Aldose reductase inhibitors for the treatment of diabetic polyneuropathy

 

Abstract

Background

Polyneuropathy, a common complication of diabetes mellitus, causes pain and sensory and motor deficits in the limbs, and is also an important independent predictor of foot ulceration. Inhibiting the metabolism of glucose by the polyol pathway using aldose reductase inhibitors is a potential mechanism to slow or reverse the neuropathy's progression.

Objectives

To assess the effects of aldose reductase inhibitors on the progression of symptoms, signs or functional disability in diabetic polyneuropathy.

Search methods

We searched the Cochrane Neuromuscular Disease Group Trials Register, MEDLINE (from January 1966 to May 2007), EMBASE (from January 1980 to May 2007) and LILACS (from 1982 to May 2007). We reviewed bibliographies of randomized trials identified, and contacted authors and experts in the field.

Selection criteria

We included randomized controlled trials comparing an aldose reductase inhibitor with control, and lasting at least six months.
The primary outcome measure was change in neurological function, measured in various ways, including strength testing, sensory examination, and composite scores of neurological examination. Secondary outcome measures were nerve conduction studies, neuropathic symptoms, quality of life, occurrence of foot ulcers and adverse effects.

Data collection and analysis

Trials included in the review were selected and assessed independently by at least two of us. Methodological criteria and study results were recorded on data extraction forms.

Main results

Thirty-two randomized controlled trials meeting the inclusion criteria were identified. Many had significant methodological flaws. Change in neurological function, our primary outcome measure, was assessed in 29 trials, but sufficient data for meta-analysis were only available in 13 studies, involving 879 treated participants and 909 controls. There was no overall significant difference between the treated and control groups (SMD -0.25, 95% CI -0.56 to 0.05), although one subgroup analysis (four trials using tolrestat) favored treatment. A benefit for neuropathic symptoms was suggested by a group of trials using a dichotomized endpoint (improvement or not), but this was contradicted by another group of trials which measured symptoms on a continuous scale. There was no overall benefit on nerve conduction parameters (27 studies) or foot ulceration (one study). Quality of life was not assessed in any of the studies. While most adverse events were infrequent and minor, three compounds had dose limiting adverse events that lead to their withdrawal from human use: severe hypersensitivity reactions with sorbinil, elevation of creatinine with zenarestat, and alteration of liver function with tolrestat.

Authors' conclusions

We found no statistically significant difference between aldose reductase inhibitors and placebo in the treatment of diabetic polyneuropathy. Any future clinical trials of aldose reductase inhibitors should be restricted to compounds proven to have substantial biological or preclinical advantages over previously tested agents.

 

Plain language summary

Aldose reductase inhibitors for the treatment of diabetic polyneuropathy

Polyneuropathy is a common complication of diabetes mellitus that causes pain and sensory and motor deficits in the arms and legs. It can also lead to foot ulcers and amputation. Aldose reductase inhibitors are a class of medications that block the breakdown of glucose by a specific metabolic pathway called the polyol pathway, and may potentially slow or reverse progression of neuropathy. The authors reviewed the results of all randomized trials that compared an aldose reductase inhibitor with a control and lasted at least six months. Many of the 32 randomized controlled trials identified had significant methodological flaws. The trials used a variety of measures to look for a benefit of treatment with aldose reductase inhibitors. The authors elected to focus primarily on changes in muscle strength and sensation. These were chosen because they are thought be the best indicator of the severity of polyneuropathy, and they have been used in a previous landmark study of the effects of intensive blood sugar control on diabetic neuropathy, as well as in studies of treatments in other types of polyneuropathy. Muscle strength or sensation were assessed in 29 trials, but sufficient data for analysis was only available in 13 studies, involving 879 treated participants and 906 controls. There was no overall significant difference between the treated and control groups. For one drug, tolrestat, there was possibly some benefit, but concerns about liver toxicity have lead to withdrawal of tolrestat from use in humans. A few trials did report that symptoms of neuropathy improved for the treated group, but this was contradicted by most other trials. No benefit was detected on electromyography (EMG) parameters (27 studies) or foot ulceration (one study). Quality of life was not assessed in any of the studies. Adverse effects were infrequent and were mostly minor, except for severe allergic reactions with sorbinil, impaired kidney function with zenarestat, and alteration of liver function with tolrestat. The authors concluded that there was no significant benefit of treatment with aldose reductase inhibitors for diabetic polyneuropathy.

