捷诺维突破2型糖尿病治疗的新希望课件

捷诺维（西格列汀） 突破2型糖尿病治疗的新希望 概 述 n2型糖尿病治疗现状及挑战 n以肠促胰岛激素为基础的治疗 n捷诺维（西格列汀）的临床数据 临床疗效 安全性 Adapted from Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:14271483; Buchanan TA Clin Ther 2003;25(suppl B):B32B46; Powers AC. In: Harrisons Principles of Internal Medicine. 16th ed. New York: McGraw-Hill, 2005:21522180; Rhodes CJ Science 2005;307:380384. 2型糖尿病的病理生理包括三方面主要缺陷 高血糖 肝脏 胰岛岛素不足 糖输出过多 胰岛素抵抗 (葡萄糖摄取减少) 胰腺 肌肉和脂肪 过多胰高糖素 胰岛 胰岛素减少 胰岛素减少 细胞 产生过多 胰高糖素 细胞 产生胰岛素 减少 不同降糖药的主要作用部位 Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:14271483; DeFronzo RA. Ann Intern Med. 1999;131:281303; Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247254. DPP-4=二肽基肽酶 4; TZDs=噻唑烷二酮类. 葡萄糖吸收葡萄糖吸收 肝脏葡萄糖肝脏葡萄糖 过度合成过度合成 胰岛素分泌受损胰岛素分泌受损 胰岛素胰岛素 抵抗抵抗 胰腺 血糖水平 肌肉和 脂肪肝脏 双胍类 TZDs双胍类 磺脲类 格列奈类 TZDs -糖苷酶 抑制剂 胃肠道 DPP-4 抑制剂 DPP-4抑制剂 双胍类 胰岛素抵抗 胰高糖素 抑制不足 细胞 功能失调 胃肠道吸收 葡萄糖 慢性细胞 功能衰竭 胰岛素 分泌不足 细胞 功能异常 2型糖尿病现有治疗选择 DeFronzo RA. Br J Diabetes Vasc Dis,2003;3(Suppl 1): S24-40 未解决未解决 二甲双胍 格列酮类 磺脲类 格列奈类 -糖苷酶 抑制剂 DPP-4抑制剂：2型糖尿病治疗新选择 DPP 4抑制剂 DeFronzo RA. Br J Diabetes Vasc Dis,2003;3(Suppl 1): S24-40 胰岛素抵抗 胰高糖素 抑制不足 细胞 功能失调 胃肠道吸收 葡萄糖 慢性细胞 功能衰竭 胰岛素 分泌不足 细胞 功能异常 二甲双胍 格列酮类 磺脲类 格列奈类 -糖苷酶 抑制剂 成人2型糖尿病患者HbA1c 达标的比例不足50% NHANES=美国人群的一项全国健康营养检查调查. Saydah SH et al. JAMA. 2004;291:335342. HbA1c 水平 7.5% 达标率（%） 25% 35% 0 10% 20% 30% 40% 50% 7.5% 40% 平均HbA1c：7.6%平均HbA1c：7.7% 副作用的增加和依从性的降低是治疗的 两大潜在障碍 美国社区单中心. N=128 2型糖尿病患者 Grant RW et al. Diabetes Care. 2003;26:14081412. 大部分与不依从相关的 常见因素 United States study; Medi-Cal claims data January 1996 through September 1998. Compliance was defined as total days of drug supply (measured by number of doses prescribed) during the follow-up period; compliance rate was calculated by dividing the number of compliance days by the number of days in the follow-up period. Dailey G et al. Clin Ther. 2001;23:13111320. 二甲双胍 (n=2,996) 磺脲类 (n=21,987) 二甲双胍磺脲类 联合治疗 (n=1,354) 多药治疗降低 患者依从性 58% 23% 8% 11% 58% 23% 8% 11% 不良反应 花费 非特异 记住药物 剂量困难 概 述 n2型糖尿病治疗现状及挑战 n以肠促胰岛激素为基础的治疗 n捷诺维（西格列汀）的临床数据 临床疗效 安全性 Time, min Control Subjects (n=8) Time, min IR Insulin, mU/L 80 60 40 20 0 18060120 0 Oral glucose loadIntravenous (IV) glucose infusion 正常的肠肠促胰岛岛激素效应应 IR = immunoreactive Adapted with permission from Nauck M et al. Diabetologia 1986;29:4652. Copyright 1986 Springer-Verlag. Vilsbll T, Holst JJ. Diabetologia 2004;47:357366. 