德谷胰岛素（新型长效胰岛素）的低血糖风险低

费城(EGMN)——美国糖尿病学会(ADA)年会上报告的数项研究显示，研究性超长效胰岛素degludec(德谷胰岛素)可改善血糖控制，同时低血糖风险较低。这些患者中很多合并肥胖而需要较大剂量胰岛素。

德谷胰岛素(IDeg)由诺和诺德生产，是一种基础胰岛素，在皮下注射后形成可溶性多六聚体，使得其半衰期显著延长至超过24 h。马里兰州内分泌学家Helena W. Rodbard博士指出，由于所产生的血液胰岛素浓度稳定，与使用甘精胰岛素者相比，试验中使用德谷胰岛素的1型和2型糖尿病患者发生低血糖的风险明显降低。目前美国食品药品管理局(FDA)正在考虑是否批准该药上市。

明尼阿波利斯国际糖尿病中心执行主任Richard M. Bergenstal博士指出，美国约有1/3的2型糖尿病患者每日需要超过60 U的基础胰岛素，有不少甚至需要80或100 U。这一情况促进了新型基础胰岛素的研发，以符合更长效、更平稳的要求。

Rodbard博士报告的Meta分析涉及5项ⅢA期、开放、随机、治疗达标、验证性、为期26~52周的试验，共纳入2,262例接受德谷胰岛素治疗和1,110例接受甘精胰岛素治疗的2型糖尿病患者，均每日注射1次。截至试验结束时，德谷胰岛素组和甘精胰岛素组中分别有35%和34%的患者每日需要使用超过60 U的基础胰岛素。

研究结束时，两组患者的糖化血红蛋白A1c值相似，估计治疗差异(ETD)只有0.05%(P=0.44)。德谷胰岛素组患者的平均空腹血糖值更低，ETD为–5.9 mg/dl。在每日需要超过60 U基础胰岛素的患者中，德谷胰岛素组患者的确证总体低血糖和夜间低血糖发生率均低于甘精胰岛素组患者。确证总体低血糖定义为自测血糖低于56 mg/dl(血浆校准)或出现需要干预的发作，确证夜间低血糖的定义是在午夜至早6点期间发生的任何经过证实的发作。

与甘精胰岛素组相比，德谷胰岛素组的确证总体低血糖发生率降低21%(P=0.02)，确证夜间低血糖发生率降低52%(P＜0.0001)。

与此同时，诺和诺德正在为胰岛素需求量大的患者开发一种200 U/ml德谷胰岛素。这一剂型名为IDeg U200，与100 U/ml剂型含有等量的胰岛素，而液量仅为后者的一半，从而使患者得以通过单次注射即可获得较大剂量的胰岛素(最高可达160 U)。

Bergenstal博士报告了一项为期26周的开放、治疗达标试验的结果，该试验比较了每日1次IDeg U200与100 U/ml甘精胰岛素的疗效和安全性，二者均与口服降糖药物联用。试验共纳入457例胰岛素初治的2型糖尿病患者，均适宜接受胰岛素治疗。将这些患者随机分组，给予IDeg U200或甘精胰岛素，均联用二甲双胍，部分患者还使用了其他药物。

截至第26周，IDeg U200使HbA1c降低了1.30%(基线水平为8.3%)，不劣于甘精胰岛素，ETD为0.04%。两组患者的空腹血糖水平下降程度相当。IDeg U200组的确证总体低血糖发生率(定义为＜56 mg/dl，或出现需要干预的发作)更低，为1.22起事件/患者-年，而甘精胰岛素组为1.42起事件/患者-年。IDeg U200组的确证夜间低血糖发生率也更低(0.18 vs. 0.28起事件/患者-年)。两组均未发生严重低血糖反应。

26周之后，两组患者的平均每日胰岛素剂量相似(IDeg U200组 vs. 甘精胰岛素组：0.62 U/kg vs. 0.66 U/kg)。在HbA1c降低的同时，两组患者均出现体重增加，分别平均增加1.9 kg和1.5 kg。两组的不良事件相似且均少见。

上述研究均由诺和诺德资助。


PHILADELPHIA (EGMN) – The investigational ultralong-acting insulin, degludec, improved glycemic control while incurring lower risks of hypoglycemia in several studies of diabetes patients, many of them obese with high insulin requirements.

