中国科技论文统计源期刊　中文核心期刊  
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医药导报
医药导报, 2023, 42(3): 416-423
doi: 10.3870/j.issn.1004-0781.2023.03.023
卡格列净治疗2型糖尿病的快速卫生技术评估*
Rapid Health Technology Assessment of Canagliflozin in the Treatment of Patients with Type 2 Diabetes Mellitus
牛子冉, 郭家梅, 都丽萍, 张波
中国医学科学院北京协和医院药剂科,北京 100730
NIU Ziran,, GUO Jiamei, DU Liping,, ZHANG Bo
Department of Pharmacy,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences,Beijing 100730,China
通信作者 都丽萍(1984-),女,江西南昌人,副主任药师,硕士,主要从事临床药学工作。电话:010-69156514,E-mail:dlppumch@163.com。

作者简介 牛子冉(1991-),女,山东临沂人,药师,硕士,主要从事临床药学工作。ORCID:0000-0002-0743-4114,电话:010-69156536,E-mail:niuziran@pumch.cn。
基金资助: * 首都卫生发展科研专项(首发2018-3-4017);中央高水平医院临床科研专项 (2022-PUMCH-A-199)
中图分类号: R977.1;R969     文献标识码: B     文章编号: 1004-0781(2023)03-0416-08
摘要:

目的 运用快速卫生技术评估方法(HTA)评价卡格列净有效性、安全性和经济性,为决策者提供循证医学证据。 方法 检索中英文数据库,由2名研究者根据纳入和排除标准进行文献筛选、质量评价和数据提取,并进行归纳性评价。 结果 纳入卫生技术评估报告2篇,系统评价及Meta分析23篇,经济学研究16篇。纳入的HTA和系统评价/Meta分析在卡格列净的有效性方面结果一致。与对照组相比,卡格列净可良好地控制血糖,还可降低收缩压和体质量。与安慰药相比,卡格列净显著降低主要心血管事件发生率和心力衰竭住院率;Meta分析显示,主要肾脏结局的相对风险较安慰药组降低30%。安全性评价结果显示,卡格列净总体耐受性良好,但显著增加生殖器感染和渗透性利尿相关不良事件的发生风险。国内外HTA经济学研究显示,对于心血管或肾脏疾病高危人群,卡格列净具有成本-效果优势。 结论 卡格列净治疗2型糖尿病具有良好的有效性和安全性,经济性方面需进一步完善。
关键词: 卡格列净; 2型糖尿病; 快速卫生技术评估

Abstract:

Objective To evaluate the efficacy,safety,and economy of canagliflozin based on rapid health technology assessment (HTA) to provide an evidence-based basis for clinical decision. Methods Core Chinese and English databases were searched systematically.The results were qualitatively analyzed after two interviewers screened the literature dependently,extracted the data, and evaluated the quality. Results Two health technology assessment reports,23 systematic reviews/meta-analyses,and 16 economic studies were included.The results suggested that canagliflozin reduced HbA1C、body weight, and blood pressure compared with placebo.Canagliflozin also demonstrated benefits on cardiovascular and renal outcomes,it can significantly reduce MACEs and heart failure incidence compared to placebo.The relative risk of the primary outcome was 30% lower in the canagliflozin group than the placebo group.Safety studies showed that canagliflozin was generally well tolerated,except for high incidence of genital mycotic infection and osmotic diuretic-related adverse events.Domestic economic research indicated that canagliflozin was more cost-effective in patients at high risk for cardiovascular or kidney disease. Conclusion Canagliflozin is effective and safe in the treatment of type 2 diabetes mellitus.Whether it is a more cost-effective option compared to other anti-diabetes therapies needs further research.
Key words: Canagliflozin; Type 2 diabetes Mellitus; Rapid health technology assessment

开放科学(资源服务)标识码(OSID)

随着对糖尿病发病机制的深入研究,新型口服降糖药不断出现,如胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)受体激动剂、二肽基肽酶-4(dipeptidyl peptidase-4,DPP-4)抑制剂、钠-葡萄糖同向转运体-2 (sodium-glucose co-transporter-2,SGLT-2)抑制剂。卡格列净是一种SGLT-2抑制剂,通过抑制葡萄糖在肾脏的重吸收,增加尿糖排出,从而降低血糖水平[1,2]。然而在临床应用中,SGLT-2抑制剂相关的泌尿生殖系感染、急性肾损伤及酮症酸中毒等不良反应也受到关注。

卫生技术评估(health technology assessment,HTA)是对卫生技术的特性、效果、成本效果和(或)其他影响进行的系统性评价[3];快速HTA则通过简化HTA/系统评价方法和流程,相对快速地评估药物的有效性、安全性和经济性。笔者在本研究拟通过文献检索,对卡格列净的有效性、安全性和经济性进行快速HTA,评价卡格列净的获益与风险,以期为各层次决策提供依据。

1 资料与方法
1.1 资料

本研究拟纳入的研究资料为符合以下标准的研究:①研究人群为2型糖尿病患者;②干预措施为卡格列净单独或联合应用,剂量和疗程不限;③对照措施为安慰药、二甲双胍、吡格列酮、艾塞那肽、格列美脲、西格列汀,剂量和疗程不限;④结局指标:有效性指标包括糖化血红蛋白(hemoglobin A1c,HbA1c)、空腹血糖(fasting plasma glucose,FPG)和体质量、收缩压、主要心血管事件(major adverse cardiovascular outcomes,MACE)发生率、心力衰竭住院率、终末期肾病、肌酐水平翻倍或肾源性死亡等主要肾脏结局终点;安全性指标包括;总体不良事件、严重不良事件、尿路感染、生殖器感染、截肢、酮症酸中毒;经济性指标包括增量成本 、质量调整生命(quality-adjusted life-years,QALYs)、增量成本-效果比。⑤研究类型为HTA报告、系统评价、Meta分析、药物经济学研究;⑥语言为中文或英文。

