2型糖尿病患儿HbA1c略升也可致治疗失败风险增加

费城(EGMN)——在美国糖尿病学会(ADA)2012科学年会上，耶鲁大学儿科内分泌学教授Sonia Caprio博士报告称，对于2型糖尿病患儿，及早将血糖控制在稳定水平将最大程度地提高长期血糖控制的几率。如果最初稳定后血红蛋白A_1c(HbA_1c)快速升高，则很可能提示需要立即加强治疗。

上述结果来自一项名为“TODAY(2型糖尿病青少年和年轻患者的治疗选择)”的研究。Caprio博士与其他TODAY研究者在会上进行了热烈的讨论。TODAY的主要终点于今年4月公布；这次的ADA发言不仅介绍了治疗失败的预测因子，还提出了2型糖尿病患儿已经存在的临床合并症这一棘手问题。

TODAY研究在699例新近诊断为2型糖尿病的患儿中评价了3种不同的治疗方案：二甲双胍单药治疗、二甲双胍加生活方式干预、二甲双胍加罗格列酮(N. Engl. J. Med. 2012 April 29 [doi:10.1056/NEJMoa1109333])。

患儿年龄介于10~17岁，二甲双胍用药剂量为2,000 mg/d，试验周期为60个月。经二甲双胍治疗后HbA_1c稳定在≤8%的水平后进行随机分组。主要终点为出现血糖控制失败(定义为HbA_1c连续6个月≥8%，或者因持续的代谢失代偿而需要接受胰岛素治疗)的时间。

总的来看，将近一半(46%)的患儿没能维持血糖控制；出现治疗失败的中位时间为11个月。但与联合治疗组相比，二甲双胍单药治疗组血糖控制失败的发生率显著增加(52% vs. 39%)。生活方式干预组的失败率为47%，与二甲双胍单药治疗组和联合治疗组相比差异均无统计学意义。

作为TODAY的研究者之一，美国俄克拉荷马大学健康科学中心的Kenneth Copeland博士称，这次最新分析主要是在这些患儿中探讨治疗应答的预测因子并评估临床合并症。结果显示，最初6个月的稳定期内HbA_1c无异常升高是决定患儿是否能获得长期治疗的持续应答的最强预测因子。

单因素分析显示，多项基线因素与治疗失败相关，包括种族(黑人失败率显著高于白人)；合并抑郁症；家庭收入低；胰岛素源性指数低以及HbA_1c低。基线时HbA_1c的差异具有统计学意义，但这种差异显然还是很小的。初始稳定期后，维持控制和控制失败的患儿中均有一部分的血糖水平仍然处于非糖尿病范围内(5.7% vs. 6.4%)。

但多因素模型显示，只有基线HbA_1c与长期治疗应答显著相关。维持血糖控制的患儿HbA_1c增幅非常小，中位值从基线的6.4%增至到试验结束时的7%左右。而治疗失败的患儿HbA_1c则快速升高，从5.7%增至7.3%左右。

Caprio博士指出：“无论接受的是哪种治疗，基线HbA_1c都是预测治疗失败的最佳因子，即便仍然处于非糖尿病范围之内。HbA_1c快速升高，即便仍处于正常范围，也与治疗失败相关，很可能提示需要及早加强治疗。”

稳定期和治疗期出现的血糖升高，很可能提示在负荷越来越大的胰腺中β细胞功能开始下降。研究者采用了两种方法来评估患儿的β细胞功能：胰岛素源性指数(胰岛素给药前后的血糖差异)和口服处置指数(β细胞在分泌胰岛素方面的功能参数)。这项分析的基线数据来自随机分组时，即经过6个月治疗后HbA_1c稳定在8%或8%以下。

6个月时，二甲双胍+罗格列酮组与其他两组之间的差异非常明显，胰岛素敏感性增加了20%，而其他组则没有变化。不过，之后二甲双胍+罗格列酮组的胰岛素敏感性开始下降直至达到一个稳定水平。试验结束时，各组的β细胞功能相似，只是治疗期间二甲双胍+罗格列酮组的β细胞功能下降得比较缓慢。这提示罗格列酮至少能在某一段时间内稳定β细胞功能。“而在其余两组中β细胞功能是快速下降，尽管在第24个月时组间差异并没有统计学意义。”

Caprio博士说：“二甲双胍+罗格列酮组在胰岛素敏感性方面的优势与我们所观察到的治疗失败率下降相关。也就是说在2型糖尿病肥胖患儿中，这种程度的胰岛素抵抗经二甲双胍单药治疗或者二甲双胍+生活方式治疗后是很难获得应答的。” 鉴于在这些患儿中采用二甲双胍治疗失败，因此可能需要在疾病早期就采用强化治疗，“可能有助于减缓β细胞功能的下降速度，并提高患儿获得持续血糖控制的几率”。

