = 63.31, 95%CI: 23.17~172.98). A total of 37 AEs not previously documented in the product labeling were identified, including ocular infarction (ROR=63.31, 95%CI: 23.17~172.98), ischemic optic neuropathy (ROR=54.52, 95%CI: 45.50~65.33) and medullary thyroid carcinoma (ROR =53.19, 95%CI: 29.84~94.81). Conclusion In the clinical application of semaglutide for treating type 2 diabetes mellitus, special vigilance should be exercised regarding gastrointestinal adverse reactions. Given the potential risks identified in this study, a rigorous pre-medication risk assessment should be conducted, and medication monitoring along with patient education should be enhanced to maximize medication safety for patients. -
Key words:
- Semaglutide /
- Adverse events /
- Signal detection
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表 1 比值失衡法四格表
Table 1. Four-grid table for the ratio imbalance measurement method
药品种类 目标不良
事件例次其他不良
事件例次合计 司美格鲁肽 a b a+b 其他药物 c d c+d 合计 a+c b+d N=a+b+c+d 表 2 司美格鲁肽相关AE报告的基础情况[n(%)]
Table 2. Basic information of Semaglutide-related AE reports [n(%)]
类别 例数 构成比(%) 性别 女 8149 57.59 男 5071 35.83 不详 931 6.58 年龄(岁) <18 8 0.06 18~44 755 5.34 45~64 4075 28.80 ≥65 4952 34.99 未知 4361 30.82 报告者 消费者 11026 77.92 律师 3 0.02 药师 1156 8.17 医师 1836 12.97 不详 34 0.24 其他健康专业人员 96 0.68 报告国家 美国 12016 84.91 日本 366 2.59 哥伦比亚 199 1.41 加拿大 192 1.36 英国 181 1.28 其他国家和地区 1197 8.45 AE类型 严重AE 6947 49.09 非严重AE 7204 50.91 转归 危及生命 271 1.92 住院 3192 22.56 残疾 244 1.72 死亡 179 1.26 先天性畸形 3 0.02 干预措施 82 0.58 其他严重的重要医疗事件 5048 35.67 表 3 司美格鲁肽相关AE发生时间
Table 3. Time of onset of Semaglutide-related AE occurrence
AE发生时间 n 构成比(%) 0~30 d 2575 62.56 31~60 d 369 8.97 61~90 d 206 5.00 91~120 d 141 3.43 121~150 d 104 2.53 151~180 d 74 1.80 181~360 d 276 6.71 >360 d 371 9.01 表 4 司美格鲁肽累及系统信号数与AE构成比
Table 4. Number of Semaglutide signals and AE proportions
SOC n 构成比(%) 信号数 胃肠系统疾病 14339 30.03 47 各类损伤、中毒及操作并发症 5657 11.85 23 全身性疾病及给药部位各种反应 4539 9.51 8 各类检查 4120 8.63 13 代谢及营养类疾病 3792 7.94 21 各类神经系统疾病 3127 6.55 6 精神病类 1620 3.39 3 眼器官疾病 1465 3.07 12 各种肌肉骨骼及结缔组织疾病 1219 2.55 2 皮肤及皮下组织类疾病 1180 2.47 4 感染及侵染类疾病 1147 2.4 3 呼吸系统、胸及纵隔疾病 852 1.78 1 各种手术及医疗操作 761 1.59 9 肾脏及泌尿系统疾病 654 1.37 1 肝胆系统疾病 539 1.13 7 产品问题 511 1.07 5 心脏器官疾病 490 1.03 0 良性、恶性及性质不明的肿瘤 448 0.94 9 血管与淋巴管类疾病 418 0.88 0 耳及迷路类疾病 171 0.36 0 免疫系统疾病 152 0.32 0 社会环境 142 0.3 3 生殖系统及乳腺疾病 131 0.27 0 血液及淋巴系统疾病 109 0.23 0 内分泌系统疾病 97 0.2 1 各种先天性家族性遗传性疾病 35 0.07 0 妊娠期、产褥期及围产期状况 28 0.06 0 总计 47743 178 注:本表包含发生AE的全部SOC。 表 5 司美格鲁肽相关AE报告例数排名前20位PT
