Efficacy and safety of co-administered once-weekly cagrilintide 2·4 mg with once-weekly semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial
Frias JP, Deenadayalan S, Erichsen L, Knop FK, Lingvay I, Macura S, Mathieu C, Pedersen SD, +1 more
Lancet (2023) · n=92
The Phase 2 type 2 diabetes trial that established CagriSema's combination signal in a diabetic cohort — 15.6% weight loss and 2.2-percentage-point HbA1c reduction at 32 weeks on CagriSema versus 5.1% / 1.8% on semaglutide alone, in 92 adults on metformin background. The cohort was small but it set the framing under which REDEFINE-2 was designed.
This Phase 2 trial is the first published randomised study of CagriSema — the fixed-dose combination of cagrilintide 2.4 mg and semaglutide 2.4 mg — in adults living with type 2 diabetes. Investigators conducted a 32-week, multicentre, randomised, double-blind, active-controlled trial at 17 US sites. 92 adults with type 2 diabetes (HbA1c 7.5–10.0%) and BMI ≥27 kg/m² on metformin background (with or without an SGLT2 inhibitor) were randomised 1:1:1 to once-weekly subcutaneous CagriSema, once-weekly semaglutide 2.4 mg, or once-weekly cagrilintide 2.4 mg — 31 / 31 / 30 participants per arm. Mean baseline age was 58 years, 59% were male, and the trial included 16 weeks of dose escalation followed by 16 weeks at target dose. The coprimary endpoints were change in HbA1c and percentage change in body weight from baseline to week 32.
The combination arm produced the largest effects on both endpoints. HbA1c reduction at week 32 was 2.2 percentage points on CagriSema versus 1.8 on semaglutide alone and 0.9 on cagrilintide alone — directionally consistent with semaglutide carrying most of the glycaemic effect and cagrilintide contributing an incremental ~0.4 percentage points beyond GLP-1 monotherapy. Mean body-weight reduction was 15.6% on CagriSema versus 5.1% on semaglutide alone and 8.1% on cagrilintide alone. The CagriSema-versus-semaglutide gap of 10.5 percentage points on the weight endpoint was substantially larger in this diabetic Phase 2 cohort than what was later observed in the much larger non-diabetic Phase 3 trial (Garvey et al. 2025), where the comparable gap under the trial-product estimand was 6.6 percentage points. The adverse-event profile was dominated by mild-to-moderate gastrointestinal effects (nausea, vomiting, constipation, dyspepsia), reported in 68–80% of participants across the three arms, concentrated during dose escalation. No severe hypoglycaemia or treatment-related deaths were reported.
This trial set the framing under which the Phase 3 REDEFINE program was designed. The combination-versus-monotherapy effect-size pattern observed here — large incremental weight benefit, small but directionally consistent incremental HbA1c benefit — was the headline signal that supported advancing CagriSema into Phase 3 in both obesity (REDEFINE-1) and type 2 diabetes (REDEFINE-2) indications.
The trial was small. With roughly 30 participants per arm, confidence intervals around the headline numbers are wide and the trial was not powered to detect rare safety events, cardiovascular signals, or subgroup-level effect heterogeneity. The 32-week duration is short relative to the 68-week Phase 3 endpoint and the trial does not address long-term durability of either the weight or the glycaemic effect — particularly relevant because incretin-class weight effects often continue to develop beyond 32 weeks and HbA1c responses often plateau earlier. The diabetic-cohort interpretation does not transfer mechanically to obesity without diabetes; the well-documented blunting of pharmacotherapy weight loss in T2D populations (visible in the SURPASS-versus-SURMOUNT and STEP-versus-SUSTAIN gaps across the GLP-1 class) means the 15.6% combination figure in this trial should not be expected to scale linearly to a non-diabetic cohort. The 17-site US-only design and metformin-plus-or-minus-SGLT2 background limit generalisability to international populations and to patients on different background regimens (sulfonylureas, insulin, GLP-1 monotherapy). Industry sponsorship by Novo Nordisk is disclosed; the trial design and analysis are consistent with the broader CagriSema program. The very large CagriSema-versus-semaglutide gap observed here (15.6% vs 5.1%) — which substantially exceeds the gap later observed in REDEFINE-1 — should be read with small-trial caution and as one input into Phase 3 hypothesis-setting rather than as the prediction the Phase 3 program eventually validated.
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