正常个体的肠促胰岛激素效应 肠促胰岛激素GLP-1和GIP的作用 由远端消化道L细胞分泌 (回肠和结 肠) 以葡萄糖依赖的模式促进胰岛素释 放 以葡萄糖依赖的模式抑制胰高糖素 分泌，从而抑制肝糖输出 在动物模型及离体人类胰岛中增强 beta细胞增殖和存活 由近端消化道K细胞分泌（十二指 肠） 以葡萄糖依赖的模式促进胰岛素释 放 在胰岛细胞系中增强beta细胞增殖 和存活 GLP-1GIP GLP-1=胰高糖素样肽 1; GIP=葡萄糖依赖性促胰岛素多肽 Adapted from Drucker DJ Diabetes Care 2003;26:29292940; Ahrn B Curr Diab Rep 2003;3:365372; Drucker DJ Gastroenterology 2002;122: 531544; Farilla L et al Endocrinology 2003;144:51495158; Trmper A et al Mol Endocrinol 2001;15:15591570; Trmper A et al J Endocrinol 2002;174:233246. Time, min IR Insulin, mU/L 80 60 40 20 0 180601200 Control Subjects (n=8) Patients With Type 2 Diabetes (n=14) Time, min IR Insulin, mU/L 80 60 40 20 0 18060120 0 Oral glucose loadIntravenous (IV) glucose infusion 正常的肠肠促胰岛岛激素效应应减弱的肠促胰岛激素效应 IR = immunoreactive Adapted with permission from Nauck M et al. Diabetologia 1986;29:4652. Copyright 1986 Springer-Verlag. Vilsbll T, Holst JJ. Diabetologia 2004;47:357366. 2型糖尿病患者的肠促胰岛激素效应减弱 2型糖尿病患者的GLP-1和GIP水平及活性 *经过性别及BMI校正 Adapted from Toft-Nielsen M-B et al J Clin Endocrinol Metab 2001;86:37173723; Nauck MA et al J Clin Invest 1993;91:301307. 2型糖尿病患者 肠促胰岛激素水平肠促胰岛激素活性 GLP-1 (p2500倍 vs. DPP-8或9 可逆性竞争性 ThornberryNA，et al. Curr Topics in Med Chem, 2007; 7: 557-568 DPP酶IC50 (nM) DPP-418 DPP-848,000 DPP-9 100,000 DPP-2, DPP-7, 100,000 l 口服西格列汀100mg和600mg的峰浓度是747nM和7000nM l 可有效抑制DPP-4 l 显著低于抑制DPP-8和DPP-9所需浓度 高度选择性保证了捷诺维无动物毒性反应 非选择性抑制剂 (DPP-8/9 2004. Abstract 6-OR. 2. Lankas GK et al. Diabetes. 2005;54:29882994. 捷诺维(西格列汀)给药24小时后 有效抑制血浆DPP- 4活性达80% 给药后时间（小时） 80% 50% 对DPP-4的抑制 与基线相比对血浆DPP-4的抑制程度 (%) 0124812162024 10 0 40 50 60 80 100 90 70 30 20 10 61014182226 OGTT 西格列汀 25 mg (n=56) 西格列汀 200 mg (n=56) 安慰剂(n=56) Herman GA, et al. J Clin Endocrinol Metab 2006; 91: 4612-4619 GLP-1 在体外保护人胰岛细胞形态 第1天 GLP-1治疗的细胞 对照 第3天 第5天 Adapted from Farilla L et al Endocrinology 2003;144:51495158. 加入GLP-1培养的胰岛 细胞能够更长时间的保 持其完整性. 捷诺维(西格列汀)使细胞与细胞比例正常 Mu, J et al. Diabetes, 2006; 55: 1695-1704 HFD/STZ mice treated with Des-F-sitagliptin for 11-weeks. Green insulin positive -cell Red glucagon positive -cell 捷诺维(西格列汀)改善胰岛功能(离体胰腺) Mu, J et al. Diabetes, 2006; 55: 1695-1704 捷诺维(西格列汀)有效改善胰腺细胞功能 动物实验研究结果西格列汀 增加-细胞数量，使细胞与细胞比例正常 增加胰岛素阳性细胞数量 增加胰腺内胰岛素含量 改善葡萄糖刺激后胰岛素分泌（离体胰腺） Mu, J et al. Diabetes, 2006; 55: 1695-1704 概 述 n2型糖尿病治疗现状及挑战 n以肠促胰岛激素为基础的治疗 n捷诺维（西格列汀）的临床数据 临床疗效 安全性 捷诺维(西格列汀) III期临床研究评估主要临床终点 uu降糖疗效降糖疗效: : 单药治疗 与其他降糖药物联合 u细胞功能细胞功能 HOMA - 胰岛素原/胰岛素比值 uu安全性安全性/ /耐受性耐受性 临床不良事件 体重改变 低血糖发生率 实验室不良事件 HbA1c (所有研究主要终终点) FPG PPG HbA1c（7%或6.5%)达标标率 29 捷诺维(西格列汀) III期临床研究汇总 l单药治疗 18周安慰剂对照研究 24周安慰剂对照研究 12周日本人群安慰剂对照研究 18周亚洲人群单药研究（PN 040） l与其它降糖药物联用 与二甲双胍联用 24周与二甲双胍联合治疗研究 52周与二甲双胍联合治疗活性对照研究 24周与吡格列酮联合治疗研究 l起始联合治疗 二甲双胍和西格列汀对肠促胰岛激素的作用 二甲双胍/西格列汀起始联合治疗 l三联治疗 52周与磺脲或磺脲加二甲双胍联合治疗 30 Adapted from Raz et al. Diabetologia. 2006;49:25642571 Adapted from American Diabetes Association. From Diabetes Care, Vol. 29,2006; 26322637 Adapted from Nonaka et al. Poster presented at the 66th Scientific Sessions, American Diabetes Association, Washington, DC, June 913, 2006. 