DPP-4抑制剂联合二甲双胍治疗T2DM的短期效果及长期药物经济学评价

发布时间：2018-01-06 23:32

本文关键词：DPP-4抑制剂联合二甲双胍治疗T2DM的短期效果及长期药物经济学评价　出处：《山东大学》2016年硕士论文　论文类型：学位论文

【摘要】：目的糖尿病是全世界人民共同面临的重大公共卫生问题,其中约900%0～95%为2型糖尿病(type 2 diabetes mellitus, T2DM)患者。T2DM是一种慢性疾病,病程较长且血糖需要长期维持在一个较好的水平上,如果血糖控制不佳会引起严重的大血管及微血管并发症,不仅影响患者生活质量,还给患者及社会带来巨大经济负担。因此,临床不仅需要疗效显著更需要经济性好的药物用于糖尿病的治疗和并发症的预防。目前临床常用的降糖药物有很多,其中二甲双胍是T2DM患者控制血糖的一线用药和联合用药中的基本药物,然而二甲双胍在用药初期疗效显著,随着病情进展往往需要与第二种降糖药物联合使用。如何选择与二甲双胍联合应用的降糖药物是一直以来我们不断探讨的问题。英国前瞻性糖尿病研究(United Kingdom Prospective Diabetes study, UKPDS)结果显示,无论采用哪种联合方式,随着糖尿病进展,胰岛细胞功能都会出现进行性衰退,最终导致血糖控制不佳,因此保护胰岛细胞功能、延缓其衰退进度是新治疗方案的一个重要靶点。二肽基肽酶-4(dipeptidyl peptidase-4, DPP-4)抑制剂的出现给患者带来希望,其不仅能提高胰高血糖素样肽-1 (glucagonlike peptide-1, GLP-1)和葡萄糖依赖性促胰岛素释放多肽(glucose-dependent insulinotropic polypeptide, GIP)的水平及其活性,还能保护胰岛p细胞,从而延缓并发症的发生和发展。其中,DPP-4抑制剂与二甲双胍联合治疗手段也受到越来越多临床医生的青睐。随着DPP-4抑制剂在临床推广使用,为能更好的指导临床实践,有必要全面了解DPP-4抑制剂联合二甲双胍的治疗效果及安全性。因此,本课题首先通过Meta分析全面、系统地评价了与二甲双胍相比,DPP-4抑制剂联合二甲双胍的短期治疗效果及各种不良反应的发生情况,同时鉴于亚洲人和高加索人人口统计学的差异,比较了两个人种之间两种用药方案差异的不同。我国药物经济学起步较晚,目前我国糖尿病领域多数药物经济学研究方法单一且对治疗方案仅进行了短期经济学评价。为进一步研究治疗方案的长期经济性,本课题从社会角度出发,在Meta分析基础上,采用药物经济学中研究较成熟的模型法,根据T2DM自然转归过程,建立Markov模型,进一步模拟DPP-4抑制剂联合二甲双胍治疗T2DM 30年的成本及效用,从长期角度评价该联合治疗方案的疗效和经济性,以期促进合理用药,降低患者和社会的经济负担。方法1 Meta分析检索Medline (pubmed)数据库、临床试验网站(www.clinicals.gov)及相关文献的参考文献列表,纳入符合标准的随机对照试验,提取所需要的糖化血红蛋白(glycosylated hemoglobin A1c, HbA1c)、空腹血糖(fasting plasma glucose, FPG)、体重、稳态β细胞功能指数(homeostasis model assessment of β-cell function index, HOMA-β)、稳态模型胰岛素抵抗指数(homeostasis model assessment of insulin resistance index, HOMA-IR)、总胆固醇(total cholesterol, TC)、低密度脂蛋白胆固醇(low-density lipoprotein cholesterol,LDL-C)、甘油三酯(triglycerides, TG)、高密度脂蛋白胆固醇(high-density lipoprotein cholesterol, HDL-C)等效果数据及低血糖、胃肠道副反应、胰腺炎等不良反应数据,应用Review Manager (RevMan) 5.3统计分析合并提取的数据。2亚洲人和高加索人之间的比较应用SPSS19软件,比较与单用二甲双胍相比,DPP-4抑制剂联合二甲双胍治疗效果在亚洲人和高加索人之间的差异。3 DPP-4抑制剂联合二甲双胍的长期药物经济学评价3.1 Markov模型的建立根据T2DM的自然转归过程,建立糖尿病无并发、糖尿病有并发症及死亡的Markov模型状态,以1年为1个Markov周期,结合Meta分析及文献研究获得模型所需要的转移概率、成本及效用值,模拟两种方案治疗30年所需要的成本及所获的质量调整生命年(Quality-adjusted Life Years, QALYs),从而进行长期的药物经济学评价。3.2模型分析运用Markov模型进行回乘分析、队列模拟获得两种治疗方案所需要的成本及效用数据,通过增量成本效用比(incremental cost-utility ratio, ICUR)评价DPP-4抑制剂联合二甲双胍治疗的长期经济性,同时对成本、效用值及贴现率进行敏感度分析,评价模型的稳定性。结果1 Meta分析根据纳入和排除标准,共纳入27篇随机对照试验,涉及患者10089名,其中DPP-4抑制剂联合二甲双胍组5569名,二甲双胍单药治疗组4520名。与单用二甲双胍相比,DPP-4抑制剂联合二甲双胍能显著降低HbA1c-0.61%(-0.69 to-0.52, p0.00001)、FPG-1.10 mmol/1 (-1.29 to-0.92, p0.00001)和TG-0.21 mmol/1 (-0.33 to-0.10, p=0.0002)的水平,并能降低TC-0.11 mmol/1 (-0.20 to-0.02, p=0.02、HOMA-IR-0.19 (-0.36 to-0.02, p=0.03)和胃肠道副作用RR 0.88 (0.79 to 0.98, p=0.02)的发生率,同时显著增加HOMA-β 8.86 (7.4 to 10.32, p0.00001)。对体重、LDL-C、HDL-C、胰腺炎及低血糖等不良反应的影响,两组之间没有显著性差异(p0.05)。敏感性分析结果示不同效应模型的结果一致,模型稳定性较好。2亚洲人和高加索人之间的比较纳入的27篇随机对照试验中4篇文献主要研究人群是亚洲人,23篇文献主要研究高加索人。与二甲双胍单剂量组相比,联合用药后,在HbA1c、FPG、体重和HOMA-IR方面,亚洲人和高加索人之间没有显著性差异,分别为-0.05%(-0.30 to 0.20, p=0.69)、0.17 mmol/1(-0.52 to 0.85,p=0.62)、-0.15kg (-0.64 to 0.35,p=0.53)和0.27(-0.98 to 1.53,p=0.64),而亚洲人HOMA-P的改善低于高加索人-5.79(-10.26 to-1.32,p=0.01)。3药物经济学评价结果通过回乘分析得出五种DPP-4抑制剂联合二甲双胍的成本效用比分别为：西格列汀+二甲双胍10713.41元/QALY、沙格列汀+二甲双胍11261.50元/QALY、维格列汀+二甲双胍11001.28元/QALY、格列汀+二甲双胍11169.58元/QALY、阿格列汀+二甲双胍10815.48元/QALY,由此看出西格列汀联合二甲双胍治疗最具成本效用。对西格列汀+二甲双胍治疗组和二甲双胍单药治疗组分别进行队列模拟,结果显示假设进入队列的人群共1000人,与二甲双胍治疗组相比,西格列汀+二甲双胍的治疗挽救了53名患者的生命。成本效用分析显示,3%的贴现率下西格列汀+二甲双胍联合治疗糖尿病30年所需成本为157808.48元,与二甲双胍组相比,增量成本为37533.14元,QALY为14.73年,比二甲双胍治疗组延长0.53年,ICUR为70817.24元/QALY,低于WHO推荐的阈值标准(3GDP),该联合治疗方案具有成本效用。敏感度分析结果显示,当各参数在设定范围内变化时不会影响模型结论。结论综上所述,本课题系统、全面的评价了DPP-4抑制剂联合二甲双胍治疗T2DM的短期效果和安全性,为临床合理用药提供了一定依据；运用Markov模型模拟该联合方案治疗30年的成本及效果,弥补了该领域研究数据不足的缺陷,综合评价治疗方案的健康产出和经济性,能在一定程度上提高患者生命质量,减轻患者和社会的经济负担。
