噻唑烷二酮类药物临床安全性评价

噻唑烷二酮类药物(TZD)是一类新型口服降糖药,主要通过激活过氧化物酶体增生物激活受体γ(PPARγ)增强胰岛素敏感性.临床资料一致表明,这类药物中的罗格列酮和吡格列酮均可显著增加心力衰竭风险.资料显示,罗格列酮可能增加缺血性心脏病变包括心肌梗死(MI)的发病风险,虽然该绝对风险极低,但吡格列酮则不增加该风险.此外,TZD可抑制骨形成,加速骨丢失,增加女性2型糖尿病患者四肢骨折风险.本文总结近年来已完成或正在进行的以及荟萃分析的TZD相关的临床研究结果,以期对TZD的临床安全性进行客观评估.     

口服降糖药物治疗Ⅱ型糖尿病的药物经济学研究

目的:选取两种口服格列酮类药物进行口服降糖药物治疗Ⅱ型糖尿病的药物经济学研究.方法:药物经济学分析方法采用成本效果分析法.结果:以本研究计算, 马来酸罗格列酮组治疗成本为2 340元,盐酸吡格列酮组治疗成本为1 014元.使糖化血红蛋白下降1%,马来酸罗格列酮组需835.71元,而盐酸吡格列酮组只需336.88元.结论:以成本效果分析, 与马来酸罗格列酮相比,盐酸吡格列酮是糖尿病患者较经济的治疗选择.     

罗格列酮和吡格列酮对65岁以上糖尿病患者心血管事件风险的meta分析

目的:系统评价罗格列酮和吡格列酮对65岁以上糖尿病患者心血管事件的风险。方法:以"罗格列酮","吡格列酮","心血管风险","心血管事件","老年患者","65岁以上",以及"队列研究"为关键词,分别检索Cochrane图书馆(1996—2010年)、PubMed(1966—2010年)、荷兰医学文摘(1966—2010年)、中国期刊全文数据库(1979—2010年)、中国生物医学文献数据库(1978—2010年)和中国科技期刊数据库(1989—2010年)。收集罗格列酮和吡格列酮治疗65岁以上糖尿病患者所致心血管事件风险比较的回顾性队列研究的文献。根据纳入标准对文献进行筛选和评估,采用RevMan 5.0软件对数据进行meta分析,计算65岁以上糖尿病患者应用罗格列酮或吡格列酮后心肌梗死、心力衰竭及全因死亡的相对危险系数(RR)和95%可信区间(CI)。结果:共获得相关文献74篇,经筛选最终纳入2008—2010年3项回顾性队列研究,共有患者295 668例,其中应用罗格列酮患者104 479例,应用吡格列酮患者191 189例。meta分析结果显示,与应用吡格列酮患者相比,应用罗格列酮患者心肌梗死、心力衰竭和全因死亡的发生率均高,其RR(95%CI)分别为1.05(0.98～1.13,P=0.17),1.22(1.05～1.40,P=0.007),1.14(1.08～1.21,P<0.000 01)。结论:老年2型糖尿病患者应用罗格列酮治疗,发生心力衰竭及全因死亡的风险较吡格列酮高。     

2004年我院门诊患者口服降糖药物使用情况的评价

目的:了解口服降糖药的药物利用情况。方法:采取回顾性调查方法,查阅糖尿病出院病历86份,对其中所使用的口服降糖药的药物利用度进行统计与分析。结果:本次调查的口服降糖药出现的频率排序为二甲双胍、格列齐特、格列喹酮、格列吡嗪、阿卡波糖、罗格列酮、瑞格列奈、格列苯脲,药物利用指数DUI<1。结论:我院口服降糖药的使用基本合理。     

