NEW ORLEANS, Louisiana (EGMN)-Patients with type 2 diabetes who were treated with once-daily liraglutide experienced significantly greater improvements in glycemic control, compared with patients who were treated with twice-daily exenatide, results from an open-label, multicenter trial showed.
The findings of the Effect of Liraglutide or Exenatide Added to an Ongoing Treatment on Blood Glucose Control in Subjects With Type 2 Diabetes (LEAD-6) were reported on June 8 at the annual scientific sessions of the American Diabetes Association by Dr. John B. Buse, chief of the division of endocrinology at the University of North Carolina, Chapel Hill. They were simultaneously published online (Lancet 2009 [doi:10.1016/S0140-6736(09)60659-0]).
Liraglutide is an investigational human glucagon-like peptide-1 (GLP-1) analogue developed by Novo Nordisk Inc., that is under review at the European Medicines Agency for licensing approval to be used in combination with existing medications for improved glycemic control in patients with type 2 diabetes.
Exenatide (Byetta, Amylin Pharmaceuticals Inc.) is an exendin-based GLP-1 receptor agonist approved for use by people with type 2 diabetes who are unsuccessful in controlling their blood sugar levels. Both agents are delivered via subcutaneous injection.
Between August 2007 and April 2008, 464 patients aged 18-80 years with type 2 diabetes were randomized to receive liraglutide 1.8 mg once daily or exenatide 10 mcg twice daily at 132 office-based sites in 15 countries. Patients were eligible for the trial if their HbA1c levels were 7%-11%, if their body mass index was 45 kg/m2 or less, and if they were on maximally tolerated doses of metformin, sulfonylurea, or both.
The primary end point of LEAD-6 was the difference in HbA1c values between the two treatment groups from baseline to week 26.
At baseline, the mean age of the patients was 56 years, 92% were white, mean BMI was 33 kg/m2, and their mean HbA1c level was 8.2%. Of the 464 patients, 231 received exenatide and 233 received liraglutide.
At 26 weeks, the mean reduction in HbA1c was 1.12% among patients in the liraglutide group, compared with 0.79% among patients in the exenatide group, a statistically significant difference. In addition, significantly more patients in the liraglutide group achieved HbA1c levels of less than 7%, compared with their counterparts in the exenatide group (54% vs. 43%, respectively).
The researchers also found that patients in the liraglutide group achieved significantly greater drops in levels of fasting plasma glucose, compared with those in the exenatide group (-1.61 mmol/L vs. 0.60 mmol/L). However, exenatide reduced plasma glucose levels more than did liraglutide after breakfast and dinner meals, which suggests that liraglutide exerts more of its effects in the premeal or fasting period.
Weight reductions in both groups were similar, at about 3 kg.
Both drugs were well tolerated, but patients in the liraglutide group experienced less persistent nausea and less frequent rates of hypoglycemia, compared with those in the exenatide group.
In a commentary accompanying the study, Dr. Christophe E.M. DeBlock and Dr. Luc F. Van Gaal of Antwerp University Hospital, Belgium, expressed concerns about FDA reports of increased rates of pancreatitis associated with liraglutide treatment. “Whether the association is causal and whether it is a class effect of GLP-1 analogues is not clear,” they wrote (Lancet 2009 [DOI:10.1016/S0140-6736(09)60942-9. “We recommend not to give GLP-1 analogues to patients at risk for pancreatitis (e.g., with cholecystolithiasis, alcoholism, or hypertriglyceridemia).”
The commentators also pointed to a briefing by the U.S. Food and Drug Administration, which is also reviewing liraglutide, that notes that the risk of rate of frequency of papillary thyroid cancer in patients taking liraglutide is 1.6% per 1,000 patient-years of exposure, compared with 0.6% per 1,000 patient-years of exposure in patients taking exenatide. They recommended that future long-term studies of the agents include careful monitoring of thyroid abnormalities.
At the meeting, Dr. Buse said that there were no signs of elevated calcitonin levels (a marker of medullary thyroid carcinoma) in the study participants. “The calcitonin levels were very low on average and indistinguishable between in the two groups,” he said.
There was one case of mild chronic pancreatitis diagnosed in a 69-year-old man 88 days after liraglutide therapy, which was judged to be unlikely related to the drug. The man had been a longtime smoker and had a history of abdominal distention and hypercholesterolemia. After another 10 weeks of treatment the patient was withdrawn from the trial due to the discovery of lung adenocarcinoma.
In the Lancet article Dr. Buse and his associates acknowledged certain limitations of the study, including its open-label design, the fact that the majority of patients were white, and the fact that the trial was “not appropriately powered to assess differences between treatments for rare clinical safety adverse events.”
Dr. Buse disclosed that he has been an investigator, consultant, or speaker for several pharmaceutical companies, including Amylin and Novo Nordisk, the trial’s sponsor. Dr. Van Gaal is an adviser to Novo Nordisk and Eli Lilly. Dr. De Block declared that had no conflicts of interest.
