新诊断2型糖尿病患者宜初始接受三联治疗

芝加哥——美国糖尿病学会(ADA)2013年会上报告的一项为期2年的随机试验证实，新诊断2型糖尿病患者初始即接受二甲双胍、吡格列酮及艾塞那肽三联治疗，优于指南推荐的二甲双胍、磺酰脲类及基础胰岛素序贯添加治疗。

德克萨斯大学医学部的Muhammad A. Abdul-Ghani博士报告称，与常规治疗组患者相比，三联治疗组患者的糖化血红蛋白A_1c(HbA_1c)下降幅度更大、持续时间更长，并且低血糖风险更低。此外，三联治疗组患者的体重有所减轻，而常规治疗组患者则出现了体重增加。


Muhammad A. Abdul-Ghani博士

Abdul-Ghani博士指出，初始三联治疗效果与安全性俱佳的研究结果表明，胰岛素抵抗和β细胞进行性衰竭是引起高血糖和2型糖尿病的关键代谢缺陷，针对这2个靶点的治疗策略优于仅专注于降低血糖。“这项研究带给我们的关键信息是，当你治疗2型糖尿病患者时，应当治疗的是病——糖尿病，而不是高血糖症状。”

这项开放标记研究纳入了155例近期被诊断为2型糖尿病的患者，其平均年龄为47岁，平均体重指数为30.5 kg/m²，平均基线HbA_1c为8.6%。三联治疗组患者初始接受二甲双胍1,000 mg/d+吡格列酮15 mg/d+艾塞那肽5 mcg、2次/d治疗。1个月后这3种药物的剂量均加倍。如果治疗3个月仍未达到HbA_1c＜6.5%的治疗目标，可将吡格列酮剂量增至45 mg/d。常规治疗组患者初始接受二甲双胍治疗，之后按需序贯添加吡格列酮和基础胰岛素，以使HbA_1c降至6.5%以下。

该研究的主要终点是2年时HbA_1c组间差异。结果显示，三联治疗组的平均HbA_1c由基线时的8.6%降至6%，显著优于常规治疗组(降至6.6%)。两组患者的中位HbA_1c分别为5.8%和6.4%。三联治疗组有60%的患者HbA_1c＜6%，而这类患者在常规治疗组中仅占27%。两组分别有92%和72%的患者达到了ADA提出的HbA_1c＜7%的治疗目标。

受试者每3个月到医院接受1次随访。治疗失败定义为连续2次随访测得的HbA_1c均高于6.5%，结果三联治疗组和常规治疗组分别有17%和42%的患者治疗失败。

尽管三联治疗组的平均HbA_1c比常规治疗组低0.5%，但在2年研究过程中，三联治疗组发生的低血糖却更少：15% vs. 46%。三联治疗组患者的体重平均降低了1.2 kg，而常规治疗组患者平均增重4.1 kg。

多变量回归分析显示，三联治疗与治疗失败风险降低84%有关。年龄较大也是一项保护性因素：从40岁开始，年龄每增加10岁，治疗失败风险即降低64%。“我们尚不清楚年龄与治疗失败风险的关联机制，或许是由于老年人的治疗依从性更好，也可能与糖尿病的病理生理学机制有关。”

研究者之所以在将二甲双胍选入三联治疗，是因为该药可纠正肝脏内的胰岛素抵抗；选择吡格列酮是由于该药可纠正脂肪细胞和肌肉中的胰岛素抵抗，并能保存β细胞功能；艾塞那肽的入选是因为它能增强β细胞功能。

与会者的质疑和研究者的答复

这项研究并未使在场的所有人信服，一些与会者指出，尽管这项研究试图推翻基于指南的临床实践，但仅从单中心招募不足200例患者显然力度不够。

Abdul-Ghani博士在接受采访时表示，他与同事正在争取开展一项更大规模的多中心随访研究，微血管并发症将是这项研究的主要终点。“每种新方法在刚问世时都会引起争议。但是，假如我们观察到的HbA_1c差异能够维持超过24个月，就可能引起微血管并发症风险的显著降低。那样一来，初始三联治疗将会改变2型糖尿病治疗的游戏规则。”

Abdul-Ghani博士还补充道，尽管缺乏有关视网膜病变和其他微血管并发症减少的数据，他仍然强烈建议临床医生对新诊断2型糖尿病患者采取初始三联治疗。“我们的数据太有力了：在不增加风险的同时可以带来如此之多的益处。”他指出，二甲双胍和吡格列酮均有廉价的仿制药可供选用，在有多种GLP-1激动剂正处于研发通道中的情况下，相对较老、需每日给药2次的艾塞那肽的价格还可能进一步下降。

这项研究由美国糖尿病学会资助，并获得了Amylin制药和武田制药的支持。Abdul-Ghani博士报告称无相关利益冲突。

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By: BRUCE JANCIN, Clinical Endocrinology News Digital Network

CHICAGO – Starting patients with newly diagnosed type 2 diabetes on the combination of metformin, pioglitazone, and exenatide from the get-go proved superior to standard guideline-recommended sequential add-on therapy with metformin, a sulfonylurea, and basal insulin in a 2-year randomized trial.

