本文關鍵詞：DPP-4抑制劑聯合二甲雙胍治療T2DM的短期效果及長期藥物經濟學評價　出處：《山東大學》2016年碩士論文　論文類型：學位論文

  更多相關文章： 二甲雙胍 DPP-4抑制劑 Meta分析 藥物經濟學 Markov模型 成本-效用分析

【摘要】：目的糖尿病是全世界人民共同面臨的重大公共衛生問題,其中約900%0～95%為2型糖尿病(type 2 diabetes mellitus, T2DM)患者。T2DM是一種慢性疾病,病程較長且血糖需要長期維持在一個較好的水平上,如果血糖控制不佳會引起嚴重的大血管及微血管并發癥,不僅影響患者生活質量,還給患者及社會帶來巨大經濟負擔。因此,臨床不僅需要療效顯著更需要經濟性好的藥物用于糖尿病的治療和并發癥的預防。目前臨床常用的降糖藥物有很多,其中二甲雙胍是T2DM患者控制血糖的一線用藥和聯合用藥中的基本藥物,然而二甲雙胍在用藥初期療效顯著,隨著病情進展往往需要與第二種降糖藥物聯合使用。如何選擇與二甲雙胍聯合應用的降糖藥物是一直以來我們不斷探討的問題。英國前瞻性糖尿病研究(United Kingdom Prospective Diabetes study, UKPDS)結果顯示,無論采用哪種聯合方式,隨著糖尿病進展,胰島細胞功能都會出現進行性衰退,最終導致血糖控制不佳,因此保護胰島細胞功能、延緩其衰退進度是新治療方案的一個重要靶點。二肽基肽酶-4(dipeptidyl peptidase-4, DPP-4)抑制劑的出現給患者帶來希望,其不僅能提高胰高血糖素樣肽-1 (glucagonlike peptide-1, GLP-1)和葡萄糖依賴性促胰島素釋放多肽(glucose-dependent insulinotropic polypeptide, GIP)的水平及其活性,還能保護胰島p細胞,從而延緩并發癥的發生和發展。其中,DPP-4抑制劑與二甲雙胍聯合治療手段也受到越來越多臨床醫生的青睞。隨著DPP-4抑制劑在臨床推廣使用,為能更好的指導臨床實踐,有必要全面了解DPP-4抑制劑聯合二甲雙胍的治療效果及安全性。因此,本課題首先通過Meta分析全面、系統地評價了與二甲雙胍相比,DPP-4抑制劑聯合二甲雙胍的短期治療效果及各種不良反應的發生情況,同時鑒于亞洲人和高加索人人口統計學的差異,比較了兩個人種之間兩種用藥方案差異的不同。我國藥物經濟學起步較晚,目前我國糖尿病領域多數藥物經濟學研究方法單一且對治療方案僅進行了短期經濟學評價。為進一步研究治療方案的長期經濟性,本課題從社會角度出發,在Meta分析基礎上,采用藥物經濟學中研究較成熟的模型法,根據T2DM自然轉歸過程,建立Markov模型,進一步模擬DPP-4抑制劑聯合二甲雙胍治療T2DM 30年的成本及效用,從長期角度評價該聯合治療方案的療效和經濟性,以期促進合理用藥,降低患者和社會的經濟負擔。方法1 Meta分析檢索Medline (pubmed)數據庫、臨床試驗網站(www.clinicals.gov)及相關文獻的參考文獻列表,納入符合標準的隨機對照試驗,提取所需要的糖化血紅蛋白(glycosylated hemoglobin A1c, HbA1c)、空腹血糖(fasting plasma glucose, FPG)、體重、穩態β細胞功能指數(homeostasis model assessment of β-cell function index, HOMA-β)、穩態模型胰島素抵抗指數(homeostasis model assessment of insulin resistance index, HOMA-IR)、總膽固醇(total cholesterol, TC)、低密度脂蛋白膽固醇(low-density lipoprotein cholesterol,LDL-C)、甘油三酯(triglycerides, TG)、高密度脂蛋白膽固醇(high-density lipoprotein cholesterol, HDL-C)等效果數據及低血糖、胃腸道副反應、胰腺炎等不良反應數據,應用Review Manager (RevMan) 5.3統計分析合并提取的數據。