Pioglitazone for type 2 diabetes mellitus

 

Abstract

Background

Diabetes has long been recognised as a strong, independent risk factor for cardiovascular disease, a problem which accounts for approximately 70% of all mortality in people with diabetes. Prospective studies show that compared to their non-diabetic counterparts, the relative risk of cardiovascular mortality for men with diabetes is two to three and for women with diabetes is three to four. The two biggest trials in type 2 diabetes, the United Kingdom Prospective Diabetes Study (UKPDS) and the University Group Diabetes Program (UGDP) study did not reveal a reduction of cardiovascular endpoints through improved metabolic control. Theoretical benefits of the newer peroxisome proliferator activated receptor gamma (PPAR-gamma) activators like pioglitazone on endothelial function and cardiovascular risk factors might result in fewer macrovascular disease events in people with type 2 diabetes mellitus.

Objectives

To assess the effects of pioglitazone in the treatment of type 2 diabetes.

Search methods

Studies were obtained from computerised searches of MEDLINE, EMBASE and The Cochrane Library.

Selection criteria

Studies were included if they were randomised controlled trials in adult people with type 2 diabetes mellitus and had a trial duration of at least 24 weeks.

Data collection and analysis

Two authors independently assessed trial quality and extracted data. Pooling of studies by means of random-effects meta-analysis could be performed for adverse events only.

Main results

Twenty-two trials which randomised approximately 6200 people to pioglitazone treatment were identified. Longest duration of therapy was 34.5 months. Published studies of at least 24 weeks pioglitazone treatment in people with type 2 diabetes mellitus did not provide convincing evidence that patient-oriented outcomes like mortality, morbidity, adverse effects, costs and health-related quality of life are positively influenced by this compound. Metabolic control measured by glycosylated haemoglobin A1c (HbA1c) as a surrogate endpoint did not demonstrate clinically relevant differences to other oral antidiabetic drugs. Occurrence of oedema was significantly raised. The results of the single trial with relevant clinical endpoints (Prospective Pioglitazone Clinical Trial In Macrovascular Events - PROactive study) have to be regarded as hypothesis-generating and need confirmation.

Authors' conclusions

Until new evidence becomes available, the benefit-risk ratio of pioglitazone remains unclear. Different therapeutic indications for pioglitazone of the two big U.S. and European drug agencies should be clarified to reduce uncertainties amongst patients and physicians.

 

Plain language summary

Pioglitazone for type 2 diabetes mellitus

Diseases of the heart and blood vessels account for approximately 70% of all mortality in people with diabetes. Compared to their non-diabetic counterparts the relative risk of mortality caused by disorders of the heart and blood vessels is two to three for men and three to four for women with diabetes. Type 2 diabetes is mainly characterised by a reduced ability of the hormone insulin to stimulate glucose uptake in body fat and muscles (insulin resistance) and affects most people suffering from diabetes. Several medications are on the market to treat diabetes, amongst them pioglitazone as a member of the 'glitazones' reduced risk factors for diseases of the heart and blood vessels. Since the two biggest trials in people with type 2 diabetes showed that improved blood glucose alone is not enough to reduce the risk of the above mentioned diseases we looked for longer-term studies investigating 24 weeks as a minimum of pioglitazone treatment on patient-oriented outcomes. As patient-oriented outcomes we defined mortality, complications of diabetes, side effects of the medication, health-related quality of life, costs and metabolic control (lowering of blood glucose to near normal levels).
Twenty-two trials randomised approximately 6200 people to pioglitazone treatment. The longest duration of pioglitazone therapy was 34.5 months. Unfortunately, the published studies of at least 24 weeks pioglitazone treatment in people with type 2 diabetes mellitus did not provide convincing evidence that patient-oriented outcomes are positively influenced by this compound. The occurrence of oedema was significantly raised. The results of the single trial with relevant endpoints (Prospective Pioglitazone Clinical Trial In Macrovascular Events - PROactive study) have to be confirmed by other independent investigations. Until new evidence becomes available (several large trials are ongoing) the place of pioglitazone in the treatment of type 2 diabetes mellitus remains unclear.
Furthermore, confusion arises due to different labelling of pioglitazone, for example in Europe and the USA. Consumers and physicians need clear guidance and transparent information about which studies exactly are used for the decisions of the relevant drug authorities.