Table 5. Top 20 preferred terms (PTs) for Semaglutide-related AE reports
首选语(PT) n ROR(95%CI) PRR(Chi-Square) IC(IC025) EBGM
(EBGM05)恶心 2638 4.57(4.39~4.75) 4.37( 6919.86 )2.12(2.06) 4.36(4.19) 食欲减退 1587 8.78(8.35~9.23) 8.52( 10498.8 )3.08(3.00) 8.47(8.05) 呕吐 1547 4.44(4.22~4.67) 4.33( 3974.39 )2.11(2.03) 4.32(4.10) 腹泻 1503 3.14(2.98~3.31) 3.07( 2119.21 )1.62(1.54) 3.07(2.91) 便秘 1272 8.00(7.56~8.46) 7.81( 7532.48 )2.96(2.87) 7.77(7.35) 体重降低 1099 5.21(4.91~5.54) 5.12( 3642.16 )2.35(2.26) 5.10(4.80) 胃排空障碍 1073 141.76(133.00~151.10) 138.60( 131634 )6.96(6.71) 124.55(116.85) 上腹痛 841 5.46(5.10~5.85) 5.38( 2999.08 )2.42(2.32) 5.37(5.01) 脱水 587 5.74(5.29~6.23) 5.69( 2261.49 )2.50(2.37) 5.66(5.22) 消化不良 479 6.49(5.93~7.10) 6.44( 2190.85 )2.68(2.53) 6.41(5.85) 腹痛 432 2.44(2.22~2.68) 2.43(363.35) 1.28(1.13) 2.42(2.21) 腹胀 419 5.34(4.85~5.88) 5.30( 1459.79 )2.40(2.25) 5.29(4.80) 腹部不适 413 3.19(2.90~3.52) 3.17(615.29) 1.66(1.51) 3.17(2.88) 血葡萄糖降低 369 9.94(8.97~11.01) 9.87( 2919.02 )3.29(3.11) 9.80(8.84) 肠梗阻 368 13.17(11.88~14.60) 13.08( 4063.79 )3.69(3.50) 12.95(11.68) 嗳气 342 25.60(22.99~28.51) 25.43( 7863.41 )4.64(4.38) 24.93(22.39) 视觉损害 301 3.09(2.76~3.46) 3.08(421.51) 1.62(1.44) 3.07(2.74) 肠胃气胀 296 6.91(6.16~7.74) 6.87( 1477.44 )2.77(2.58) 6.84(6.10) 视物模糊 282 2.71(2.41~3.04) 2.70(300.90) 1.43(1.25) 2.69(2.39) 情绪困扰 276 2.90(2.57~3.26) 2.88(339.63) 1.53(1.34) 2.88(2.56) 表 6 司美格鲁肽相关AE信号强度排名前20位PT(按ROR值进行排序)
Table 6. Top 20 preferred terms for Semaglutide-related AE signal intensity (ranked by ROR values)
首选语(PT) n ROR(95%CI) PRR(Chi-Square) IC(IC025) EBGM(EBGM05) 周期性呕吐综合征 127 540.67(438.66~666.40) 539.24( 47299.5 )8.55(6.29) 374.13(303.54) 胃排空障碍 1073 141.76(133.00~151.10) 138.60( 131634 )6.96(6.71) 124.55(116.85) 眼梗死 4 63.31(23.17~172.98) 63.30(233.17) 5.91(0.90) 60.23(22.04) 缺血性视神经病变 123 54.52(45.50~65.33) 54.39( 6170.63 )5.70(4.94) 52.10(43.48) 甲状腺髓样癌 12 53.19(29.84~94.81) 53.17(588.64) 5.67(2.58) 50.99(28.61) 阻塞性胰腺炎 21 44.37(28.70~68.59) 44.35(858.60) 5.42(3.26) 42.83(27.71) 饥饿性酮症酸中毒 5 44.16(18.09~107.78) 44.15(203.50) 5.41(1.22) 42.64(17.47) 皮肤松懈 11 43.96(24.09~80.23) 43.95(445.62) 5.41(2.40) 42.45(23.26) 肠系膜脂膜炎 8 36.79(18.21~74.35) 36.79(270.36) 