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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

Lau, David CW; Erichsen, Lars; Francisco, Ann Marie; Satylganova, Altynai; le Roux, Carel W; McGowan, Barbara; Pedersen, Sue D; ... Batterham, Rachel L; + view all (2021) 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. The Lancet , 398 (10317) pp. 2160-2172. 10.1016/S0140-6736(21)01751-7. Green open access

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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/m^{2} or at least 27 kg/m^{2} 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. FUNDING: Novo Nordisk A/S.

Type: Article
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
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/S0140-6736(21)01751-7
Publisher version: https://doi.org/10.1016/S0140-6736(21)01751-7
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Experimental and Translational Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/10155031
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