吡格列酮治疗2型糖尿病的临床疗效观察

目的观察吡格列酮单用及分别与二甲双胍、格列美脲联用治疗2型糖尿病的临床疗效及不良反应。方法 2型糖尿病患者93例,随机分为3组各31例:单用吡格列酮治疗组给予吡格列酮口服控制血糖治疗;吡格列酮联合二甲双胍控制血糖治疗;吡格列酮联合格列美脲控制血糖治疗。观察3组患者在空腹血糖(FBG)、餐后2 h血糖(2hPG)、糖化血红蛋白(HbA1c)等指标的变化情况及药物不良反应。结果治疗8周后,3组患者在控制FBG、2hPBG、HbA1c各项指标达标率方面均取得较好疗效,联合用药治疗组的指标达标率均高于单用吡格列酮治疗组,但联合用药组不良反应发生率亦较单用吡格列酮治疗组不良反应发生率增高。结论吡格列酮单用能较好的控制2型糖尿病患者的血糖水平,与格列美脲或二甲双胍合用在控制2型糖尿病的血糖方面则取得更好的临床疗效,但合用组易发生低血糖不良反应,尤以吡格列酮与格列美脲联用为明显。     

吡格列酮和罗格列酮治疗老年2型糖尿病的疗效对比(英文)

目的 探讨吡格列酮和罗格列酮对2型糖尿病患者血糖、血脂水平的影响.方法 将我院内分泌科门诊及病房收治的符合1997年WHO诊断标准的2型糖尿病患者64例.予以饮食控制,运动治疗,且同时口服降糖药物固定在1mo以上,空腹血糖仍≥7 mmol·L-1的患者,随机分为吡格列酮组和罗格列酮组,分别加用吡格列酮或罗格列酮12 wk.结果 ①吡格列酮组和罗格列酮组的空腹血糖、餐后2 h血糖、糖化血红蛋白、胰岛素抵抗指数均较治疗前明显降低(P＜0.05),两者之间降低的程度没有显著性差异.②毗格列酮组血三酰甘油和总胆固醇水平较治疗前明显降低(P＜0.05),但罗格列酮组无明显变化(P＞0.05).③2组的高密度脂蛋白水平均比治疗前明显升高(P＜0.05和P＜0.01),但吡格列酮组升高的幅度大于罗格列酮组.结论 吡格列酮和罗格列酮治疗后均能有效控制血糖,但吡格列酮能更明显地改善血脂.     

吡格列酮与盐酸罗格列酮治疗2型糖尿病疗效比较

目的：比较吡格列酮与罗格列酮治疗2型糖尿病的临床疗效.方法：60例磺酰脲类和双胍类治疗而空腹血糖控制不佳（7.0 mmol·L-1≤空腹血糖（FBG）≤13.0 mmol·L-1）的2型糖尿病患者,随机分入吡格列酮15 mg·d-1组与罗格列酮4mg·d-1组,治疗12周后比较2组疗效.结果：12周后,2组空腹和餐后2 h血糖、胰岛素和糖化血红蛋白均明显下降（P〈0.01）,但2组间差异无统计学意义（P〉0.05）.吡格列酮组总费用合计为189.84元、罗格列酮组为440.16元,2组均无严重不良反应发生.结论：吡格列酮与罗格列酮治疗2型糖尿病疗效相似,但吡格列酮的费用明显低于罗格列酮.     

我院2005—2007年口服降糖药应用情况分析

目的了解医院口服降糖药的产品结榭和使用情况。方法采用用药频度（DDDs）排序、金额排序进行比较。结果2005—2007年3年间临床治疗2型糖尿病的方案普遍以二甲双胍及磺酰脲类的格列本脲及格列吡嗪、格列齐特作为一线药物,辅以阿卡波糖、罗格列酮、吡格列酮、瑞格列奈等,用药结构比较合理。结论该院口服降糖药的临床应用较为合理,高效、低毒、服用方便、价格便宜的药物受到临床青睐。     

