PMID-40544432 — REDEFINE-2: CagriSema vs Semaglutide in T2D + Obesity (Phase 3)

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

Citation

Davies MJ, Aroda VR, Blüher M, Frias JP, Garvey WT, Hansen MB, Hardtstock F, Kalra S, Kushner RF, Linneberg A, Lingvay I, Nørregaard K, Rubino DM, Suzuki S, on behalf of the REDEFINE-2 Trial Investigators. CagriSema versus Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes (REDEFINE-2). N Engl J Med. 2025;392(25):2457-2467. doi: 10.1056/NEJMoa2503081. PMID: 40544432.

Study Design

Phase: 3
Design: Multicenter, randomized, double-blind, double-dummy, active-comparator
Randomization: 1:1 to CagriSema (cagrilintide 2.4 mg + semaglutide 2.4 mg) or semaglutide 2.4 mg monotherapy
Duration: 68 weeks treatment
N: 1,206 participants
Setting: Multinational

Population

Adults ≥18 years with BMI ≥27 kg/m² and type 2 diabetes (HbA1c 6.5-10%)
Adjunct to reduced-calorie diet and increased physical activity; background T2D therapy continued (metformin permitted; SGLT2i or insulin permitted per protocol)

Intervention

CagriSema: Fixed-dose combination cagrilintide 2.4 mg + semaglutide 2.4 mg SC weekly (titrated)
Active comparator: Semaglutide 2.4 mg SC weekly (Wegovy standard titration)

Outcomes

Primary — Mean body weight change at week 68

CagriSema: -13.7% mean body weight reduction
Semaglutide 2.4 mg: -10.6%
Treatment difference: -3.1 percentage points (P<0.001) — superiority demonstrated

Key Secondary

HbA1c reduction: CagriSema -1.5% vs semaglutide -1.3% (numerical advantage CagriSema)
Proportion achieving ≥5%, ≥10%, ≥15% weight loss — CagriSema > semaglutide
Waist circumference and systolic BP: additional CagriSema advantage
Safety profile broadly comparable, with slightly higher GI adverse event rates in CagriSema arm

Key Findings

REDEFINE-2 demonstrates that adding cagrilintide to semaglutide produces incrementally greater weight loss than semaglutide monotherapy in a T2D + obesity population. The effect size (3.1-percentage-point difference) is clinically meaningful, though smaller than the REDEFINE-1 placebo-controlled effect (reflecting the high efficacy of the semaglutide active comparator).

Clinical implications:

CagriSema offers incremental benefit over high-efficacy standard-of-care (semaglutide 2.4 mg) in T2D.
Amylin augmentation of GLP-1 is a pharmacologically meaningful add-on mechanism.
Safety profile does not worsen disproportionately despite dual mechanism.

Important authorship note: First author is Davies MJ, not Garvey. Prior manifests that attributed REDEFINE-2 to Garvey are incorrect; Garvey is the REDEFINE-1 first author. This matters for faculty attribution, CE evidence tables, and guideline-committee cross-references.

Relationship to REDEFINE-1

REDEFINE-1 (Garvey WT et al.) = CagriSema vs placebo in non-T2D obesity, -22.7% weight loss, 3,417 participants.
REDEFINE-2 (Davies MJ et al.) = CagriSema vs semaglutide 2.4 mg in T2D + obesity, -13.7% vs -10.6% weight loss, 1,206 participants.
Together they form the CagriSema regulatory package for the obesity/overweight + T2D indication space.

Safety Profile

GI adverse events: Numerically higher in CagriSema arm (nausea, vomiting), consistent with dual anorexigenic action.
Hypoglycemia: Low in both arms; no excess with CagriSema despite greater weight loss.
Discontinuation due to adverse events: Slightly elevated with CagriSema.
No new safety signals beyond parent compound profiles.

Limitations (Author-acknowledged)

68-week duration; long-term durability not characterized.
Semaglutide 2.4 mg is the active comparator — tirzepatide 15 mg is a plausible alternative comparator not tested.
Background T2D therapy heterogeneity; subgroup analyses underpowered.

Evidence Level

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

Linked Peptides

Related Studies

DOI-10-1056-NEJMoa2502081 – REDEFINE-1 CagriSema Obesity (placebo-controlled companion)
PMID-35658024 – SURMOUNT-1 Tirzepatide for Obesity (cross-trial comparator)
PMID-33667417 – STEP 2 Semaglutide in T2D Obesity (STEP 2 comparator in T2D)

Orchestrator Notes

Funded by Novo Nordisk.
Presented at ADA Scientific Sessions June 2025; simultaneous NEJM publication.
First author Davies MJ is the lead author of the 2025 EASO Framework (PMID-40743997 – EASO Framework Obesity Pharmacological Treatment).

PMID-40544432 – REDEFINE-2 CagriSema vs Semaglutide