The triple-therapy group achieved significantly greater and more durable reductions in hemoglobin A1c with less risk of hypoglycemia than patients on the conventional treatment strategy. They also experienced weight loss rather than the weight gain seen with conventional management, Dr. Muhammad A. Abdul-Ghani reported at the annual scientific sessions of the American Diabetes Association.
 
The observed differences in therapeutic effectiveness and safety validate the strategy behind initial triple therapy, namely that it’s better to target the insulin resistance and progressive beta cell failure that constitute the core metabolic defects responsible for hyperglycemia and type 2 diabetes instead of simply focusing on lowering plasma glucose, added Dr. Abdul-Ghani of the University of Texas Health Science Center, San Antonio.

"My take home message for you is when you treat people with type 2 diabetes, treat the disease – diabetes – not the symptom of hyperglycemia," he declared.

The open-label study comprised 155 patients who had been recently diagnosed with type 2 diabetes. Average age was 47 years, average body mass index was 30.5 kg/m2, and average baseline HbA1c was 8.6%. Those randomized to triple therapy started on metformin at 1,000 mg/day, pioglitazone at 15 mg/day, and exenatide at 5 mcg twice daily. After 1 month, the doses of all three drugs were doubled. If 3 months into the study a patient hadn’t achieved the goal of an HbA1c below 6.5%, pioglitazone was boosted to 45 mg/day.

The conventional treatment group started on metformin followed by sequential addition of glipizide and then basal insulin as needed in an effort to reach an HbA1c below 6.5%.

The primary outcome was the HbA1c difference between the two groups at 2 years. The mean HbA1c decreased from 8.6% at baseline to 6% in the triple-therapy group, significantly better than the 6.6% with conventional therapy. The median HbA1c was 5.8% with triple therapy compared to 6.4% with add-on therapy. In the triple therapy group, 60% had an HbA1c below 6% compared to 27% of controls. In the triple therapy, 92% met the ADA target of an HbA1c below 7% compared to 72% on conventional therapy.

Participants were seen in the clinic every 3 months. Treatment failure, defined as an HbA1c above 6.5% on two consecutive visits 3 months apart, occurred in 17% of the triple-therapy group and 42% on conventional therapy.

Even though the mean HbA1c was 0.5% lower in the triple-therapy group, their incidence of hypoglycemia over the course of 2 years was also significantly lower: 15% versus 46% in the conventional therapy group, the diabetologist continued.

Patients receiving triple therapy had a mean 1.2-kg weight loss over 24 months versus a 4.1-kg weight gain with conventional therapy.

In a multivariate regression analysis, triple-therapy was associated with an 84% reduction in the risk of treatment failure. The other protective factor was age: for each decade beyond age 40 years, a patient’s risk of treatment failure was reduced by 64%.

"We don’t know yet whether this is an issue of patient compliance with therapy or there is something in the pathophysiology of the disease that makes age protective against treatment failure," Dr. Abdul-Ghani said.

Metformin was selected for inclusion in the triple-drug regimen because it corrects insulin resistance in the liver, pioglitazone because it corrects insulin resistance in adipocytes and muscle along with preserving beta cell function, and exenatide because it enhances beta cell function, the physician explained.

Several audience members called the study controversial, noting that it was a single-center study with fewer than 200 patients, yet it aims to overturn current guideline-based clinical practice.

In an interview, Dr. Abdul-Ghani said he and his coinvestigators are trying to drum up support for a larger, multicenter follow-up study featuring microvascular complications as a primary endpoint.

"Every novel approach is controversial at first. But if the difference we’ve seen in A1c can be maintained for longer than 24 months it could result in a substantially reduced risk of microvascular complications. That would really be a game changer in terms of attitudes toward patient treatment," he observed.

He added that even in the absence of data showing a reduction in retinopathy and other microvascular complications, he would "absolutely" recommend that physicians start applying initial triple therapy in their patients with newly diagnosed type 2 diabetes.

"Our data are so strong: there is no increased risk, and so many benefits," according to Dr. Abdul-Ghani.

Both metformin and pioglitazone are available as low-cost generics, and with so many new GLP-1 agonists in the developmental pipeline, the cost of an older, twice-daily agent such as exenatide might come down, he said.

The study was funded by the American Diabetes Association with support from Amylin Pharmaceuticals and Takeda. Dr. Abdul-Ghani reported having no conflicts of int