2亞洲人和高加索人之間的比較應用SPSS19軟件,比較與單用二甲雙胍相比,DPP-4抑制劑聯合二甲雙胍治療效果在亞洲人和高加索人之間的差異。3 DPP-4抑制劑聯合二甲雙胍的長期藥物經濟學評價3.1 Markov模型的建立根據T2DM的自然轉歸過程,建立糖尿病無并發、糖尿病有并發癥及死亡的Markov模型狀態,以1年為1個Markov周期,結合Meta分析及文獻研究獲得模型所需要的轉移概率、成本及效用值,模擬兩種方案治療30年所需要的成本及所獲的質量調整生命年(Quality-adjusted Life Years, QALYs),從而進行長期的藥物經濟學評價。3.2模型分析運用Markov模型進行回乘分析、隊列模擬獲得兩種治療方案所需要的成本及效用數據,通過增量成本效用比(incremental cost-utility ratio, ICUR)評價DPP-4抑制劑聯合二甲雙胍治療的長期經濟性,同時對成本、效用值及貼現率進行敏感度分析,評價模型的穩定性。結果1 Meta分析根據納入和排除標準,共納入27篇隨機對照試驗,涉及患者10089名,其中DPP-4抑制劑聯合二甲雙胍組5569名,二甲雙胍單藥治療組4520名。與單用二甲雙胍相比,DPP-4抑制劑聯合二甲雙胍能顯著降低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)和胃腸道副作用RR 0.88 (0.79 to 0.98, p=0.02)的發生率,同時顯著增加HOMA-β 8.86 (7.4 to 10.32, p0.00001)。對體重、LDL-C、HDL-C、胰腺炎及低血糖等不良反應的影響,兩組之間沒有顯著性差異(p0.05)。敏感性分析結果示不同效應模型的結果一致,模型穩定性較好。2亞洲人和高加索人之間的比較納入的27篇隨機對照試驗中4篇文獻主要研究人群是亞洲人,23篇文獻主要研究高加索人。與二甲雙胍單劑量組相比,聯合用藥后,在HbA1c、FPG、體重和HOMA-IR方面,亞洲人和高加索人之間沒有顯著性差異,分別為-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),而亞洲人HOMA-P的改善低于高加索人-5.79(-10.26 to-1.32,p=0.01)。3藥物經濟學評價結果通過回乘分析得出五種DPP-4抑制劑聯合二甲雙胍的成本效用比分別為：西格列汀+二甲雙胍10713.41元/QALY、沙格列汀+二甲雙胍11261.50元/QALY、維格列汀+二甲雙胍11001.28元/QALY、格列汀+二甲雙胍11169.58元/QALY、阿格列汀+二甲雙胍10815.48元/QALY,由此看出西格列汀聯合二甲雙胍治療最具成本效用。對西格列汀+二甲雙胍治療組和二甲雙胍單藥治療組分別進行隊列模擬,結果顯示假設進入隊列的人群共1000人,與二甲雙胍治療組相比,西格列汀+二甲雙胍的治療挽救了53名患者的生命。成本效用分析顯示,3%的貼現率下西格列汀+二甲雙胍聯合治療糖尿病30年所需成本為157808.48元,與二甲雙胍組相比,增量成本為37533.14元,QALY為14.73年,比二甲雙胍治療組延長0.53年,ICUR為70817.24元/QALY,低于WHO推薦的閾值標準(3GDP),該聯合治療方案具有成本效用。敏感度分析結果顯示,當各參數在設定范圍內變化時不會影響模型結論。結論綜上所述,本課題系統、全面的評價了DPP-4抑制劑聯合二甲雙胍治療T2DM的短期效果和安全性,為臨床合理用藥提供了一定依據；運用Markov模型模擬該聯合方案治療30年的成本及效果,彌補了該領域研究數據不足的缺陷,綜合評價治療方案的健康產出和經濟性,能在一定程度上提高患者生命質量,減輕患者和社會的經濟負擔。
[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.

【學位授予單位】：山東大學
【學位級別】：碩士
【學位授予年份】：2016
【分類號】：R587.1

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