加拿大卡尔加里大学卡明医学院David C W Lau团队研究了每周一次cagrilintide用于超重和肥胖人群体重管理的效果。相关论文发表在2021年11月16日出版的《柳叶刀》杂志上。

天然胰淀素是一种引起饱腹感的胰腺激素。Cagrilintide是一种长效胰淀素类似物，正被研究用于体重管理。该研究评估了cagrilintide对体重、安全性和耐受性的剂量-反应关系。

研究组在10个国家（加拿大、丹麦、芬兰、爱尔兰、日本、波兰、塞尔维亚、南非、英国和美国）的57个机构（包括医院、专科诊所和初级保健中心），进行了一项多中心、随机、双盲、安慰剂对照和主动对照、剂量发现的临床2期试验。符合条件的参与者为年龄至少18岁、无糖尿病、体重指数至少为30 kg/m²或至少为27 kg/m²且患有高血压或血脂异常的成年人。

将参与者按6：1随机分配，每周皮下注射一次cagrilintide（0.3、0.6、1.2、2.4或4.5 mg）、每天注射一次利拉鲁肽（3.0 mg）或剂量匹配的安慰剂（共6个安慰剂组）。该试验有26周的治疗期，包括长达6周的剂量递增期，以及6周的无治疗随访期。

参与者和研究者双盲。主要终点是从基线检查到第26周体重的百分比变化，根据试验产品评估（假设所有参与者均坚持治疗）和治疗政策评估（无论是否坚持治疗），对所有随机分配的参与者进行评估。对至少接受一剂随机治疗的所有参与者进行安全性评估。

2019年3月1日至8月19日，研究组随机将706名受试者分为0.3-4.5 mg cagrilintide剂量组（每组100-102人），99名受试者分到3.0 mg利拉鲁肽组，101名受试者分到安慰剂组。各治疗组的永久性停药（10%）发生率相似，主要由于不良事件（4%）。共有29名参与者（4%）退出了试验。

根据试验产品评估，与安慰剂组（减重3.0%）相比，所有剂量的cagrilintide组（0.3-4.5 mg，减重6.0%-10.8%）与基线检查时相比，平均体重减轻百分比更大。Cagrilintide 4.5 mg组与利拉鲁肽3.0 mg组相比体重减轻也更大（分别减重10.8%与9.0%）。

在治疗政策评估中也观察到类似的体重减轻。最常见的不良事件是胃肠道疾病（如恶心、便秘和腹泻）和给药部位反应。与安慰剂组相比，注射0.3–4.5 mg cagrilintide的受试者出现胃肠道不良事件的比例更高（41%–63%对32%），主要是恶心（20%–47%对18%）。

研究结果表明，对超重和肥胖患者而言，使用cagrilintide治疗可显著减轻体重，且耐受性良好。

附：英文原文

Title: Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial

Author: David C W Lau, Lars Erichsen, Ann Marie Francisco, Altynai Satylganova, Carel W le Roux, Barbara McGowan, Sue D Pedersen, Kirsi H Pietilinen, Domenica Rubino, Rachel L Batterham

Issue&Volume: 2021-11-16

Abstract:

Background

Natural amylin is a pancreatic hormone that induces satiety. Cagrilintide is a long-acting amylin analogue under investigation for weight management. We assessed the dose–response relationship of cagrilintide regarding the effects on bodyweight, safety, and tolerability.

Methods

We conducted a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial at 57 sites including hospitals, specialist clinics, and primary care centres in ten countries (Canada, Denmark, Finland, Ireland, Japan, Poland, Serbia, South Africa, the UK, and the USA). Eligible participants were adults aged at least 18 years without diabetes, with a body-mass index of at least 30 kg/m2 or at least 27 kg/m2 with hypertension or dyslipidaemia. Participants were randomly assigned (6:1) to subcutaneous self-injections of once-weekly cagrilintide (0·3, 0·6, 1·2, 2·4, or 4·5 mg), once-daily liraglutide 3·0 mg, or volume-matched placebo (for six placebo groups). The trial had a 26-week treatment period, including a dose-escalation period of up to 6 weeks, and a 6-week follow-up period without treatment. Participants and investigators were masked to the assigned study treatment with respect to active versus pooled placebo treatment, but not to different active treatments. The primary endpoint was the percentage change in bodyweight from baseline to week 26, assessed in all randomly assigned participants according to the trial product estimand (assuming all participants were adherent to treatment) and to the treatment policy estimand (regardless of adherence to treatment). Safety was assessed in all participants who received at least one dose of randomised treatment. This trial is registered with ClinicalTrials.gov, NCT03856047, and is closed to new participants.

Findings

Between March 1 and Aug 19, 2019, we randomly assigned 706 participants to cagrilintide 0·3–4·5 mg (100–102 per dose group), 99 to liraglutide 3·0 mg, and 101 to placebo. Permanent treatment discontinuation (n=73 [10%]) occurred similarly across treatment groups, mostly due to adverse events (n=30 [4%]). In total, 29 participants (4%) withdrew from the trial. According to the trial product estimand, mean percentage weight reductions from baseline were greater with all doses of cagrilintide (0·3–4·5 mg, 6·0%–10·8% [6·4–11·5 kg]) versus placebo (3·0% [3·3 kg]; estimated treatment difference range 3·0%–7·8%; p<0·001). Weight reductions were also greater with cagrilintide 4·5 mg versus liraglutide 3·0 mg (10·8% [11·5 kg] vs 9·0% [9·6 kg]; estimated treatment difference 1·8%, p=0·03). Similar weight loss reductions were observed with the treatment policy estimand. The most frequent adverse events were gastrointestinal disorders (eg, nausea, constipation, and diarrhoea) and administration-site reactions. More participants receiving cagrilintide 0·3–4·5 mg had gastrointestinal adverse events compared with placebo (41%–63% vs 32%), primarily nausea (20%–47% vs 18%).

Interpretation

Treatment with cagrilintide in people with overweight and obesity led to significant reductions in bodyweight and was well tolerated. The findings support the development of molecules with novel mechanisms of action for weight management.

DOI: 10.1016/S0140-6736(21)01751-7

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)01751-7/fulltext