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 DCW, Erichsen L, Francisco AM, Satylganova A, le Roux CW, McGowan B, Pedersen SD, Pietiläinen KH, +2 more
Lancet (2021) · n=706
The Phase 2 dose-finding monotherapy trial that established cagrilintide-alone performance — 10.8% weight loss at 26 weeks on cagrilintide 4.5 mg versus 9.0% on liraglutide 3.0 mg and 3.0% on placebo, a result consistent with an amylin agonist that operates through partially overlapping but mechanistically distinct satiety pathways from the GLP-1 class.
This is the Phase 2 dose-finding monotherapy trial that established the cagrilintide-alone weight-loss envelope and the basis for the dose selection carried into REDEFINE-1. Investigators conducted a 26-week, multicentre, randomised, double-blind, placebo-controlled and active-controlled (versus once-daily liraglutide 3.0 mg) trial at 57 sites across ten countries. 706 adults without diabetes with BMI ≥30 kg/m² (or ≥27 with hypertension or dyslipidaemia) were randomised to subcutaneous once-weekly cagrilintide at 0.3, 0.6, 1.2, 2.4, or 4.5 mg, to once-daily subcutaneous liraglutide 3.0 mg, or to volume-matched placebo. The trial included a 6-week follow-up after end of treatment. The primary endpoint was percentage change in body weight from baseline to week 26.
Mean body-weight reduction at week 26 followed a dose-response curve across the cagrilintide arms: 6.0%, 6.8%, 8.6%, 10.5%, and 10.8% on cagrilintide 0.3, 0.6, 1.2, 2.4, and 4.5 mg respectively. The comparator arms produced 3.0% on placebo and 9.0% on liraglutide 3.0 mg. The 4.5 mg cagrilintide dose was numerically superior to liraglutide 3.0 mg on the weight endpoint — a result consistent with an amylin agonist that operates through partially overlapping but mechanistically distinct satiety pathways from the GLP-1 class. The adverse-event profile was dominated by gastrointestinal effects, primarily nausea, concentrated during dose escalation and mostly mild to moderate; rates of discontinuation due to adverse events were broadly comparable across the active arms. No injection-site reactions or hypersensitivity events required trial-wide modifications.
The trial's design choice — including a once-daily liraglutide active-comparator arm rather than once-weekly semaglutide — was a function of the regulatory landscape in 2017–2019 when the protocol was designed: semaglutide 2.4 mg was not yet an obesity-approved product, and liraglutide 3.0 mg (Saxenda) was the comparator that mattered for a regulatory submission. The choice means the trial does not address how cagrilintide monotherapy compares to the modern weight-management GLP-1 standard of care, a question that the CagriSema combination program (Frias et al. 2023, Garvey et al. 2025) addressed indirectly by adding cagrilintide on top of semaglutide 2.4 mg rather than testing the two head-to-head as monotherapies.
The 26-week duration is short relative to the chronic-weight-management framing the molecule now carries; cagrilintide monotherapy has not been tested in a Phase 3 obesity trial, and the longer-term durability of the monotherapy effect remains uncharacterised in the peer-reviewed literature. The active comparator was liraglutide 3.0 mg, not semaglutide 2.4 mg — a choice that was appropriate for the regulatory landscape at trial design but limits the most-asked head-to-head comparison in 2026. The trial enrolled adults without diabetes; the diabetic cohort was addressed separately in the Phase 2 type 2 diabetes study (Frias et al. 2023). The dose-finding design — five active cagrilintide doses plus liraglutide plus placebo — meant per-arm sample sizes (n ≈ 100) were modest for detecting subgroup effects or rare adverse events; the trial powered for the primary weight endpoint but not for cardiovascular or pancreatic safety signals of the kind that would later be addressed in dedicated Phase 3 safety analyses. Industry sponsorship by Novo Nordisk is disclosed; the trial design and analysis are consistent with the published Phase 1b (Enebo et al. 2021) and the REDEFINE Phase 3 program. The trial population was 88% White and skewed female (75%), a recruitment pattern consistent with the broader European-and-Canadian obesity-trial baseline of the period; generalisability to Black, Hispanic, and Asian populations rests on the parallel Phase 1b cohort and on subsequent program-level subgroup analyses rather than on this paper.
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