1.2 方法

1.2.1 检索方法 系统检索PubMed、Embase、Web of Science、the Cochrane Library、中国知网(China National Knowledge Internet,CNKI)、万方数据库,同时检索国际卫生技术评估机构协作网(International Network of Agencies for Health Technology Assessment, INAHTA)、加拿大药物卫生技术局(Canadian Agency for Drugs and Technologies in Health,CADTH)、英国国家临床卓越研究所(National Institute for Health and Clinical Excellence,NICE)等HTA机构官方网站,检索时限从建库至2021年6月30日。

英文检索关键词:canagliflozinAND systematic review、canagliflozin AND meta analysis、canagliflozin AND cost、canagliflozin AND economic、canagliflozin AND.HTA。中文检索关键词:“卡格列净OR坎格列净”AND“系统评价ORMeta分析OR荟萃分析OR成本OR费用OR经济OR卫生技术评估OR卫生技术评价”。

1.2.2 文献筛选、数据提取和质量评价 由2位研究者独立根据纳入排除标准筛选文献,存在争议时,通过讨论或咨询第3位研究者解决。按照预先设计好的数据提取表,由1位评价者独立提取数据,另外1位评价者核对数据。分别采用AMSTAR量表[4](a measurement tool to assess systematic reviews)和CHEERS量表[5](consolidated health economic evaluation reporting standards)对纳入的系统评价/Meta分析和药物经济学研究进行质量评价。

1.2.3 证据的合成和分析 本研究对纳入的HTA报告、系统评价/Meta分析、经济学研究进行以定性为主的综合分析,主要研究对象包括纳入研究的主要研究目的、研究方法、研究结果和结论等。临床结局指标的效应量包括加权平均差(weihgted mean difference,WMD)、比值比(oddsratio,OR)、风险比(riskratio,RR)及相应95%置信区间(confidence interval,CI),统计学显著性标准依据原文。对同一个结局指标有多个结果数据的,通过权衡研究质量、发表时间、患者例数等选择最优数据报告。

2 结果
2.1 文献检索结果

系统检索各数据库,共得到文献1967篇。经剔除重复文献、阅读题名和摘要初筛、获取全文复筛,最终纳入文献41篇,包括HTA报告2篇、系统评价/Meta分析23篇、经济学研究16篇。文献筛选流程见图1。


图1 文献筛选流程图

Fig.1 Flow chart of literature screening

2.2 纳入文献的基本特征与质量评价

纳入的2篇HTA报告分别由NICE和CADTH在2014年和2015年发布[6,7]。CADTH报告纳入2项III期随机对照研究及1项成本-效果研究;NICE报告纳入了Meta分析1项、随机对照研究6项和药物经济学研究1项,对于临床效果,2篇报告均未进行定量合并分析。纳入的23篇系统评价/Meta分析,发表时间为2014年至2021年,均为英文文献[8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32];AMSTAR得分1篇为6分,2篇为7分,其他均在8~11分,总体研究质量较好。纳入药物经济学研究16篇[33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48],其中来自中国3篇,CHEERS量表>20分,文献总体研究质量良好。纳入文献的基本特征见表1—2。