伊格列净联合其他口服降糖药治疗2型糖尿病的有效性及安全性的系统评价

目的:系统评价伊格列净与其他口服降糖药联合治疗2型糖尿病的有效性和安全性,为其临床应用提供依据。方法:检索PubMed、Cochrane图书馆、Embase、Medline、中国知网、万方、维普、中国生物医学文献数据库中伊格列净联合其他口服降糖药治疗2型糖尿病的随机对照试验(randomized controlled trial,RCT),检索时限为建库起至2016年12月,对纳入研究进行质量评价和Meta分析。结果:5项RCT符合纳入标准,共计863例患者。Meta分析结果显示:与安慰剂组相比,使用伊格列净联用其他口服降糖药治疗患者的糖化血红蛋白水平和空腹血糖水平降低更明显[MD=-0.82,95%CI(-1.17,-0.46),P<0.05;-29.53,95%CI(-40.55,-18.50),P<0.05],而HbA1c<7.0%的比例更高[OR=3.70,95%CI(2.46,5.58),P<0.05]。安全性方面,伊格列净联用其他口服降糖药发生低血糖、尿路感染以及生殖道感染的风险和安慰剂组相比差异无显著性[OR=1.57,95%CI(0.43,5.71),P>0.05;OR=0.98,95%CI(0.42,2.25),P>0.05;OR=0.46,95%CI(0.12,1.74),P>0.05]。结论:与安慰剂组相比,伊格列净联用其他口服降糖药治疗能更加有效地降低糖化血红蛋白以及空腹血糖水平,且发生低血糖等不良反应的风险低。受纳入研究方法学限制,该结论尚需大样本、多中心的RCT进一步验证。     

吡格列酮和罗格列酮治疗2型糖尿病伴高脂血症的疗效比较

目的:观察吡格列酮和罗格列酮对2型糖尿病伴高脂血症患者血糖、胰岛素抵抗和血脂水平的影响。方法:将空腹血糖水平在7.0~13.0mmol.L-1和三酰甘油水平在1.7~6.9mmol.L-1的初诊2型糖尿病患者随机分为吡格列酮或罗格列酮组。吡格列酮每日30mg治疗24周;罗格列酮8mg治疗24周。结果:于24周时,吡格列酮和罗格列酮两组空腹血糖、餐后2h血糖、糖化血红蛋白、空腹胰岛素、胰岛素抵抗指数均较治疗前明显降低(P<0.01),两者之间降低的程度没有显著性差异(P>0.05)。吡格列酮组血三酰甘油和总胆固醇水平较治疗前明显降低(P<0.01),但罗格列酮组无明显变化(P>0.05)。两组的高密度脂蛋白胆固醇水平均比治疗前明显升高(P<0.05)和(P<0.01),但吡格列酮组升高的幅度大于罗格列酮组(P<0.05)。吡格列酮组的低密度脂蛋白胆固醇水平无明显变化(P>0.05),但罗格列酮组的低密度脂蛋白胆固醇水平比治疗前增高(P<0.05)。结论:吡格列酮和罗格列酮均能有效地控制2型糖尿病患者的血糖,降低胰岛素抵抗。但两者对血脂的影响明显不同,吡格列酮对血脂的影响明显优于罗格列酮。     

Pioglitazone, rosiglitazone, and rosiglitazone + metformin: new drugs. Glitazone + oral antidiabetic combination: inadequately evaluated

