Metformin併用胰島素可能不會降低死亡率


  【24drs.com】根據線上發表於4月19日英國醫學期刊的系統回顧與統合分析結果,對於降低第2型糖尿病患各種原因或心血管之死亡率,併用metformin和胰島素並未優於單用胰島素。
  
  Brian K. Irons博士受邀在電子郵件訪問中發表獨立評論時表示,質疑這會改變現有的實務或影響任何的專業共識建議。
  
  Irons博士是德州科技大學健康科學中心藥學院藥學執業副教授、日間護理部門負責人。Irons博士解釋,事實上,這篇研究實際提供了更多證據支持併用metformin和胰島素,因為併用可以減少使用胰島素相關的體重增加。Metformin或許在限制糖質新生這方面仍可提供某些幫助,略為改善胰島素敏感性,而有助於減少病患的胰島素需要量,特別是過重或肥胖者。
  
  這篇使用統合分析和試驗序列分析之隨機臨床試驗的系統回顧目標,在於比較併用metformin和胰島素與單用胰島素對第2型糖尿病患的利益及傷害。丹麥哥本哈根大學醫院臨床介入研究中心、哥本哈根試驗組博士生Bianca Hemmingsen等人搜尋了相關隨機對照試驗的文獻。
  
  這篇研究包括了至2011年3月止的Cochrane Library、MEDLINE、Embase、Science Citation Index Expanded、Latin American Caribbean Health Sciences Literature以及CIANHL等資料庫。其他資源包括發表於美國糖尿病協會以及歐洲糖尿病研究協會的摘要,各試驗的參考書目,美國食品藥物管理局網站。回顧者也聯絡了相關試驗與藥廠的研究者。
  
  納入統合分析的研究規範為,比較併用metformin和胰島素與單用胰島素、有用或沒有安慰劑的隨機臨床試驗,病患年紀18歲以上、患有第2型糖尿病。介入期必須12週以上,至於發表語言或狀態、預先定義和報告的結果、納入前使用的抗糖尿病介入方式等都不是排除原因。
  
  確認的26篇隨機試驗中,共納入了2,286名研究對象,其中23篇試驗、2,117名資料可用;各試驗的偏見風險高,少有病患相關結果。
  
  與單用胰島素相比,併用metformin和胰島素與各種原因死亡率(相對風險[RR],1.30;95%信心區間[CI],0.57 - 2.99)或心血管死亡率(RR,1.70;95% CI,0.35 - 8.30)都沒有顯著差異。試驗序列分析發現,需要更多試驗,以讓這些結果成為可靠的結論。
  
  根據固定效應模組而非隨機效應模組(RR,2.83;95% CI,1.17 - 6.86),併用metformin和胰島素時,嚴重低血糖確實比單用胰島素更頻繁發生。隨機效應模組中,與單用胰島素相比,併用metformin、胰島素和降低HbA1c與減少體重增加、降低胰島素劑量有關,試驗序列分析顯示,有足夠證據顯示,降低HbA1c 0.5 %,減少體重增加約1公斤、減少胰島素劑量5 U/天。
  
  研究作者寫道,對於第2型糖尿病患,與單用胰島素相比,沒有證據或趨勢顯示併用metformin和胰島素可改善各種原因死亡率或心血管死亡率,資料的限制因素包括,明顯缺乏病患相關結果的報告、偏見控制不佳。
  
  Irons博士表示,就我所知,這是第一篇直接比較併用metformin和胰島素與單用胰島素的統合分析,這是令人欽佩的統合分析結果,著重在各種原因和心血管死亡率。
  
  不過,個別試驗並未聚焦在死亡率(心血管或各種原因),正因為如此,各組之間的總數相當小,也限制了適當比較的能力。因為這些限制,這些研究無法回答「併用metformin和胰島素時對於可能的心血管或各種原因死亡率是否有幫助?」這個問題。
  
  Irons博士指出,其他研究限制包括,樣本小,多數試驗的研究期間相對較短。只有2篇研究持續超過1年,大部分小於6個月。因為是典型的統合分析,各試驗之間的結果確認和納入/排除規範通常有異。
  
  Irons博士結論表示,根據一篇前瞻臨床試驗的觀點,metformin的心血管死亡率效益證據力有限,和其他糖尿病製劑比較並沒有更有效,如果真的想要個答案,metformin對心血管死亡率的好處因為加入胰島素而被保留,需要大型的前瞻研究,以適當強度探究這個差異。
  
  資料來源:http://www.24drs.com/professional/list/content.asp?x_idno=6799&x_classno=0&x_chkdelpoint=Y
  

Adding Metformin to Insulin May Not Reduce Mortality

By Laurie Barclay, MD
Medscape Medical News

April 23, 2012 — The combination of metformin and insulin was no better than insulin alone for reducing all-cause or cardiovascular mortality in patients with type 2 diabetes, according to the results of a systemic review and meta-analysis published online April 19 in the British Medical Journal.

"I doubt this will change how we currently practice nor affect any professional consensus recommendations," Brian K. Irons, PharmD, told Medscape Medical News in an email interview when asked for independent comment.

