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Victoza (liraglutide,利拉鲁肽注射剂)-II型糖尿病最有效治疗

2010-02-22 10:04:42  作者:新特药房  来源:中国新特药网  浏览次数:206  文字大小:【】【】【
简介: 美国食品药品管理局(FDA)近日批准Victoza (liraglutide,利拉鲁肽)注射剂用于部分成年患者2型糖尿病的治疗。Victoza属胰高血糖素样肽1(GLP-1)类似物药物(注射剂,每日注射一次),能够在患者进食 ...

 美国食品药品管理局(FDA)近日批准Victoza (liraglutide,利拉鲁肽)注射剂用于部分成年患者2型糖尿病的治疗。Victoza属胰高血糖素样肽1(GLP-1)类似物药物(注射剂,每日注射一次),能够在患者进食后促使其胰腺分泌更多胰岛素,对于没有进行适当的饮食控制和运动的患者,Victoza不被推荐单独用于糖尿病的初期治疗。

FDA药品审评与研究中心新陈代谢与内分泌室主任、医学博士Mary Parks说,“糖尿病是引起死亡和致残的一个主要原因,每年新诊断出的糖尿病患者超过了1500万人。对于预防或控制长期的糖尿病并发症来看,控制血糖水平是非常重要的,Victoza为部分2型糖尿病患者提供了控制血糖水平的备选方案。”

Victoza最常见的不良反应包括头痛、恶心和腹泻。其他不良反应包括荨麻疹等过敏样反应。有3900位患者参加的5个临床试验结果显示,使用Victoza的患者发生胰腺炎(胰腺的一种炎症)的可能性要大于使用其他治疗药物的患者。当患者出现严重腹痛,伴随或未伴随恶心、呕吐时,应停止使用Victoza,当确诊为胰腺炎后,不应再次使用Victoza进行治疗。有胰腺炎病史的患者应慎用。动物试验显示,Victoza会引起大鼠和小鼠出现甲状腺瘤。因此,尚不能确认是否会引起人甲状腺瘤或癌,为此,在继续进行研究以证明可以扩大使用之前,Victoza不能作为治疗2型糖尿病的一线药物,也不能用于治疗已患甲状腺髓样癌的患者。

为确保该产品的安全性和有效性,FDA要求生产企业制定包括用药指南与交流计划在内的风险评估与降低计划(EMS),以助患者和医生了解该产品安全性方面的相关信息。

 Victoza (liraglutide) Medication for Diabetes

FDA Approves New Treatment for Type 2 Diabetes

The U.S. Food and Drug Administration today approved Victoza (liraglutide), a once-daily injection to treat type 2 diabetes in some adults.

Victoza is intended to help lower blood sugar levels along with diet, exercise, and selected other diabetes medicines. It is not recommended as initial therapy in patients who have not achieved adequate diabetes control on diet and exercise alone.

Insulin is a hormone that helps prevent sugar (glucose) from building up in the blood. People with type 2 diabetes have difficulty making and using insulin. Victoza is in a class of medicines known as glucagon-like peptide-1 (GLP-1) receptor agonists that help the pancreas make more insulin after eating a meal.

"Diabetes is a leading cause of death and disability, with more than 1.5 million new cases diagnosed annually," said Mary Parks, M.D., director, Division of Metabolism and Endocrinology Products in the FDA's Center for Drug Evaluation and Research. "Controlling blood sugar levels is very important to preventing or reducing the long term complications of diabetes, and Victoza offers certain patients with type 2 diabetes a treatment option for controlling their blood glucose levels."

In five clinical trials involving more than 3,900 people, pancreatitis (inflammation of the pancreas) occurred more often in patients who took Victoza than in patients taking other diabetes medicines. Victoza should be stopped if there is severe abdominal pain, with or without nausea and vomiting, and should not be restarted if pancreatitis is confirmed by blood tests. Victoza should be used with caution in people with a history of pancreatitis.

The most common side effects observed with Victoza were headache, nausea, and diarrhea. Other side effects included allergic-like reactions such as hives.

Victoza was not associated with an increased risk for cardiovascular events in people who were mainly at low risk for these events. FDA approved Victoza, however, with several post-marketing requirements under the Food and Drug Administration Amendments Act (FDAAA) to ensure that the company will conduct studies to provide additional information on the safety of this product.

