The Ohio State University, Columbus, OH, USA.
Clínica Juaneda, Endocrinología, Palma de Mallorca, Spain.
Lancet. 2014 Oct 11;384(9951):1349-57. doi: 10.1016/S0140-6736(14)60976-4. Epub 2014 Jul 10.
BACKGROUND: Dulaglutide and liraglutide, both glucagon-like peptide-1 (GLP-1) receptor agonists, improve glycaemic control and reduce weight in patients with type 2 diabetes. In a head-to-head trial, we compared the safety and efficacy of once-weekly dulaglutide with that of once-daily liraglutide in metformin-treated patients with uncontrolled type 2 diabetes. METHODS: We did a phase 3, randomised, open-label, parallel-group study at 62 sites in nine countries between June 20, 2012, and Nov 25, 2013. Patients with inadequately controlled type 2 diabetes receiving metformin (≥1500 mg/day), aged 18 years or older, with glycated haemoglobin (HbA1c) 7·0% or greater (≥53 mmol/mol) and 10·0% or lower (≤86 mmol/mol), and body-mass index 45 kg/m(2) or lower were randomly assigned to receive once-weekly dulaglutide (1·5 mg) or once-daily liraglutide (1·8 mg). Randomisation was done according to a computer-generated random sequence with an interactive voice response system. Participants and investigators were not masked to treatment allocation. The primary outcome was non-inferiority (margin 0·4%) of dulaglutide compared with liraglutide for change in HbA1c (least-squares mean change from baseline) at 26 weeks. Safety data were collected for a further 4 weeks' follow-up. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01624259. FINDINGS: We randomly assigned 599 patients to receive once-weekly dulaglutide (299 patients) or once-daily liraglutide (300 patients). 269 participants in each group completed treatment at week 26. Least-squares mean reduction in HbA1c was -1·42% (SE 0·05) in the dulaglutide group and -1·36% (0·05) in the liraglutide group. Mean treatment difference in HbA1c was -0·06% (95% CI -0·19 to 0·07, pnon-inferiority<0·0001) between the two groups. The most common gastrointestinal adverse events were nausea (61 [20%] in dulaglutide group vs 54 [18%] in liraglutide group), diarrhoea (36 [12%] vs 36 [12%]), dyspepsia (24 [8%] vs 18 [6%]), and vomiting (21 [7%] vs 25 [8%]), with similar rates of study or study drug discontinuation because of adverse events between the two groups (18 [6%] in each group). The hypoglycaemia rate was 0·34 (SE 1·44) and 0·52 (3·01) events per patient per year, respectively, and no severe hypoglycaemia was reported. INTERPRETATION: Once-weekly dulaglutide is non-inferior to once-daily liraglutide for least-squares mean reduction in HbA1c, with a similar safety and tolerability profile. FUNDING: Eli Lilly and Company.
背景：胰高血糖素样肽-1（GLP-1）受体激动剂度拉鲁肽和利拉鲁肽均可改善 2 型糖尿病患者的血糖控制并减轻体重。在一项头对头试验中，我们比较了每周一次给予度拉鲁肽与每日一次给予利拉鲁肽在接受二甲双胍治疗但血糖控制不佳的 2 型糖尿病患者中的安全性和疗效。
方法：我们在 9 个国家的 62 个地点进行了一项 3 期、随机、开放标签、平行分组研究。纳入标准为：正在接受二甲双胍（≥1500mg/天）治疗、年龄≥18 岁、糖化血红蛋白（HbA1c）＞7.0%（≥53mmol/mol）和≤10.0%（≤86mmol/mol）、且体重指数（BMI）＜45kg/m2的 2 型糖尿病患者。患者被随机分配接受每周一次度拉鲁肽（1.5mg）或每日一次利拉鲁肽（1.8mg）治疗。随机分组是根据带有交互式语音应答系统的计算机生成的随机序列进行的。参与者和研究者对治疗分组均不知情。主要终点为度拉鲁肽组与利拉鲁肽组相比 HbA1c 改变的非劣效性（差值 0.4%，边缘值），其评估指标为 26 周时的最小二乘均数变化（自基线的变化）。进一步随访了 4 周的安全性数据。分析采用意向治疗。该研究在 ClinicalTrials.gov 注册，编号为 NCT01624259。
结果：我们随机分配 599 例患者接受每周一次度拉鲁肽（299 例）或每日一次利拉鲁肽（300 例）治疗。每组各有 269 例患者完成了 26 周的治疗。度拉鲁肽组的 HbA1c 降低的最小二乘均数为-1.42%（SE 0.05），利拉鲁肽组为-1.36%（0.05）。两组之间 HbA1c 的平均治疗差异为-0.06%（95%CI-0.19 至 0.07，p非劣效性＜0.0001）。最常见的胃肠道不良事件为恶心（度拉鲁肽组 61 例[20%]，利拉鲁肽组 54 例[18%]）、腹泻（36 例[12%] vs 36 例[12%]）、消化不良（24 例[8%] vs 18 例[6%]）和呕吐（21 例[7%] vs 25 例[8%]），两组因不良事件而停止研究或研究药物治疗的发生率相似（每组各 18 例[6%]）。低血糖发生率分别为 0.34（SE 1.44）和 0.52（SE 3.01）例患者-年，且均未报告严重低血糖。
结论：每周一次度拉鲁肽在降低 HbA1c 的最小二乘均数方面与每日一次利拉鲁肽相当，且具有相似的安全性和耐受性。
资金来源：礼来公司。
Nat Rev Drug Discov. 2025-4-25
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