CagriSema Beats Tirzepatide in Phase 3 Head-to-Head Trial REIMAGINE 5
TL;DR: CagriSema beat tirzepatide 12.4% vs 9.1% weight loss in Phase 3 REIMAGINE 5, Novo Nordisk reported 21 Sept 2026.
What's New: CagriSema Wins a Head-to-Head Trial Against Tirzepatide
Novo Nordisk announced topline results on 21 September 2026 from two Phase 3 trials of its investigational cagrilintide/semaglutide combination, CagriSema: REIMAGINE 5, a head-to-head trial against Eli Lilly's tirzepatide in adults with type 2 diabetes, and REDEFINE 9, a placebo-controlled obesity trial.[1] In REIMAGINE 5, CagriSema produced statistically superior weight loss to tirzepatide — the first time a Novo Nordisk trial has beaten Lilly's incretin drug head-to-head, after CagriSema fell short of tirzepatide in the earlier REDEFINE-4 trial in February 2026.[2]
We covered that earlier miss, and the underlying REDEFINE-1 and REDEFINE-2 pivotal data, in our retatrutide vs CagriSema comparison. This article covers only what's new: the REIMAGINE 5 and REDEFINE 9 results, why they don't simply overturn the REDEFINE-4 finding, and what the data means for researchers tracking the wider incretin field that retatrutide sits within.
What Did REIMAGINE 5 Actually Test and Report?
Design: approximately 1,000 adults with type 2 diabetes inadequately controlled on metformin, an SGLT2 inhibitor, or both, were randomised to once-weekly CagriSema 1.0mg/1.0mg or tirzepatide 5mg over 68 weeks, with dual primary endpoints of HbA1c change and relative body-weight change. Result: CagriSema produced 12.4% mean weight loss versus 9.1% for tirzepatide, meeting superiority. HbA1c fell by 1.71 percentage points on CagriSema versus 1.67 on tirzepatide, meeting non-inferiority. Novo Nordisk reported CagriSema was well tolerated, with a safety profile consistent with earlier trials.[1]
Source: Novo Nordisk company announcement, 21 Sept 2026; trade-press reporting (Healio, BioPharm International, RTTNews)
The comparator dose matters: tirzepatide 5mg is Lilly's lowest approved maintenance dose, well below the 15mg dose CagriSema was compared against — and lost to — in REDEFINE-4. REIMAGINE 5 also enrolled a type 2 diabetes population rather than obesity-only, and ran for 68 weeks rather than 84. None of that invalidates the result, but it means REIMAGINE 5 answers a narrower question than "which drug wins outright": specifically, how the two compounds compare at these particular doses, in this particular population.
What Did REDEFINE 9 Report in Obesity?
Design: approximately 300 adults with overweight or obesity were randomised to once-weekly CagriSema 1.7mg/1.7mg, CagriSema 1.0mg/1.0mg, or placebo, over 68 weeks. Result: the CagriSema 1.0mg/1.0mg arm produced 21.0% mean weight loss versus 2.0% on placebo, meeting the pre-specified primary superiority endpoint. Novo Nordisk also reported greater improvement than placebo on supportive endpoints including systolic blood pressure, waist-to-height ratio and fasting lipid profile.[1]
Source: Novo Nordisk company announcement, 21 Sept 2026
REDEFINE 9 is a placebo-controlled trial, not a head-to-head comparator study, so it doesn't itself bear on how CagriSema stacks up against tirzepatide or retatrutide. Its main value is confirming that a lower CagriSema dose than the 2.4mg/2.4mg tested in the original REDEFINE-1 pivotal trial still clears a placebo comparison by a wide margin, which is relevant to how Novo Nordisk may eventually position its dosing range.
How Does This Square With CagriSema's Earlier Loss to Tirzepatide?
| Trial | Population | Doses compared | Duration | Result |
|---|---|---|---|---|
| REDEFINE-4 (23 Feb 2026) | Obesity only (n=809) | CagriSema 2.4/2.4mg vs tirzepatide 15mg | 84 wks | CagriSema lost: −23.0% vs −25.5%, missed non-inf. |
| REIMAGINE 5 (21 Sept 2026) | Type 2 diabetes (n≈1,000) | CagriSema 1.0/1.0mg vs tirzepatide 5mg | 68 wks | CagriSema won: −12.4% vs −9.1%, superior |
Figures as reported by Novo Nordisk in each respective company announcement. The two trials used different doses of both drugs and different patient populations, so this is a side-by-side reference table, not evidence that one trial "corrects" the other.
Read together, the two trials say less about which drug is categorically stronger than about how sensitive these comparisons are to dose and population. CagriSema lost to tirzepatide's higher, obesity-approved dose in REDEFINE-4; it beat tirzepatide's lowest maintenance dose in a diabetes population in REIMAGINE 5. A trial matching both drugs at their respective maximum approved and applied-for doses, in the same population, has not been published. Researchers comparing the two compounds should treat each trial as evidence about its own specific dose-and-population pairing, not as a general verdict on either molecule.
What Does This Mean for the Wider GLP-1 Pipeline, Including Retatrutide?
The Novo-vs-Lilly contest is now genuinely two-sided
Before REIMAGINE 5, every published head-to-head trial of CagriSema against a Lilly incretin drug had gone to Lilly. A single superiority win against tirzepatide's lowest dose doesn't close that gap, but it does mean researchers can no longer treat CagriSema as a straightforward laggard in every comparison.
Retatrutide is not directly implicated by either trial
Neither REIMAGINE 5 nor REDEFINE 9 involved retatrutide, and Lilly's own triple-receptor Phase 3 TRIUMPH-1 figures (up to 30.3% weight loss at 104 weeks) remain larger than either CagriSema result reported here. See our TRIUMPH-1 data summary for the full published figures.
