Metformin對第二型糖尿病患可能有長期助益

作者：Laurie Barclay, MD  
出處：WebMD醫學新聞

　　April 10, 2009 — 根據一篇發表在3月23日內科學誌的隨機分派安慰組控制研究結果，Metformin對第二型糖尿病患可能有長期助益。
　　
　　荷蘭阿姆斯特丹醫學院的Adriaan Kooy博士與同事寫到，幾個短期的研究顯示，用胰島素治療的第二型糖尿病病患，在使用metformin後能改善血糖控制與減少胰島素的需求和控制體重。就我們的認知，關於長期好處的試驗尚未進行。我們假設，第二型糖尿病患使用胰島素和metformin，然後與安慰劑做比較，對於代謝的影響是有好處的，甚至在相同的血糖控制下能減少心血管事件的發生。
　　
　　在三家醫院的門診病患，有390人以胰島素治療，隨機接受metformin hydrochloride 850毫克或安慰劑（一天一至三次）；主要試驗終點要看追蹤4.3年間微血管及大血管罹病率與致死率，次要終點則衡量微血管及大血管罹病率與致死率的分數，好比像糖化血色素、胰島素需求、血脂肪、血壓、體重與身體質量指數。
　　
　　相較於安慰劑組，metformin組能預防體重增加（平均增加體重為-3.07公斤；範圍是-3.85到-2.28公斤；P < .001），有較好的血糖控制（平均降低糖化血色素值0.4%，95%信賴區間為0.55-0.25；P < .001），以及較低胰島素需求（平均一天減少19.63單位；95%信賴區間為減少24.91-14.36單位；P < .001）。
　　
　　雖然metformin無法改善主要試驗終點，但改善了次要的大血管試驗終點（危險比值0.61，95%信賴區間為0.40-0.94; P = .02），這可能部分解釋體重在這兩組的差異。每治療16.1人就有一人能避免一項大血管事件的發生（95%信賴區間為9.2-66.6）。
　　
　　希臘色雷斯德默克列特斯大學助理教授Nikolaos Papanas獨立發表於Medscape糖尿病與內分泌學，增加metformin能改善血糖控制及減少體重與胰島素需求，Metformin並不能改善主要試驗終點，但能改善40%的次要大血管試驗終點。
　　
　　Papanas博士注意到在大血管疾病的明顯好處，與近期在英國糖尿病研究報告20年追蹤的結果相符，能降低33%心肌梗塞的發生率（N Engl J Med 2008;359:1577–1589）。
　　
　　本研究的強度為第一個探討metformin對於已接受胰島素治療病患效果的隨機控制研究，再者它有較長的追蹤期（為期4.3年），且有達到本研究想要的受試者人數。
　　
　　這項研究的限制包括樣本數目相對較小、且最終統計力量有限；合併計算小血管與大血管臨床事件；兩個治療組織之間在隨機分派後仍有不均等的現象；可能缺乏應用到接受較不密集照護病患的一般性；多重分析的表現，代表次要試驗終點可能是源自於機率問題。
　　
　　Papanas博士表示，進一步的限制包括沒有可以解釋所觀察到效果的清楚機轉。確實，長期使用metformin，與體重增加幅度下降以及代謝控制的改善有關，同時對於血壓與血脂肪還有非常些微的益處。
　　
　　因為使用metformin的禁忌症，metformin應該避免使用於高風險病患，以避免乳酸中毒的危險（Acta Clin Belg. 2009; 64:42-48）。目前這項研究作者的結論是，其研究發現支持，除非有禁忌症，對任何一位第二型糖尿病病患，在開始使用胰島素後仍然繼續使用metformin治療。
　　
　　Papanas博士的結論是，未來需要針對接受胰島素治療的第二型糖尿病病患進行研究，以了解metformin對於這些病患心血管發病率的長期效應。我們也需釐清metformin好處的機轉，以及找出該效應對體重降低與胰島素需求量到減輕胰島素抗性，甚至可能的，還有穩定粥狀動脈硬化斑塊作用的程度有多少。
　　
　　Altana、Lifescan、E. Merck/Sante、Merck、Sharpe & Dohme以及Novo Nordisk公司贊助這項研究。這項研究的作者們與Papanas博士表示沒有相關資金上的往來。

Metformin May Have Long-Term Benefits in Patients With Type 2 Diabetes

By Laurie Barclay, MD
Medscape Medical News

April 10, 2009 — Metformin may have long-term benefits in patients with type 2 diabetes mellitus (DM2), according to the results of a randomized, placebo-controlled trial reported in the March 23 issue of the Archives of Internal Medicine.