TODAY数据安全性与监测委员会主席、美国华盛顿大学儿童临床研究中心主任Neil White博士说，TODAY的受试者也与2型糖尿病成年患者一样合并其他临床问题。虽然这些受试者的糖尿病病程非常短，在二甲双胍稳定期之前刚刚确诊了5~7个月，但那时已经有34%出现了高血压；10%存在LDL胆固醇水平异常，54%存在甘油三酯水平升高；还有20%左右合并有微量白蛋白尿，提示可能会进展为肾病。

无论治疗分组和结局如何，所有患儿均存在一定程度的左心室和右心房指标异常。超声心动图显示，这些患儿的左房直径达到了2.4 cm/m身高，超过了一般人群的中位值。所有患儿的左室重量指数也超过了30 g/m²的人群中位值，有的甚至接近45 g/m²。White博士说：“这些患儿的心脏普遍偏大，将来患上心脏病的几率比较大。”

试验结束时，大部分患儿(523例)都接受了眼底照相检查以评估其视网膜病变情况。大约14%存在一定程度的非增生性视网膜病变，这与糖尿病预防计划中观察到的2型糖尿病成年患者(平均年龄55岁)的患病率基本持平。

Caprio博士说：“根本问题在于胰岛素抵抗性，而二甲双胍对此没有任何作用。即便我们在试验中采用了2种目前最好的药物二甲双胍和罗格列酮，但仍然没能改善大约50%的患儿的临床结局。”

Copeland博士对此表示赞同：“50%的患儿治疗失败说明这是一种非常棘手的疾病。ADA亟需解答的是‘我们如何才能预防儿童糖尿病？’因为儿童一旦患病，就很难有效干预了。”

Caprio博士还总结道，这项研究表明对于糖尿病患儿，找到能预测治疗方案成败的新型标志物是非常必要的。“我们需要确定提示应加强治疗的特定阈值，可能是在确诊时，也可能是在治疗一段时间之后，或者当患者达到了某一HbA_1c 阈值时。”

TODAY由美国国立糖尿病、消化病及肾病研究所资助。所有发言者均声明与日本第一三共株式会社之间存在经济利益关系，但表示与TODAY研究无关。

 

PHILADELPHIA (EGMN)–Getting a firm, early grip on blood glucose confers the best chance for durable glycemic control in children with type 2 diabetes.

Any rapid increase in hemoglobin A1c after initial stabilization probably signals the need to quickly gear up treatment, Dr. Sonia Caprio said at the annual scientific sessions of the American Diabetes Association.

“The best single predictor of treatment failure – regardless of therapy – is baseline [hemoglobin A1c], even if it’s in the nondiabetic range,” after stabilization, said Dr. Caprio, a professor of pediatric endocrinology at Yale University in New Haven, Connecticut. “A rapidly rising HbA1c, even if it’s still in the normal range, is associated with failure, and suggests the need for more intense treatment.”

These new findings from the TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study mean that physicians may need new treatment markers for diabetes regimens in youth, she said. “We need to identify specific thresholds for intensifying therapy, perhaps at diagnosis, perhaps after a certain period of treatment, or when the patient reaches a certain HbA1c threshold.”

Dr. Caprio joined other TODAY investigators in a lively discussion of the study. TODAY’s primary end points were released in April; the ADA presentation not only broke down predictors of treatment failure, but pointed up a disturbing scenario of the medical comorbidities that already haunt children with type 2 diabetes.

Hypertension, enlarged hearts, retinopathy, dyslipidemia, and incipient kidney dysfunction were all common among the 699 children who participated in the study, said Dr. Neil White of Washington University, St. Louis. The problems occurred early and frequently.

“Within 7-8 months after diagnosis, 14% already had nonproliferative retinopathy. That number is similar to the amount found in the Diabetes Prevention Program study, for a population that was an average of 55 years old. These subjects are getting the signs of disease during childhood that older adults have.”

TODAY examined three different treatment regimens among 699 children with newly diagnosed type 2 diabetes: metformin alone, metformin plus lifestyle modifications, and metformin plus rosiglitazone (N. Engl. J. Med. 2012 April 29 [doi:10.1056/NEJMoa1109333]).

The 60-month trial started all patients aged 10-17 years on metformin 2,000 mg/day. Randomization occurred after HbA1c stabilized at 8% or lower with metformin therapy. The primary end point was time to the failure of glycemic control (defined as an HbA1c 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 of the metformin mono- or combination therapy groups.