In addition to a cardiovascular safety study to specifically evaluate the cardiovascular safety of Victoza in a higher risk population, the company also is required to conduct a 5-year epidemiological study using a health claims database to evaluate thyroid and other cancer risks as well as risks for seriously low blood glucose levels (hypoglycemia), pancreatitis, and allergic reactions. To specifically evaluate the risk of medullary thyroid cancer, the company is required to establish a cancer registry to monitor the rate of this type of cancer in the United States over the next 15 years.

In animal studies, Victoza caused tumors of the thyroid gland in rats and mice. Some of these tumors were cancers, which were significantly increased in rats who received excessive doses that were 8-times higher than what humans would receive.

It is not known if Victoza could cause thyroid tumors or a very rare type of thyroid cancer called medullary thyroid cancer in people. For this reason, Victoza should not be used as the first-line treatment for diabetes until additional studies are completed that support expanded use. Also, Victoza should not be used in people already at risk for medullary thyroid cancer, such as those who have medullary thyroid cancer in the family or those with a rare genetic condition known as Multiple Endocrine Neoplasia syndrome type 2.

To ensure the safe and effective use of this product, Victoza was approved with a Risk Evaluation and Mitigation Strategy consisting of a Medication Guide and a Communication Plan to help patients and providers understand the risks of Victoza and to ensure that the benefits of the drug outweigh the risk of acute pancreatitis and the potential risk of medullary thyroid cancer.

Victoza is manufactured by Novo Nordisk of Bagsvaerd, Denmark.

2010年1月25日美国FDA批准利拉鲁肽(liraglutide),一种胰高血糖素-样肽-1(GLP-1)受体激动剂在2型糖尿病成年中,可每天用1次改善血糖控制。在仔细权衡几种复杂安全性-相关担忧和获益考虑的基础上批准。
在临床试验中,利拉鲁肽加至其它抗糖尿病治疗使用导致平均糖化血红蛋白浓度与安慰剂比较从0.8减低1.4百分率点数。当与用一种磺酰脲类单药治疗比较,利拉鲁肽伴较低风险的低葡萄糖血症。其它潜在获益包括比用某些阳性对照药体重减轻更大,和对肾受损患者无需调整剂量。
另一方面,存在某些潜在的安全性担忧。首先,来自啮齿类研究资料提示利拉鲁肽伴有甲状腺C-细胞灶性增生和C-细胞肿瘤风险增加。啮齿类中,C-细胞增生被认为是一种癌前病变导致髓性甲状腺癌1。在大鼠和小鼠研究显示:在批准人用剂量导致相似于血浆药物水平的利拉鲁肽给药时,良性C-细胞腺瘤发生率增加。在大鼠和小鼠都观察到恶性C-细胞癌,而且在雄性大鼠用利拉鲁肽的剂量,高于人接受最大推荐剂量8倍所造成血浆药物水平发生率统计显著增加。在大鼠或小鼠中,利拉鲁肽-诱发髓性甲状腺癌发生率 不影响总生存率。
虽然这些结果是令人担忧,它们与人类关联不清楚。在美国髓性甲状腺癌的发生率接近每年600例— 使之进行伴用利拉鲁肽暴露增加这类癌风险的临床试验不可行。然而,降钙素,甲状腺C-细胞分泌的一种激素,在临床上被用作检测髓性甲状腺癌的生物标志物;在临床试验中常规监测降钙素水平可能是有用的指示。血清降钙素水平低于10 pg/mL被认为是没有髓性甲状腺癌的证据,而水平高于100 pg/mL是高于预测髓性甲状腺癌2。在对照临床试验中,利拉鲁肽治疗比对照患者发生降钙素水平增加的百分率略微较高;虽然增高是从低于分析的检测限度(0.7 ng/mL)偏移至略微高于此限度,降钙素水平仍在正常范围内。此外,从一项长期研究资料,利拉鲁肽和对照组间2年随访平均降钙素水平未发现任何注目的差别(见图)。
 
