Rosiglitazone for type 2 diabetes mellitus
Editorial Group: Cochrane Metabolic and Endocrine Disorders Group
Published Online: 18 JUL 2007
Assessed as up-to-date: 29 APR 2007
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
How to Cite
Richter B, Bandeira-Echtler E, Bergerhoff K, Clar C, Ebrahim SH. Rosiglitazone for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD006063. DOI: 10.1002/14651858.CD006063.pub2.
- Publication Status: Edited (no change to conclusions)
- Published Online: 18 JUL 2007
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 peroxisome proliferator activated receptor gamma (PPAR-gamma) activator rosiglitazone on endothelial function and cardiovascular risk factors might result in fewer macrovascular disease events in people with type 2 diabetes mellitus.
To assess the effects of rosiglitazone in the treatment of type 2 diabetes.
Studies were obtained from computerised searches of MEDLINE, EMBASE and The Cochrane Library.
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 fixed-effects meta-analysis could be performed for adverse events only.
Eighteen trials which randomised 3888 people to rosiglitazone treatment were identified. Longest duration of therapy was four years with a median of 26 weeks. Published studies of at least 24 weeks rosiglitazone treatment in people with type 2 diabetes mellitus did not provide 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 (OR 2.27, 95% confidence interval (CI) 1.83 to 2.81). The single large RCT (ADOPT - A Diabetes Outcomes Progression Trial) indicated increased cardiovascular risk. New data on raised fracture rates in women reveal extensive action of rosiglitazone in various body tissues.
New studies should focus on patient-oriented outcomes to clarify the benefit-risk ratio of rosiglitazone therapy. Safety data and adverse events of all investigations (published and unpublished) should be made available to the public.
Plain language summary
Rosiglitazone 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 rosiglitazone as a member of the 'glitazones' reduced risk markers 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 rosiglitazone 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).
Eighteen trials randomised 3888 people to rosiglitazone therapy. The longest duration of rosiglitazone treatment was four years, most trials lasted around half a year. Unfortunately, the published studies of at least 24 weeks rosiglitazone treatment in people with type 2 diabetes mellitus did not provide relevant evidence that patient-oriented outcomes are positively influenced by this agent. The chance of developing oedema was approximately doubled, the risk of cardiovascular diseases increased. The single large randomised controlled trial showed evidence of raised cardiovascular risk after rosiglitazone treatment. Moreover, new safety data show increased numbers of broken bones in women. This finding was published years after approval of this agent by drug regulatory authorities. New ways of exploring drug effects, for example by early long-term studies in many people, as well as public access to all safety data of published and unpublished investigations have to be established.
糖尿病長久以來被認知為心血管疾病重要的獨立危險因子，在糖尿病患者死亡原因中有７０％的為心血管疾病。前瞻前的研究顯示當對照非糖尿病患，因心血管疾病死亡在男性相對危險性為兩倍到三倍，在女性則為三倍到四倍。第二型糖尿病中兩個最大型的研究:United Kingdom Prospective Diabetes Study (UKPDS)及University Group Diabetes Program (UGDP)並未顯示改善代謝控制可以減少心血管疾病的發生。理論上, rosiglitazone 作用在peroxisome proliferator activated receptor gamma (PPARgamma),因此可能可以改善內皮功能及心血管危險因子，而使得第二型糖尿病大血管疾病的發生變少。
相關研究由電腦搜尋MEDLINE、EMBASE 及The Cochrane Library取得。
總共選了十八個關於rosiglitazone的試驗，試驗中隨機分配共三千八百八十八個人。最長的治療時間為四年，中位數為二十六個星期。在對於第二型糖尿病患使用rosiglitazone追蹤至少二十四週的研究發表中無法提供證據顯示藥物正面影響病人的預後，如致死率、併發症、副作用、花費、健康相關生活品質。如以糖化血色素為替代滿足點表示代謝控制的程度，臨床上無法發現與其它口服降血糖藥的不同。水腫的發生率有明顯的上升(OR 2.27, 95% confidence interval (CI) 1.83 to 2.81)。單一大型隨機對照試驗(ADOPT A Diabetes Outcomes Progression Trial)顯示上升心血管疾病的危險。新的資料發現女生的骨折率上升，顯示rosiglitazone作用在全身的組織上。
此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。
因為安全考量，rosiglitazone在第二型糖尿病患好處與危險性的關聯需要迫切的釐清。心臟及血管疾病占糖尿病患死因中的70%。對應於非糖尿病患，糖尿病患因心臟及血管致死的相對危險，在男性為二倍到三倍，在女性為三倍到四倍。第二型糖尿病主要的特色為胰島素在刺激脂肪及肌肉對血糖的攝取方面的能力下降(胰島素阻抗)，且影響大部分的糖尿病患。市場上有幾類藥物可治療糖尿病，其中rosiglitazone為減少心血管危險標誌的“glitazones”類。然而兩個針對第二型糖尿病患的大型試驗顯示改善血糖不足以減少心血管疾病的危險性，因此我們找尋rosiglitazone至少二十四週的長期研究來探討病人導向的預後。 病人導向的預後我們定義為糖尿病的死亡率、併發症、藥物的副作用、健康相關生活品質、花費及代謝控制(降低血糖到近乎正常值)。 在十八個隨機分配三千八百八十八個人rosiglitazone治療的試驗中,最長研究期間為四年，而大部分的研究為持續半年。不幸的，在為期超過二十四週發布的研究中，這個藥沒有辦法提供相關證據顯示對於病人導向的預後有正面的影響。發生水腫的機會將近兩倍，且心血管疾病的危險性上升。惟一大型的隨機對照試驗顯示rosiglitazone治療會增加心血管疾病的危險性。此外，新的安全資料顯示在女性會增加骨折。這些是在藥物規範機構通過這個藥物的數年後才發現的。新的方式來探討藥物效果須要被建立，比如說早期病人的長期研究，及公布所有已發布及未發表的研究數據。