(1) When single-agent therapy provides inadequate glycaemic control for patients with type 2 diabetes, most guidelines recommend metformin in combination with a glucose-lowering sulphonylurea as standard treatment, despite the lack of any proven impact on morbidity or mortality. Other options include switching to insulin or abandoning the target of strict glycaemic control. (2) Pioglitazone and rosiglitazone are approved for use in combination with a glucose-lowering sulphonylurea when metformin is poorly tolerated or contraindicated, and in combination with metformin in overweight patients. (3) A fixed-dose combination containing 1 or 2 mg of rosiglitazone plus 500 mg of metformin (hydrochloride) was launched onto the French market in October 2004. (4) The indication for rosiglitazone was extended to include its use as triple-agent therapy in combination with metformin and a glucose-lowering sulphonylurea. (5) No clinical trials assessing effects on mortality or morbidity have evaluated rosiglitazone or pioglitazone in combination with other oral antidiabetic drugs. (6) Several trials have compared the glucose-lowering effects of dual-agent therapy using rosiglitazone or pioglitazone plus a glucose-lowering sulphonylurea or metformin versus dual-agent therapy with metformin and a glucose-lowering sulphonylurea. (7) These clinical trials indicate that in terms of HbA1c level, dual-agent therapy based on rosiglitazone or pioglitazone is about as effective as combination therapy with metformin plus a glucose-lowering sulphonylurea. (8) The main known adverse effect of pioglitazone and rosiglitazone is water-sodium retention, which can provoke oedema and haemodilution anaemia, and can aggravate or reveal heart failure. (9) Pioglitazone has a positive effect on the lipid profile, whereas rosiglitazone increases the LDL-cholesterol level. (10) Dual-agent therapy with pioglitazone and a sulphonylurea causes more weight gain than metformin plus a sulphonylurea. (11) Several trials have assessed triple-agent regimens containing a glitazone. Three placebo-controlled double-blind trials have tested pioglitazone (one trial, nearly 300 patients) or rosiglitazone (two trials, about 1200 patients) for 12 to 26 weeks in patients whose glycaemia was poorly controlled by dual-agent therapy with a sulphonylurea plus metformin. The glycated haemoglobin level fell by 0.3% to 1.1% (in absolute values), depending on the trial and the dosage, but at a cost of the usual adverse effects such as weight gain, anaemia and oedema. Three unblinded trials have compared oral triple-agent regimens containing glitazone versus insulin plus metformin, alone or in combination with a glucose-lowering sulphonylurea; the treatment including glitazone was no more effective in terms of the glycated haemoglobin level, but was associated with an increase in adverse effects and dropouts. (12) Given the limited clinical data available in early 2005, pioglitazone and rosiglitazone have no place in the management of type 2 diabetes.     

Genetic predisposition of life-threatening antiepileptic-induced skin reactions

Background: Thiazolidinediones (TZDs) are widely used antidiabetic drugs with proven efficacy regarding mainly surrogate markers of diabetes management. However, efficacy on surrogate markers may not always translate into benefits in clinical outcomes. Thiazolidinediones are usually well tolerated; however, their use may be associated with several adverse effects. The first TZD, troglitazone, was withdrawn from the market owing to serious hepatotoxicity. However, this does not seem to be the case with newer TZDs. Objective: The aim of the present review is to discuss the safety profile of this drug class. Methods: We searched PubMed up to July 2008 using relevant keywords. Conclusions: Common side effects associated with TZDs include edema, weight gain, macular edema and heart failure. Moreover, they may cause hypoglycemia when combined with other antidiabetic drugs as well as decrease hematocrit and hemoglobin levels. Increased bone fracture risk is another TZD-related side effect. Thiazolidinediones tend to increase serum low density lipoprotein cholesterol levels, with rosiglitazone having a more pronounced effect compared with pioglitazone. Moreover, rosiglitazone increases low density lipoprotein particle concentration in contrast to pioglitazone where a decrease is observed. Rosiglitazone has been associated with an increase in myocardial infarction incidence. On the other hand, pioglitazone may reduce cardiovascular events. Overall, TZDs are valuable drugs for diabetes management but physicians should keep in mind that they are associated with several adverse events, the most prominent of which is heart failure.     

Thiazolidinediones in diabetes: current status and future outlook

Thiazolidinediones have recently emerged as promising antidiabetic drugs. Unlike other oral antidiabetic drugs, thiazolidinediones function to ameliorate insulin resistance, a primary factor for the development of type 2 diabetes. Thiazolidinediones are ligands of the nuclear receptor, peroxisome proliferator-activated receptor-gamma, and their antidiabetic effects appear to be mediated by activation of this receptor. The two currently marketed thiazolidinediones, rosiglitazone and pioglitazone, display similar efficacies in their glucose lowering activities, but interestingly display slightly different clinical and side effect profiles. Understanding the molecular basis for these differences will help in the development of next generation thiazolidinediones that are more efficacious and safer for the treatment of type 2 diabetes.     

