REDEFINE: The Full CagriSema Trial Program (2026)

CagriSema is Novo Nordisk's once-weekly fixed-dose injection that pairs cagrilintide (a long-acting amylin analog) with semaglutide (the GLP-1 receptor agonist in Ozempic and Wegovy) — two appetite mechanisms in one pen. The REDEFINE program is the phase-3 evidence package behind Novo's December 2025 FDA filing, and it is one of the more revealing stories in obesity drug development: the headline number was genuinely large, yet the market reaction was repeatedly negative. REDEFINE 1, in adults with obesity but without diabetes, delivered 22.7% mean weight loss on the trial-product (adherent) estimand and 20.4% on the treatment-policy estimand at 68 weeks (Garvey 2025^[1]) — but that fell short of the roughly 25% Novo had guided investors toward, and shares fell about 20% the day the topline came out. Then in February 2026, the head-to-head REDEFINE 4 trial showed CagriSema lost to tirzepatide and missed its non-inferiority endpoint. This article walks the entire program — what each REDEFINE trial actually measured, the dose-flexibility/adherence caveat that explains the gap between expectation and result, and how the numbers stack up against semaglutide and tirzepatide. For the shorter overview, see what the CagriSema REDEFINE trials actually showed.

The honest summary

• REDEFINE 1 (no diabetes): 22.7% adherent, 20.4% overall. In 3,417 adults with obesity or overweight-plus-complications, CagriSema produced 22.7% mean weight loss on the trial-product estimand and 20.4% on the treatment-policy estimand at 68 weeks, versus 2.3-3.0% with placebo (Garvey 2025^[1]). It also beat both single agents: 14.9% with semaglutide alone and 11.5% with cagrilintide alone.
• REDEFINE 2 (type 2 diabetes): 13.7% overall, 15.7% adherent. In 1,206 adults with type 2 diabetes, CagriSema produced 13.7% mean weight loss on the treatment-policy estimand (15.7% adherent) versus 3.4% placebo, plus meaningful HbA1c improvement (Davies 2025^[2]). Weight loss is consistently smaller in diabetes — a pattern seen across the whole GLP-1 class.
• The number disappointed anyway. Novo had guided toward ~25% in REDEFINE 1; 22.7% (adherent) / 20.4% (overall) undershot it, and the stock dropped roughly 20% on the December 20, 2024 topline. The science was strong; the expectations were higher.
• The dose-flexibility caveat is the key to the story. REDEFINE 1 let investigators keep patients on a submaximal dose; only about 57% reached the top 2.4/2.4 mg dose by week 68. Analysts argued the “true” full-dose effect was likely larger than the headline — which is exactly what later high-dose and adherence sub-analyses probed.
• REDEFINE 4 (head-to-head vs tirzepatide): CagriSema lost. In an 809-patient open-label trial, CagriSema reached 23.0% (efficacy estimand) versus tirzepatide 15 mg at 25.5%, and missed its non-inferiority endpoint (readout February 23, 2026). It is the first randomized comparison and it did not favor CagriSema.
• REDEFINE 3 is the cardiovascular outcomes trial. A ~7,000-patient event-driven CVOT in people with established cardiovascular disease is ongoing, with a roughly 3-year follow-up — the data that would matter for a cardiovascular label and for Medicare-type coverage.
• Status: filed, not approved. Novo submitted the US NDA on December 18, 2025; as of mid-2026 CagriSema is not FDA-approved and not on the market. Everything here is investigational trial data.

What CagriSema is — two appetite levers in one pen

Most approved weight-loss injections pull a single hormonal lever. Wegovy and Ozempic are semaglutide, a GLP-1 receptor agonist; Zepbound and Mounjaro are tirzepatide, which hits GLP-1 and GIP. CagriSema takes a different combination: it adds cagrilintide, a long-acting analog of amylin — a hormone co-secreted with insulin that promotes satiety and slows gastric emptying through a separate pathway from GLP-1. The bet is mechanistic complementarity: stack an amylin agonist on top of a GLP-1 agonist and you should suppress appetite more than either alone.

That bet had early support. Cagrilintide on its own reached about 10.8% weight loss at 26 weeks in its dose-finding phase 2 trial (Lau 2021^[3]), and a phase 1b study confirmed cagrilintide and semaglutide 2.4 mg could be co-administered safely with a tolerability profile in line with the GLP-1 class (Enebo 2021^[4]). REDEFINE 1 then tested the hypothesis directly with a four-arm design — and the combination did beat each monotherapy. For more on the amylin half specifically, see cagrilintide, the amylin analog behind CagriSema.

REDEFINE 1 — the obesity (no-diabetes) trial

REDEFINE 1 (Garvey 2025^[1], New England Journal of Medicine) was a 68-week, phase 3a, double-blind, placebo- and active-controlled trial in 3,417 adults without diabetes who had a BMI of 30 or higher, or 27 or higher with at least one obesity-related complication. Participants were randomized in a 21:3:3:7 ratio to once-weekly CagriSema 2.4/2.4 mg, semaglutide 2.4 mg alone, cagrilintide 2.4 mg alone, or placebo — all on top of lifestyle intervention. The four-arm design is what makes it more than a single-number readout: it isolates how much the amylin half actually adds.

