A combination of low doses of rosiglitazone and metformin reduced the relative risk of developing type 2 diabetes by 66% in high-risk adults, according to data published online in The Lancet on June 3.

Both rosiglitazone and metformin can reduce the risk of developing type 2 diabetes in adults with impaired glucose tolerance, but this study is the first to combine the two drugs to test for similar effectiveness with fewer side effects, said Dr. Bernard Zinman of Mount Sinai Hospital in Toronto, and colleagues.

In this study, 103 participants were randomized to a combination of 2 mg rosiglitazone and 500 mg metformin in a single capsule twice daily, while 104 participants received a placebo capsule. The study, known as the Canadian Normoglycemia Outcomes Evaluation (CANOE) trial, also included a structured lifestyle intervention of five individual counseling sessions during the first year of the study, followed by educational materials that were mailed or e-mailed to participants (Lancet 2010 June 3 [doi: 10.1016/S0140-6736(10)60746-5]).

The primary outcome was a diagnosis of type 2 diabetes, based on two fasting plasma glucose values of 7.0 mmol/L or more, or one positive oral glucose tolerance test with a 2-hour plasma glucose value greater than 11.0 mmol/L.

After an average follow-up period of 3.9 years, 14 patients (14%) in the treatment group and 41 (39%) patients in the placebo group developed type 2 diabetes, for a relative risk reduction of 66%. The absolute risk reduction was 26%, and the number needed to treat was 4.

In addition, significantly more individuals in the treatment group compared with the placebo group had attained normal glucose tolerance levels by the end of the study (80% vs. 53%, respectively). “The magnitude of this effect is equivalent to that of any of the published diabetes prevention strategies,” the researchers said.

The average age of the patients was 55 years in the placebo group and 50 years in the treatment group. The breakdown of gender and ethnicity, and the values of baseline risk factors including total cholesterol, blood pressure, body mass index, and insulin resistance were similar between the two groups.

The treatment group showed no significant increase in myocardial infarction, heart failure fractures, and weight gain or loss of 2 kg or more compared with the placebo group, and the researchers found no significant interaction between statin use and treatment outcome. No significant differences in beta-cell function were noted, but decreased C-reactive protein levels and reduced alanine aminotransferase levels in the treatment group compared with baseline suggest reduced inflammation and improved liver function, the researchers noted.

The study was not powered to address the long-term effects of combination therapy on cardiovascular safety, the researchers noted. The study also was limited by the inability to show whether the effects of the combination drug indicate the prevention or early treatment of type 2 diabetes.

The CANOE study data suggest that combining low doses of rosiglitazone and metformin can reduce the risk of type 2 diabetes with fewer side effects, but the conclusions are not definitive, wrote Dr. Thomas A. Buchanan of the University of Southern California, Los Angeles, and Dr. Anny H. Xiang of Kaiser Permanente Southern California in Pasadena.

“The issue of whether prevention provides better long-term outcomes than does early treatment remains unknown,” they said (Lancet 2010 June 3 [doi: 10.1016/S0140-6736(10)60900-2]).

The study was funded by GlaxoSmithKline, from which and Dr. Zinman has received consulting fees, honoraria, and grant support. Dr. Buchanan and Dr. Xiang have received research support from Takeda Pharmaceuticals, and Dr. Buchanan has served on a speakers’ panel and received travel and accommodation expenses from Takeda.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

据6月3日在线发表于《柳叶刀》(The Lancet)上的数据，联合应用低剂量的罗格列酮和二甲双胍可以使高危成人2型糖尿病的相对发病风险降低66%。

 

罗格列酮和二甲双胍均能使伴有糖耐量受损成人的2型糖尿病发病风险降低，但该研究首次对联用这2种药物是否能产生类似效果且副作用更小进行了调查，多伦多西奈山医院的Bernard Zinman博士及其同事说。

 

在该研究中，有103例受试者被随机分配每天服用2次含有2mg罗格列酮和500mg二甲双胍的单粒胶囊，而另外104例受试者则被分配服用安慰剂胶囊。该研究[即加拿大正常血糖效果评估(CANOE)试验]还包括在研究第1年期间向患者提供有关结构化生活方式干预的5次个体化咨询会谈服务，之后再通过邮寄或电子邮件将咨询材料发送给受试者(Lancet 2010 June 3 [doi: 10.1016/S0140-6736(10)60746-5])。

 

该研究的主要结局指标是2型糖尿病诊断，诊断依据是2次检测空腹血糖值≥7.0 mmol/L，或某次口服糖耐量试验结果阳性，即2h血浆葡萄糖浓度>11.0 mmol/L。

 

在平均随访3.9年后，治疗组和安慰剂组分别有14例 (14%)患者和41例 (39%)患者发生了2型糖尿病，其相对风险降低了66%。绝对风险降低了26%，有4例患者需要进行治疗。

 

此外，与安慰剂组相比，治疗组患者在研究结束时糖耐量水平维持正常的人数显著更多(分别为80% 对 53%)。“该效应的大小与任何业已发表的糖尿病预防策略所取得的效果等同，”研究者们说。

 

安慰剂组患者的平均年龄为55岁，治疗组则为50岁。两组患者的性别与种族分类及危险因素(包括总胆固醇水平、血压、体重指数和胰岛素抵抗) 的基线值相似。

 

在心肌梗死、心力衰竭、骨折和增重或减重≥2kg等指标上，治疗组较安慰剂组均无显著增长，此外，研究者们还发现，应用他汀类药物与治疗结果并不存在明显的交互作用。研究并未发现β细胞功能存在任何显著差异，但治疗组患者的C反应蛋白和丙氨酸氨基转移酶水平较基线水平下降，这表明患者炎症减少且肝功能改善，研究者指出。

 

该研究的检验效能不足以阐明联合治疗对心血管安全的长期影响，研究者们指出。该研究的局限性还在于其无法证明联合用药有效是否意味着有必要将其用于2型糖尿病的预防或早期治疗。

 

CANOE研究的数据显示，联合应用低剂量的罗格列酮和二甲双胍可以降低2型糖尿病的发病风险，且带来更小的副作用，但这尚非最终结论，洛杉矶市南加州大学的Thomas A. Buchanan博士和南加利福尼亚州帕萨迪纳市Kaiser Permanente的Anny H. Xiang博士写道。

 

 “就预防用药的长期临床转归是否比早期治疗更佳这一问题而言，其结论目前尚不清楚，”他们说(Lancet 2010 June 3 [doi: 10.1016/S0140-6736(10)60900-2])。

 

该研究由葛兰素史克资助，Zinman博士接受了该公司的顾问费、酬金和资金支持。Buchanan博士和Xiang博士接受了武田制药公司的研究资金支持，Buchanan博士还在武田制药公司的演讲人小组任职，并接受了该公司的差旅费及住宿费。

 

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