应用磺脲类药物和二甲双胍治疗2型糖尿病失效后补充第3种降糖药的选择

目的:对应用磺脲类药物和二甲双胍后血糖仍控制不佳的2型糖尿病患者,观察补充第3种药物控制血糖的效果和安全性。方法:119例2型糖尿病患者(年龄(56.1±14.0)岁,糖化血红蛋白A(1HbA1c)(9.1±1.6)%)分为3组,分别随机补充甘精胰岛素、罗格列酮、阿卡波糖,根据血糖调整3种药物用量。补充药物治疗24周前、后,分别测定3组患者的HbA1c、空腹血糖(FPG)、体质量等指标变化。结果:甘精胰岛素组血糖(HbA1c(-1.66±0.24)%,FPG(-3.68±0.28)mmol·L-1)改善比罗格列酮组(HbA1c(-1.15±0.17)%,FPG(-2.85±0.26)mmol·L-1)、阿卡波糖组(HbA1c(-0.75±0.22)%,FPG(-1.85±0.26)mmol·L-1)更明显(P<0.05)。与口服降糖药(罗格列酮或者阿卡波糖)比较,甘精胰岛素组患者外周水肿、胃肠道反应等发生几率更少或更轻微(P<0.05),仅体质量增加比阿卡波糖组明显(P<0.05)。3组患者低血糖发生率和治疗费用差异无统计学意义(P>0.05)。结论:对应用磺脲类药物和二甲双胍后血糖仍控制不佳的2型糖尿病患者,补充甘精胰岛素比补充口服降糖药(罗格列酮或者阿卡波糖)降糖效力更强,且副作用无明显增加。     

Vildagliptin: the evidence for its place in the treatment of type 2 diabetes mellitus

Introduction:

Type 2 diabetes is increasing in prevalence worldwide and is a leading cause of morbidity and mortality, mainly due to the development of complications. Vildagliptin is an inhibitor of dipeptidyl peptidase 4 (DPP-4), a new class of oral antidiabetic agents.

Aims:

To evaluate the role of vildagliptin in the management of type 2 diabetes.

Evidence review:

Clear evidence shows that vildagliptin improves glycemic control (measured by glycosylated hemoglobin and blood glucose levels) more than placebo in adults with type 2 diabetes, either as monotherapy or in combination with metformin. Vildagliptin is as effective as pioglitazone and rosiglitazone, and slightly less effective than metformin, although better tolerated. Further glycemic control is achieved when adding vildagliptin to metformin, pioglitazone, or glimepride. There is evidence that vildagliptin improves beta-cell function and insulin sensitivity. Vildagliptin does not appear to be associated with weight gain or with a higher risk of hypoglycemia than placebo or other commonly used oral antidiabetic agents. Economic evidence is currently lacking.

Place in therapy:

Vildagliptin improves glycemic control with little if any weight gain or hypoglycemia in adult patients with type 2 diabetes when given alone or in combination with metformin, thiazolidinediones, or sulfonylureas. Since many diabetic patients require combination therapy, the complementary mechanism of action of vildagliptin and other commonly prescribed antidiabetic drugs represents an important new therapeutic option in diabetes management.     

A comparison of pioglitazone and rosiglitazone for hospitalization for acute myocardial infarction in type 2 diabetes

