Washington Center for Weight Management and Research, Arlington, Virginia.
Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge.
JAMA. 2022 Jan 11;327(2):138-150. doi: 10.1001/jama.2021.23619.
Phase 3 trials have not compared semaglutide and liraglutide, glucagon-like peptide-1 analogues available for weight management.
To compare the efficacy and adverse event profiles of once-weekly subcutaneous semaglutide, 2.4 mg, vs once-daily subcutaneous liraglutide, 3.0 mg (both with diet and physical activity), in people with overweight or obesity.
DESIGN, SETTING, AND PARTICIPANTS: Randomized, open-label, 68-week, phase 3b trial conducted at 19 US sites from September 2019 (enrollment: September 11-November 26) to May 2021 (end of follow-up: May 11) in adults with body mass index of 30 or greater or 27 or greater with 1 or more weight-related comorbidities, without diabetes (N = 338).
Participants were randomized (3:1:3:1) to receive once-weekly subcutaneous semaglutide, 2.4 mg (16-week escalation; n = 126), or matching placebo, or once-daily subcutaneous liraglutide, 3.0 mg (4-week escalation; n = 127), or matching placebo, plus diet and physical activity. Participants unable to tolerate 2.4 mg of semaglutide could receive 1.7 mg; participants unable to tolerate 3.0 mg of liraglutide discontinued treatment and could restart the 4-week titration. Placebo groups were pooled (n = 85).
The primary end point was percentage change in body weight, and confirmatory secondary end points were achievement of 10% or more, 15% or more, and 20% or more weight loss, assessed for semaglutide vs liraglutide at week 68. Semaglutide vs liraglutide comparisons were open-label, with active treatment groups double-blinded against matched placebo groups. Comparisons of active treatments vs pooled placebo were supportive secondary end points.
Of 338 randomized participants (mean [SD] age, 49 [13] years; 265 women [78.4%]; mean [SD] body weight, 104.5 [23.8] kg; mean [SD] body mass index, 37.5 [6.8]), 319 (94.4%) completed the trial, and 271 (80.2%) completed treatment. The mean weight change from baseline was -15.8% with semaglutide vs -6.4% with liraglutide (difference, -9.4 percentage points [95% CI, -12.0 to -6.8]; P < .001); weight change with pooled placebo was -1.9%. Participants had significantly greater odds of achieving 10% or more, 15% or more, and 20% or more weight loss with semaglutide vs liraglutide (70.9% of participants vs 25.6% [odds ratio, 6.3 {95% CI, 3.5 to 11.2}], 55.6% vs 12.0% [odds ratio, 7.9 {95% CI, 4.1 to 15.4}], and 38.5% vs 6.0% [odds ratio, 8.2 {95% CI, 3.5 to 19.1}], respectively; all P < .001). Proportions of participants discontinuing treatment for any reason were 13.5% with semaglutide and 27.6% with liraglutide. Gastrointestinal adverse events were reported by 84.1% with semaglutide and 82.7% with liraglutide.
Among adults with overweight or obesity without diabetes, once-weekly subcutaneous semaglutide compared with once-daily subcutaneous liraglutide, added to counseling for diet and physical activity, resulted in significantly greater weight loss at 68 weeks.
ClinicalTrials.gov Identifier: NCT04074161.
重要性： 尚未比较可用于体重管理的两种胰高血糖素样肽-1 类似物，即司美格鲁肽和利拉鲁肽的 3 期临床试验。
目的： 比较每周皮下注射 2.4mg 司美格鲁肽与每日皮下注射 3.0mg 利拉鲁肽（均联合饮食和身体活动）在超重或肥胖成年人中的疗效和不良事件谱，这些成年人的身体质量指数（BMI）为 30 或更高，或 27 或更高，伴有 1 种或多种与体重相关的合并症，但无糖尿病。
设计、地点和参与者： 2019 年 9 月 11 日（入组：9 月 11 日至 11 月 26 日）至 2021 年 5 月 11 日（随访结束：5 月 11 日）期间，在美国 19 个地点进行了一项随机、开放标签、68 周、3b 期试验，共纳入 338 名成年人，他们的 BMI 为 30 或更高，或 27 或更高，伴有 1 种或多种与体重相关的合并症，但无糖尿病（N=338）。
干预措施： 参与者被随机（3:1:3:1）分配至每周皮下注射 2.4mg 司美格鲁肽（16 周递增期；n=126）或匹配安慰剂，或每日皮下注射 3.0mg 利拉鲁肽（4 周递增期；n=127）或匹配安慰剂，均联合饮食和身体活动。不能耐受 2.4mg 司美格鲁肽的参与者可接受 1.7mg 司美格鲁肽；不能耐受 3.0mg 利拉鲁肽的参与者停止治疗并可重新开始 4 周滴定。安慰剂组（n=85）被合并。
主要结局和测量： 主要终点是体重变化的百分比，确认的次要终点是 10%或更多、15%或更多和 20%或更多的体重减轻，分别在第 68 周时评估司美格鲁肽与利拉鲁肽的疗效。司美格鲁肽与利拉鲁肽的比较是开放标签的，活性治疗组相对于匹配的安慰剂组是双盲的。活性治疗与合并安慰剂的比较是支持性次要终点。
结果： 在 338 名随机参与者中（平均[标准差]年龄，49[13]岁；265 名女性[78.4%]；平均[标准差]体重，104.5[23.8]kg；平均[标准差]身体质量指数，37.5[6.8]），319 名（94.4%）完成了试验，271 名（80.2%）完成了治疗。与利拉鲁肽相比，司美格鲁肽的平均体重变化从基线下降了-15.8%，而利拉鲁肽的平均体重变化为-6.4%（差异，-9.4 个百分点[95%CI，-12.0 至-6.8]；P<0.001）；合并安慰剂的体重变化为-1.9%。与利拉鲁肽相比，司美格鲁肽使参与者达到 10%或更多、15%或更多和 20%或更多体重减轻的可能性显著更高（70.9%的参与者比 25.6%[比值比，6.3[95%CI，3.5 至 11.2]），55.6%比 12.0%[比值比，7.9[95%CI，4.1 至 15.4]），38.5%比 6.0%[比值比，8.2[95%CI，3.5 至 19.1]）；所有 P<0.001）。因任何原因停止治疗的参与者比例分别为司美格鲁肽组为 13.5%，利拉鲁肽组为 27.6%。司美格鲁肽组和利拉鲁肽组分别有 84.1%和 82.7%的参与者报告了胃肠道不良事件。
结论和相关性： 在没有糖尿病的超重或肥胖成年人中，与每日皮下注射 3.0mg 利拉鲁肽相比，每周皮下注射 2.4mg 司美格鲁肽联合饮食和身体活动咨询，在 68 周时体重减轻更显著。
试验注册：ClinicalTrials.gov 标识符：NCT04074161。
