DOI-10-1056-NEJMoa2502081 — REDEFINE-1: CagriSema in Obesity (Phase 3)

[DRAFT — authored 2026-04-18. Requires Medical Director review.]

Citation

Garvey WT, Lingvay I, Blüher M, Frias JP, Hansen MB, Hardtstock F, Kalra S, Kushner RF, Linneberg A, Nørregaard K, Rubino DM, Suzuki S, Aroda VR, on behalf of the REDEFINE-1 Trial Investigators. Efficacy and Safety of CagriSema in Adults with Overweight or Obesity without Type 2 Diabetes (REDEFINE-1). N Engl J Med. 2025;392(25):2445-2456. doi: 10.1056/NEJMoa2502081.

External URL: NEJM DOI resolver

Study Design

Phase: 3
Design: Multicenter, randomized, double-blind, placebo-controlled
Randomization: 3:1 to CagriSema (cagrilintide 2.4 mg + semaglutide 2.4 mg fixed-dose combination) or placebo
Duration: 68 weeks treatment; additional 7-week follow-up
N: 3,417 participants
Setting: Multinational, >12 countries

Population

Adults ≥18 years with BMI ≥30 kg/m², or ≥27 kg/m² with weight-related complication, without type 2 diabetes
Adjunct to reduced-calorie diet and increased physical activity

Intervention

CagriSema: Fixed-dose combination of cagrilintide (long-acting amylin analog) 2.4 mg + semaglutide 2.4 mg, administered once weekly SC, titrated over 16 weeks
Placebo: Matching once-weekly SC injection

Outcomes

Primary — Mean body weight change at week 68

CagriSema: -22.7% mean body weight reduction
Placebo: -2.3%
Treatment difference: -20.4 percentage points (P<0.001) — statistically superior to placebo; clinically substantial

Key Secondary

Proportion achieving ≥5%, ≥10%, ≥15%, ≥20%, ≥25% weight loss — all favoring CagriSema
Approximately 40% of CagriSema-treated participants achieved ≥25% weight loss
Improvements in waist circumference, systolic BP, lipid profile, CRP

Key Findings

REDEFINE-1 is the definitive Phase 3 evidence for the amylin + GLP-1 combination weight-loss approach.

The 22.7% mean weight reduction is the largest mean weight-loss effect published for any approved or late-phase combination in chronic weight management as of publication.
Positions CagriSema competitively with tirzepatide 15 mg (~22.5% in SURMOUNT-1, PMID-35658024 – SURMOUNT-1 Tirzepatide for Obesity), but mechanism is distinct: amylin analog + GLP-1 agonist vs GIP/GLP-1 dual agonist.
Amylin contribution: Cagrilintide (long-acting amylin analog) adds satiety signaling via calcitonin receptor and RAMP-modified amylin receptors; acts synergistically with GLP-1-mediated appetite suppression.
Safety profile: class-consistent GI adverse events (nausea, vomiting, diarrhea) — numerically higher than semaglutide monotherapy but manageable with titration.

Safety Profile

GI adverse events: Nausea (71% CagriSema vs 17% placebo), vomiting (44% vs 5%), diarrhea (26% vs 12%), constipation (25% vs 10%)
Discontinuation due to adverse events: ~8% CagriSema vs ~3% placebo
Pancreatitis, gallbladder disease: Incidence consistent with GLP-1 class expectations
No new unexpected safety signals beyond the known profiles of cagrilintide and semaglutide

Regulatory Positioning

CagriSema approval pathway pending as of April 2026. Novo Nordisk submitted to regulators following REDEFINE-1 and -2 results.
If approved, positions as next-generation weight-management option competing with tirzepatide in the weight-loss-magnitude tier.

Relationship to REDEFINE-2

REDEFINE-2 (Davies MJ et al., PMID: 40544432) compared CagriSema directly to semaglutide 2.4 mg monotherapy. Whereas REDEFINE-1 establishes CagriSema superiority over placebo, REDEFINE-2 addresses the more clinically relevant question: Does adding cagrilintide to semaglutide improve outcomes beyond semaglutide alone?

Limitations (Author-acknowledged)

68-week duration; longer-term maintenance durability (2+ years) not yet captured
No head-to-head vs tirzepatide
Non-T2D population; REDEFINE-2 addresses the T2D population

Evidence Level

Level Ib (Oxford CEBM) — adequately-powered Phase 3 RCT with pre-specified primary endpoint.

Linked Peptides

Related Studies

PMID-40544432 – REDEFINE-2 CagriSema vs Semaglutide
PMID-35658024 – SURMOUNT-1 Tirzepatide for Obesity (cross-trial comparator)
PMID-33567185 – Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1 comparator)

Orchestrator Notes

Funded by Novo Nordisk.
Presented at ADA Scientific Sessions June 2025; simultaneous NEJM publication.
First author Garvey is a senior obesity-guideline figure (also STEP 5 first author).

DOI-10-1056-NEJMoa2502081 – REDEFINE-1 CagriSema Obesity