表1 纳入系统评价/Meta分析的研究的基本特征
Tab.1 Basic characteristics of studies included in systematic reviews or Meta-analysis
作者与出版年 人群 研究数 总例数 干预组 对照组 结局指标
MENG2016[8] T2DM 6 RCTs 4670 卡格列净 安慰药 HbA1c、FPG、体质量
PARVEEN2016[9] T2DM 13 RCTs 7658 卡格列净 安慰药、其他降糖药 HbA1c、不良事件、严重不良事件
XIONG2016[10] T2DM 7 RCTs 5215 卡格列净 安慰药 HbA1c、FPG、体质量、β细胞功能、总体不良事件、严
重不良事件、渗透性利尿相关的不良事件、容量过
低相关的不良事件、尿路感染、生殖器感染
YANG2015[11] T2DM 6 RCTs 2877 卡格列净 安慰药 HbA1c、FPG、体质量、总体不良事件、严重不良事件
YANG2014[12] T2DM 10 RCTs 6701 卡格列净 安慰药、其他降糖药 HbA1c、FPG、体质量、SBP、DBP、脂质、低血糖、
尿路感染、生殖器感染
ZACCARDI2016[13] T2DM 38 RCTs 23 997 SGLT2抑制剂 安慰药、其他降糖药 低血糖、生殖器感染
KHAN2019[14] T2DM 5 RCTs 13 158 卡格列净 安慰药、其他降糖药 体质量、SBP、DBP
MONAMI2017[15] T2DM合并心血管疾病 71 Trial 47 287 SGLT-2抑制剂 安慰药或其他降糖药 全因死亡率、心血管死亡、心肌梗死、卒中
RYAN2018[16] T2DM 6 Cohorts 714 582 卡格列净 其他降糖药 膝下下肢截肢、心力衰竭
TANG2016[17] T2DM合并心血管疾病 37 RCTs 29 859 SGLT-2抑制剂 安慰药、其他降糖药 全因死亡率、主要心血管事件
USMAN2018[18] T2DM合并心血管疾病 35 RCTs 34 987 SGLT-2抑制剂 安慰药 全因死亡率、主要心血管不良事件、非致死性心肌梗
死、心力衰竭或因心力衰竭住院、非致死性卒中、
心房纤颤、不稳定性心绞痛
ZELNIKER2019[19] T2DM合并肾脏病 3 RCTs 34 322 SGLT-2抑制剂 安慰药 主要心血管不良事件、因心力衰竭住院、肾脏疾病进
展、截肢、骨折、酮症酸中毒
SEIDU2018[20] T2DM合并肾脏病 40 RCTs 29 954 SGLT-2抑制剂 安慰药 eGFR、BUN、血清肌酐值、UACR、尿白蛋白、肾脏复
合终点事件
ZHANG2018[21] T2DM合并中等肾损伤 7 RCTs 3307 SGLT-2抑制剂 安慰药、其他降糖药 低血糖、尿路感染、生殖器感染、eGFR
DONNAN2019[22] T2DM 109篇 112个 SGLT-2抑制剂 安慰药、其他降糖药 急性肾损伤、酮症酸中毒、尿路感染、骨折和下肢截
文献 随机 人群 肢
BUNDHUNP2018[23] T2DM 5 study 2322 卡格列净 安慰药、西格列汀 总体不良事件、严重不良事件、因不良事件而退出、
尿路感染、低血糖、生殖器感染、容量过低相关的
不良事件
LI2017[24] T2DM 52 RCTs 36 689 SGLT-2抑制剂 安慰药、其他降糖药 尿路感染和生殖器感染
研究 人群 研究数 总例数 干预组 对照组 结局指标
LIU2017[25] T2DM 77 RCTs 50 820 SGLT-2抑制剂 安慰药、生活方式、其 尿路感染、生殖器感染
他降糖药
TANG2017[26] T2DM 46 RCTs 34 569 SGLT-2抑制剂 安慰药、其他降糖药 癌症
RUANPENG2017[27] T2DM 20 RCTs 8286 SGLT-2抑制剂 安慰药 骨折
TANG2016[28] T2DM 38 RCTs 30 384 SGLT-2抑制剂 安慰药、其他降糖药 骨折
AZHARUDDIN2018[29] T2DM 40 RCTs 32 343 SGLT-2抑制剂 安慰药、其他降糖药 骨折
MONAMI2017[30] T2DM 72 RCTs 43 322 SGLT-2抑制剂 安慰药、其他降糖药 酮症酸中毒

表1 纳入系统评价/Meta分析的研究的基本特征

Tab.1 Basic characteristics of studies included in systematic reviews or Meta-analysis

表2 纳入经济学研究的文献基本特征
Tab.2 Basic characteristics of studies included in economic studies
研究 国家 视角 研究方法 时限 患者人群 干预措施 对照措施
EKTARE2014[31] 美国 管理医疗支付方 自建模型 1年 T2DM 卡格列净+二甲双 西格列汀+二甲双胍+磺
胍+磺脲类 脲类
LAFEUILLE2015[32] 美国 真实世界 多元回归和非参数 1年 T2DM 卡格列净 西格列汀
自举
NESLUSAN2018[33] 美国 第三方健康保健系统 成本-效果 30年 T2DM 卡格列净 达格列净
RAVASIO2016[34] 意大利 国民健康服务 成本最小化 1年 T2DM 卡格列净+二甲双胍 格列美脲或西格列汀+二
甲双胍
SABAPATHY2016[35] 加拿大 卫生药品和技术署 成本-效果 终生 T2DM 卡格列净+二甲双 西格列汀+二甲双胍+磺
胍+磺酰类 脲类
SCHUBERT2017[36] 阿拉伯联合 支付方 贝叶斯网络Meta分析 26±4周 T2DM 卡格列净 达格列净、恩格列净
酋长国
STAFFORD2022[37] 加拿大 支付方和社会 成本-效果 40年 T2DM 卡格列净300 mg,qd 司美格鲁肽1 mg,QW
SINGHAL2019[38] 美国 真实世界 真实世界 - T2DM 卡格列净 GLP-1受体激动剂
DURKIN2021[39] 美国 - 基于RCT的预测模型 - T2DM 卡格列净 安慰药
JORISSEN2022[40] 比利时 医疗保健系统 成本-效果 10年 T2DM合并肾脏病 卡格列净+标准治疗 标准治疗
CHEN2020[41] 美国 医疗保健系统 真实世界 - 伴心血管疾病 卡格列净 非SGLT-2抑制剂降糖药
的T2DM
WILLIS2021[42] 英国 NHS 自建模型 10年 T2DM合并肾脏病 卡格列净+标准治疗 标准治疗
BALL2020[43] 英国 NHS 自建模型 40年 T2DM合并肾脏病 卡格列净+标准治疗 标准治疗
HOU2019[44] 中国 中国健康保健服务 COMT模型 终身 T2DM 卡格列净 达格列净
提供者
WU2020[45] 中国 中国健康保健服务 COMT模型 终身 T2DM 卡格列净 西格列汀
提供者
WU2019[46] 中国 中国健康保健服务 COMT模型 终身 T2DM合并肾脏病 卡格列净 对照组
提供者