In fact, Dr. Irons explains, the study actually provides “additional data to support the combination of both metformin and insulin, as the combination can limit the weight gain associated with insulin use." Dr. Irons is division head of ambulatory care and associate professor of pharmacy practice at the School of Pharmacy, Texas Tech University Health Sciences Center in Lubbock. "Metformin may still provide some benefit in limiting gluconeogenesis and to a lesser extent improve insulin sensitivity, which may help attenuate the amount of insulin that is needed for a given patient, particularly in those who are overweight or obese."

The goal of this systematic review of randomized clinical trials, which used meta-analyses and trial sequential analyses, was to compare the benefits and harms of metformin and insulin vs insulin alone in patients with type 2 diabetes. Bianca Hemmingsen, PhD student at the Copenhagen Trial Unit, Centre for Clinical Intervention Research at Rigshospitalet, Copenhagen University Hospital in Denmark, and colleagues searched the literature for pertinent randomized, controlled trials.

This search included the Cochrane Library, MEDLINE, Embase, Science Citation Index Expanded, Latin American Caribbean Health Sciences Literature, and CIANHL until March 2011. Other sources included abstracts presented at the American Diabetes Association and European Association for the Study of Diabetes, bibliographies of identified trials, and the US Food and Drug Administration Web site. The reviewers also contacted investigators of pertinent trials and pharmaceutical companies.

Inclusion criteria for studies in the meta-analysis were randomized clinical trials comparing metformin and insulin vs insulin alone, with or without placebo, in patients older than age 18 years with type 2 diabetes. The intervention period had to be 12 weeks or longer. Publication language or status, predefined and reported outcomes, and antidiabetic interventions used before enrollment were not reasons for exclusion.

Of 26 randomized trials identified, enrolling a total of 2286 participants, 23 trials enrolling a total of 2117 participants had usable data. Risk of bias was high for all trials, and there were few data for patient-relevant outcomes.

Compared with insulin alone, metformin and insulin were not associated with any significant difference in all-cause mortality (relative risk [RR], 1.30; 95% confidence interval [CI], 0.57 - 2.99) or cardiovascular mortality (RR, 1.70; 95% CI, 0.35 - 8.30). Trial sequential analyses revealed that additional trials were needed to allow reliable conclusions concerning these outcomes.

Severe hypoglycemia occurred significantly more frequently with metformin and insulin than with insulin alone, according to a fixed-effect model but not a random-effects model (RR, 2.83; 95% CI, 1.17 - 6.86). Compared with insulin alone, metformin and insulin were associated with reduced hemoglobin A1c, weight gain, and insulin dose in a random-effects model. Trial sequential analyses showed sufficient evidence for lowering of hemoglobin A1c by 0.5 percentage point, weight gain by 1 kg, and insulin dose by 5 U/day.

"There was no evidence or even a trend towards improved all-cause mortality or cardiovascular mortality with metformin and insulin, compared with insulin alone in type 2 diabetes," the study authors write. "Data were limited by the severe lack of data reported by trials for patient relevant outcomes and by poor bias control."

Strengths and Limitations

"This is the first meta-analysis that I know of that directly compares the combination of metformin with insulin compared to insulin alone," Dr. Irons said. He notes that it is admirable that the primary outcomes of the meta-analysis were focused on all-cause and cardiovascular mortality.

However, “[t]he individual trials were not focused on mortality (cardiovascular or all-cause), and as such, the total number of outcomes between groups is quite small and limits the ability for adequate comparison," Dr. Irons said. "Due to its limitations, [the study] cannot answer the question of 'is there still a potential cardiovascular or all-cause mortality benefit of metformin when insulin is added to it?'"

Other limitations noted by Dr. Irons included small size and relatively short duration of most of the trials. Only 2 of the evaluated studies lasted longer than 1 year, and most were less than 6 months in duration. As is typical for meta-analyses, determination of outcomes and inclusion/exclusion criteria often differed among the individual trials.

"Metformin's cardiovascular mortality benefit, from a prospective clinical trial standpoint, has only minimal support and has not been shown to be more effective in this capacity when compared to other diabetes agents," Dr. Irons concluded. "If you truly want to answer the question: is a cardiovascular mortality benefit of metformin retained with the addition of insulin, then large, prospective studies adequately powered to detect this difference are needed."

The Copenhagen Trial Unit funded this study. All study authors declare that: the study received funding from the Copenhagen Insulin and Metformin Therapy Trial Group. Four of the authors have reported equity in Novo Nordisk A/S; 2 have received fees from Novo Nordisk A/S for speech making; and one was employed at Steno Diabetes Centre, Gentofte, Denmark, when the systematic review began. Another author is employed at Steno Diabetes Center, which is an academic institution owned by Novo Nordisk A/S. After the initial draft of the present manuscript, 1 of the authors became employed at Boehringer Ingelheim in Germany. Dr. Irons has disclosed no relevant financial relationships.

BMJ. Published online April 19, 2012.

    
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