二甲双胍单药治疗儿童2型糖尿病50%失效

波士顿(EGMN)——科罗拉多儿童医院的Phil Zeitler博士在儿科学会(PAS)年会上报告了TODAY试验(青少年与年轻成人2型糖尿病的治疗选择试验)的结果：52%的2型糖尿病患儿不能通过二甲双胍单药治疗持续控制住血糖。

这一结果提示，很多2型糖尿病患儿在获得诊断后数年内就不得不加用其他口服降糖药物或胰岛素。这项研究同期在线发表在《新英格兰医学杂志》上(doi:10.1056/NEJMoa1109333)。Zeitler博士指出：“二甲双胍对儿童的失效时间比对成人更快，后者每年的失效率仅为6%~10%。尽管加用罗格列酮可使血糖失控率下降23%，但失效时间却未改变。”

在这项为期60个月的试验中，699例年龄10~17岁的2型糖尿病患儿开始接受2,000 mg/d二甲双胍治疗，直至糖化血红蛋白(HbA1c)水平稳定在8%。然后将这些患儿随机分为三组：二甲双胍单药组、二甲双胍+生活方式干预组，以及二甲双胍+罗格列酮组。主要终点为至血糖失控(定义为HbA1c水平≥8%的时间达到6个月，或者因持续性代谢失代偿而需要胰岛素治疗)的时间。

结果显示，近半数患儿(46%)未能维持血糖控制，至血糖失控的中位时间为11个月。但与二甲双胍+罗格列酮组相比，二甲双胍单药组患儿的血糖失控率明显更高(39% vs. 52%)。二甲双胍+生活方式干预组患儿的血糖失控率为47%，与二甲双胍单药组、二甲双胍+罗格列酮组均无显著差异；该组患儿虽然体重下降更明显，但这并未转化为长期血糖控制情况的改善。Zeitler博士认为，上述差异并非由依从性所致。“实际上，血糖失控患儿的依从性甚至比其他患儿更好，这可能与医生更注意督促HbA1C水平升高患儿依从治疗有关。”

血糖失控率似乎存在性别和种族差异。对于女性患儿，二甲双胍+罗格列酮显著优于二甲双胍单药或加用生活方式干预；而对于男性患儿，二甲双胍+生活方式干预明显优于另两种方案。黑人患儿对二甲双胍单药治疗的应答尤其不佳，治疗12个月就已有50%的患儿失效，而加用罗格列酮或生活方式干预可明显改善疗效；在西班牙裔患儿中，三种治疗之间均无显著差异；对于白人患儿，二甲双胍单药与或加用生活方式干预的效果相似，而加用罗格列酮可带来额外益处但不具有显著性。这提示疗效差异可能与生理特质有关。

尽管加用罗格列酮可给部分患儿带来益处，但鉴于成人使用该药会增加心血管事件风险，因此研究者不建议对年轻的2型糖尿病患儿加用该药。

研究者总结指出，TODAY试验结果表明，二甲双胍单药治疗对于半数年轻患者而言是不够的，下一步要做的是想办法在诊断时即预测出哪些患儿会迅速发生血糖失控，从而指导治疗方案的选择。

本项研究由美国国立糖尿病、消化病和肾病研究所资助。Zeitler博士报告称无相关利益冲突，但数位合著者报告与包括第一三共、默克、百时美-施贵宝、雀巢和美敦力在内的多家制药公司有利益关系。

爱思唯尔  版权所有

BY MICHELLE G. SULLIVAN

Elsevier Global Medical News

Breaking News

BOSTON (EGMN) – For about half of children with type 2 diabetes, metformin alone is not enough to produce durable glycemic control, a study has shown.

The TODAY trial found that 52% of children failed monotherapy – many by 11 months, Dr. Phil Zeitler said at the annual meeting of the Pediatric Academic Societies.

And although the addition of rosiglitazone to metformin did improve results, the take-home message about monotherapy is clear, he said: Many young people with type 2 diabetes are going to need multiple medications, or insulin, within a few years of diagnosis.

