Metformin monotherapy for type 2 diabetes mellitus

 

Abstract

Background

Metformin is an anti-hyperglycaemic agent used for the treatment of type 2 diabetes mellitus. Type 2 diabetes may present long-term complications: micro- (retinopathy, nephropathy and neuropathy) and macrovascular (stroke, myocardial infarction and peripheral vascular disease). Two meta-analyses have been published before, although only secondary outcomes were assessed.

Objectives

To assess the effects of metformin monotherapy on mortality, morbidity, quality of life, glycaemic control, body weight, lipid levels, blood pressure, insulinaemia, and albuminuria in patients with type 2 diabetes mellitus.

Search methods

Studies were obtained from computerised searches of multiple electronic databases and hand searches of reference lists of relevant trials identified.

Selection criteria

Trials fulfilling the following inclusion criteria: Diabetes mellitus type 2, metformin versus any other oral intervention, assessment of relevant clinical outcome measures, use of random allocation.

Data collection and analysis

Two reviewers extracted data, using a standard data extraction form. Data were summarised under a random effects model. Dichotomous data were expressed as relative risk. We calculated the risk difference (RD), and the Number Needed to Treat, when it was possible. We collected data of mean and standard deviation from changes to baseline. However many trials reported end point data. This limitation lead to the expression of the results as standardised mean differences (SMD) and an overall SMD was calculated. Heterogeneity was tested for using the Z score and the I-squared statistic. Subgroup, sensitivity analysis and meta-regression were used to explore heterogeneity.

Main results

We included for analysis 29 trials with 37 arms (5259 participants), comparing metformin (37 arms and 2007 participants) with sulphonylureas (13 and 1167), placebo (12 and 702), diet (three and 493), thiazolidinediones (three and 132), insulin (two and 439), meglitinides (two and 208), and glucosidase inhibitors (two and 111). Nine studies reported data on primary outcomes. Obese patients allocated to intensive blood glucose control with metformin showed a greater benefit than chlorpropamide, glibenclamide, or insulin for any diabetes-related outcomes (P = 0.009), and for all-cause mortality (P = 0.03). Obese participants assigned to intensive blood glucose control with metformin showed a greater benefit than overweight patients on conventional treatment for any diabetes-related outcomes (P = 0.004), diabetes-related death (P = 0.03), all-cause mortality (P = 0.01), and myocardial infarction (P = 0.02). Patients assigned to metformin monotherapy showed a significant benefit for glycaemia control, weight, dyslipidaemia, and diastolic blood pressure. Metformin presents a strong benefit for HbA1c when compared with placebo and diet; and a moderated benefit for: glycaemia control, LDL cholesterol, and BMI or weight when compared with sulphonylureas.

Authors' conclusions

Metformin may be the first therapeutic option in the diabetes mellitus type 2 with overweight or obesity, as it may prevent some vascular complications, and mortality. Metformin produces beneficial changes in glycaemia control, and moderated in weight, lipids, insulinaemia and diastolic blood pressure. Sulphonylureas, alpha-glucosidase inhibitors, thiazolidinediones, meglitinides, insulin, and diet fail to show more benefit for glycaemia control, body weight, or lipids, than metformin.

 

Plain language summary

Metformin monotherapy for type 2 diabetes mellitus

Our review confirm that tight glycaemia control with metformin monotherapy is one of the main therapeutic options for type 2 diabetes in patients with overweight or obesity, since it may prevent some events of macrovascular and microvascular complications, and mortality. With the exception of more benefit achieved in overweight and obese participants on metformin, there are not specific data across trials to perform subgroup analyses of patients with other cardiovascular risk factors, such as hyperlipidaemia, hypertension, impaired fibrinolysis, or older than 65, which could allow us to predict those who would benefit more from metformin monotherapy. There are not long term trials which compare more recent drugs, such as some sulphonylureas, thiazolidinediones, meglitinides, and alpha glucosidase inhibitors, with metformin for primary outcomes. Metformin produces strong beneficial changes in glycaemia control, and moderated in weight, lipids, insulinaemia and diastolic blood pressure. Sulphonylureas, alpha-glucosidase inhibitors, thiazolidinediones, meglitinides, insulin, and diet fail to show more benefit for glycaemia control, body weight, or lipids, than metformin.

