Once-weekly exenatide reduced hemoglobin A1c to a significantly greater degree than did either sitagliptin or pioglitazone in DURATION-2, a 26-week randomized, double-blind trial of 491 patients with type 2 diabetes who had baseline HbA1c levels of 8.5% or higher despite metformin treatment.
The study, funded by Amylin Pharmaceuticals and Eli Lilly, was published online June 26 to coincide with a presentation of its results by lead author Dr. Richard M. Bergenstal at the annual scientific sessions of the American Diabetes Association (Lancet 2010 June 26 [doi:10.1016/S0140-6736(10)60590-9]).
Patients received treatment in 72 sites in the United States, India, and Mexico. All had been treated with a stable metformin regimen for at least 2 months before screening and continued to take metformin throughout the study. The patients were randomized to one of three regimens: 2-mg exenatide injection once weekly plus oral placebo once daily, 100 mg oral sitagliptin once daily plus placebo injection once weekly, and 45 mg oral pioglitazone once daily with placebo injections once weekly.
Patients and staff in DURATION-2 (A Study to Compare the Glycemic Effects, Safety, and Tolerability of Exenatide Once Weekly to Those of Sitagliptin and a Thiazolidinedione in Subjects With Type 2 Diabetes Treated With Metformin) were all blinded to treatment allocation during the 26 weeks of treatment, said Dr. Bergenstal of the International Diabetes Center at Park Nicollet, Minneapolis, and his associates.
Of the 514 participants randomly allocated to treatment, those who received at least one treatment (491) were included in the intention-to-treat analysis. Fewer patients withdrew from treatment with sitagliptin (13%) than did those receiving exenatide once weekly (21%) or pioglitazone (21%), most of whom withdraw consent.
At 26 weeks, mean HbA1c values were 7.2% for exenatide, 7.7% for sitagliptin, and 7.4% for pioglitazone. From baseline to week 26, reduction in HbA1c with once-weekly exenatide was significantly greater than with the other two drugs, at 1.5 percentage points, compared with 0.9 and 1.2 percentage points with sitagliptin and pioglitazone, respectively.
When the data were stratified by baseline HbA1c, once-weekly exenatide was associated with a significantly greater reduction in HbA1c than was sitagliptin in all patients, but for exenatide versus pioglitazone the difference was significant only in patients with baseline HbA1c of 9% or higher, the investigators reported.
All three treatments improved fasting plasma glucose, but once-weekly exenatide resulted in a significantly greater reduction than did sitagliptin – 32 vs. 16 mg/dL – but not pioglitazone, which produced a reduction in fasting plasma glucose of 27 mg/dL. Fasting insulin was significantly increased at week 26 with once-weekly exenatide compared with both sitagliptin and pioglitazone, they said.
Weight loss at 26 weeks was significantly greater with exenatide than with sitagliptin, 2.3 vs. 0.8 kg, while the pioglitazone group gained an average of 2.8 kg. Over 75% of the patients on once-weekly exenatide lost body weight, compared with 61% of those on sitagliptin and 21% of those on pioglitazone.
Reductions in systolic blood pressure were significantly greater with once-weekly exenatide than with sitagliptin, but did not differ from those seen with pioglitazone. Change in diastolic pressure at week 26 did not differ between the three groups. Significant improvement in HDL cholesterol was recorded with all treatments, and improvement was significantly greater with pioglitazone than with exenatide. Pioglitazone was the only treatment associated with a significant reduction in triglycerides and total cholesterol, Dr. Bergenstal and his associates noted.
The most common treatment-emergent adverse events for patients on exenatide and sitagliptin were nausea and diarrhea, whereas pioglitazone patients’ most common adverse events were upper respiratory tract infection and peripheral edema. Vomiting was more common with exenatide than with sitagliptin or pioglitazone.
Adverse events leading to withdrawal from the study drug occurred in 10 patients on exenatide, 5 on sitagliptin, and 6 on pioglitazone. Of the 26 serious adverse events during treatment, one was fatal but the others resolved. Two led to study withdrawal: cryptogenic organizing pneumonia on exenatide and necrotizing pancreatitis on pioglitazone. There were no episodes of major hypoglycemia, and the frequency of minor hypoglycemic events was low and similar between treatment groups, they reported.
The study was funded by Amylin Pharmaceuticals and Eli Lilly.
Dr. Bergenstal’s institution has received consultancy fees or research grant support, or both, with receipt of travel and accommodation expenses in some cases, from Abbott Diabetes Care, Amylin, Bayer, Eli Lilly, Intuity Medical, Hygieia Medical, LifeScan, Mannkind, Medtronic-Minimed, U.S. National Institutes of Health, Novo Nordisk, ResMed, Roche, Sanofi-Aventis, United Health Group, and Valeritas; all research activity, and advisory or consultancy services were done under contract with the nonprofit International Diabetes Center at Park Nicollet. Dr. Bergenstal also owns stock in Merck. One coauthor has similar disclosures, six are employees of Amylin Pharmaceuticals, and one is an employee of Eli Lilly.
Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
一项名为DURATION-2的为期26周的随机双盲试验显示，在491例经二甲双胍治疗后基线HbA1c 水平仍≥8.5%的2型糖尿病患者中，每周1次艾塞那肽比西他列汀和吡格列酮能更显著地降低血红蛋白A1c(HA1c)。
该研究由Amylin制药公司和礼来公司资助，已于6月26日在线发表；与此同时，第一作者Richard M. Bergensta也在美国糖尿病协会年度科学会议上对该研究结果进行了报告(Lancet 2010 June 26 [doi:10.1016/S0140-6736(10)60590-9])。
患者在美国、印度和墨西哥的72个研究中心接受治疗。所有患者在筛查前曾接受稳定二甲双胍方案治疗至少2个月，并在研究期间继续服用二甲双胍。患者随机接受以下3种治疗之一： 每周1次注射艾塞那肽2 mg +每日1次口服安慰剂、每日1次口服100 mg西他列汀+每周1次注射安慰剂、每日1次口服45 mg吡格列酮+每周1次注射安慰剂。
明尼阿波利斯Park Nicollet国际糖尿病中心的Bergenstal博士及其同事表示，在26周治疗期间，DURATION-2(每周1次艾塞那肽与西他列汀和噻唑烷二酮类在二甲双胍治疗的2型糖尿病患者中的降糖作用、安全性和耐受性对比研究)中的患者和研究人员均对治疗分组情况不知情。
在514例接受随机治疗的患者中，491例接受至少1次治疗的患者被纳入意向治疗分析。 西他列汀组退出治疗的患者 (13%) 少于每周1次艾塞那肽组(21%)和吡格列酮组(21%)，这些患者中多数撤销同意书。
26周时，艾塞那肽组、西他列汀组和吡格列酮组的平均HbA1c分别为7.2%、7.7%和7.4%。每周1次艾塞那肽组26周时的HbA1c相比基线降低了1.5%，降幅显著大于西他列汀组(0.9%)和吡格列酮组(1.2%)。
研究者指出，根据基线HbA1c对数据进行分层后发现，与西他列汀组相比，每周1次艾塞那肽组所有患者的HbA1c降低幅度均明显更大，但与吡格列酮组相比，艾塞那肽组仅基线HbA1c ≥9%的患者HbA1c降低幅度明显更大。
他们表示，所有3种治疗均可降低空腹血浆葡萄糖，但每周1次艾塞那肽组的空腹血浆葡萄糖降幅比西他列汀组明显更大(32 mg/dl对16 mg/dl)，但与吡格列酮组(27 mg/dl)相比无显著差异。 与西他列汀组和吡格列酮组相比，每周1次艾塞那肽组26周时的空腹胰岛素显著增加。
26周时，艾塞那肽组体重降幅显著大于西他列汀组(2.3 kg对0.8 kg,)，而吡格列酮组体重平均增加了2.8 kg。每周1次艾塞那肽组体重下降的患者比例超过75%，西他列汀组和吡格列酮组相应比例分别为61%和21%。
每周1次艾塞那肽组的收缩压降幅比西他列汀组明显更大，但与吡格列酮组相比无差异。 26周时，3组之间的舒张压变化无差异。所有治疗均可显著改善HDL胆固醇。但吡格列酮组改善程度明显大于艾塞那肽组。Bergenstal 博士及其同事指出，吡格列酮是唯一与甘油三酯和总胆固醇显著降低相关的治疗方案。
最常见的治疗中出现的不良事件在艾塞那肽组和西他列汀组中为恶心和腹泻，在吡格列酮组中为上呼吸道感染和周围水肿。艾塞那肽组呕吐发生率高于西他列汀组和吡格列酮组。
他们指出，艾塞那肽组10例、西他列汀组5例及吡格列酮组6例患者因不良事件而停用研究药物。治疗期间共出现26件严重不良事件，其中1件为致死性，而其他均治愈。2件导致患者退出研究：隐源性机化性肺炎(艾塞那肽组)和坏死性胰腺炎(吡格列酮组)。所有治疗组均无严重低血糖发作事件，并且各组间轻度低血糖事件的发生率相似，均较低。
该研究由Amylin制药公司和礼来公司资助。
Bergenstal博士的单位从雅培糖尿病护理公司、Amylin、拜耳、礼来、Intuity Medical、Hygieia Medical、LifeScan、Mannkind、美敦力-Minimed、美国国立卫生研究院、诺和诺德、瑞思迈、罗氏、赛诺菲-安万特、联合健康集团和Valeritas公司获得顾问费或研究资金支持(或两者兼有)或差旅费和住宿费(某些情况下)；所有研究活动和咨询或顾问服务均按与该Park Nicollet非营利国际糖尿病中心签订的合同进行。Bergenstal博士还持有默沙东的股份。1位作者的经济利益冲突声明与上述相似，6位作者为Amylin制药公司的员工，1位为礼来公司的员工。
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