"Several short-term studies in insulin-treated patients with DM2 have shown that metformin can improve glycemic control and reduce insulin requirements and weight gain," write Adriaan Kooy, MD, PhD, from the Academic Medical Center in Amsterdam, the Netherlands, and colleagues. "To our knowledge, the long-term beneficial effects of metformin in such patients have not been studied. We hypothesized that, in patients with DM2 treated with insulin, metformin, compared with placebo, will have sustained beneficial metabolic effects, even at the same level of glycemic control, and thus decrease (cardio) vascular disease."

In the outpatient clinics of 3 hospitals, 390 patients treated with insulin were randomly assigned to receive metformin hydrochloride, 850 mg, or placebo (1 – 3 times daily), added to insulin therapy. The main study outcome was an aggregate of microvascular and macrovascular morbidity and mortality during a follow-up period of 4.3 years. Secondary outcome measures were separate aggregate scores for microvascular and macrovascular morbidity and mortality, as well as effects on glycated hemoglobin, insulin requirement, lipid levels, blood pressure, body weight, and body mass index.

Compared with the placebo group, the metformin group had prevention of weight gain (mean weight gain, ?3.07 kg; range, ?3.85 to ?2.28 kg; P < .001), better glycemic control (mean reduction in glycated hemoglobin level, 0.4%; 95% confidence interval [CI], 0.55 – 0.25; P < .001), and lower insulin requirements (mean reduction, 19.63 U/day; 95% CI, 24.91 – 14.36 U/day; P < .001).

Although metformin was not associated with an improvement in the main outcome, it was associated with an improvement in the secondary, macrovascular end point (hazard ratio, 0.61; 95% CI, 0.40 – 0.94; P = .02), which was partly explained by the difference in weight between groups. To prevent 1 macrovascular end point, the number needed to treat was 16.1 (95% CI, 9.2 – 66.6).

"Add-on metformin improved glycemic control and reduced body weight and insulin requirements," Nikolaos Papanas, MD, DSc, an assistant professor in internal medicine at Democritus University of Thrace in Greece, told Medscape Diabetes & Endocrinology when asked for independent comment. "Metformin did not improve the primary endpoint. However, the drug was associated with an almost 40% improvement in the secondary macrovascular endpoint."

Dr. Papanas notes that this significant effect on macrovascular disease agrees with recent data from the United Kingdom Prospective Diabetes Study at 20-year follow-up, which showed a 33% reduction in myocardial infarction (N Engl J Med 2008;359:1577–1589).

"The strengths of the study [are that] it is the first randomized controlled trial on the effects of metformin specifically in insulin-treated patients," Dr. Papanas said. "A further strength is the relatively long follow-up period (4.3 years). Moreover, the authors achieved a sustained participation of patients in the trial."

Limitations of this study include its relatively small sample size, and consequently limited power; the combination of separate microvascular and macrovascular clinical events; an imbalance between the 2 treatment groups after randomization; apossible lack of generalizability to patients receiving less intensive care; and the performance of multiple analyses, suggesting that the positive finding on the secondary end point might possibly be a result of chance.

"A further limitation is the absence of a clearly documented mechanism by which the observed effects could be explained," Dr. Papanas said. "Indeed, long-term use of metformin contributes to the reduction of weight gain and to the improvement in metabolic control, while it may also have a very modest beneficial effect on blood pressure and serum lipids."

Because of contraindications to metformin use, metformin should be avoided in high-risk patients to avoid the danger of lactic acidosis (Acta Clin Belg. 2009;64:42–48). The authors of the present study conclude that their findings support the policy to continue metformin treatment after insulin is introduced in any patient with DM2, unless contraindicated.

"Future research is needed into the long-term effect of metformin on cardiovascular morbidity in insulin-treated type 2 diabetic patients," Dr. Papanas concludes. "We also need to clarify the mechanisms of the beneficial action of metformin and identify to what extent this action is attributable to the reduction of body weight and insulin requirements, to the amelioration of insulin resistance and, possibly, to additional pleiotropic actions."

Altana; Lifescan; E. Merck/Sante; Merck, Sharpe, & Dohme; and Novo Nordisk supported this study. The study authors and Dr. Papanas have disclosed no relevant financial relationships.

Arch Intern Med. 2009;169:616–625.