 

摘要

背景

Pioglitazone對於第2型糖尿病的效果

糖尿病長久以來均被視為心血管疾病約佔糖尿病患者所有死因之70% −之顯著且獨立的危險因子。前瞻性的研究指出：與無糖尿病者相較，糖尿病患者因心血管疾病死亡的風險，在男性約為2至3倍，而在女性則為3至4倍。2個與第2糖尿病相關的最大研究：the United Kingdom Prospective Diabetes Study(UKPDS)和the University Group Diabetes Program(UGDP)study均未指出改善患者的代謝情況，即可減低心血管疾病的發生機會。新型的peroxisome proliferator activated receptor gamma(PPARgamma)activators，如pioglitazone，於理論上可藉由對血管內皮及心血管危險因子的有益作用，來減少第2型糖尿病患者發生大血管疾病的機會。

目標

評估pioglitazone對於第2型糖尿病的治療效果。

搜尋策略

我們利用電腦搜尋MEDLINE、EMBASE和the Cochrane Library等資料庫來找出相關的研究。最後的搜尋於2006年8月時進行。

選擇標準

我們收錄於成年之第2型糖尿病患者身上進行，且持續至少24週的隨機對照試驗。

資料收集與分析

兩位作者個別評估試驗的品質和萃取資料。以集中研究資料來進行的隨機效應統合分析僅被用於分析不良反應。

主要結論

共有22個，包括6200名受試者，以評估pioglitazone的治療效果為目的的隨機對照試驗被找出。最長的治療期間達到了34.5個月。根據已公佈的研究，並無說服力夠強的證據顯示，第2型糖尿病的病患在接受至少24週的pioglitazone治療之後，其以患者導向的結果，諸如死亡率、罹病率、不良反應、花費和健康相關的生活品質等項，有因使用此藥而獲得正向的改善。如以醣化血色素(HbA1c)作為測量代謝控制的替代終點，則其結果亦未顯示出與其他的口服糖尿病藥物有臨床上顯著的不同。而水腫的發生率則有明顯的上升。至於評估相關臨床終點之單一試驗(Prospective Pioglitazone Clinical Trial In Macrovascular Events  PROactive study)的結果，則必須視為產生新的假設，並需進一步的檢證。

作者結論

直到有新的證據出現之前，使用pioglitazone之利弊仍然未明。美國和歐洲的兩大藥政機關，應區別使用pioglitazone的不同適應症，以減少患者和醫師間的不明確之處。

翻譯人

本摘要由臺灣大學附設醫院林志弘翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

新一代的口服糖尿病藥物pioglitazone對於患者導向結果的影響目前尚不清楚。 心臟及血管的疾病，約佔了糖尿病患者所有死因的70%。與非糖尿病患相較，糖尿病患因心臟和血管病變死亡的相對風險，在男性為2至3倍，在女性則為3至4倍。第2型糖尿病的主要特徵，為胰島素刺激身體脂肪及肌肉攝取葡萄糖的能力減弱(胰島素抗性)，並影響大多數的糖尿病患者。市面上數種治療糖尿病的藥物，包括屬於glitazone類的pioglitazone在內，可減低心臟及血管疾病的危險因子。既然2個與第2型糖尿病相關的最大試驗，皆指出僅降低血糖，並不足以減低上述疾病的風險，我們便尋找以pioglitazone治療至少24週，且目標為患者導向之結果的較長期研究。這裡所指的患者導向之結果，其定義包含了死亡、發生糖尿病的併發症、藥物的不良反應、健康相關的生活品質、費用及代謝控制(將血糖降低至接近正常的濃度)。共有22個評估pioglitazone治療的隨機對照試驗，共包括6200名受試者。其中接受pioglitazone治療的最長時間為34.5個月。很不幸的，依這些讓第2型糖尿病患者接受至少24週pioglitazone治療的研究所公佈的結果，並無法提出有力的證據，證明此一藥物可使患者導向的結果獲得正向的改善。而發生水腫的機會則有顯著的增加。至於評估相關臨床終點之單一試驗(Prospective Pioglitazone Clinical Trial In Macrovascular Events  PROactive study)的結果，必須以其他獨立的調查來確認。直到有新的證據出現之前(目前已有數個大型試驗進行中)，pioglitazone於治療第2型糖尿病的地位仍不明確。更甚者，不同的註記，諸如在歐洲和在美國，會造成混淆。關於相關藥政機關是以哪一個試驗作為決策的依據，消費者和醫師應有明確的指導方針及清晰的資訊。