表2 纳入经济学研究的文献基本特征

Tab.2 Basic characteristics of studies included in economic studies

2.3 有效性评价

2.3.1 HTA报告 CADTH报告显示[6],与安慰药相比,卡格列净300和100 mg均显著降低患者HbA1c、FPG和体质量(P<0.001)。与西格列汀100 mg相比,卡格列净300 mg在降低HbA1c、FPG和体质量方面均更优,同时还可显著降低收缩压[-5.91 mmHg(1 mmHg=0.133 kPa),95%CI:-7.64 ~-4.18]和舒张压[-2.73 mmHg,95%CI:-3.81~-1.66]。

NICE报告显示[7],以二甲双胍为基础的双联降糖方案中,在降低HbA1c方面,第52周时,与西格列汀相比,300 mg对糖化血红蛋白的降低具有统计学意义,300 mg(减去西格列汀)为0.37%(95%CI:-0.50~-0.25)。100和300 mg卡格列净联合二甲双胍可分别降低患者HbA1c值(减去安慰药)0.627%(95%CI:-0.758~-0.481)和 0.77% (95%CI:-0.914~-0.636)。卡格列净100 mg降低HbA1c的程度在数值上优于西格列汀100 mg和达格列净10 mg,卡格列净300 mg则在数值上优于吡格列酮30 mg、艾塞那肽10 μg、格列美脲、西格列汀100 mg和达格列净10 mg,但均差异无统计学意义;在降低体质量方面,卡格列净100或300 mg组效果显著优于西格列汀100 mg、格列美脲、吡格列酮30 mg,与达格列净10 mg类似,效果不如GLP-1类似物。在降低收缩压方面,卡格列净100或300 mg组在降低收缩压方面显著优于格列美脲、利拉鲁肽1.2 mg和西格列汀100 mg。

NICE还评价了以二甲双胍和磺脲类为基础的三联降糖方案中卡格列净的有效性[6]。在降低HbA1c方面,二甲双胍和磺脲类基础上加用卡格列净300 mg降低HbA1c的程度在数值上优于分别加用西格列汀100 mg和艾塞那肽10 μg,100 mg卡格列净与其他两种降糖药物效果相似。在降低体质量方面,卡格列净100或300 mg在数值上优于西格列汀100 mg,与艾塞那肽效果类似。在降低收缩压方面,卡格列净100或300 mg方面优于西格列汀100 mg(-5.76 mmHg,95%CI:-9.02~-2.53;-5.16 mmHg,95%CI:-6.94~-3.38)。

2.3.2 系统评价/Meta分析 研究指出[8,9,10,11,12,13],卡格列净作为单一疗法时,HbA1c相对于安慰药绝对降低(WMD=-1.08%,95%CI:-1.25~0.90,P<0.000 01),而与西格列汀和格列美脲相比,卡格列净也可显著降低HbA1c (WMD=0.21%,95% CI:-0.33~-0.08,P=0.001)。PARVEEN的报道显示,与安慰药相比,卡格列净100和 300 mg显著降低FPG。HbA1c<7%患者比例卡格列净100 mg组从27.3%到44.5%(P<0.001)。相较于安慰药,100和300 mg卡格列净干预组体质量可降低,卡格列净降糖效果和减轻体质量效果优于西格列汀。卡格列净治疗可显著降低收缩压[14]。

在心血管结局方面,分析均显示,与安慰药相比,卡格列净显著降低主要心血管事件(major adverse cardiovascular outcomes,MACE)发生率(OR 0.85,95%CI:0.75~0.97,P=0.02)和心力衰竭或因心力衰竭而住院的发生率显著降低(OR 0.69,95%CI:0.54~0.90,P=0.006),与安慰药相比,卡格列净仅在数值上降低非致死性MI发生率(OR 0.84,95%CI:0.68~-1.03,P=0.10),但结果差异无统计学意义,对卒中、心房纤颤等发生率差异无统计学意义[16,17,18,19]。

在肾脏结局方面,卡格列净组主要肾脏结局的相对风险较安慰药组降低 30%,事件发生率分别为43.2/1000和61.2/1000患者年(HR0.70,95%CI,0.59~0.82,P=0.000 01)。终末期肾病、肌酐水平翻倍或肾源性死亡的肾脏特异性复合物的相对风险降低了34%(HR 0.66,95% CI,0.53~0.81,P<0.001),终末期肾病的相对风险降低了 32%(HR 0.68,95%CI,0.54~0.86,P=0.002)[19,20,21]。

2.4 安全性评价

2.4.1 HTA报告 CADTH研究报告指出[6],与安慰药和西格列汀相比,卡格列净增加泌尿生殖道不良事件发生风险;与安慰药相比,卡格列净联合磺脲类药物增加低血糖的发生风险。

NICE研究报告指出[7],卡格列净组总体不良事件、严重不良事件和死亡事件发生率与对照组(安慰药和西格列汀)相近,但卡格列净组药物不良事件发生率(100 mg,33.6%;300 mg,29.4%)高于对照组(21.8%)。此外,卡格列净组女性(100 mg,14.7%;300 mg,13.9%)和男性(100 mg,7.3%;300 mg,9.3%)生殖器感染发生率均高于对照组(女性3.1%,男性1.6%)。

2.4.2 系统评价/Meta分析 综合系统评价/Meta分析研究结果[22,23,24,25],与安慰药相比,卡格列净组低血糖事件发生率较高[29]。与安慰药和其他降糖药相比,卡格列净显著增加渗透性利尿相关不良事件发生风险(RR=3.93,95%CI:2.25~6.86,P<0.0001)。SGLT-2抑制剂与总体癌症高发生风险无显著相关性,但可能增加患膀胱癌风险[26]。

