ST LOUIS (MD Consult) - On July 31, 2009, the US Food and Drug Administration (FDA) and the Bristol-Myers Squibb Co announced the approval of Onglyza (saxagliptin) for the treatment of type 2 diabetes mellitus in adults. Onglyza is a dipeptidyl peptidase-4 inhibitor, and it acts by stimulating the pancreas to produce more insulin postprandially.

 

Onglyza can be used in combination with commonly prescribed oral antidiabetic medications (eg, metformin, sulfonylureas, or thiazolidinediones [TZDs]) or as a monotherapy. The drug has not been studied in combination with insulin.

 

According to the manufacturer, the FDA approval of Onglyza was granted on the basis of clinical development program data. Trials involved approximately 5,000 patients, more than 4,000 of whom received Onglyza. As part of the development program, Onglyza, with diet and exercise, was studied as add-on therapy with other oral antidiabetic medications including metformin, the sulfonylurea glyburide, and TZDs. The drug was also studied as monotherapy. In addition, it was given to adult patients who had not been previously treated with antidiabetic medication. These patients received metformin and Onglyza in combination.

Throughout the phase 3 development program, treatment with Onglyza at all doses produced clinically relevant and statistically significant reductions in all 3 key measures of glucose control studied: hemoglobin A1c, fasting plasma glucose, and postprandial glucose. These improvements were evident when Onglyza was partnered with other commonly used oral antidiabetic agents or when the drug was used as monotherapy. Compared with placebo, Onglyza was weight and lipid neutral.

In clinical trials, the overall incidence of adverse effects for Onglyza at doses of 2.5 and 5 mg was similar to placebo (72% and 72.2% vs 70.6%, respectively). The most common adverse events reported with Onglyza 5 mg (≥5% and more commonly than placebo) were upper respiratory tract infection (7.7% vs 7.6%, respectively), urinary tract infection (6.8% vs 6.1%, respectively), and headache (6.5% vs 5.9%, respectively). In adult patients treated with Onglyza 2.5 mg, only headache (6.5%) was reported at ≥5% and more commonly than in adult patients treated with placebo. Discontinuation of therapy as a result of adverse events occurred in 2.2%, 3.3%, and 1.8% of patients receiving Onglyza 2.5 mg, Onglyza 5 mg, and placebo, respectively. A dose-related mean decrease in absolute lymphocyte count was observed in patients taking Onglyza.

 

The application seeking approval for Onglyza was submitted before the FDA recommended that manufacturers of new diabetes drugs design and evaluate their clinical trials for cardiovascular safety. In studies, Onglyza was not associated with an increased risk for cardiovascular events in patients who were mainly at low risk for these events. However, the FDA is requiring that a postmarketing study of patients at higher cardiovascular risk be carried out, with the intent of specifically evaluating cardiovascular safety in this population.

 

Onglyza is taken once daily, regardless of mealtime, at a dose of 2.5 or 5 mg. A dose of 2.5 mg is recommended for patients with moderate or severe renal impairment, or end-stage renal disease requiring hemodialysis. Onglyza has not been studied in patients undergoing peritoneal dialysis. Assessment of renal functio n is recommended before initiation of Onglyza therapy and periodically thereafter.

 

圣路易斯(MD Consult)——2009年7月31日，美国食品药品管理局(FDA)与百时美施贵宝公司联合宣布，Onglyza (saxagliptin)已获准用于治疗成人2型糖尿病。Onglyza是一种二肽基肽酶-4抑制剂，其作用机制为刺激胰腺于餐后分泌更多的胰岛素。

Onglyza可与常用口服降糖药[如二甲双胍、磺脲类药物或噻唑烷二酮类药物(TZD)]联合或作为单药治疗。尚无该药物与胰岛素联用的研究。

据生产厂家称，FDA对该药物的审批是基于临床研发项目的资料。相关试验中包括约5,000例患者，其中4,000例以上接受了Onglyza治疗。在部分研发项目中，Onglyza作为饮食、运动和其他口服降糖药(包括二甲双胍、磺脲类药物优降糖和TZD)基础上的辅助治疗。也对该药物进行了单药治疗研究。还对既往未接受过降糖药治疗的成人患者进行了Onglyza治疗研究，这些患者采用的治疗方式为二甲双胍与Onglyza联合治疗。

在3期研发项目中，各种剂量的Onglyza治疗均使研究中的3种血糖控制关键指标(血红蛋白A1c、空腹血糖和餐后血糖)发生有临床意义和统计学意义的降低。在Onglyza与其他常用口服降糖药联用或Onglyza单药治疗时，这些指标均发生明显改善。与安慰剂相比，Onglyza对体重和血脂无影响。

临床试验中，在2.5 mg和5 mg的剂量水平，Onglyza治疗不良反应的总发生率与安慰剂相似(分别为72%、 72.2%和 70.6%)。报告中Onglyza 5 mg治疗后最常见(发生率≥5%，且高于安慰剂)的不良事件为上呼吸道感染(分别为7.7%和7.6%)、泌尿系感染(分别为6.8%和6.1%)和头痛(分别为6.5%和5.9%)。在接受Onglyza 2.5 mg治疗的成人患者中，发生率≥5%且高于接受安慰剂组的不良事件仅为头痛。接受Onglyza 2.5 mg、Onglyza 5 mg及安慰剂治疗的患者中，因不良事件停止治疗的发生率分别为2.2%、3.3%和1.8%。在接受Onglyza治疗的患者中，观察到与剂量相关的淋巴细胞绝对计数降低。

接受关于Onglyza的审批申请之后，FDA建议新型糖尿病治疗药物的生产商对临床试验中的心血管安全性进行设计和评估。研究显示，接受Onglyza治疗与心血管事件风险增加无关，但这些研究中的患者多数为心血管事件低危人群。FDA要求针对心血管风险较高患者的进行上市后研究，尤其要注意评估在这一人群中的心血管安全性。

Onglyza的用法为每日一次，餐前、餐时和餐后均可，每次剂量为2.5或5 mg。对中重度肾功能受损或终末期肾病需透析治疗的患者建议使用2.5 mg的剂量。尚无对腹膜透析患者的研究。建议在开始Onglyza治疗前评估肾功能，并在开始治疗后定期复查。