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路易斯安那州新奥尔良(EGMN)——一项开放性多中心临床试验显示，2型糖尿病患者接受每日1次注射的利拉鲁肽(liraglutide)较每日2次艾塞那肽(exenatide)在血糖控制方面有显著改善。
在6月8日举行的美国糖尿病协会年度科学会议上，北卡罗来纳大学教堂山分校内分泌学系主任John B. Buse博士做了题为“2型糖尿病治疗中加入利拉鲁肽或艾塞那肽的疗效观察”的报告。该研究结果同时刊载于《柳叶刀》的网络版(Lancet 2009 [doi:10.1016/S0140-6736(09)60659-0])。
利拉鲁肽是诺和诺德公司开发的一种人胰高糖素样肽-1(GLP-1)类似物，用于与现有的口服降糖药合用，以改善2型糖尿病患者的血糖控制，目前正在美国FDA和欧洲药品管理局的批准审核中。
艾塞那肽(亦称Byetta，Amylin制药公司产品)是一种基于exendin的GLP-1受体激动剂，获批用于不能充分控制血糖的2型糖尿病患者。这两种药物均为皮下注射针剂。
2007年8月至2008年4月，试验共纳入15个国家132家医疗单位计464例年龄在18～80岁的2型糖尿病患者，受试者随机接受了利拉鲁肽(1.8mg，每日1次)或艾塞那肽(10mcg，每日2次)治疗。受试纳入标准为对二甲双胍、磺酰脲类或二甲双胍与磺酰脲类联合应用的最大安全剂量耐受、或糖化血红蛋白水平为7%～11%、或身体质量指数小于等于45 kg/m2者。
该研究(LEAD-6，利拉鲁肽相关临床研究系列6)的主要终点是两个治疗组的26周糖化血红蛋白值与基线值的差异。
患者基线平均年龄为56岁、白人比例为92%、平均体重指数为33 kg/m2、平均糖化血红蛋白水平为8.2%。在总计464例患者中，分别有231例和233例随机接受艾塞那肽和利拉鲁肽治疗。
治疗26周后，利拉鲁肽组患者的糖化血红蛋白水平平均降低1.12%，而艾塞那肽组患者降低0.79%，两者在统计学上有显著性差异。此外，与艾塞那肽组相比，利拉鲁肽组糖化血红蛋白水平低于7%的患者更多(分别为43%和54%)。
研究人员还发现，与艾塞那肽组相比，利拉鲁肽组患者的空腹血糖水平显著下降(分别为0.60 mmol/L 和-1.61 mmol/L)。而艾塞那肽则在降低餐后(早餐和晚餐)血糖水平上优于利拉鲁肽，这表明利拉鲁肽在餐前或禁食状态下疗效更好。
两组患者的体重减轻幅度相似，大约为3 kg。
患者对这两种药物均具有良好的耐受性。与艾塞那肽组相比，利拉鲁肽组患者出现恶心的时间较短，且发生低血糖的频率更低。
在该文章的一篇评述中，比利时安特卫普大学医院Christophe E.M. De Block博士和Luc F. Van Gaal博士表达了他们担忧——美国FDA的一份报告称利拉鲁肽与胰腺炎风险增加相关。“这究竟是一种因果关系还是GLP-1类似物的典型效应目前尚不清楚。“他们在评述中写道 (Lancet 2009. DOI:10.1016/S0140-6736(09)60942-9) ，“我们建议对有胰腺炎罹患风险的2型糖尿病患者，如有胆囊结石、酗酒或高甘油三酯血症病史的患者，不宜使用GLP-1类似物。”
他们同时还指出，美国FDA的一份简报上称接受利拉鲁肽治疗的患者乳头状甲状腺癌罹患风险为1.6%每1,000患者年，而艾塞那肽为0.6%每1,000患者年。他们建议，今后在对此类药物的长期研究中应包括对甲状腺异常的认真监测。
Buse博士在这次会议上指出，受试对象没有出现降钙素水平升高(甲状腺髓样癌的标志)的迹象。“降钙素水平在两个试验组中均很低，且没有差别。”他说。
1名69岁男子在利拉鲁肽治疗88天后诊断为轻度慢性胰腺炎，他们认为这与药物服用无关。该男子是一名长期吸烟者，有腹胀及高胆固醇血症病史。在继续接受了10个星期治疗后，该患者因发现罹患肺腺癌而终止试验。
在《柳叶刀》的这篇文章中，Buse博士和他的同事承认该研究具有一定的局限性，包括开放性的设计、纳入患者以白人为主以及不恰当地把临床上罕见的安全性不良事件作为评价差异性的指标。
Buse博士披露他目前是多家制药公司的研究人员、顾问和宣讲成员，其中包括资助了此项研究的诺和诺德和Amylin公司。Van Gaal博士是诺和诺德和礼来公司的顾问。De Block博士表示没有相关的利益冲突。
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