[Abstract]:Objective: diabetes is a major public health problem facing the people of the world, which is about 900%0 ~ 95% for type 2 diabetes (type diabetes 2 mellitus, T2DM).T2DM patients is a chronic disease, longer duration and blood glucose to maintain long-term at a higher level, if poor glycemic control may cause serious vascular and microvascular complications, not only affects the quality of life of patients, to patients and society bring huge economic burden. Therefore, the clinical curative effect not only need more drugs and good economy for the prevention of diabetes treatment and complications. At present there are many commonly used medications, including metformin is the basic control of blood glucose in patients with T2DM first-line treatment and combined medication, but metformin efficacy in initial medication significantly, with the progression of the disease often need to combine with second kinds of hypoglycemic drugs Use. How to choose antidiabetic drugs combined with metformin as we continue to explore the problem. Since the UK Prospective Diabetes Study (United Kingdom Prospective Diabetes study, UKPDS) the results showed that either the United way, with the development of diabetes, islet cell function appears to decline, resulting in poor glycemic control therefore, the protection of islet cell function, delay the decline of progress is an important target for new therapies. Two peptide peptidase -4 (dipeptidyl peptidase-4 DPP-4) inhibitors appears to the patients hope, it can not only improve the glucagon like peptide -1 (glucagonlike peptide-1 GLP-1) and Glucose dependent insulinotropic insulin releasing polypeptide (glucose-dependent insulinotropic, polypeptide, GIP) and the level of activity, but also to protect the islet P cells, thus delaying the complications. Health and development. Among them, the DPP-4 inhibitor and metformin treatment has attracted more and more attention. Clinicians with the use of DPP-4 inhibitors in clinical practice, to guide clinical practice better, it is necessary to fully understand the efficacy and safety of DPP-4 inhibitors combined with metformin. Therefore, this paper first through Meta analysis comprehensively, systematically the evaluation compared with metformin and DPP-4 inhibitors combined with metformin treatment effect and short-term adverse reaction conditions, at the same time, in view of the differences between Asian and Caucasian population statistics, comparison between the two races of two regimens for different drugs. Economics in China started late, the current single research methods the majority of our field of diabetes drug economics and the treatment only short-term economic evaluation. For the further study of