关于截肢的发生风险,基于RCT的Meta分析结果显示,卡格列净组截肢发生风险较安慰药组显著增加(OR1.89,95%CI:1.37~2.60)。然而基于真实世界观察性研究的Meta研究指出,与非SGLT-2抑制剂相比,卡格列净治疗组并不增加截肢风险(HR=0.75,95%CI:0.40~1.41)和(HR=1.01,95%CI:0.93~1.10)[27,28,29]。

卡格列净对于酮症酸中毒的发生风险无一致性研究结果。在基于RCT的Meta分析研究中,SGLT-2抑制剂组酮症酸中毒的发生风险与安慰药相比差异无统计学意义;但另有研究显示,SGLT-2抑制剂组酮症酸中毒发生风险显著高于安慰药2倍[21,30]。

2.5 经济性评价

2.5.1 HTA报告 CADTH研究报告采用成本-效果分析方法,比较了卡格列净(100,300 mg)和西格列汀(100 mg)联合二甲双胍和磺脲类或吡格列酮治疗2型糖尿病成人患者终生(40年)的经济性情况。结果显示,以西格列汀100 mg一天的价格为2.62美元计算,卡格列净(300,100 mg) 的经济性优于西格列汀100 mg[6]。

NICE研究报告采用ECHO-T2DM模型,比较了卡格列净(100,300 mg)和DPP-4抑制剂、达格列净等药物治疗2型糖尿病成人患者终身(40年)的经济性情况。在联合二甲双胍双药治疗、联合二甲双胍和磺脲类或噻唑烷二酮类三药治疗的2型糖尿病患者中,由于卡格列净和DPP-4抑制剂、达格列净之间的成本和QALYs的差异非常小[7]。

2.5.2 经济学研究 来自国外13篇经济学研究[31,32,33,34,35,36,37,38,39,40,41,42,43],分别从国家健康系统、第三方医疗保健系统和支付者的角度分析了卡格列净的经济性结局。一项基于Truven数据库和Optum数据库真实的研究,对于已确诊的心血管疾病患者,与非SGLT-2抑制剂降糖药治疗相比,心力衰竭费用分别占使用卡格列净和非SGLT2抑制剂降糖药患者住院费用的0.36% 和3.43%。卡格列净全因总医疗费用比非SGLT2抑制剂低449美元(95%CI:402~495美元,P<0.001)。利用CREDEM-DKD经济微观模拟模型,在基础病例中卡格列净治疗后透析开始减少20% ;HHF、MI和卒中事件分别减少36%,16%和18%;平均增加0.08生命年,卡格列净治疗预计将透析延迟约13年,节约医疗成本。从英国和比利时医保角度得出在糖尿病肾病标准治疗方案中增加卡格列净100 mg可以改善患者预后,同时降低总成本。

对于国内人群的经济学研究中[44,45,46],其中2篇发表于2019年,1篇发表于2020年,在中国背景下评估了卡格列净 100 mg与达格列净 10 mg在二甲双胍控制不佳的2型糖尿病患者中的经济结果。与达格列净10 mg相比,联合卡格列净100 mg使患者寿命延长0.015个预期寿命年,降低患者终生平均治疗成本129美元。从中国医疗健康保健服务提供者的角度,卡格列净100 mg联合二甲双胍治疗2型糖尿病患者比达格列净10 mg更具有成本效果优势,在联合二甲双胍治疗方案下,100 mg卡格列净与100 mg西格列汀的成本-效果相比,卡格列净100 mg增加每位患者额外0.022预期生命年,比西格列汀节省成本538美元。

3 讨论

本研究纳入的HTA和系统评价/Meta分析在卡格列净的有效性方面结果一致。根据文献证据,卡格列净无论单独还是联合应用,相对于安慰药均具有良好的血糖控制效果,对于其他降糖药,在数值上优于多种降糖药,但均差异无统计学意义。同时卡格列净可显著降低收缩压,降低体质量效果体现出异质性,可能与联合应用的其他降糖药物有关。

综合系统评价/Meta分析结果,卡格列净均显示出明确的心血管和肾脏获益。可显著降低MACE及心衰事件发生率,但对非致死性MI、卒中、心房纤颤等无显著性效果,《2021ESC急性和慢性心力衰竭诊断和治疗指南》对于射血分数降低的心衰治疗,已推荐SGLT2i加入新四联疗法[47]。全球肾脏病预后组织 (Kidney Disease:Improving Global Outcomes,KDIGO)2020年指南建议[48],eGFR 达标的患者,无论血糖是否达标,均应联合使用 SGLT-2抑制剂。目前FDA已批准卡格列净用于治疗糖尿病肾病。SGLT-2抑制剂的心血管和肾脏受益受到越来越多关注,在合并心血管或肾脏并发症的糖尿病患者中应用逐渐广泛。

在安全性方面,纳入的报告和系统评价/Meta分析中结果较一致,卡格列净增加泌尿系感染风险。卡格列净与截肢的发生风险相关性研究,目前尚无基于RCT的Meta分析评价卡格列净与截肢风险的相关性,而2019年9月27日FDA批准的卡格列净片药品说明书警示了关于下肢截肢的风险。因此,关于卡格列净与截肢风险的相关性需要持续关注。系统评价/Meta分析显示,与安慰药相比,SGLT-2抑制剂对酮症酸中毒的发生风险无显著不同。另一项研究显示,SGLT-2抑制剂组酮症酸中毒发生风险较安慰药高2倍,患者可能存在 DKA 诱发因素或属于 DKA 高危人群。SGLT-2抑制剂刺激机体释放胰高血糖素,可能导致酮体生成增加。上述不一致的结果可能与酮症酸中毒发生率低(<1‰/年)和样本量不足有关。因此,对于卡格列净引发酮症酸中毒的风险需进一步临床试验结果予以证明。仅1篇Meta分析研究SGLT-2抑制剂与膀胱癌发生风险的关联性,但研究基于相对短期的RCT结果,长期影响仍需进一步关注。

