研究性基础胰岛素夜间低血糖发生率低

芝加哥——美国糖尿病学会(ADA)2013年会上公布的300 U/ml甘精胰岛素Ⅲ期EDITION I 试验结果显示，这种新的更长效基础胰岛素制剂在控制血糖方面可与100 U/ml甘精胰岛素(来得时)相媲美，并且可使严重夜间低血糖事件发生率降低21%。

主要研究者、俄勒冈健康科学中心内科教授Matthew C. Riddle博士报告称，该研究性药物又被称为U300，与甘精胰岛素U100类似，同属于每天用药1次的长效胰岛素类似物。但U300具有更为平稳且持续时间更长的药效学特点，从而具有更低的低血糖风险。


Matthew Riddle(中)博士在会场上回答有关EDITION I试验的提问。

EDITION I试验纳入807例2型糖尿病成年患者，他们接受至少42 U/day的基础甘精胰岛素或中效胰岛素(NPH)+餐时胰岛素，同时服用或不服用二甲双胍。受试者的平均病程为15.8年，平均体重指数(BMI)为36.6 kg/m2。他们被随机分组，在继续接受餐时胰岛素治疗的同时，分别每晚接受1次U300或U100的开放标签治疗，共计6个月。逐渐调整基础胰岛素剂量，使空腹血糖水平达到80~100 mg/dl。

主要疗效终点指标为6个月与基线相比糖化血红蛋白A1c的(HbA1c)变化。结果显示，两组HbA1c均平均下降0.83%，未见组间差异。次要终点指标为3~6个月出现≥1次严重和(或)明确的夜间血糖≤70 mg/dl事件。U300组发生率为36.1%，而U100组为46%，前者风险显著降低21%。在6个月研究期间，发生任何夜间低血糖的患者比例分别为45.3%和59.7%，前者相对风险下降24%。

EDITION I是该研究性药物的首个全球大规模Ⅲ期系列临床试验。最近刚刚完成的EDITION II 试验再次印证了EDITION I试验结果，即U300降低血糖的效果与来得时相似但严重夜间低血糖事件减少。该试验纳入了811例接受基础胰岛素和口服降糖药物治疗的早期2型糖尿病患者。目前正在进行的EDITION III试验对象为2型糖尿病初治患者，EDITION IV试验则重点关注1型糖尿病患者， 目前正在日本开展的EDITION JP I 和 II试验则旨在评价比较U100与试验药物在一般临床实践中的表现。

Riddle博士指出，目前的问题是尚不清楚这种新药对多少患者可产生有临床意义的疗效差异。U100(来得时)的确是一种成功的胰岛素类似物，弃用该药物的可能性很低。我们将来很可能最终会将接受基础胰岛素治疗的患者一分为二：一部分继续使用来得时，而另一部分使用U300这种更长效胰岛素。U300是一种选择，但不是唯一的选择。如果考虑到支付能力，使用任何胰岛素都比不用要好。

Riddle博士接受了多家制药公司的研究基金资助并担任有偿顾问，其中包括EDITION试验的赞助商赛诺菲制药公司。

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By: BRUCE JANCIN, Clinical Endocrinology News Digital Network

CHICAGO – A new longer-acting basal insulin glargine formulation was as effective as the familiar insulin glargine 100 U/mL/Lantus in controlling glycemia while producing a 21% lower rate of severe nocturnal hypoglycemic events in the phase III EDITION I trial.

The investigational formulation contains insulin glargine 300 U/mL and is known as U300. Like insulin glargine U100, the investigational agent is a once-daily, long-acting insulin analog. But U300 has an even flatter, longer, and more stable pharmacodynamic profile, which translates into a lower risk of hypoglycemia, as shown in the EDITION I trial, principal investigator Dr. Matthew C. Riddle explained at the annual scientific sessions of the American Diabetes Association.

EDITION I included 807 adults with type 2 diabetes who were on an established treatment with at least 42 U/day of basal glargine or NPH along with mealtime insulin with or without metformin. Their mean duration of diabetes was 15.8 years, and their mean body mass index was 36.6 kg/m2. They were randomized to 6 months of open-label insulin glargine U300 or insulin glargine U100 once daily in the evening while continuing on their mealtime insulin. The basal insulin was titrated to achieve a fasting plasma glucose of 80-100 mg/dL.

The primary efficacy endpoint was change in hemoglobin A1c from baseline through month 6. The reductions were the same in both groups: a mean decrease of 0.83%.

The chief secondary endpoint was the occurrence of one or more episodes of severe and/or confirmed nocturnal hypoglycemia to a level of 70 mg/dL or less during months 3-6. The rate was 36.1% in the U300 group, compared with 46% with U100, for a highly significant 21% risk reduction, said Dr. Riddle, professor of medicine at the Oregon Health and Science Center, Portland.

Any nocturnal hypoglycemia during the 6-month study occurred in 45.3% of patients on U300 vs. 59.7% on U100, for a 24% relative risk reduction, he added.

EDITION I is the first in a large worldwide series of phase III trials of the investigational insulin. The recently completed EDITION II trial replicated the EDITION I findings blood glucose reductions similar to those seen in patients taking Lantus, with fewer serious nocturnal hypoglycemic events – in 811 type 2 diabetic patients with earlier-stage disease as evidenced by the enrollment requirement that they be established on basal insulin and oral antidiabetic therapy. EDITION III is ongoing in insulin-naive type 2 diabetic patients, EDITION IV focuses on patients with type 1 diabetes, and EDITION JP I and II are ongoing in Japan. These trials are designed to assess the relative performance of U100 and the investigational insulin in a range of common clinical scenarios.

"The question is what proportion of patients is going to have a clinically relevant difference in success with the new formulation versus the old one. I don’t know the answer to that yet," Dr. Riddle said in an interview. "U100 has been a really successful insulin, and the likelihood of it going away is really, really low. We’ll probably end up dividing the basal insulin patients into a good many continuing on Lantus U100, and a good many others using newer, longer-acting insulins, U300 being one, but not the only one. When affordability is an issue, taking any insulin is better than not taking it at all."

Dr. Riddle receives research grant support from and is paid consultant to several pharmaceutical companies, among them Sanofi, which sponsors the EDITION trials.