7.4 7.6 8.0 8.4 Placebo (n=244) Sitagliptin 100 mg (n=229) 24-week Study Time (weeks) 0 6 12 18 24 -0.79% (p0.001) Japanese 12-week Study -1.05% (p0.001) Placebo (n=75) Sitagliptin 100 mg (n=75) Time (weeks) 04812 7.6 8.0 8.4 7.2 6.8 Dchange vs. placebo* 18-week Study Placebo (n=74) Sitagliptin 100 mg (n=168) Time (weeks) 061218 7.2 7.6 8.0 8.4 -0.6% (p0.001) = 捷诺维一天一次单药治疗持续显著降低HbA1C Monotherapy HbA1c (% SE) HbA1c (% SE) HbA1c (% SE) 7.2 8.2 7.4 7.0 6.6 6.4 7.8 8.2 31 捷诺维在亚洲人群(中国、印度、韩国)降糖效果显著 HbA1c 从基线的改变 (FAS Population) 9.2 9.0 8.8 8.6 8.4 8.2 8.0 7.8 061218 Time, weeks Mean SE Change in HbA1c, % FAS=full analysis set; qd=once a day; SE=standard error. Mohan V et al. Diabetes Res Clin Pract. 2009;83:106116. Sitagliptin 100 mg qd (n=339) Placebo (n=169) Monotherapy -1.03% 32 Screening Single-blind placebo Double-blind treatment period: Sulfonylurea or sitagliptin 100 mg/day Metformin monotherapy Week 2: Eligible if HbA1c 6.5% to 10% If on an OHA, D/C Continue/start metformin Day 1 RandomizationWeek 52 D/C = discontinued; OHA = oral antihyperglycemic agent; T2DM = type 2 diabetes. *Specifically, glipizide 5 mg/day increased to 20 mg/day (dose not uptitrated if finger stick 110 mg/dL or hypoglycemia). Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194205. 52周西格列汀联合二甲双胍vs格列吡嗪联合二甲双胍对照研究 研究设计 2型糖尿病患者随机，双盲，平行，活性对照，非劣效性研究 (N=1172) 治疗 西格列汀100 mg/day，二甲双胍1500 mg/day 磺脲* 最大剂量20 mg/day，二甲双胍 1500 mg/day Metformin (stable dose 1500 mg/day) Add-on 2 33 HbA1c (% SE) LSM change from baseline (for both groups): 0.67% 达到首要假设： 疗效非劣效于磺脲 LSM = least-squares mean. aSpecifically, glipizide; bsitagliptin (100 mg/day) with metformin (1500 mg/day); per-protocol population. Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194205. 52周西格列汀联合二甲双胍vs格列吡嗪联合二甲双胍对照研究 与二甲双胍联用时， 捷诺维一天一次降糖效果不低于磺脲类(52周) Weeks 5.8 6.0 6.2 6.4 6.6 6.8 7.0 7.2 7.4 7.6 7.8 0612182430384652 Sulfonylureaa + metformin (n=411) Sitagliptinb + metformin (n=382) Add-on 2 34 aSpecifically, glipizide; bsitagliptin (100 mg/day) with metformin (1500 mg/day); per-protocol population. Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194205. Sulfonylurea + metformin Baseline HbA1C Category Change from baseline in HbA1c (%) n=117 n=11711217916782823321 7%7 to 8%8 to 9%9% -0.14 -0.59 -1.11 -1.76 -0.26 -0.53 -1.13 -1.68 -2.0 -1.8 -1.6 -1.4 -1.2 -1.0 -0.8 -0.6 -0.4 -0.2 0.0 Sitagliptinb + metformin 52周西格列汀联合二甲双胍vs格列吡嗪联合二甲双胍对照研究 基值越高，HbA1c 降幅越大 Add-on 2 35 Patients at HbA1c goal (%) HbA1c7% at week 52 *Specifically, glipizide. Per-protocol population. Mean baseline HbA1c levels: sitagliptin 100 mg, 7.48%; glipizide, 7.52%. Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194205. n=240n=242 52周西格列汀联合二甲双胍vs格列吡嗪联合二甲双胍对照研究 捷诺维联合二甲双胍组更多的患者达到血糖控制目标 Add-on 2 36 52周西格列汀联合二甲双胍vs格列吡嗪联合二甲双胍对照研究 捷诺维组体重下降且低血糖发生率显著低于对照组 Sulfonylurea + metformin (n=584) Sitagliptin 100 mg/day + metformin (n=588) Hypoglycemiab P0.001 32% 5% 0 10 20 30 40 50 Week 52 低血糖发生率(%) LSM change in body weight over timeb 体重 (kg SE) LSM = least-squares mean. aSpecifically, glipizide; ball-patients-treated population. LSM between-group difference at week 52 (95% CI): in body weight = 2.5 kg 3.1, 2.0 (P0.001); LSM change from baseline at week 52: glipizide: +1.1 kg; sitagliptin: 1.5 kg (P0.001). Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194205. Sulfonylurea + metformin (n=416) Sitagliptin 100 mg/day + metformin (n=389) Add-on 2 37 bid=twice daily; qd=daily; R=randomization. Williams-Herman D et al. Curr Med Res Opin. 2009;25(3):569583. Week 2Day 1 Single- Blind Placebo Run-In Period Eligible if HbA1c 7.5%11% Week 24 Placebo Sitagliptin 100 mg qd Metformin 500 mg bid Metformin 1000 mg bid Sitagliptin 50 mg/ metformin 500 mg bid Sitagliptin 50 mg/ metformin 1000 mg bid R 研究设计 Week 54 Metformin 1,000 mg bid Sitagliptin 100 mg qd Metformin 500 mg bid Metformin 1000 mg bid Sitagliptin 50 mg/ metformin 500 mg bid Sitagliptin 50 mg/ metformin 1000 mg bid 24-Week (Phase A)30-Week Continuation Phase Initial Combination 38 西格列汀与二甲双胍起始联合治疗 HbA1c 24周时自基线的改变 aLeast squares mean change from baseline with adjustment for placebo. bWithin-group mean change from baseline. bid=twice daily; qd=daily. Goldstein B et al. Diabetes Care. 2007;30:19791987. Please note: Dr. Goldstein is currently a Merck employee but was not at the time this study was conducted or when the publication was written. 117 2.9b Metformin 1000 mg bid Sitagliptin 100 mg qd Sitagliptin 50 mg + metformin 500 mg bid Metformin 500 mg bid Sitagliptin 50 mg + metformin 1000 mg bid HbA1c Change From Baseline, % 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 0.5 178177183178175n= 0.8a 1.0a 1.3a 1.6a 2.1a 24-Week Placebo-Adjusted Results Mean HbA1c = 8.8% Open-Label Mean Change From Baseline Mean HbA1c= 11.2% All-Patients-Treated Population HbA1c change from baseline at week 24 for placebo group (n=165) = 0.17% Initial Combination 39 西格列汀与二甲双胍起始联合治疗 54周时改善细胞功能指标 Sita 50 mg + met 1000 mg bidSita 50 mg + met 500 mg bid Met 1000 mg bidMet 500 mg bidSita 100 mg qd n=88n=102n=126n=133n=143 n=61n=75n=114n=100n=130 Proinsulin-to-Insulin Ratio n=88n=102n=126n=133n=143 HOMA- Change bid=twice daily; HOMA=homeostasis model assessment; LSM=least-squares mean; met=metformin; qd=daily; Sita=sitagliptin. Williams-Herman D et al. Curr Med Res Opin. 2009;25(3):569583. Continuation All-Patients-Treated Population Initial Combination 40 西格列汀与二甲双胍起始联合治疗 54周内持续降低HbA1c Sita 50 mg + met 1000 mg bid (n=153) Met 1000 mg bid (n=134) Sita 100 mg qd (n=106) Sita 50 mg + met 500 mg bid (n=147) Met 500 mg bid (n=117) APT=all-patients-treated; bid=twice daily; LSM=least-squares mean; Met=metformin; qd=daily; Sita=sitagliptin. Reproduced with permission from Williams-Herman D et al. Curr Med Res Opin. 2009;25(3):569583. 