胰島素或Metformin治療可能無法減少糖尿病的發炎生物標記
作者：Laurie Barclay, MD
出處：WebMD醫學新聞
September 15, 2009 — 根據9月16日美國醫學會期刊的一篇隨機控制試驗結果，最近發病的第2型糖尿病患中，相較於安慰劑，胰島素或metformin治療可改善血糖的控制，但未降低發炎生物標記。
布萊根婦女醫院與哈佛醫學院的Aruna D. Pradhan醫師等人寫道，已知發炎前機轉和beta細胞不足與胰島素阻抗性的核心代謝缺損有關，而高敏感度C-反應蛋白 (hsCRP)、IL-6 [介白素6]、以及可溶腫瘤壞死因子受體2 (sTNFr2)等發炎生物標記值升高，可預測顯然健康者的第2型糖尿病發作。有關是否改善血糖控制、胰島素阻抗性、降血糖藥物胰島素和metformin等對於發炎的改善證據有限。
這個開放標籤胰島素glargine和安慰劑控制metformin的2乘2階乘試驗，目標在評估單用胰島素或併用metformin是否會降低最近發生第2型糖尿病患者的hsCRP、IL-6和sTNFr2值。
在2006年10月至2008年12月間，總共有來自美國診間為基礎的500名第2型糖尿病成人病患(離診斷之時間的中位數為2.0年)、血糖控制未臻理想、hsCRP值升高者被納入，且隨機指派接受四種治療之一(只有安慰劑metformin、安慰劑metformin與胰島素glargine、只有有藥性的metformin、有藥性的metformin與胰島素glargine)。調整劑量以達目標之空腹血糖值小於110 mg/dL。
本研究的主要終點是從開始到14週時的hsCRP值變化，其他結果測量是IL-6和TNFr2值的變化。
相較於安慰劑組，活性治療組顯著降低血糖與糖化血色素值(HbA1c；所有的P 值都 < .001)。全部四組的hsCRP值都降低。胰島素組(-11.8%; 95%信心區間[CI]，-18.7%至-4.4%)、無胰島素組(-17.5%；95% CI，-23.9%至-10.5%；差異P 值= .25)、有藥性metformin組(-18.1%；95% CI，-24.4%至-11.1%)或安慰劑metformin組 (-11.2%；95% CI，-18.1%至-3.7%；差異P 值= .17)，各組的hsCRP值降低程度並沒有顯著差異。
儘管在治療組的血糖控制有不同效果，單用安慰劑(-19.0%；95% CI，-27.8%至-9.1%)與metformin組 (-16.1%；95% CI，-25.1%至-6.1%；相較於安慰劑之P = .67)和metformin加胰島素組(-20.1%；95% CI，-28.8%至-10.4%；相較於安慰劑之P = .87)的hsCRP值降低程度並沒有差異。相較於安慰劑，只用胰島素與降低hsCRP值有關(-2.9%；95% CI，-13.2%至8.6%；P = .03)。IL-6和sTNFr2值的發現類似。
研究作者寫道，降低血糖和改變hsCRP、IL-6或sTNFr2等值而改善發炎狀態的關聯並無定論。儘管血糖控制有明顯改善，胰島素或metformin都未能減少主要評估的發炎標記值，各治療組之間比較的結果也未能減少。相較於沒有藥物介入者，觀察介入方式之間的交互作用，分派到單用胰島素者的發炎減少有顯著降低，分派到使用metformin和胰島素或單用metformin者則未觀察到這種效果。
研究限制包括使用心血管疾病風險的替代指標、缺乏內臟脂肪改變的資料、無法一般化到所有第2型糖尿病患。
研究作者結論表示，從臨床觀點來看，除非有另外的終點試驗資料，這些資料強調了需堅持改善治療順從性，以減少糖尿病患的心血管事件，這些治療包括運動；體重控制；戒菸；血壓控制；再者，對於適當的病患來說，可用抗血小板和statin類藥物治療。
Sanofi-Aventis資助本研究，且和資深作者、Paul M. Ridker醫師有各種財務關係，Paul M. Ridker醫師也宣告和國家心臟肺臟暨血液研究中心、國家癌症研究中心、Donald W. Reynolds基金會、Leducq基金會、Astra-Zeneca、Novartis、Merck、Abbott、Roche、Merck-Schering Plough、ISIS, Dade-Behring與Vascular Biogenic等藥廠有各種財務關係。他也是布萊根婦女醫院擁有的心血管疾病和糖尿病發炎生物標記專利之共同發明者，該專利授權給Siemens和Astra-Zeneca。
Insulin or Metformin Therapy May Not Reduce Inflammatory Biomarkers in Diabetes
By Laurie Barclay, MD
Medscape Medical News
September 15, 2009 — In patients with recent-onset type 2 diabetes, treatment with insulin or metformin vs placebo improves glucose control but does not lower levels of inflammatory biomarkers, according to the results of a randomized controlled trial reported in the September 16 issue of the Journal of the American Medical Association.