在经济学方面,国内外HTA报告和经济学研究显示可产生经济学获益,对于心血管或肾脏疾病高危人群,卡格列净治疗降低肾脏、心血管和死亡率事件,减少住院率,与用药成本相抵消。

国外的药物成本及医疗保险等与我国均有所不同,SGLT-2抑制剂3种药物已于2019年进入我国医保目录,目前价格降幅较大,此前针对国内人群经济学的评价为进入医保前价格,相对于西格列汀和达格列净显示出经济学优势,不能完全反映出最新经济学,此为本研究局限性。各种降糖药也先后进入医保目录,有必要基于最新的数据进行重新评估,有必要在我国重新收集成本数据,开展基于中国医保体系的药物经济学研究,进一步探究其经济学价值。并与其他降糖药经济学比较。

综上所述,卡格列净单独或联合治疗2型糖尿病可良好地控制血糖、减轻体质量、降低收缩血压,在心血管结局和肾脏结局方面有一定获益。卡格列净总体安全性良好,但显著增加生殖器感染和渗透性利尿相关不良事件的发生风险。卡格列净对截肢和酮症酸中毒的发生风险尚无一致性研究结果,有待进一步全面评估。国内外经济学研究显示出其一定的优势,但目前SGLT-2抑制剂已经进入医保目录,应收集国内最新的数据进行经济学评估与比较。