The new analyses examined predictors of response, and looked at medical comorbidities among the patients. A seemingly innocuous increase in HbA1c during the initial 6-month stabilization phase was the strongest predictor of whether a child would achieve a durable response to the long-term therapy, said Dr. Kenneth Copeland, a TODAY investigator and the Milburn Endowed Chair of Pediatrics at the University of Oklahoma Health Sciences Center, Oklahoma City.

In a univariate analysis, a number of baseline factors were associated with failure, including race (with blacks doing significantly worse than whites); the presence of depression; lower household income; lower insulinogenic index, and lower HbA1c.

The baseline difference in HbA1c was statistically significant, but still apparently small, he said. After initial stabilization, those who maintained and failed control still had blood glucose levels in the nondiabetic range (5.7% vs. 6.4%).

But in a multivariate model, only baseline HbA1c strongly predicted response to long-term therapy. Those who maintained glucose control had very moderate HbA1c increases, from a median of 6.4% to about 7% by the end of the study. Those who failed therapy had a much steeper increase, rising from 5.7% at baseline to about 7.3% at the end.

 “Baseline HbA1c appears to be the best predictor of failure, regardless of whether it is still in the nondiabetic range. A rapidly rising level – even in the normal range – is associated with incipient failure and may suggest the need to intensify treatment early.”

The increases in blood sugar that arose during stabilization and treatment probably signaled beta-cell decline in an increasingly stressed pancreas, Dr. Caprio said. The analysis used two algorithms to assess beta-cell function: the insulinogenic index (the difference in blood glucose before and after insulin administration) and the oral disposition index (a measure of beta-cell function relative to insulin). The baseline for this analysis was the point of randomization, when glucose was stabilized at 8% or lower after 6 months of treatment.

 “At 6 months, we saw a dramatic difference between the rosiglitazone/metformin arm and the other arms,” with a 20% increase in insulin sensitivity compared with no change in the other groups. Thereafter, however, insulin sensitivity started to decrease in the rosiglitazone group, until it plateaued.

By the end of the study, beta-cell function was also similar between the groups, but those in the rosiglitazone group showed a slower decline during the treatment period. This indicated that rosiglitazone was able to stabilize function for at least a period of time. “In contrast, we saw a dramatic fall-off in the beta-cell function in the other two groups, although by 24 months there were no differences among any of them.”

“The favorable changes relative to insulin sensitivity were responsible for the observed reduced failure rate in the rosiglitazone group; telling is that this profound degree of insulin resistance in obese youth with type 2 diabetes is unresponsive to the effect of metformin, alone or with lifestyle therapy,” Dr. Caprio said.

Because metformin failed those children, the better alternative appears to be more aggressive treatment early in the disease. “The introduction of such aggressive therapy early in the course of the disease appears to slow the decline of beta-cell adaptation and improve the chance or durable control.”

Children in TODAY were plagued with much the same medical issues as are adults with type 2 diabetes, said Dr. Neil White, chairman of the TODAY data safety and monitoring committee.

The subjects had a very short duration of diabetes, having been diagnosed 5-7 months before the metformin stabilization period. At that point, 34% already had hypertension. Abnormal LDL cholesterol levels were present in 10%, and high triglycerides in 54%. Some 20% had microalbuminuria, suggesting possible progression to kidney disease.

All of the children, regardless of their treatment group or outcome, showed somewhat abnormal left ventricular and right auricular measurements, noted Dr. White, who is also director of the pediatric clinical research unit at Washington University.

Echocardiography showed that the children had a left auricular diameter of up to 2.4 cm/m height, greater than the population median. All also had a left ventricular mass greater than the population median of 30 g/m², with some reaching almost 45 g/m².

“These youngsters had big hearts that are going to predispose them to heart disease in the future,” Dr. White said.

At the end of the study, most children (523) underwent fundus photography to evaluate retinopathy. About 14% of them had some degree of nonproliferative retinopathy, putting the young group’s prevalence squarely in line with prevalence in adults with type 2 diabetes.

 “This profound insulin resistance was a culprit ... against which metformin had no effect at all,” Dr. Caprio said. “Even with the two best drugs we had at the time of this study – metformin and rosiglitazone – we were not able to improve outcomes in 50% of these kids.”

Dr. Copeland agreed.

 “The finding that 50% of our children failed therapy indicates that this is an incredibly tough disease to treat by any modality we have. Our target as a society needs to be ‘How do we prevent diabetes in children?’ because once they get it, it’s going to be really tough to intervene effectively.”

TODAY was funded by the U.S. National Institute of Diabetes and Digestive and Kidney Diseases. All of the presenters disclosed financial relationships with Daiichi Sankyo, but said these were not relevant to the TODAY study.