24-Week (Phase A)30-Week Continuation Phase Mean SE Change in HbA1c, % 6.0 6.5 7.0 7.5 8.0 8.5 9.0 0612182430384654 Weeks Continuation All-Patients-Treated Population Initial Combination 41 0 6 12 18 24 30 38 46 54 62 70 78 91 104 6 6.5 7 7.5 8 8.5 9 *Completers population Sita = sitagliptin; Met = metformin 西格列汀与二甲双胍起始联合治疗 持续2年降低HbA1c Time (weeks) 24-Week PhaseContinuation Phase Extension Phase HbA1c (LS mean change %) Sita 100 mg q.d. (n=22)Met 500 mg b.i.d. (n=26) Met 1000 mg b.i.d. (n=53) Sita 50 mg b.i.d. + Met 500 mg b.i.d. (n=64) Sita 50 mg b.i.d. + Met 1000 mg b.i.d. (n=77) 2008 EASD Initial Combination 42 捷诺维联合格列吡嗪或格列吡嗪/二甲双胍 *=Pioglitazone 30 mg QD Screening Period Patients with treated or untreated T2DM, ages 18 to 78 years Placebo Sitagliptin 100 mg QD Single-blind Placebo Week 24 Continue/start regimen of glimepiride metformin Single-blind eligible if A1C 7.5% to 10.5% 24-Week Phase R Stratum 1: Glimepiride (4 mg/d) Stratum 2: Glimepiride + Metformin (1500 mg/d) Continuation Phase Week 54 Patients not requiring rescue medication in 24-week phase could continue through 54 weeks. Active Treatment* Week 0 入选病例： 441例随机化病例，平均56岁， 53% 男性 糖尿病平均病程为8.8年，平均基线 A1C = 8.34% Add-on to SU Triple Combination 43 各组A1c自基线的改变 Placebo-controlled Add-on to Glimepiride (+/- metformin) Study *Difference in LS Mean change from baseline -0.9%* -0.6%* Add-on to glimepiride + metformin Weeks 06121824 A1C (%) 7.2 7.6 8.0 8.4 8.8 Sitagliptin +Glim + MF Placebo + Glim + MF Sitagliptin + Glim Placebo + Glim Adapted from Hermansen et al. Diabetes Obes Metab 2007;9:733-745 Mean duration of T2DM: 8.8 years Triple Combination 44 Baseline (pmol/L/pmol/L): Sitagliptin = 0.517; Placebo = 0.491 p=n.s. 三联治疗中捷诺维改善细胞功能指标 Sitagliptin Placebo Proinsulin/Insulin Ratio Baseline : Sitagliptin = 50.7; Placebo = 47.4 *p=0.021 HOMA- * Adapted from Hermansen et al. Diabetes Obes Metab 2007;9:733-745 -0.08 -0.06 -0.04 -0.02 0.00 0.02 Triple Combination 45 联合治疗中捷诺维改善细胞功能指标 Baseline: proinsulin-to-insulin ratio (sitagliptin + pioglitazone=0.41 pmol/L/pmol/L; placebo + pioglitazone=0.40 pmol/L/pmol/L); HOMA- (sitagliptin=36.2%, placebo=39.6%). Add-on HOMA- = homeostasis model assessment-; LSM = least-squares mean. All-patients-treated population. Adapted from Charbonnel et al. Diabetes Care. 2006;29:26382643; Adapted from Rosenstock et al. Clin Ther. 2006;28:15561568. 