5.16(1.90) 35.74(17.69) 胃动力减退 5 35.43(14.56~86.21) 35.42(162.54) 5.11(1.19) 34.45(14.16) 胆囊损伤 43 29.66(21.92~40.15) 29.64( 1161.66 )4.86(3.71) 28.96(21.40) 贪食 95 28.82(23.51~35.33) 28.77( 2487.80 )4.81(4.16) 28.13(22.95) 肠梗阻(机能性) 252 27.28(24.07~30.91) 27.14( 6206.92 )4.73(4.41) 26.57(23.44) 嗳气 342 25.60(22.99~28.51) 25.43( 7863.41 )4.64(4.38) 24.93(22.39) 食物厌恶 30 24.85(17.31~35.68) 24.84(672.58) 4.61(3.27) 24.36(16.97) 眼睑皮肤松垂 3 24.37(7.77~76.43) 24.37(65.92) 4.58(0.37) 23.91(7.63) 痛觉异常 17 22.75(14.08~36.76) 22.74(346.86) 4.48(2.67) 22.34(13.83) 急性坏死性胆囊炎 5 21.61(8.92~52.32) 21.61(96.55) 4.41(1.09) 21.25(8.78) 饥饿感 194 20.74(17.99~23.91) 20.66( 3569.55 )4.35(4.00) 20.33(17.64) 注射部位分泌物 64 20.62(16.10~26.40) 20.59( 1173.38 )4.34(3.61) 20.27(15.83) 表 7 司美格鲁肽新发现的可疑AE
Table 7. Newly identified suspected AEs of Semaglutide
系统器官分类(SOC) 首选语(PT) 眼器官疾病 眼梗死、缺血性视神经病变、眼睑皮肤松垂、新生血管性年龄相关性黄斑变性、黄斑裂孔、玻璃体分离、视觉损害 胃肠系统疾病 肠系膜脂膜炎、胃阻塞、糖尿病性胃轻瘫、胰石病、胰腺衰竭、胰腺囊肿、胰腺炎(非急性)、口臭 皮肤及皮下组织类疾病 皮肤松懈、皮肤敏感化、皮肤皱纹 良性、恶性及性质不明的肿瘤 甲状腺髓样癌、甲状腺乳头状癌、胰腺神经内分泌肿瘤、甲状腺良性肿瘤、胰腺肿瘤 各种肌肉骨骼及结缔组织疾病 颈部肿块、肌肉萎缩 各类神经系统疾病 痛觉异常、韦尼克脑病、脑雾、嗅觉异常 各类检查 胃pH值下降 感染及侵染类疾病 肾脓肿、病毒性胃肠炎 肝胆系统疾病 胆囊炎、胆囊扩大、胆绞痛 代谢及营养类疾病 酮症、酮症酸中毒 表 8 眼器官疾病信号
Table 8. Ocular organ disease signals
首选语(PT) n ROR(95%CI) PRR(Chi-Square) IC(IC025) EBGM(EBGM05) 眼梗死 4 63.31(23.17~172.98) 63.30(233.17) 5.91(0.90) 60.23(22.04) 缺血性视神经病变 123 54.52(45.50~65.33) 54.39( 6170.63 )5.70(4.94) 52.10(43.48) 眼睑皮肤松垂 3 24.37(7.77~76.43) 24.37(65.92) 4.58(0.37) 23.91(7.63) 糖尿病性视网膜病 39 15.09(11.00~20.70) 15.08(506.38) 3.90(3.01) 14.91(10.87) 糖尿病性视网膜水肿 5 13.13(5.44~31.70) 13.13(55.44) 3.70(0.93) 13.00(5.39) 玻璃体出血 15 7.06(4.25~11.74) 7.06(77.62) 2.81(1.63) 7.03(4.23) 视网膜病 20 6.92(4.46~10.74) 6.92(100.72) 2.78(1.80) 6.89(4.44) 新生血管性年龄相关性黄斑变性 6 5.93(2.66~13.23) 5.93(24.47) 2.56(0.70) 5.91(2.65) 黄斑裂孔 5 4.87(2.02~11.71) 4.87(15.30) 2.28(0.38) 4.85(2.02) 玻璃体分离 7 4.32(2.06~9.07) 4.32(17.80) 2.11(0.58) 4.30(2.05) 视觉损害 301 3.09(2.76~3.46) 3.08(421.51) 1.62(1.44) 3.07(2.74) 视物模糊 282 2.71(2.41~3.04) 2.70(300.90) 1.43(1.25) 2.69(2.39) 注:报告例数<10的PT仅作为潜在风险提示,不能用于因果推断。 表 9 良性、恶性及性质不明的肿瘤信号
Table 9. Signals of benign,malignant,and tumors of uncertain nature
