From the Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool (J.P.H.W.), University College London Centre for Obesity Research, Division of Medicine, University College London (R.L.B.), the National Institute of Health Research, UCLH Biomedical Research Centre (R.L.B.), the Centre for Weight Management and Metabolic Surgery, University College London Hospital (R.L.B.), and the Department of Diabetes and Endocrinology, Guy's and St. Thomas' NHS Foundation Trust (B.M.M.), London, and the Diabetes Research Centre, University of Leicester (M.D.) and the NIHR Leicester Biomedical Research Centre (M.D.), Leicester - all in the United Kingdom; Novo Nordisk, Søborg, Denmark (S.C., M.T.D.T., N.Z.); the Department of Endocrinology, Diabetology, and Metabolism, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium (L.F.V.G.); the Departments of Internal Medicine/Endocrinology and Population and Data Sciences, University of Texas Southwestern Medical Center (I.L.), and the Dallas Diabetes Research Center at Medical City (J.R.) - both in Dallas; the Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia (T.A.W.); York University, McMaster University and Wharton Weight Management Clinic, Toronto (S.W.); the Department of Endocrinology, Hematology, and Gerontology, Graduate School of Medicine, Chiba University and Department of Diabetes, Metabolism, and Endocrinology, Chiba University Hospital, Chiba, Japan (K.Y.); and the Division of Endocrinology, Feinberg School of Medicine, Northwestern University, Chicago (R.F.K.).
N Engl J Med. 2021 Mar 18;384(11):989-1002. doi: 10.1056/NEJMoa2032183. Epub 2021 Feb 10.
Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed.
In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions.
The mean change in body weight from baseline to week 68 was -14.9% in the semaglutide group as compared with -2.4% with placebo, for an estimated treatment difference of -12.4 percentage points (95% confidence interval [CI], -13.4 to -11.5; P<0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was -15.3 kg in the semaglutide group as compared with -2.6 kg in the placebo group (estimated treatment difference, -12.7 kg; 95% CI, -13.7 to -11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]).
In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935).
肥胖是一个全球性的健康挑战，目前几乎没有有效的药物治疗方法。肥胖成年人在生活方式干预的基础上，每周接受一次 2.4mg 司美格鲁肽治疗，能否减轻体重，目前尚未得到证实。
这项双盲试验纳入了 1961 名体重指数（BMI，即体重除以身高的平方，单位为千克/米 2 ）≥30（≥27 者同时存在 1 种及以上与体重相关的并存疾病）的成年人，他们没有糖尿病，按 2:1 的比例随机分配，接受 68 周每周一次皮下注射司美格鲁肽（2.4mg）或安慰剂联合生活方式干预。主要复合终点为体重相对于基线的变化百分比和体重减轻≥5%。主要估计值（准确描述治疗效果的概念，反映临床试验的目标）评估了无论是否停药或接受解救治疗的治疗效果。
与安慰剂组相比，司美格鲁肽组从基线到第 68 周的体重变化为-14.9%，估计治疗差异为-12.4 个百分点（95%置信区间[CI]，-13.4 至-11.5；P<0.001）。与安慰剂组相比，司美格鲁肽组更多的参与者体重减轻 5%或更多（1047 名参与者[86.4%] vs. 182 名[31.5%]）、10%或更多（838 名[69.1%] vs. 69 名[12.0%]）和 15%或更多（612 名[50.5%] vs. 28 名[4.9%]）（所有三个比较的比值均 P<0.001）。与安慰剂组相比，司美格鲁肽组从基线到第 68 周的体重变化为-15.3kg（估计治疗差异，-12.7kg；95%CI，-13.7 至-11.7）。与安慰剂组相比，接受司美格鲁肽治疗的患者在心血管代谢风险因素方面有更大的改善，在身体功能方面有更大的改善（与基线相比），参与者报告的身体功能改善。与安慰剂组相比，司美格鲁肽组更常见的胃肠道不良事件包括恶心和腹泻；这些不良事件通常是短暂的，且为轻至中度，随时间推移而减轻。与安慰剂组相比，司美格鲁肽组因胃肠道事件而停药的患者更多（59 名[4.5%] vs. 5 名[0.8%]）。
在超重或肥胖的参与者中，每周一次接受 2.4mg 司美格鲁肽联合生活方式干预可持续显著降低体重。（由 Novo Nordisk 资助；STEP 1 ClinicalTrials.gov 编号，NCT03548935）
