Jeschke Marc G, Abdullahi Abdikarim, Burnett Marjorie, Rehou Sarah, Stanojcic Mile
*Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada †Sunnybrook Research Institute, Toronto, Ontario, Canada ‡Division of Plastic and Reconstructive Surgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada §Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Ann Surg. 2016 Sep;264(3):518-27. doi: 10.1097/SLA.0000000000001845.
To determine whether metformin can achieve glucose control no worse than insulin (noninferiority) without the danger of hypoglycemia (superiority). In addition, to assess whether metformin has any additional effects on lipolysis and inflammation that will enhance burn recovery (superiority).
Hyperglycemia and insulin resistance after burn injury are associated with increased morbidity and mortality. Insulin administration improves postburn infections, severity of sepsis, and morbidity, but also causes a 4-5-fold increase in hypoglycemia, which is associated with a 9-fold increase in mortality.
Severely burned adult patients with burns over 20% total body surface area (TBSA) burn were prospectively randomized in this Phase II clinical trial to either metformin or insulin (standard of care) treatment. Primary outcomes were glucose levels and incidence of hypoglycemia. Secondary outcomes included glucose and fat metabolism, and clinical outcomes.
Forty-four patients were enrolled in this Phase II clinical trial, 18 metformin and 26 insulin patients. Demographics, burn size, concomitant injuries, and mortality were comparable between both groups. Metformin controlled blood glucose as equally as insulin with no difference between the 2 treatment groups, P > 0.05. While there was a 15% incidence of hypoglycemia in the insulin group, there was only 1 mild hypoglycemic episode (6%) in the metformin group, P < 0.05. Oral glucose tolerance tests at discharge revealed that metformin significantly improved insulin sensitivity, P < 0.05. Furthermore, metformin had a strong antilipolytic effect after burn injury when compared with insulin and was associated with significantly reduced inflammation, P < 0.05.
Metformin decreases glucose equally as effective as insulin without causing hypoglycemia, with additional benefits including improved insulin resistance and decreased endogenous insulin synthesis when compared with insulin controls. These results indicate that metformin is safe in burn patients and further supports the use of metformin in severely burned patients for postburn control of hyperglycemia and insulin resistance.
确定二甲双胍在不引发低血糖风险（优越性）的情况下，控制血糖的效果是否不劣于胰岛素（非劣效性）。此外，评估二甲双胍对脂肪分解和炎症是否具有任何额外作用，从而促进烧伤恢复（优越性）。
烧伤后高血糖和胰岛素抵抗与发病率和死亡率增加相关。胰岛素治疗可改善烧伤后感染、脓毒症严重程度和发病率，但也会使低血糖发生率增加4至5倍，而低血糖与死亡率增加9倍相关。
在这项II期临床试验中，将烧伤总面积超过20%的成年重度烧伤患者前瞻性随机分为二甲双胍治疗组或胰岛素（标准治疗）治疗组。主要结局为血糖水平和低血糖发生率。次要结局包括葡萄糖和脂肪代谢以及临床结局。
44例患者参与了这项II期临床试验，其中18例接受二甲双胍治疗，26例接受胰岛素治疗。两组患者的人口统计学特征、烧伤面积、合并损伤和死亡率具有可比性。二甲双胍控制血糖的效果与胰岛素相当，两组之间无差异，P>0.05。胰岛素组低血糖发生率为15%，而二甲双胍组仅有1例轻度低血糖事件（6%），P<0.05。出院时的口服葡萄糖耐量试验显示，二甲双胍显著改善了胰岛素敏感性，P<0.05。此外，与胰岛素相比，二甲双胍在烧伤后具有强大的抗脂肪分解作用，并与炎症显著减轻相关，P<0.05。
二甲双胍降低血糖的效果与胰岛素相当且不会引发低血糖，与胰岛素对照组相比，还具有改善胰岛素抵抗和减少内源性胰岛素合成等额外益处。这些结果表明，二甲双胍在烧伤患者中是安全的，并进一步支持在重度烧伤患者中使用二甲双胍来控制烧伤后的高血糖和胰岛素抵抗。
