A once-weekly formulation of exenatide reduced hemoglobin A1c to a greater degree than did once-daily insulin glargine in DURATION-3, a phase III, 26-week open-label randomized trial of 456 patients with type 2 diabetes who had suboptimal control despite use of metformin with or without sulfonylureas.
The overall greater lowering of HbA1c with exenatide was due to significantly lower postprandial glucose excursions, since fasting plasma glucose was actually lower among the patients randomized to insulin glargine. DURATION-3 (Efficacy of Once-Weekly Exenatide Long-Acting Release and Once-Daily Insulin Glargine in Patients With Type 2 Diabetes Treated With Metformin Alone or in Combination With Sulfonylurea) was conducted in 72 sites around the world, funded by Amylin Pharmaceuticals and Eli Lilly and Co. (Lancet 2010;375:2234-43).
Patients randomized to exenatide received a 2-mg dose injected once a week. Those in the insulin glargine group started with 10 IU per day injected at bedtime, and were instructed to adjust insulin doses to achieve target fasting glucose values of 72-99 mg/dL. Metformin doses were kept constant, but patients taking sulfonylureas were advised to reduce that dose. The study design did not allow for blinding, noted Dr. Michaela Diamant, of VU University, Amsterdam, and her associates.
Mean doses of insulin glargine rose from 10 IU to 31 IU per day, and nearly one in four patients reduced their sulfonylurea dose. Metformin doses were about 2,000 mg/day throughout the study.
At 26 weeks, hemoglobin A1c in the exenatide group had dropped 1.5 percentage points, compared with 1.3 in those receiving glargine, and 60% percent of the exenatide patients achieved an HbA1c of less than 7%, compared with 48% for the glargine group, both significant differences. The proportions achieving HbA1c values less than 6.5% were 35% and 23%, respectively.
Mean fasting serum glucose concentrations were reduced in both groups, but to a significantly greater degree with insulin glargine (38 vs. 50 mg/dL), Dr. Diamant and her associates noted.
Whereas exenatide was associated with a progressive decrease in body weight, those taking insulin glargine had progressive increases. At 26 weeks, the exenatide group had lost an average of 2.6 kg, while the glargine group had gained 1.4 kg. In the exenatide group, reductions in body weight occurred in both those who reported nausea (3.5 kg) and those who did not (2.2 kg), they said.
Gastrointestinal events including nausea and diarrhea were among the most frequently reported adverse events in the exenatide group. Nausea was reported by 13% with exenatide vs. 1% with glargine, and diarrhea by 9% and 4%, respectively. All were mild or moderate in intensity. No serious adverse events were reported by more than one patient except for chest pain in two patients. No deaths occurred in either group. Discontinuations owing to adverse events were greater with exenatide (5% vs. 1%), due in part to injection-site reactions (2% vs. 0%).
At 26 weeks, five exenatide and no glargine patients had elevated amylase or lipase concentrations and one patient taking exenatide had edematous pancreatitis, an adverse event that has been reported previously with the currently available twice-daily exenatide. That patient was fully recovered by 2 months.
Patients in both groups who were taking sulfonylureas had more frequent hypoglycemic events, but the occurrence was consistently lower with exenatide than with glargine. Mean heart rate at 26 weeks was raised compared with baseline in the exenatide but not the glargine group. No other cardiovascular measures differed between the groups. The clinical importance of the small but significant increase in heart rate with exenatide treatment is unclear, they said.
In an accompanying editorial, Dr. Anoop Misra and Dr. Shashank Joshi pointed out that the nausea, although less common with once-weekly exenatide versus the twice-daily formulation, could still be troublesome in patients who are taking multiple drugs, including metformin, and in those who have diabetic gastroparesis. They also noted that cardiovascular safety data is still needed for this drug, and strict monitoring of pancreatic effects will be necessary.
Both the long-acting and the twice-daily exenatide formulations have been linked to renal dysfunction, and to attenuation of the response among the 6%-9% who develop antibodies to the drug, Dr. Misra and Dr. Joshi said (Lancet 2010;375:2198-9).
Nonetheless, this or other drugs in the glucagon-like peptide-1 receptor analogue class might be suitable for patients with type 2 diabetes who are obese or those in whom hypoglycemia is a clinical concern. “Currently, there is more promise, few disadvantages, and some unknowns about treatment with long-acting exenatide for diabetes,” they concluded.
The study was funded by Amylin Pharmaceuticals and Eli Lilly and Co.
Dr. Diamant is a consultant and speaker for Eli Lilly, Novo Nordisk, and Merck, Sharpe, and Dohme, and a consultant for Sanofi-Aventis. The VU University has also received research grants from those companies as well Amylin Pharmaceuticals, Novartis, and Takeda. Three of the coauthors are employees of Lilly, and one works for Amylin. The other coauthors disclosures similar to those of Dr. Diamant.
Dr. Misra has received lecture fees and research funding from Sanofi-Aventis, Merck, Novo Nordisk, and Eli Lilly. Dr. Joshi stated that he had no conflicts of interest.