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[20] SEIDU S, KUNUTSOR S K, COS X, et al. SGLT2 inhibitors and renal outcomes in type 2 diabetes with or without renal impairment:a systematic review and meta-analysis[J]. Prim Care Diabetes, 2018, 12(3):265-283.
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[21] ZHANG L, ZHANG M, LV Q, et al. Efficacy and safety of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes and moderate renal function impairment:a systematic review and meta-analysis[J]. Diabetes Res Clin Pract, 2018, 140:295-303.
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[22] DONNAN J R, GRANDY C A, CHIBRIKOV E, et al. Comparative safety of the sodium glucose co-transporter 2 (SGLT-2) inhibitors:a systematic review and meta-analysis[J]. Br Med J open, 2019, 9(1):e022577.
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[23] BUNDHUN P K, HUANG F. Adverse drug events associated with sitagliptin versus canagliflozin for the treatment of patients with type 2 diabetes mellitus:a systematic comparison through a meta-analysis[J]. Diabetes Ther, 2018, 9(5):1883-1895.
DOI:10.1007/s13300-018-0481-6      URL    
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[24] LI D, WANG T, SHEN S, et al. Urinary tract and genital infections in patients with type 2 diabetes treated with sodium-glucose co-transporter 2 inhibitors:a meta-analysis of randomized controlled trials[J]. Diabetes Obes Metab, 2017, 19(3):348-355.
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[25] LIU J, LI L, LI S, et al. Effects of SGLT-2 inhibitors on UTIs and genital infections in type 2 diabetes mellitus:a systematic review and meta-analysis[J]. Sci Rep, 2017, 7(1):2824.
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[26] TANG H, DAI Q, SHI W, et al. SGLT-2 inhibitors and risk of cancer in type 2 diabetes:a systematic review and meta-analysis of randomised controlled trials[J]. Diabetologia, 2017, 60(10):1862-1872.
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[27] RUANPENG D, UNGPRASERT P, SANGTIAN J, et al. Sodium-glucose cotransporter 2 (SGLT-2) inhibitors and fracture risk in patients with type 2 diabetes mellitus:a meta-analysis[J]. Diabetes Metab Res Rev, 2017, 33(6):e2903.
DOI:10.1002/dmrr.2903      URL    
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[28] TANG H L, LI D D, ZHANG J J, et al. Lack of evidence for a harmful effect of sodium-glucose co-transporter 2 (SGLT-2) inhibitors on fracture risk among type 2 diabetes patients:a network and cumulative meta-analysis of randomized controlled trials[J]. Diabetes Obes Metab, 2016, 18(12):1199-1206.
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[29] AZHARUDDIN M, ADIL M, GHOSH P, et al. Sodium-glucose cotransporter 2 inhibitors and fracture risk in patients with type 2 diabetes mellitus:a systematic literature review and Bayesian network meta-analysis of randomized controlled trials[J]. Diabetes Res Clin Pract, 2018, 12(146):180-190.
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[30] MONAMI M, NREU B, ZANNONI S, et al. Effects of SGLT-2 inhibitors on diabetic ketoacidosis:a meta-analysis of randomised controlled trials[J]. Diabetes Res Clin Pract, 2017, 8(130):53-60.
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[31] EKTARE V U, LOPEZ J M, MARTIN S C, et al. Cost efficiency of canagliflozin versus sitagliptin for type 2 diabetes mellitus[J]. Am J Manag Care, 2014, 20(10 Suppl):S204-S215.
To compare 1-year clinical outcomes and cost efficiency of treating adults with type 2 diabetes mellitus (T2DM) with canagliflozin (300 mg/day) or sitagliptin (100 mg/day), both added on a background of metformin and sulfonylurea. An economic model integrated data from an active-controlled, randomized trial, claims database analyses, and published literature. The model adopted a US managed care payer perspective and included the clinical and economic impact of achieving specific clinical quality goals. The model was run separately for 2 single clinical quality metrics, glycated hemoglobin (A1C) < 7% (used as base case) or < 8%, and 4 composite metrics (A1C < 7% or < 8% combined with body mass index < 30 kg/m2 and blood pressure < 140/90 mm Hg or low-density lipoprotein cholesterol < 100 mg/dL). Cost savings of achieving versus not achieving metrics were derived from a claims database analysis. Drug and adverse event costs were included. In the base case, compared with sitagliptin 100 mg, treatment with canagliflozin 300 mg resulted in $215 in annual cost savings and 12.3 absolute percentage points more patients achieving goal. Similar findings were found across all other quality metrics (difference in proportion achieving goal ranging from 6.7% to 19.0% and annual savings ranging from $1 to $669). Canagliflozin remained cost saving versus sitagliptin in sensitivity analyses. Canagliflozin 300 mg may represent a cost-efficient T2DM treatment option versus sitagliptin 100 mg for patients on metformin plus sulfonylurea due to lower overall costs and better achievement of A1C and quality composite goals.
PMID:25495002     
[本文引用:2]
[32] LAFEUILLE M H, GRITTNER A M, GRAVEL J, et al. Economic simulation of canagliflozin and sitagliptin treatment outcomes in patients with type 2 diabetes mellitus with inadequate glycemic control[J]. J Med Econ, 2015, 18(2):113-125.
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[33] NESLUSAN C, TESCHEMAKER A, WILLIS M, et al. Cost-effectiveness analysis of canagliflozin 300 mg versus dapagliflozin 10 mg added to metformin in patients with type 2 diabetes in the United States[J]. Diabetes Ther, 2018, 9(2):565-581.
DOI:10.1007/s13300-018-0371-y      URL    
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[34] RAVASIO R, PISARRA P, PORZIO R, et al. Economic evaluation of canagliflozin versus glimepiride and sitagliptin in dual therapy with metformin for the treatment of type 2 diabetes in Italy[J].Glob Reg Heath Tech, 2016,3(2):GRHTA5000229.
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[35] SABAPATHY S, NESLUSAN C, YOONG K, et al. Cost-effectiveness of canagliflozin versus sitagliptin when added to metformin and sulfonylurea in type 2 diabetes in Canada[J]. J Popul Ther Clin Pharmacol, 2016, 23(2):e151-168.
BackgroundCanagliflozin, an agent that inhibits sodium glucose co-transporter 2, is approved as add-on to metformin plus sulfonylurea for the treatment of type 2 diabetes in Canada. Canagliflozin offers greater glycemic control, as well as important additional benefits such as weight loss and blood pressure reductions, versus dipeptidyl peptidase-4 inhibitors such as sitagliptin.  ObjectiveThis analysis evaluated the cost-effectiveness of canagliflozin 300 mg and canagliflozin 100 mg versus sitagliptin 100 mg in patients with type 2 diabetes inadequately controlled on metformin plus sulfonylurea from the perspective of the Canadian Agency for Drugs and Technologies in Health. MethodsA 40-year cost-effectiveness analysis was performed using the validated Economic and Health Outcomes Model of Type 2 Diabetes Mellitus (ECHO-T2DM). Patient characteristics, treatment effects, and rates of hypoglycemia and adverse events were sourced from the canagliflozin clinical program. Canada-specific costs and utilities were applied. Sensitivity analyses were conducted using alternative values for key model inputs. ResultsBoth canagliflozin 300 and 100 mg dominated sitagliptin 100 mg over 40 years, providing quality-adjusted life-year gains of 0.31 and 0.28, and cost offsets of $2,217 and $2,560, respectively. Both canagliflozin doses dominated sitagliptin in each of the sensitivity analyses. ConclusionsSimulation results suggested that canagliflozin 300 and 100 mg provided better health outcomes and lower costs than sitagliptin 100 mg as a third-line therapy added-on to metformin and sulfonylurea in patients with type 2 diabetes in Canada.