首选语(PT)中文名 n ROR(95%CI) PRR(Chi~Square) IC(IC025) EBGM(EBGM05) 甲状腺髓样癌 12 53.19(29.84~94.81) 53.17(588.64) 5.67(2.58) 50.99(28.61) 胰腺腺癌 13 12.87(7.45~22.23) 12.87(140.82) 3.67(2.02) 12.74(7.38) 甲状腺乳头状癌 15 11.56(6.95~19.22) 11.55(143.26) 3.52(2.07) 11.46(6.89) 转移性胰腺癌 22 9.84(6.47~14.97) 9.84(173.29) 3.29(2.22) 9.77(6.42) 胰腺神经内分泌肿瘤 4 8.28(3.10~22.13) 8.27(25.41) 3.04(0.45) 8.23(3.08) 甲状腺良性肿瘤 4 7.02(2.63~18.77) 7.02(20.55) 2.81(0.37) 6.99(2.62) 胰腺肿瘤 5 5.29(2.20~12.73) 5.29(17.32) 2.40(0.44) 5.27(2.19) 胰腺癌 62 2.71(2.12~3.48) 2.71(66.89) 1.44(1.03) 2.71(2.11) 注:报告例数<10的PT仅作为潜在风险提示,不能用于因果推断。 -
[1] Drucker D J. Efficacy and safety of GLP-1 medicines for type 2 diabetes and obesity[J]. Diabetes Care, 2024, 47(11): 1873-1888. doi: 10.2337/dci24-0003 [2] Kunutsor S K, Balasubramanian V G, Zaccardi F, et al. Glycaemic control and macrovascular and microvascular outcomes: A systematic review and meta-analysis of trials investigating intensive glucose-lowering strategies in people with type 2 diabetes[J]. Diabetes Obes Metab, 2024, 26(6): 2069-2081. doi: 10.1111/dom.15511 [3] 纪立农. 胰高血糖素样肽1受体激动剂周制剂中国证据与专家指导建议[J]. 中国糖尿病杂志, 2022, 30(6): 405-411. doi: 10.3969/j.issn.1006-6187.2022.06.002 [4] Shetty R, Basheer F T, Poojari P G, et al. Adverse drug reactions of GLP-1 agonists: A systematic review of case reports[J]. Diabetes Metab Syndr Clin Res Rev, 2022, 16(3): 102427. doi: 10.1016/j.dsx.2022.102427 [5] Gosho M, Ishii R, Ohigashi T, et al. Multivariate generalized mixed-effects models for screening multiple adverse drug reactions in spontaneous reporting systems[J]. Front Pharmacol, 2024, 15: 1312803. doi: 10.3389/fphar.2024.1312803 [6] Hou Y, Ye X, Wu G, et al. A comparison of disproportionality analysis methods in national adverse drug reaction databases of China[J]. Expert Opin Drug Saf, 2014, 13(7): 853-857. doi: 10.1517/14740338.2014.915938 [7] Xia L, Li K, Li Y, et al. Comparison of statistical signal detection methods in adverse events following immunization - China, 2011-2015[J]. China CDC Wkly, 2024, 6(16): 350-356. doi: 10.46234/ccdcw2024.066 [8] Sakaeda T, Tamon A, Kadoyama K, et al. Data mining of the public version of the FDA adverse event reporting system[J]. Int J Med Sci, 2013, 10(7): 796-803. doi: 10.21203/rs.3.rs-4378458/v1 [9] Yin Y, Shu Y, Zhu J, et al. A real-world pharmacovigilance study of FDA Adverse Event Reporting System (FAERS) events for osimertinib[J]. Sci Rep, 2022, 12: 19555. doi: 10.1038/s41598-022-23834-1 [10] 广东省药学会. 胰高血糖素样肽-1受体激动剂(GLP-1RA)临床应用医药专家共识[J]. 