24周与二甲双胍联用研究 24周与吡格列酮联用研究 Baseline: Proinsulin-to-insulin ratio (sitagliptin = 0.357 pmol/L/pmol/L, placebo = 0.369 pmol/L/pmol/L), HOMA- (sitagliptin = 46.4%, placebo = 45.1%). 单药治疗中捷诺维显著改善细胞功能指标 All-patients-treated population. HOMA- = homeostasis model assessment-. Adapted from Raz et al. Diabetologia. 2006;49:25642571. Adapted from Aschner et al. Diabetes Care. 2006;29:26322637. At Week 18 (18-Week, Monotherapy, Placebo- Controlled Study) At Week 24 (24-Week, Monotherapy, Placebo-Controlled Study) Monotherapy 捷诺维(西格列汀)治疗组与非西格列汀治疗组间 总体不良事件相似 Sitagliptin N=3145 n (%) Nonexposed N=2724 n (%) Between-Groups Difference, % (95% CI)a 1次或多次临床不良事件2150 (63.0)1711 (62.8)0.1 (2.3, 2.6) 药物相关临床不良事件b 440 (12.9)483 (17.7)4.8 (6.7, 3.0) 严重临床不良事件 230 (6.7)184 (6.8)0.0 (1.3, 1.2) 药物相关临床不良事件b 8 (0.2)8 (0.3)0.1 (0.4, 0.2) 死亡， n (%)11 (0.3)16 (0.6)0.3 (0.7, 0.1) 中止治疗, n (%) 临床不良事件 药物相关临床不良事件 严重临床不良事件 药物相关严重临床不良事件 106 (3.1) 30 (0.9) 51 (1.5) 4 (0.1) 101 (3.7) 40 (1.5) 47 (1.7) 4 (0.1) 0.6 (1.5, 0.3) 0.6 (1.2, 0.1) 0.2 (0.9, 0.4) 0.0 (0.3, 0.2) AE=adverse experience; CI=confidence interval. aPositive differences indicate that the proportion for the sitagliptin group is higher than the proportion for the nonexposed group. “0.0” represents rounding for values that are slightly less than zero. bDetermined by the investigator to be possibly, probably, or definitely drug related. Williams-Herman D et al. BMC Endocr Disord. 2008;8:14. Copyright BioMed Central. Pooled safety and tolerability analysis 任一组发生的3%的临床不良事件 Sitagliptin N=3415 n (%) Nonexposed N=2724 n (%) Between-Groups Difference, % (95% CI)a 任一组中3%的临床不良事件 腹泻 170 (5.0)144 (5.3)0.3 (1.4, 0.8) 支气管炎 135 (4.0)83 (3.0)0.9 (0.0, 1.8) 流感 145 (4.2)127 (4.7)0.4 (1.5, 0.6) 鼻咽炎 244 (7.1)162 (5.9)1.2 (0.1, 2.4) 上呼吸道感染 265 (7.8)228 (8.4)0.6 (2.0, 0.8) 尿道感染 134 (3.9)100 (3.7)0.3 (0.7, 1.2) 低血糖b 117 (3.4)296 (10.9)7.4 (8.8, 6.1) 关节痛 113 (3.3)92 (3.4)0.1 (1.0, 0.8) 背痛 142 (4.2)108 (4.0)0.2 (0.8, 1.2) 头痛 169 (4.9)129 (4.7)0.2 (0.9, 1.3) 高血压 110 (3.2)89 (3.3)0.0 (1.0, 0.8) aPositive differences indicate that the proportion for the sitagliptin group is higher than the proportion for the nonexposed group. “0.0” represents rounding for values that are slightly greater and slightly less than zero, respectively. bIncludes studies in which a sulfonylurea was an active comparator or a background agent. Williams-Herman D et al. BMC Endocr Disord. 2008;8:14. Copyright BioMed Central. Pooled safety and tolerability analysis 安全性荟萃分析： 可能与免疫功能相关的临床不良事件 Sitagliptin N=3415 n (%) Nonexposed N=2724 n (%) Between-Groups Difference, % (95% CI)a 发生率1%的可能与免疫功能相关的临床不良事件 支气管炎 135 (4.0)83 (3.0)0.9 (0.0, 1.8) 蜂窝织炎 28 (0.8)26 (1.0)0.1 (0.6, 0.3) 肠胃炎 68 (2.0)48 (1.8)0.2 (0.5, 0.9) 病毒性肠胃炎 29 (0.8)27 (1.0)0.1 (0.7, 0.3) 流感 145 (4.2)127 (4.7)0.4 (1.