treatment regimens The long-term economy, from the social point of view, based on the Meta analysis, the model research of mature drug economics, according to the T2DM natural history process, establish the Markov model, the cost and utility of further simulation of DPP-4 inhibitors combined with metformin in the treatment of T2DM for 30 years, and the economic evaluation of the efficacy of combination therapy in the long-term the angle, in order to promote the rational use of drugs, reduce the financial burden of patients and society. Methods 1 Meta Medline (PubMed) database retrieval analysis, clinical trial site (www.clinicals.gov) and the reference lists of relevant literature, randomized controlled trials with standard, glycosylated hemoglobin extract the need (glycosylated hemoglobin, A1c, HbA1c) fasting blood glucose (fasting plasma, glucose, FPG), body weight, stable beta cell function index (homeostasis model assessment of -cell function index HO beta. MA- beta), HOMA IR (homeostasis model assessment of insulin resistance index, HOMA-IR), total cholesterol (total, cholesterol, TC), low density lipoprotein cholesterol (low-density lipoprotein, cholesterol, LDL-C), triglycerides (triglycerides, TG), high density lipoprotein cholesterol (high-density lipoprotein cholesterol, HDL-C) etc. data and hypoglycemia, gastrointestinal side effects, pancreatitis and other adverse reactions, the application of Review Manager (RevMan) 5.3 statistical analysis with.2 data extraction between Asian and Caucasian compared with SPSS19 software, compared with the single metformin compared to long-term drug treatment effect of metformin combined with DPP-4 inhibitor economic differences between Asian and Caucasian.3 DPP-4 the 3.1 inhibitors combined with metformin Markov model is established according to T2DM self evaluation The transfer process, the establishment of diabetic without concurrent, diabetes complications and death Markov model state to 1 years for the 1 Markov cycle, combined with the analysis and literature research Meta transfer probability model is needed, the cost and utility value, simulation of two therapeutic schemes for 30 years required by quality and cost adjusted life year (Quality-adjusted Life Years, QALYs), so as to carry out the pharmacoeconomic evaluation of long-term.3.2 model analysis using Markov model to take the analysis, cost utility and the number of queue simulation of two kinds of treatment according to the need, through the incremental cost utility ratio (incremental cost-utility ratio, ICUR) long-term economic evaluation of DPP-4 inhibitors combined with at the same time of metformin treatment and cost sensitivity analysis of utility value and the discount rate, the stability evaluation model. The results of 1 Meta analysis according to the inclusion and exclusion criteria, 27 randomized controlled trials were included, involving 10089 patients, of which 5569 DPP-4 inhibitors combined with metformin group, metformin monotherapy group was 4520. Compared with metformin alone, DPP-4 inhibitors combined with metformin can significantly reduce the HbA1c-0.61% (-0.69 to-0.52 p0.00001), FPG-1.10 