Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus

 

Abstract

Background

Metformin is an oral anti-hyperglycemic agent that has been shown to reduce total mortality compared to other anti-hyperglycemic agents, in the treatment of type 2 diabetes mellitus. Metformin, however, is thought to increase the risk of lactic acidosis, and has been considered to be contraindicated in many chronic hypoxemic conditions that may be associated with lactic acidosis, such as cardiovascular, renal, hepatic and pulmonary disease, and advancing age.

Objectives

To assess the incidence of fatal and nonfatal lactic acidosis, and to evaluate blood lactate levels, for those on metformin treatment compared to placebo or non-metformin therapies.

Search methods

A comprehensive search was performed of electronic databases to identify studies of metformin treatment. The search was augmented by scanning references of identified articles, and by contacting principal investigators.

Selection criteria

Prospective trials and observational cohort studies in patients with type 2 diabetes of least one month duration were included if they evaluated metformin, alone or in combination with other treatments, compared to placebo or any other glucose-lowering therapy.

Data collection and analysis

The incidence of fatal and nonfatal lactic acidosis was recorded as cases per patient-years, for metformin treatment and for non-metformin treatments. The upper limit for the true incidence of cases was calculated using Poisson statistics. In a second analysis lactate levels were measured as a net change from baseline or as mean treatment values (basal and stimulated by food or exercise) for treatment and comparison groups. The pooled results were recorded as a weighted mean difference (WMD) in mmol/L, using the fixed-effect model for continuous data.

Main results

Pooled data from 347 comparative trials and cohort studies revealed no cases of fatal or nonfatal lactic acidosis in 70,490 patient-years of metformin use or in 55,451 patients-years in the non-metformin group. Using Poisson statistics the upper limit for the true incidence of lactic acidosis per 100,000 patient-years was 4.3 cases in the metformin group and 5.4 cases in the non-metformin group. There was no difference in lactate levels, either as mean treatment levels or as a net change from baseline, for metformin compared to non-metformin therapies.

Authors' conclusions

There is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared to other anti-hyperglycemic treatments.

 

Plain language summary

Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus

Metformin, a medication used to lower glucose levels in patients with diabetes mellitus, has long been thought to increase the risk for a metabolic disorder known as lactic acidosis. This review summarised data from all known comparative and observational studies lasting at least one month, and found no cases of fatal or nonfatal lactic acidosis in 70,490 patient-years of metformin use, or in 55,451 patient-years for those not on metformin. Average lactate levels measured during metformin treatment were no different than for placebo or for other medications used to treat diabetes. In summary, there is no evidence at present that metformin is associated with an increased risk for lactic acidosis when prescribed under the study conditions.

 

摘要

背景

第2型糖尿病患者使用metformin引起致命和非致命乳酸中毒之風險

Metformin是一種使用於治療第2型糖尿病的口服降血糖藥。UK Prospective Diabetes Study的結果顯示：相較於其他降血糖療法，使用metformin治療，可降低總死亡率。然而，metformin被認為會增加乳酸中毒的風險，因此在諸如心血管、腎臟、肝臟、肺臟疾病，以及老年等許多可能與乳酸中毒有關的慢性缺氧情況，metformin都被認為是不宜使用的。

目標

分析相較於使用安慰劑或其他降血糖療法，在第2型糖尿病患者使用metformin所引發之致命和非致命乳酸中毒之機率。而次要目標則是分析接受metformin和安慰劑/非metformin治療的患者，其血中乳酸濃度的差異。

搜尋策略

我們搜尋了Cochrane Library (至8/2005), MEDLINE (至8/2005), EMBASE (至11/2000), OLD MEDLINE, and REACTIONS (至8/2005)，以找出從1966年到2005年8月所有和metformin治療有關的研究。我們並利用Cumulated Index Medicus來搜尋1959至1965年間的相關文獻。我們掃描尋找到的文章之參考文獻，並聯絡主要的研究者，來協助搜尋。最近一次搜尋於2005年8月時進行。

選擇標準

我們選擇在糖尿病患者身上進行超過1個月，單獨使用metformin或與其他治療合併，與安慰劑或任何其他降血糖療法進行比較的前瞻性試驗。而持續超過1個月，對metformin治療的觀察性世代研究亦被收錄。

資料收集與分析

兩位回顧者獨立地選擇收錄的試驗，分析其品質並自其中擷取數據。對於接受metformin治療和接受安慰劑或其他治療者，發生致命及非致命乳酸中毒的機會，以發生案例/患者年的方式記錄。至於在metformin及非metformin組中案例的真實發生率上限，則以Poisson統計法加以推算。在次要分析中，治療組和比較組的乳酸濃度，則以自基礎值的淨改變或平均治療值(基礎和受食物或運動刺激後)來測量。匯集的結果，其連續數據則以固定效率模式處理，並依加權平均差(WMD)，以毫莫耳/升作為單位記錄。

主要結論

由206個比較性試驗及世代研究中所集中的數據顯示：無論是在metformin組的47846位患者年，或是在非metformin組的38221位患者年中，均未出現致命或非致命性乳酸中毒的案例。如以Poisson統計法來推算與metformin相關的乳酸中毒之真實發生率的上限，在95%的信賴區間內，得出的結果為6.3個案例/100000位患者年。而在非metformin組的乳酸中毒之真實發生率的上限，則為7.8個案例/100000位患者年。至於乳酸濃度，無論是平均治療濃度或是與自基礎值的淨改變，metformin組和安慰劑/非biguanide療法組相較，並無差異。與pnehformin相較，接受metformin治療的平均乳酸濃度有略微的降低(WMD −0.75毫莫耳/升，95%信賴區間 −0.86至 −0.15)。

作者結論

根據前瞻性的比較試驗和觀察性的世代研究，並無證據指出:如在與研究相同的環境下處方，和其他降血糖治療相較，metformin並不會使發生乳酸中毒的風險上升，亦不會使乳酸濃度上升。

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

使用metformin可能與乳酸中毒的風險沒有直接關聯。 Metformin，一種使用在糖尿病患者身上的降血糖藥物，長久以來一直被認為會使一種代謝異常狀況乳酸中毒的風險增加。本篇回顧總結了所有已知持續一個月以上的比較性及觀察性研究的數據，無論是使用metformin的47846位患者年，或是不使用metformin的38221位患者年中，均未發現致命或非致命性乳酸中毒的案例。在接受metformin治療時的平均乳酸濃度，與使用安慰劑或其他治療糖尿病的藥物相較，並無不同。總括而言，目前並無證據指出：如在與研究相同的環境下處方，metformin會使發生乳酸中毒的風險上升。