Dose-matched, single-population head-to-heads remain the evidence gap
Across the retatrutide, CagriSema and tirzepatide literature, most of the largest reported effect sizes come from separate placebo-controlled trials rather than shared head-to-head designs. That gap is exactly why a single new head-to-head result, in either direction, tends to move the conversation more than its underlying dose caveats might justify.
What's Next for CagriSema's Regulatory Timeline?
Neither REIMAGINE 5 nor REDEFINE 9 is part of the CagriSema New Drug Application Novo Nordisk filed with the FDA on 18 December 2025, which rests on the earlier REDEFINE-1 and REDEFINE-2 pivotal trials.[3] That filing remains under standard review, with Novo Nordisk guiding to a decision in the fourth quarter of 2026. REIMAGINE 5 and REDEFINE 9 are supplementary trials that will likely inform CagriSema's label and marketing positioning relative to tirzepatide rather than the initial approval decision itself.
Trade press noted Novo Nordisk's share price fell on the day of the announcement despite the positive REIMAGINE 5 result, which several outlets attributed to the trial's narrower scope (a low tirzepatide dose, a diabetes-only population) falling short of the head-to-head win at matched high doses that investors had been positioned for.[4] That market reaction is a useful signal of how the trial was read commercially, though it says nothing about the trial's scientific validity.
Does This Affect UK Research-Reagent Supply?
No. CagriSema remains an unapproved, patent-protected Novo Nordisk investigational combination product confined to registered clinical trials and a pending FDA application; it is not available for purchase, compounding or research use from any lawful source. Tirzepatide is a licensed pharmaceutical medicine (Mounjaro, Zepbound), also not sold by Velox Peptides. Both drugs' published data are presented here purely as third-party scientific context for researchers tracking the incretin-receptor field that retatrutide research sits within.
Retatrutide is supplied as a research reagent only. It is not a medicine and has not been evaluated by the MHRA or FDA. Not for human or veterinary use. CagriSema and tirzepatide are not Velox Peptides products and are not available for sale. See our Research Use Policy and MHRA Statement.
References
- Novo Nordisk. Novo's CagriSema delivers superior weight loss versus tirzepatide in REIMAGINE 5 trial. Company announcement, 21 September 2026. globenewswire.com
- Novo Nordisk. CagriSema versus tirzepatide head-to-head Phase 3 trial (REDEFINE-4), topline results. Company announcement, 23 February 2026, ClinicalTrials.gov NCT06131437. novonordisk.com
- Novo Nordisk. Novo Nordisk files for FDA approval of CagriSema, the first once-weekly combination of GLP‑1 and amylin analogues for weight management. Press release, 18 December 2025. prnewswire.com
- RTTNews. Novo Nordisk's CagriSema Improves Weight Management In Phase 3 Prior To Q4 FDA Decision; Stock Down. 21 September 2026. rttnews.com
- Velox Peptides. Retatrutide vs CagriSema: Comparing Triple-Agonist and GLP-1/Amylin Trial Data. See our full earlier comparison guide for REDEFINE-1, REDEFINE-2 and REDEFINE-4 background.
Frequently Asked Questions
What did REIMAGINE 5 report about CagriSema and tirzepatide?
REIMAGINE 5, a Phase 3 head-to-head trial in around 1,000 adults with type 2 diabetes inadequately controlled on metformin and/or an SGLT2 inhibitor, reported that CagriSema 1.0mg/1.0mg produced 12.4% mean body-weight loss versus 9.1% for tirzepatide 5mg over 68 weeks, a statistically superior result. HbA1c reduction was non-inferior between arms: 1.71 percentage points for CagriSema versus 1.67 for tirzepatide. Topline results were announced by Novo Nordisk on 21 September 2026.
What did REDEFINE 9 report?
REDEFINE 9, a placebo-controlled Phase 3 trial in around 300 adults with overweight or obesity, reported that CagriSema 1.0mg/1.0mg produced 21.0% mean weight loss versus 2.0% on placebo at 68 weeks, meeting its pre-specified primary superiority endpoint. Novo Nordisk also reported improvements versus placebo across supportive endpoints including systolic blood pressure, waist-to-height ratio and fasting lipids.
Does this contradict CagriSema's earlier REDEFINE-4 result against tirzepatide?
Not directly. REDEFINE-4 (topline 23 February 2026) compared higher doses of both drugs, CagriSema 2.4mg/2.4mg versus tirzepatide 15mg, in an obesity-only population over 84 weeks, and CagriSema missed its non-inferiority endpoint there. REIMAGINE 5 compared lower doses, 1.0mg/1.0mg versus tirzepatide 5mg, in a type 2 diabetes population over 68 weeks. Different doses, populations and durations mean the two trials are not directly comparable, and neither individually settles how the drugs compare at matched maximum doses.
When will the FDA decide on CagriSema?
Novo Nordisk filed CagriSema's New Drug Application on 18 December 2025, based on the earlier REDEFINE-1 and REDEFINE-2 pivotal trials, and has guided to an FDA decision in the fourth quarter of 2026. REIMAGINE 5 and REDEFINE 9 are supplementary trials rather than part of that pending application.
Are CagriSema or tirzepatide available as research reagents from Velox Peptides?
No. CagriSema is an unapproved, patent-protected Novo Nordisk investigational product with a pending FDA application, and tirzepatide is a licensed pharmaceutical medicine (Mounjaro, Zepbound). Neither is sold by Velox Peptides. Velox supplies retatrutide, Eli Lilly's own triple-receptor investigational compound, strictly as an HPLC-verified in vitro research reagent. Order for research →