降钙素值的几何均数在1079例患者2-年试验中,其中利拉鲁肽,格列美脲或安慰剂被加至二甲双胍治疗。数据来自随机,双盲治疗期第0周至第52周。第52周后数据来自一项开放,自愿延伸期试验。在每个时间点,未得到所有患者数据。无刺激的降钙素值50 ng/mL或更高提示可能是髓性甲状腺癌信号2。
FDA结论是:啮齿类中癌发生率增加转化至对人低风险,因为统计学上显著增加仅预计在人中发生在药物暴露剂量水平高许多倍,而且癌增加不影响总生存率。然而,很难从动物研究发现外推至人。为进一步研究髓性甲状腺癌和利拉鲁肽使用间关联的可能性,FDA行使美国药品食品管理修正法赋予的权力要求在动物进行另外研究并在今后15年期间建立癌登记注册,以监查髓性甲状腺癌的年发生率。
另一安全性担忧是增加胰腺炎风险的可能性由于药物通过GLP-1通路作用。这种担忧来自提交给FDA的不良事件报告系统,关于胰腺炎伴使用艾塞那肽(exenatide)和西他列汀(sitagliptin)的上市后报告,这两个药物均此通路作用。上市后报告的局限性(如, 资料不完全),加上在糖尿病患者中胰腺炎的基线率高达无糖尿病人群三倍的可能性3,使之难以确定自发性报告表明用这些药物是否是风险增加的原因。尽管这种不确定性,我们要求艾塞那肽和西他列汀的制造商们在药物说明书中突出增加胰腺炎风险可能性和动物中进行附加研究。
在利拉鲁肽是2期和3期试验中,4257例利拉鲁肽治疗患者中报道7例胰腺炎而在对比物组2381例患者中只有1例。在调整暴露于利拉鲁肽更多患者-年,利拉鲁肽和对比物组间胰腺炎的发现代表4:1不平衡。事件的小数量使之难以对因果关心得出结论,但对艾塞那肽和西他列汀不平衡的担忧,导致FDA要求承办单位在动物中执行批准后机制研究和利用大型保险索赔数据库进行流行病学评价。开处方者和患者应认识到利拉鲁肽常见副作用包括恶心和呕吐,但持久或严重恶心和呕吐时应仔细评价,因为它们可能是胰腺炎的早期表现和因此需要及时中断利拉鲁肽治疗。
最后一个问题是从抗糖尿病治疗是否有可能除去心血管事件风险增加的可能性。在2008年12月,the FDA发表工业指导原则概述建议评估新抗糖尿病药物赋予任何心血管风险4。为获得这类药物的批准, 承办人将不得不比较接受被研究药物组与对比物组心血管事件的发生率并且显示95%可信双侧区间的上限估计风险比率是小于1.8。符合这个标准的药物可被批准上市,在批准后需要更严格心血管风险的评价 (导致可信上限小于1.3。
对利拉鲁肽的临床开发计划在指导原则发布前完成,但来自2期和3期试验合并心血管事件的分析显示本药符合排除心血管风险,不可接受增加标准。批准前临床试验时心血管事件总发生率低,然而,不符合批准后评价纲要更严格的标准。所以FDA要求批准后心血管安全性研究。
在批准利拉鲁肽中,FDA认识到对尽管患者用另一种抗糖尿病治疗糖尿病控制不充分时可能有效益。. 明显改善血糖控制减少来自糖尿病微血管合并症的风险和是治疗糖尿病的基石。FDA还认识到为治疗2型糖尿病所有批准产品,包括长期-上市产品,带有风险。Several of 利拉鲁肽的几种潜在安全性问题将被进一步研究。需要风险评价和缓和策略(mitigation strategy)包括药物指南和为教育开处方者关于药物的风险和获益的沟通交流计划,以及事实是不推荐为为用饮食和运动未被证明可控制糖尿病患者的一线治疗。FDA 希望从要求的批准后研究和临床试验更多地了解关于利拉鲁肽的安全性。在此期间,医生们将需要仔细复习处方资料和决定效益-风险图形是否有利于每个个体患者。
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Source Information
From the Division of Metabolism和Endocrinology Products (M.P.)和the Office of Drug Evaluation II (C.R.), Office of 新Drugs, Center for Drug Evaluation和Research, Food和Drug Administration, Silver Spring, MD.
This article (10.1056/NEJMp1001578) was published on February 17, 2010, at NEJM.org.
References
1.    McConnell EE, Solleveld HA, Swenberg JA, Boorman GA. Guidelines for combining neoplasms for evaluation of rodent carcinogenesis studies. J Natl Cancer Inst 1986;76:283-289. [Web of Science][Medline]
2.    Costante G, Meringolo D, Durante C, et al. Predictive value of serum calcitonin levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 5817 consecutive patients with thyroid nodules. J Clin Endocrinol Metab 2007;92:450-455. [Free Full Text]
3.    Noel RA, Braun DK, Patterson RE, Bloomgren GL. Increased risk of acute pancreatitis and biliary disease observed in patients with type 2 diabetes: a retrospective cohort study. Diabetes Care 2009;32:834-838. [Free Full Text]
4.    Guidance for industry: diabetes mellitus — evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Silver Spring, MD: Food and Drug Administration, 2008. (Accessed February 12, 2010, at

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