mmol/1 (-1.29 to-0.92, p0.00001 TG-0.21 and mmol/1 (-0.33) to-0.10, p=0.0002) level, and can reduce the TC-0.11 mmol/1 -0.20 (to-0.02, p=0.02, HOMA-IR-0.19 (-0.36 to-0.02 p=0.03) and gastrointestinal side effects of RR 0.88 (0.79 to 0.98, p=0.02) and a significant increase in the incidence of HOMA- beta 8.86 (7.4 to 10.32, p0.00001). The body weight, LDL-C, HDL-C. The adverse effect of pancreatitis and hypoglycemia, there is no significant difference between the two groups (P0.05). The sensitivity analysis results showed different effect model results, better stability of.2 Asian model And the comparison between Caucasians included 27 randomized controlled trials in 4 papers mainly study population are Asians, 23 papers mainly study Caucasians. Compared with the single dose metformin group, in combination, HbA1c, FPG, weight and HOMA-IR, there was no significant difference between Asian and Caucasus, respectively, -0.05% (-0.30 to 0.20, p=0.69), 0.17 mmol/1 (-0.52 to 0.85, p=0.62), -0.15kg (-0.64 to 0.35, p=0.53) and 0.27 (-0.98 to 1.53, p=0.64), and HOMA-P significantly lower than Caucasian Asians -5.79 (-10.26 to-1.32, p=0.01.3) through the results of pharmacoeconomic evaluation to take out five kinds of cost utility analysis DPP-4 inhibitors combined with metformin respectively than sitagliptin plus metformin for 10713.41 yuan /QALY, 11261.50 yuan /QALY Shah Glenn Dean + metformin and vildagliptin metformin + two 11001.28 yuan /QALY, Glenn + two armor Biguanide 11169.58 yuan /QALY, Agger 4 + metformin 10815.48 yuan /QALY, from that of sitagliptin and metformin in treatment of the most cost utility. The sitagliptin plus metformin treatment group and metformin group were the cohort simulation, results show that entering the queue among 1000 people, compared with metformin treatment group, treatment sitagliptin plus metformin 53 saved the lives of patients. The cost utility analysis showed that 3% of the discount rate of sitagliptin and metformin in treatment of diabetes for 30 years the cost of 157808.48 yuan, compared with metformin group, the incremental cost is 37533.14 yuan, QALY for 14.73 years, 0.53 years longer than the metformin treatment group ICUR, 70817.24 yuan /QALY, WHO lower than the recommended threshold standard (3GDP), the combination therapy has cost effectiveness. The sensitivity analysis results show that when the parameters in the set range Within the changes will not affect the model conclusions. In conclusion, this paper systematically, comprehensively evaluate the short-term efficacy and safety of DPP-4 inhibitors combined with metformin in the treatment of T2DM, provide a basis for clinical rational use of drugs; the cost and effect of applying Markov model to simulate the combined treatment plan for 30 years, to make up for deficiencies in the research in the field of data the lack of health outcomes and economic comprehensive evaluation of treatment, can improve the quality of life of patients to a certain extent, reduce the financial burden of patients and society.

【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R587.1

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