Novo Nordisk’s insulin degludec (IDeg), which is under consideration for approval by the U.S. Food and Drug Administration, is a basal insulin that forms soluble multihexamers after subcutaneous injection, extending its half-life significantly longer than 24 hours. The resulting steady blood levels of insulin confer a significantly lower risk of hypoglycemia in type 1 and type 2 patients taking degludec, compared with those taking insulin glargine, the comparator in many clinical trials, according to Dr. Helena W. Rodbard, an endocrinologist who practices in Rockville, Md.

About a third of patients with type 2 diabetes in the United States require more than 60 U just as the basal component, with quite a few requiring 80 or 100 U of insulin, noted Dr. Richard M. Bergenstal, executive director of the International Diabetes Center at Park Nicollet, Minneapolis. This demand for ever-increasing units has led to the development of new basal insulins that are even longer-acting, smoother, and flatter in terms of their pharmacokinetic and pharmacodynamic profiles, he said.

Dr. Rodbard presented the results of a meta-analysis of five phase IIIA, open-label, randomized, treat-to-target, confirmatory, 26- or 52-week trials in which a total of 2,262 type 2 diabetes patients received degludec and 1,110 received glargine, both injected once daily. Among those, 35% of the degludec group and 34% of the glargine group required more than 60 U of basal insulin per day by the end of the trials.

At study completion, hemoglobin A1c values were similar in both groups, with an insignificant estimated treatment difference (ETD) of just 0.05% (P = .44). The mean fasting plasma glucose values at the end of the trials were lower with degludec than with glargine, with an ETD of –5.9 mg/dL, Dr. Rodbard reported.

Overall confirmed and nocturnal hypoglycemia rates were lower in patients requiring more than 60 U of insulin on degludec than on glargine, with confirmed hypoglycemia defined as self-measured blood glucose less than 56 mg/dL (plasma calibrated) or any episode requiring assistance. Nocturnal confirmed hypoglycemia was defined as any confirmed episode with onset between midnight and 6:00 a.m.

Compared with glargine, there was a 21% lower rate of overall confirmed hypoglycemic episodes with degludec (P = .02) and a 52% lower rate of nocturnal confirmed hypoglycemic episodes (P less than.0001).

The reduction of risk of hypoglycemia with degludec was particularly significant for nocturnal hypoglycemia, the “important area of concern,” Dr. Rodbard said in an interview.

Novo Nordisk is also developing a 200 U/mL formulation of insulin degludec specifically for patients with high insulin requirements. This formulation, known as IDeg U200, contains equal units of insulin in half the volume of the 100-U/mL formulation, thus allowing larger insulin doses (up to 160 U) to be administered in a single injection with a prefilled pen device.

Dr. Bergenstal presented data from a 26-week, open-label, treat-to-target trial that compared the efficacy and safety of once-daily IDeg U200 vs. 100 U/mL of insulin glargine, both in combination with oral antidiabetic drugs, in a total of 457 insulin-naive type 2 diabetes patients who qualified for insulin treatment. They were randomized to either IDeg U200 or glargine, both in combination with metformin and some also using other medications.

By 26 weeks, IDeg U200 reduced HbA1c by 1.30 percentage points (from a baseline of 8.3%) and was noninferior to glargine, with an estimated treatment difference of 0.04 percentage points.

Fasting glucose levels were similarly equally reduced. Rates of overall confirmed hypoglycemia (defined as less than 56 mg/dL, or having an episode requiring assistance) were lower with IDeg U200, at 1.22 episodes per patient per year, compared with 1.42 for glargine.

Rates of nocturnal confirmed hypoglycemia (defined as occurring between midnight and 6:00 a.m.) also were lower with IDeg U200 (0.18 vs. 0.28 episodes per patient-year, respectively). There were no severe hypoglycemic reactions in either group.

Mean daily basal insulin dose was similar after 26 weeks (0.62 U/kg for IDeg U200; 0.66 U/Kg for glargine). Weight gain occurred with a reduction in HbA1c in both groups, by 1.9 kg with IDeg U200 and 1.5 kg with glargine. Adverse events were similar and infrequent in both groups, said Dr. Bergenstal, who is the president of medicine and science at the American Diabetes Association.

“Insulin degludec 200 U/mL allows patients who require larger daily doses of basal insulin [to] use prefilled pen devices to administer up to 160 U in a single injection,” he concluded.

All of the reported studies were funded by Novo Nordisk.