“Metformin is not as good a medicine as we all thought it was. This is a much more rapid loss of control than we see in adults, in which metformin failure is about 6%-10% per year. And while the addition of rosiglitazone reduced the loss of glycemic control by 23%, the time to failure was unchanged,” said Dr. Zeitler, a lead investigator in the Treatment Options for Type 2 Diabetes in Adolescents and Youth trial.

The study’s third arm – a combination of metformin and lifestyle modification – was not significantly different than either monotherapy or dual therapy. Patients using the combination of nutritional and activity counseling plus medication did lose significantly more weight than did those in the medication-only arms, but that did not translate into a longer period of glycemic control.

The study was simultaneously publishedin the online edition of the New England Journal of Medicine (2012 April 29 [doi:10.1056/NEJMoa1109333]).

The 60-month trial started 699 patients aged 10-17 years on 2,000 mg/day metformin; this treatment was continued until hemoglobin A1c stabilized at 8%. The group was then randomized to one of the three treatment arms. The primary end point was time to the failure of glycemic control, defined as an HbA1c level of at least 8% for 6 months, or sustained metabolic decompensation that required insulin treatment.

Overall, nearly half of the cohort (46%) failed to maintain glycemic control; the median time to failure was 11 months. However, compared with the combination therapy group, significantly more of those taking metformin alone failed glycemic control (52% vs. 39%). The failure rate in the lifestyle intervention group was 47% – not significantly different from that for metformin monotherapy or combination therapy.

Physiology rather than compliance probably drove the differences, said Dr. Zeitler, head of pediatric endocrinology at the Children’s Hospital Colorado, Aurora.

“There was no reason to suspect that differences [in any of the results] were due to lack of adherence,” he said. “In fact, if we look at a comparison of those who failed compared to those who did not, adherence was generally better in those who failed, which might have reflected the efforts of the sites to enforce adherence as the HbA1C levels began to rise.”

However, Dr. Zeitler said, the results differed significantly between sexes and racial/ethnic groups. For girls, metformin plus rosiglitazone was significantly better than monotherapy or the combination of metformin and lifestyle modification. For boys, the combination of metformin and lifestyle changes was significantly better than for the other groups.

“While we saw distinct gender differences in the response, we can only speculate about the reasons behind that,” Dr. Zeitler said.

Blacks responded especially poorly to metformin alone, he said, “such that by 12 months, almost 50% had failed treatment. We saw increased [statistically significant] efficacy with the addition of either rosiglitazone or lifestyle changes.”

Among Hispanics, there were no statistically significant differences between any of the treatment arms, although Dr. Zeitler said that lifestyle intervention tended to be less effective than drug therapy.

Among whites, there was no difference between metformin and metformin with lifestyle changes. These patients had a better response with the addition of rosiglitazone, but it was not statistically significant, he said.

“These very distinct differences in gender and ethnicity suggest that there is something biologic going on here. But we need to analyze a variety of things that could also be factors, including adherence, socioeconomic status, site location, depression, and other things. We do have those data, and those analyses will be forthcoming,” Dr. Zeitler said.

Despite the benefit rosiglitazone conferred to some patients, it can’t be recommended as an add-on therapy for young people with type 2 diabetes, he said in an interview. “It’s been shown to increase cardiovascular events in adults, although we don’t know how it would affect young people who are typically more cardiovascularly healthy.”

TODAY made it clear that metformin alone isn’t enough for about half of these young patients. However, Dr. Zeitler said, this glass is not just half-empty.

“Half of the youngsters do seem to maintain long-term control irrespective of treatment, and this is something we don’t want to lose sight of,” he said. “This suggests there are two cohorts of patients: One that will continue to do well on monotherapy, and one that will fail very rapidly. If we could predict who those children will be at the time of diagnosis, that could have a substantial effect on our choice of treatment.”

The study was sponsored by the U.S. National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Zeitler said he had no relevant financial disclosures. However, several of the coauthors did note financial relationships with various pharmaceutical companies, including Daiichi-Sankyo, Merck, Bristol-Meyers-Squibb, Jenny Craig/Nestle, and Medtronic.