 

摘要

背景

醛糖還原脢抑制劑用於治療糖尿病多發性神經病變

多發性神經病變是一種常見的糖尿病併發症，它會造成肢體的疼痛、知覺和運動功能障礙，同時也是一個跟足部潰瘍相關的獨立預測因子。使用醛糖還原脢抑制劑來抑制葡萄糖進入多元醇通路，或許可以減慢或逆轉神經病變的進行。

目標

評估醛糖還原脢抑制劑對糖尿病多發性神經病變在症狀的進行上、病徵上、機能性失能上的效果。

搜尋策略

我們搜尋了Cochrane Neuromuscular Disease Group Trials Register, MEDLINE (1966年1月至2007年5月), EMBASE (1980年1月至2007年5月) 及 LILACS (1982年至2007年5月)。我們檢閱了找到的隨機臨床試驗文獻，並連絡了他們的作者和相關領域的專家。

選擇標準

我們選用了至少進行6個月以上，比較醛糖還原脢抑制劑和對照組比較的隨機臨床試驗。主要成果指標是神經學功能上的改變，包含肌力、感覺、及神經學檢查結果的加權評分。次要成果指標包括：神經傳導研究、神經病變症狀、生活品質、是否出現足部潰瘍、副作用。

資料收集與分析

本篇評論的收集的臨床試驗都經過至少兩位人員的獨立的檢閱。這些研究的方法學標準和研究結果會被紀錄到資料萃取表上。

主要結論

我們找到32個符合選取標準的隨機對照試驗。許多試驗在方法學上有明顯的瑕疵。神經功能上的變化，也就是我們的主要成果指標，在其中29個試驗中有進行評估，但是只有13個試驗提供了足夠我們進行後設分析的資料；這一共是879位治療組和909位控制組。儘管在次分組分析中(使用tolrestat的4個試驗)出現有利於治療組的結果；整體來說，治療組和控制組之間並沒有明顯的差別(標準化均數差 −0.25，95%信賴區間 −0.56 – 0.05)。在神經病變症狀方面，一些使用二分化結果(是否有進步)進行評估的研究指出有幫助，但是另外一些使用連續尺標的研究卻提出一些反證。整體來說在神經傳導方面(27個研究)和足部潰瘍方面(1個研究)也沒有幫助。沒有任何一個研究評估了生活品質。大多數副作用是輕微或不常見的，除了3個化合物的副作用限制了投藥的劑量，進而導致它們不再使用在人類身上，這些副作用分別是：sorbinil造成的嚴重過敏反應、zenarestat造成的肌酸酐上升，以及tolrestat造成的肝功能變化。

作者結論

醛糖還原脢抑制劑和安慰劑在治療糖尿病多發性神經病變上，並沒有統計學上顯著的差異。任何日後有關醛糖還原脢的臨床試驗，只能使用比目前這些藥物，在實際生物試驗或臨床前期試驗上有明顯優點的藥物。

翻譯人

本摘要由新光醫院黃心樂翻譯。

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

總結

多發性神經病變是一種常見的糖尿病併發症，它會造成手腳的疼痛、知覺和運動功能喪失。它也會引發足部潰瘍，甚至到需要截肢。醛糖還原脢抑制劑是一類阻礙葡萄糖透過多元醇通路代謝的藥物；或許有減緩或逆轉神經病變的功效。此篇評論檢閱了所有進行6個月以上，比較醛糖還原脢抑制劑和對照組的隨機臨床試驗。一共收錄了32個臨床試驗的資料，但是這其中有相當多的試驗在方法學上有明顯的瑕疵。這些試驗使用多種方法評估醛糖還原脢的療效，我們的作者群特別把重心放在肌力和感覺方面，因為它們跟神經病變的嚴重度最有關係；而且這兩樣指標也常在評估嚴格控制血糖的功效和研究其他類神經病變時用到。29個驗有評估肌力和感覺，但是只有13個試驗有足夠的資料供我們分析；這一共是879個治療組和906個對照組。整體說來治療組和對照組之間並沒有顯著的不同。但是有一種藥，tolrestat，或許有一些療效；但是此藥因為它對肝臟的毒性，已不再使用於人體。有一些報告指出治療組在神經病變的症狀上有改善，但是另外一些試驗卻提出相反的結果。在電神經學檢查(27個研究)和足部潰瘍方面(1個研究)，並沒有發現任何好處。沒有研究評估到病人的生活品質。除了sorbinil引發的過敏反應、zenarestat引發的腎功能損壞、和tolrestat造成的肝功能變化，藥物的副作用並不常見也大多不嚴重。我們的結論是醛糖還原脢抑制劑對於治療糖尿病多發性神經病變，並沒有明顯的好處。