PMID:27463416     
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[36] SCHUBERT A, BUCHHOLT A T,EL KHOURY A C,et al. Evaluating the costs of glycemic response with canagliflozin versus dapagliflozin and empagliflozin as add-on to metformin in patients with type 2 diabetes mellitus in the United Arab Emirates[J]. Curr Med Res Opin, 2017, 33(6):1155-1163.
This study evaluates the cost of achieving glycemic control with three sodium glucose co-transporter 2 (SGLT2) inhibitors, canagliflozin, dapagliflozin, and empagliflozin, in patients with type 2 diabetes mellitus (T2DM) from the payer perspective in the United Arab Emirates (UAE). A systematic literature review identified randomized controlled trials of antihyperglycemic agents as add-on to metformin in patients with T2DM of 26 ± 4 weeks in duration, published by 10 September 2014. A Bayesian network-meta analysis (NMA) compared HbA1c changes with canagliflozin 100 and 300 mg versus dapagliflozin 10 mg and empagliflozin 10 and 25 mg. The cost associated with a 1% placebo-adjusted HbA1c reduction with each SGLT2 inhibitor as add-on to metformin was calculated based on NMA results and UAE drug costs. In the NMA, canagliflozin 100 and 300 mg were associated with HbA1c reductions (-0.67% and -0.79%) compared with dapagliflozin 10 mg (-0.41%) and empagliflozin 10 and 25 mg (-0.57% and -0.64%). Probabilities of canagliflozin 100 mg performing better were 79%, 60%, and 53% versus dapagliflozin 10 mg and empagliflozin 10 and 25 mg, respectively; probabilities for canagliflozin 300 mg performing better were 88%, 72%, and 65%, respectively. The cost per 1%-point reduction in HbA1c was projected to be lower with canagliflozin 100 and 300 mg ($448 and $422) compared with dapagliflozin 10 mg ($785) and empagliflozin 10 and 25 mg ($527 and $563). Canagliflozin may provide a greater glycemic response at a lower effective cost than dapagliflozin or empagliflozin for patients with T2DM inadequately controlled with metformin from the payer perspective in the UAE.
DOI:10.1080/03007995.2017.1310091      PMID:28323512     
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[37] STAFFORD S, BECH PG, FRIDHAMMAR A, et al. Cost-effectiveness of once-weekly semaglutide 1 mg versus canagliflozin 300 mg in patients with type 2 diabetes mellitus in a canadian setting[J]. Appl Health Econ Health Policy, 2022, 20(4):543-555
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[38] SINGHAL M, TAN H, COLEMAN CI, et al. Effectiveness,treatment durability,and treatment costs of canagliflozin and glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes in the USA[J]. Br Med J Open Diabetes Res Care, 2019, 7(1):e000704.
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[39] DURKIN M, BLAIS J. Linear projection of estimated glomerular filtration rate decline with canagliflozin and implications for dialysis utilization and cost in diabetic nephropathy[J]. Diabetes Ther, 2021, 12(2):499-508.
Diabetes is a common cause of end-stage kidney disease leading to dialysis or kidney transplantation. Estimated glomerular filtration rate (eGFR) measures kidney function, and differences in the rate (slope) of eGFR decline can be used to assess treatment effects on kidney function over time. In the CREDENCE trial, the sodium glucose co-transporter 2 inhibitor canagliflozin slowed the rate of eGFR decline by 60% compared to placebo in patients with diabetes and chronic kidney disease. This analysis utilized eGFR slopes from CREDENCE to estimate the difference in time to dialysis by treatment arm and estimated the economic value of that delay. A linear decline in eGFR and maintenance of stable therapy were assumed for the canagliflozin and placebo arms in CREDENCE. Mean eGFR over time was calculated using acute (baseline to week 3) and chronic (week 3 onward) slopes. Reaching eGFR of 10 ml/min/1.73 m was assumed to represent the need for chronic dialysis. The difference in time to dialysis between treatments was calculated. Based on the average duration of dialysis, annual dialysis costs were determined, discounting 2020 US dollars at an inflation rate of 4%. Following the acute and chronic eGFR slopes, the projected time to dialysis was 22.85 years for canagliflozin and 9.90 years for placebo. Based on 95% confidence intervals from CREDENCE, the model-estimated difference in time to dialysis was 9.27-17.48 years. With a mean baseline participant age of 63 years, the delay in dialysis with canagliflozin would be associated with a reduction in dialysis costs of approximately $170,000 per patient in 2020 dollars. Using clinical trial data, canagliflozin treatment was projected to delay dialysis by approximately 13 years, which could translate to a substantial cost savings. More precise estimates should be investigated with considerations for nonlinear eGFR slope trajectory, competing risks, and patient characteristics. ClinicalTrials.gov identifier, NCT02065791.
DOI:10.1007/s13300-020-00953-4      PMID:33340064     
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[40] JORISSEN W, ANNEMANS L, LOUIS N, et al. Health economic modelling of diabetic kidney disease in patients with type 2 diabetes treated with Canagliflozin in Belgium[J]. Acta Clin Belg, 2022, 77(6):945-954.
DOI:10.1080/17843286.2021.2015554      URL    
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[42] WILLIS M, NILSSON A, KELLERBORG K, et al. Cost-effectiveness of canagliflozin added to standard of care for treating diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM) in England:estimates using the CREDEM-DKD model[J]. Diabetes Ther, 2021, 12(1):313-328.
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[43] BALL P, WILLIS M, NILSSON A, et al. Use of a new discrete event simulation model to predict the cost effectiveness of canagliflozin added to standard of care for treating diabetic kidney disease (DKD) in patients with type 2 diabetes in England[J]. Value Health, 2020, 2(Suppl2):s511.
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[45] WU B, MA M. Cost-effectiveness of canagliflozin versus sitagliptin in Chinese patients with type 2 diabetes on background metformin monotherapy[J]. Value Health Reg Issues, 2020, 22(Suppl):S33.
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[46] WU B. Cost-effectiveness of canagliflozin treatment in Chinese patients with type 2 diabetes and kidney disease[J]. Value Health, 2019, 19:S584.
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[48] NAVANEETHAN S D, ZOUNGAS S, CARAMORI M L, et al. Diabetes management in chronic kidney disease:synopsis of the 2020 KDIGO clinical practice guideline[J]. Ann Intern Med, 2021, 174(3):385-394.
DOI:10.7326/M20-5938      URL    
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关键词（key words）
卡格列净
2型糖尿病
快速卫生技术评估
Canagliflozin
Type 2 diabetes Mellitus
Rapid health technology a...
作者
牛子冉
郭家梅
都丽萍
张波
NIU Ziran
GUO Jiamei
DU Liping
ZHANG Bo