"Proinflammatory mechanisms have been linked to the core metabolic defects of beta-cell insufficiency and insulin resistance, and elevations in levels of inflammatory biomarkers, including high-sensitivity C-reactive protein (hsCRP), IL-6 [interleukin 6], and soluble tumor necrosis factor receptor 2 (sTNFr2), predict incident type 2 diabetes among apparently healthy individuals," write Aruna D. Pradhan, MD, MPH, from Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts, and colleagues. "Evidence is limited on whether improvement in glycemic control, insulin resistance, or both with antidiabetic agents such as insulin and metformin may beneficially change inflammation."
The goal of this 2 x 2-factorial trial of open-label insulin glargine and placebo-controlled metformin was to assess whether insulin alone or in combination with metformin would lower hsCRP, IL-6, and sTNFr2 levels in patients with recent-onset type 2 diabetes mellitus.
Between October 2006 and December 2008, a total of 500 adults with type 2 diabetes (median time from diagnosis, 2.0 years), suboptimal glycemic control, and elevated hsCRP levels were recruited from US office-based practices and randomly assigned to 1 of 4 treatments (placebo metformin only, placebo metformin and insulin glargine, active metformin only, or active metformin and insulin glargine). Dose titration was used to target fasting blood glucose levels less than 110 mg/dL.
The primary endpoint of the study was change in hsCRP level from baseline to 14 weeks. Other outcome measures were change in IL-6 and sTNFr2 levels.
Compared with the placebo group, active treatment groups had significantly lower levels of glucose and glycated hemoglobin (HbA1c; all P values < .001). All 4 groups had reduction in hsCRP levels. Reduction in hsCRP levels was not significantly different among those assigned to insulin (?11.8%; 95% confidence interval [CI], ?18.7% to ?4.4%), no insulin (?17.5%; 95% CI, ?23.9% to ?10.5%; P for difference = .25), active metformin (?18.1%; 95% CI, ?24.4% to ?11.1%), or placebo metformin (?11.2%; 95% CI, ?18.1% to ?3.7%; P for difference = .17).
Despite different effects on glucose control in the individual treatment groups, reductions in hsCRP levels were no different than reductions with placebo alone (?19.0%; 95% CI, ?27.8% to ?9.1%) in the metformin group (?16.1%; 95% CI, ?25.1% to ?6.1%; P = .67 vs placebo) and the metformin plus insulin group (?20.1%; 95% CI, ?28.8% to ?10.4%; P = .87 vs placebo). Compared with placebo, only insulin was associated with decreased hsCRP levels (?2.9%; 95% CI, ?13.2% to 8.6%; P = .03). Findings were similar for IL-6 and sTNFr2 levels.
"No consistent association was found between glucose reduction and improvement in inflammatory status ascertained by change in levels of hsCRP, IL-6, or sTNFr2," the study authors write. "Despite substantially improving glucose control, neither insulin nor metformin reduced inflammatory biomarker levels for the main effects evaluated or in comparisons between the individual treatment groups. An interaction between interventions was observed such that, compared with no pharmacologic intervention, those allocated to insulin alone had a significant attenuation of inflammation reduction, an effect not observed among those allocated to metformin and insulin or to metformin alone."
Limitations of this study include use of surrogate markers of cardiovascular disease risk, lack of data on change in visceral fat, and lack of generalizability to all individuals with type 2 diabetes.
"From a clinical perspective, until other end-point trial data become available, these data underscore the need to improve adherence with therapies that do reduce cardiovascular events among diabetic patients, including exercise; weight management; smoking cessation; blood pressure control; and, in appropriate patients, antiplatelet and statin therapy," the study authors conclude.
Sanofi-Aventis funded this study and has various financial relationships with senior author Paul M. Ridker, MD, MPH, who also has disclosed various financial relationships with the National Heart, Lung, and Blood Institute; the National Cancer Institute; the Donald W. Reynolds Foundation; the Leducq Foundation; Astra-Zeneca; Novartis; Merck; Abbott; Roche; Merck-Schering Plough, ISIS, Dade-Behring, and Vascular Biogenics. He is also listed as a coinventor on patents held by the Brigham and Women's Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease and diabetes, which have been licensed to Siemens and Astra-Zeneca.
JAMA. 2009;302:1186-1194.