The two estimands answer two different questions. The treatment-policy estimand (20.4%) measures the effect regardless of whether people stayed on the drug or dose — closest to real-world expectations. The trial-product estimand (22.7%) estimates the effect if everyone had taken the drug as intended — closest to the drug's biological ceiling. Both are legitimate; press headlines usually quoted the higher 22.7%. Among adherent patients, the responder rates were striking: 97.6% lost at least 5% of body weight, 60.2% lost at least 20%, 40.4% lost at least 25%, and 23.1% lost at least 30% (Garvey 2025^[1]).

The dose-flexibility / adherence caveat

The most important nuance in REDEFINE 1 is in the protocol design. The trial used a flexible dosing scheme that let investigators hold patients at a submaximal dose if that was judged better for the individual (for tolerability, for example). By week 68, only about 57% of CagriSema patients were on the maximum 2.4/2.4 mg dose. That matters in two directions. First, it means the headline 20.4% reflects a population where roughly four in ten were not at full dose — so the “true” full-dose, fully-adherent effect (closer to the 22.7% trial-product figure) is arguably the more honest read of the drug's ceiling. Second, it complicates cross-trial comparison: tirzepatide's pivotal SURMOUNT-1 used a fixed dose-escalation. The dose-flexibility story is the single biggest reason the disappointment narrative may have overshot the actual pharmacology.

REDEFINE 2 — the type 2 diabetes trial

REDEFINE 2 (Davies 2025^[2], NEJM) ran the same 68-week phase 3a design in 1,206 adults with type 2 diabetes (BMI 27 or higher, HbA1c 7-10%), randomized 3:1 to once-weekly CagriSema 2.4/2.4 mg or placebo plus lifestyle intervention. Weight loss was 13.7% on the treatment-policy estimand (15.7% on the trial-product/adherent estimand) versus 3.4% placebo, alongside a clinically meaningful drop in HbA1c. As with the entire GLP-1 class, weight loss is reliably smaller in people with diabetes than in those without — so the lower REDEFINE 2 number is expected biology, not a failure.

On tolerability, REDEFINE 2 was consistent with the class: gastrointestinal adverse events occurred in about 79.6% of CagriSema participants versus 39.9% on placebo, dominated by nausea, vomiting, constipation and diarrhea, mostly mild-to-moderate and transient. This is the familiar GLP-1 side-effect signature, and it is the practical limiter on how fast patients can be titrated to the top dose.

REDEFINE 4 — the head-to-head versus tirzepatide that missed

If REDEFINE 1 set expectations and REDEFINE 2 confirmed the diabetes use case, REDEFINE 4 is the trial that reframed CagriSema's competitive position. It was an 84-week, open-label, phase 3 trial in 809 adults with obesity, randomizing once-weekly CagriSema 2.4/2.4 mg against once-weekly tirzepatide 15 mg — the first direct randomized comparison of the two. The topline read out on February 23, 2026.

The primary endpoint was non-inferiority of CagriSema versus tirzepatide on weight loss at 84 weeks — and it was not met. CagriSema lost a large amount of weight in absolute terms, but tirzepatide lost more, and the trial could not statistically establish that CagriSema was no worse. Coming after the December 2024 expectations miss, this was a second blow to the “CagriSema as best-in-class” thesis, and it triggered analyst downgrades. For the broader context on how those two drugs compare, see the 2026 guide to weight-loss injections.

REDEFINE 3 — the cardiovascular outcomes trial

The piece of the program that will matter most for a broad label is REDEFINE 3, an event-driven cardiovascular outcomes trial (CVOT) of once-weekly CagriSema versus placebo in roughly 7,000 adults with established cardiovascular disease, with or without type 2 diabetes. It is ongoing, with a treatment period on the order of three years. CVOTs are what let a weight-loss drug claim a cardiovascular-risk-reduction benefit — the route by which Wegovy earned its cardiovascular indication and, in turn, certain payer and Medicare pathways. Until REDEFINE 3 reports, CagriSema's case rests on weight loss and glycemic control, not on hard cardiovascular outcomes.

Regulatory status — filed, not approved

Novo Nordisk submitted the US New Drug Application for CagriSema on December 18, 2025, covering adults with obesity or overweight plus at least one weight-related comorbidity, based on the REDEFINE 1 and REDEFINE 2 data. As of mid-2026, CagriSema is not approved in the US or EU and is not available to patients outside of clinical trials. Any clinic, telehealth service, or compounding pharmacy offering “CagriSema” today is not dispensing an FDA-approved product — a distinction worth stating plainly. For where this fits among other not-yet-approved drugs, see the GLP-1 pipeline guide.

Bottom line

The REDEFINE program tells a consistent story with a counterintuitive market reaction. The science delivered: REDEFINE 1 showed 22.7% adherent / 20.4% overall weight loss in adults without diabetes, beating both semaglutide and cagrilintide alone (Garvey 2025^[1]); REDEFINE 2 showed 13.7% with added glycemic benefit in type 2 diabetes (Davies 2025^[2]). Yet the program repeatedly disappointed against expectations — first by undershooting the ~25% Novo had guided toward (a roughly 20% stock drop in December 2024), then by missing non-inferiority versus tirzepatide in the head-to-head REDEFINE 4 readout in February 2026. The dose-flexibility caveat (only ~57% reached the top dose) means the drug's true ceiling is probably higher than the headline overall number, and the ongoing REDEFINE 3 CVOT could still reshape the picture. CagriSema is a powerful, large-effect combination that was filed with the FDA in December 2025 — but it remains investigational and not approved, and the head-to-head data so far place it alongside, not ahead of, tirzepatide.