BACKGROUND: Recent studies have raised concerns about potential increased cardiovascular (CV) risk in type 2 diabetes patients treated with some peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonists. OBJECTIVE: To ascertain the risk of hospitalization for acute myocardial infarction (AMI) in type 2 diabetes patients treated with pioglitazone relative to rosiglitazone. METHODOLOGY: Using data covering 2003-2006 from a large health care insurer in the US, a retrospective cohort study was conducted in patients who initiated treatment with pioglitazone or rosiglitazone. The hazard ratio (HR) of incident hospitalization for AMI after initiation of treatment with these drugs was estimated from multivariate Cox's proportional hazards survival analysis; similarly, the HR was ascertained for hospitalization for the composite endpoint of AMI or coronary revascularization (CR). RESULTS: A total of 29 911 eligible patients were identified in the database; 14 807 in the pioglitazone and 15 104 in the rosiglitazone group. Baseline demographics, medical history, and dispensed medications were generally well balanced between groups. The unadjusted HR for hospitalization for AMI was 0.82, 95%CI: 0.67-1.01. After adjustment for baseline covariates the HR was 0.78, 95%CI: 0.63-0.96. The adjusted HR for the composite of AMI or CR was 0.85, 95%CI: 0.75-0.98. CONCLUSION: This retrospective cohort study showed that pioglitazone, in comparison with rosiglitazone, is associated with a 22% relative risk reduction of hospitalization for AMI in patients with type 2 diabetes.     

Benefits of combination low-dose pioglitazone plus fish oil on aged type 2 diabetes mice

The elderly patients with type 2 diabetes suffer more adverse drug events than young adults due to pharmacokinetic and pharmacodynamic changes associated with aging. Reducing the risks of these medication-related problems are equally important for the clinical care of older type 2 diabetes patients. Pioglitazone is used for treating type 2 diabetes as an oral antidiabetic drug. Despite pioglitazone is used helpful insulin sensitizers, the accumulation of subcutaneous fat is considered a major adverse effect of pioglitazone therapy. We investigated to reduce the adverse effect of pioglitazone by combination with fish oil rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in aged diabetic KK mice. The accumulation of subcutaneous fat associated with high-dose pioglitazone is reduced by fish oil, suppressing lipogenesis and stimulating fatty acid β-oxidation in the liver. Our data suggest that adding fish oil to low-dose pioglitazone results in antidiabetic efficacy similar to that of the high-dose without concomitant body weight gain.     

罗格列酮的临床研究进展

综述罗格列酮的临床研究进展及不良反应。通过对2型糖尿病病人的空腹血糖和糖基化血红蛋白HbA1c均值变化的比较，发现该药与其他抗糖尿病药联合用药优于单独用药，对只接受过饮食疗法的病人的效果优于接受过其他抗糖尿病药治疗的病人；另外，该药的不良反应轻微，对肝功能无明显影响。     

The Influence of Oral Antidiabetic Drugs on Cellular Drug Uptake Mediated by Hepatic OATP Family Members

As patients with type 2 diabetes receiving oral antidiabetic drugs are often concomitantly treated with other drugs, they are of increased risk for drug interactions. Drugs have to be taken up into hepatocytes before their intracellular drug action or before they are metabolized, and therefore, uptake transporters are important modulators of drug pharmacokinetics and drug effects. To gain more insights into the role of uptake transporters for drug interactions, we investigated whether frequently prescribed oral antidiabetic drugs interact with the transport of drugs, mediated by the hepatic uptake transporters OATP1B1 (gene symbol SLCO1B1), OATP1B3 (gene symbol SLCO1B3) and OATP2B1 (gene symbol SLCO2B1). Using HEK293 cells recombinantly over‐expressing these uptake transporters, we analysed whether glibenclamide, glimepiride, nateglinide and pioglitazone influence the transport of the model transport substrate bromosulfophthalein. Furthermore, we investigated the influence of the same oral antidiabetic drugs and of repaglinide and rosiglitazone on the uptake of the HMG‐CoA‐reductase inhibitor atorvastatin. The oral antidiabetic drugs glibenclamide, glimepiride and nateglinide inhibited the transport of the model substrate bromosulfophthalein, particularly the OATP2B1‐mediated uptake. The OATP‐mediated atorvastatin uptake was inhibited in a similar manner. For glibenclamide, inhibitory constants (K_i values) of 13.6 μM, 8.1 μM and 0.5 μM for OATP1B1‐, OATP1B3‐ and OATP2B1‐mediated BSP uptake were determined. In conclusion, these in vitro results demonstrate that several oral antidiabetic drugs may influence hepatic OATP‐mediated drug uptake. The in vivo consequences of these results have to be analysed in further studies.