 

摘要

背景

單用metformin治療第2型糖尿病之成效

Metformin是用來治療第2型糖尿病的降血糖藥物。第2型糖尿病可能產生長期併發症，包含小血管性(眼病變、腎病變、神經病變)與大血管性(中風、心肌梗塞、周邊血管疾病)。之前已有2篇統合分析(meta analysis)被發表，雖然只有分析次要結果。

目標

分析單用metformin治療第2型糖尿病患之死亡率、殘疾率、生活品質、血糖控制、體重、血脂、血壓、血中胰島素和尿蛋白變化。

搜尋策略

研究取自多個電子資料庫的搜尋和手工尋找相關研究的參考文獻。最後一次的搜尋資料的時間為2003年9月。

選擇標準

納入分析的試驗必須符合下列條件：第2型糖尿病、metformin和其他口服藥物比較、分析相關的臨床結果、和使用隨機分配。

資料收集與分析

2位審查者利用標準的擷錄表單來收集資料。資料是在隨機效果模式下統整。不同的數據會以相對風險來表示。如果可能的話，我們會計算風險差異(risk difference, RD)和需要治療人數。我們收集平均值和從基礎值改變的標準差。然而，許多研究只發表最終結果資料。這項限制使得結果以標準平均差(standardised mean differences)和總平均差來表示。為了使用Z score和餘平方統計(Isquared statistic)，異質性(heterogeneity)有被測試。次群體、敏感性分析以及總迴歸分析(metaregression)被用來測試異質性。

主要結論

我們收集了29個研究，包含了37個次研究群組，共5259位受試者參與。研究比較metformin(37組，2007位受試者)與sulphonylurea(13組，208位受試者)、安慰劑(12組，702位受試者)、飲食(3組，111位受試者)、thiazolidinediones (3組，132位受試者)、胰島素(2組，439位受試者)、meglitinides(2組，208位受試者)、glucosidase inhibitors(2組，111位受試者)之間的差異。有9篇研究報告了初級結果資料。被分配到嚴格控制血糖組的肥胖的病人，使用metformin比使用chlorpropamide、glibenclamide或胰島素在任何糖尿病相關預後(p = 0.009)和總死亡率(p = 0.03)上均有更大的好處。被分配到以metformin嚴格控制血糖組的肥胖病人比被分配一般治療組的過重病人，不管在任何糖尿病相關預後(p = 0. 004)、糖尿病相關死亡(p = 0. 03)、總死亡率(p = 0. 01)和心肌梗塞(p = 0. 02)上均有更大的好處。被分配到單用metformin治療的病人，在血糖控制、體重、血脂異常和血壓方面均有顯著的好處。Metformin和安慰劑、飲食控制相比，對醣化血色素(HbA1C)有很強的好處。Metformin和sulphonylurea相比，對血糖控制、低密度脂蛋白膽固醇和身體質量指數或體重有中等程度的好處。

作者結論

對於肥胖或過重的第2型糖尿病病人，metformin可能是首選用藥，因它可預防一些血管的併發症和死亡。Metformin提供了在血糖控制、體重、血脂、高胰島素血症、舒張壓等方面的好處。Sulphonylurea、alphaglucosidase inhibitors、thiazolidinediones、meglitinides、胰島素和飲食控制等在血糖控制、體重和血脂這些方面並未比metformin有更多的好處。

翻譯人

本摘要由臺灣大學附設醫院張然舜翻譯。

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

總結

我們的回顧文獻確認單用metformin做嚴格的血糖控制是治療肥胖或過重的第2型糖尿病病人的主要選擇之一，因為它可能可以預防大、小血管的併發症和死亡。除了對肥胖或過重病人有更多好處外，對於有其他心血管風險的族群，例如高血脂、高血壓、纖維蛋白溶解缺損、65歲以上病患，並無特別的資料可以提供各試驗間的次群組分析，以預測單用metformin治療是否有更多好處。目前並沒有長期試驗比較metformin和更近期的藥物的初級預後，例如一些sulphonylurea、thiazolidinediones、meglitinides和alphaglucosidase inhibitors。Metformin提供了在血糖控制、體重、血脂、高胰島素血症、舒張壓方面的好處。Sulphonylurea、alphaglucosidase inhibitors、thiazolidinediones、meglitinides、胰島素和飲食控制等在血糖控制、體重和血脂這些方面並未比metformin有更多的好處。