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-3的为期26周的III期开放随机试验显示，每周1次艾塞那肽比每日1次甘精胰岛素能更大程度地降低HbA1c。该试验共入选456例经二甲双胍单药治疗或二甲双胍/磺脲类联合治疗后血糖控制仍不佳的2型糖尿病患者。
鉴于实际上甘精胰岛素组患者的空腹血浆葡萄糖更低，艾塞那肽组HbA1c总体降低幅度更大主要源于餐后血糖漂移幅度明显更低。 URATION-3(每周1次艾塞那肽长效缓释与每日1次甘精胰岛素在二甲双胍单药治疗或二甲双胍/磺脲类联合治疗的2型糖尿病患者中的对比研究)在全球的72个中心开展，由Amylin制药公司和礼来公司资助(Lancet 2010;375:2234-43)。
艾塞那肽组患者接受注射剂量为 2 mg，每周1次。甘精胰岛素组患者开始时每日睡前注射10 U，随后对胰岛素剂量进行调整，以达到空腹血糖72~99 mg/dl的目标值。二甲双胍剂量保持不变，但建议同时服用磺脲类的患者降低磺脲类的剂量。阿姆斯特丹VU大学的Michaela Diamant博士及其同事指出，研究设计不允许设盲。
甘精胰岛素平均剂量从10 U/天增至31 U/天，每4例患者中约有1例降低磺脲类的剂量。 整个研究期间，二甲双胍剂量约为2,000 mg/天。
26周时，艾塞那肽组HbA1c降低1.5%，甘精胰岛素组降低1.3%，差异显著；艾塞那肽组HbA1c <7%的患者比例为60%，甘精胰岛素组相应患者比例为48%，差异亦显著。两组中HbA1c <6.5%的患者比例分别为35%和23%。
Diamant博士及其同事指出，两组的平均空腹血清葡萄糖浓度均降低，但甘精胰岛素组降低幅度明显更大(38 对 50 mg/dl)。
艾塞那肽组患者体重呈进行性降低，而甘精胰岛素组则呈进行性增加。他们表示，26周时，艾塞那肽组平均体重降低2.6 kg，而甘精胰岛素组增加1.4 kg。在艾塞那肽组，体重降低同时见于出现恶心的患者(3.5 kg)和未出现恶心的患者(2.2 kg)。
在艾塞那肽组，恶心和腹泻等胃肠道事件是最常见的不良事件。艾塞那肽组和甘精胰岛素组的恶心发生率分别为13%和1%，腹泻发生率为9%和4%。所有不良事件的程度均为轻度或中度。 除了两例胸痛之外，其他严重不良事件均不超过1例。两组均无死亡病例。 艾塞那肽组因不良事件引起的停药率更高(5%对1%)，部分是由注射部位反应引起(2%对0)。
26周时，艾塞那肽组5例患者(甘精胰岛素组0例)的淀粉酶或脂肪酶水平升高，1例出现水肿型胰腺炎(这种不良事件此前曾见于服用目前市售的每日2次艾塞那肽剂型的患者)。 该患者的水肿型胰腺炎在2月内完全恢复。
两组中同时服用磺脲类的患者更常出现低血糖事件，但艾塞那肽组的发生率始终低于甘精胰岛素组。26周时，艾塞那肽组平均心率较基线时增加，但甘精组未见增加。两组在其他心血管指标方面无差异。他们表示，艾塞那肽组轻微但具有显著意义的心率增加的临床意义尚不清楚。
Anoop Misra博士和Shashank Joshi博士在随刊编者按中指出，尽管每周1次艾塞那肽的恶心发生率低于每日2次剂型，但这一不良事件对服用二甲双胍等多种药物的患者和糖尿病胃轻瘫患者而言仍是一种困扰。他们还指出，仍需要对该药的心血管安全性进行研究，并需密切监测该药对胰腺的影响。
Misra博士和Joshi博士表示，艾塞那肽长效剂型和每日2次剂型均与肾功能不全相关，且与对该药产生抗体的6%~9%患者的反应性降低相关(Lancet 2010;375:2198-9)。
然而，属于胰高血糖素样肽1受体类似物类的该药或其他药物或许适用于合并肥胖或低血糖已演变成临床问题的2型糖尿病患者。他们总结说：“目前，应用长效艾塞那肽治疗糖尿病利多弊少，但还存在一些未知的方面。”
该研究由Amylin制药公司和礼来公司资助。
Diamant博士是礼来、诺和诺德和默沙东公司的顾问和讲师，并担任赛诺菲-安万特公司的顾问。VU大学也从这些公司及Amylin制药公司、诺华公司和武田制药公司获得研究资金。有3位作者是礼来公司的员工，1位作者是Amylin制药公司的员工。其他作者的经济利益冲突声明与Diamant博士的相似。
Misra博士从赛诺菲-安万特、默沙东、诺和诺德和礼来公司获得演讲费和研究资助。Joshi博士声明无任何经济利益冲突。
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