今日药学, 2024, 34(10): 721-735. doi: 10.12048/j.issn.1674-229X.2024.10.001 [11] Shu Y, He X, Wu P, et al. Gastrointestinal adverse events associated with semaglutide: A pharmacovigilance study based on FDA adverse event reporting system[J]. Front Public Health, 2022, 10: 996179. doi: 10.3389/fpubh.2022.996179 [12] Rehfeld J F, Knop F K, Asmar M. Gastrin secretion in normal subjects and diabetes patients is inhibited by glucagon-like peptide 1: A role in the gastric side effects of GLP-1-derived drugs[J]. Scand J Gastroenterol, 2019, 54(12): 1448-1451. doi: 10.1080/00365521.2019.1690673 [13] Luo Z Y, Li X, Chen C T, et al. Ocular adverse events associated with GLP-1 receptor agonists: A real-world study based on the FAERS database and network pharmacology[J]. Expert Opin Drug Saf, 2025, 24(3): 287-296. doi: 10.1080/14740338.2024.2419989 [14] Varadhan L, Humphreys T, Walker A B, et al. The impact of improved glycaemic control with GLP-1 receptor agonist therapy on diabetic retinopathy[J]. Diabetes Res Clin Pract, 2014, 103(3): e37-e39. 041. [15] Zheng D, Li N, Hou R, et al. Glucagon-like peptide-1 receptor agonists and diabetic retinopathy: Nationwide cohort and Mendelian randomization studies[J]. BMC Med, 2023, 21(1): 40. doi: 10.1186/s12916-023-02753-6 [16] Wang J, Kim C H. Differential risk of cancer associated with glucagon-like peptide-1 receptor agonists: Analysis of real-world databases[J]. Endocr Res, 2022, 47(1): 18-25. doi: 10.1080/07435800.2021.1955255 [17] Bezin J, Gouverneur A, Pénichon M, et al. GLP-1 receptor agonists and the risk of thyroid cancer[J]. Diabetes Care, 2023, 46(2): 384-390. doi: 10.2337/dc22-1148 [18] Elashoff M, Matveyenko A V, Gier B, et al. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies[J]. Gastroenterology, 2011, 141(1): 150-156. doi: 10.1053/j.gastro.2011.02.018 [19] Nachnani J S, Bulchandani D G, Nookala A, et al. Biochemical and histological effects of exendin-4 (exenatide) on the rat pancreas[J]. Diabetologia, 2010, 53(1): 153-159. doi: 10.1007/s00125-009-1515-4 [20] 廖清船, 余薇, 王泉. 司美格鲁肽与2型糖尿病患者恶性肿瘤风险相关性的Meta分析[J]. 中国药房, 2025, 36(1): 117-123. doi: 10.6039/j.issn.1001-0408.2025.01.20 [21] 廖嘉琳, 高日丽, 关海霞. 胰高糖素样肽-1受体激动剂与甲状腺癌: 争议与证据[J]. 中华糖尿病杂志, 2026, 18(7): 590-596. doi: 10.3760/cma.j.cn115791-20251108-00593 -
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