REDEFINE is the phase 3 program behind CagriSema, an investigational once-weekly combination of the amylin analogue cagrilintide and the GLP-1 receptor agonist semaglutide, and its headline result is human clinical evidence: roughly 20 percent mean body weight reduction over 68 weeks in adults with obesity or overweight and no type 2 diabetes. That number sits alongside broad improvement in waist circumference, blood pressure, triglycerides and glucose regulation, all of which are surrogate markers rather than demonstrated reductions in heart attacks or strokes. CagriSema is not approved in any major market, having been submitted to the U.S. FDA in December 2025 with a decision anticipated in late 2026, so the REDEFINE results describe trial evidence under regulatory review rather than an available prescription option.
In REDEFINE 1, a 68-week phase 3 trial of roughly 3,400 adults, the cagrilintide and semaglutide combination produced a mean body weight reduction of about 20 percent against about 15 percent for semaglutide 2.4 mg alone, about 11 to 12 percent for cagrilintide 2.4 mg alone and about 3 percent for placebo.
REDEFINE is a family of phase 3 trials rather than one study, which is why the published record reports it trial by trial instead of as a single pooled number. Each trial was carved out for a different population or a different question, and the four-arm layout of the anchor trial is what lets the combination be judged against its own components instead of against placebo alone.
REDEFINE 1 randomized roughly 3,400 adults across four arms over 68 weeks, and every arm including placebo received background diet and physical activity counseling, so the reported differences measure what the drug added on top of behavioral intervention rather than drug versus nothing.
The single figure quoted from REDEFINE 1 is a mean reduction of about 20 percent at week 68, but the arm-by-arm breakdown carries more information than the headline does. It shows the combination outperformed its own GLP-1 component by roughly five percentage points, and that the two effects are not additive, since 15 plus 11 does not arrive at 26, which fits overlapping appetite pathways rather than two independent mechanisms. The roughly 20 percent also landed below the 25 percent many analysts had anticipated, and that expectation gap, not any signal of failure, is what drove the negative market reaction when the results were first released.
| Trial arm, REDEFINE 1 at week 68 | Mean body weight reduction |
|---|---|
| Cagrilintide 2.4 mg plus semaglutide 2.4 mg | About 20 percent |
| Semaglutide 2.4 mg alone | About 15 percent |
| Cagrilintide 2.4 mg alone | About 11 to 12 percent |
| Placebo | About 3 percent |
Roughly 60 percent of participants in the combination arm reached a body weight reduction of 20 percent or more, a threshold almost no placebo participant reached, while the prespecified analysis assuming participants stayed on the intended dose put the mean nearer 22 to 23 percent.
Weight loss was smaller in REDEFINE 2 than in REDEFINE 1, and the literature treats that as expected rather than disappointing. People with type 2 diabetes consistently lose several percentage points less on incretin-based therapy, a pattern documented across the whole drug class and attributed to insulin and sulfonylurea use, altered energy balance once glucose stops spilling into the urine, and differences in underlying appetite regulation. That degree of glucose lowering alongside heavy weight loss also created a practical trial-management issue, since participants on insulin or insulin secretagogues can become over-treated as insulin sensitivity improves, which put background medication adjustment and hypoglycemia monitoring into the protocol.
| Measure at week 68 | REDEFINE 1, no diabetes | REDEFINE 2, type 2 diabetes |
|---|---|---|
| Participants randomized | About 3,400 | About 1,200 |
| Mean weight reduction, combination | About 20 percent | About 14 percent |
| Mean weight reduction, placebo | About 3 percent | About 3 percent |
| HbA1c at or below 6.5 percent | Not applicable | About 74 percent, against about 16 percent on placebo |
Participants in REDEFINE 2 entered with a mean HbA1c near 8.0 percent, and roughly 74 percent of those on the combination finished at or below 6.5 percent against about 16 percent on placebo, so the glycemic result outran the smaller 14 percent weight effect.
Beyond the scale, the trials tracked the cluster of measurements clinicians actually use to judge cardiometabolic risk, and each moved in the same direction as the weight in the combination arms relative to placebo. The honest interpretive caveat is that most of these improvements travel with the weight loss rather than representing separate drug effects.
Blood pressure, lipids and HbA1c are surrogate endpoints rather than outcomes, and whether these improvements translate into fewer heart attacks, strokes and cardiovascular deaths is exactly what the program's dedicated event-driven cardiovascular trial was built to test.
Dose flexibility turned out to be the most contested design feature of REDEFINE 1. The protocol permitted participants to remain at a lower dose or step down rather than requiring escalation to and maintenance of the top dose, so the population feeding the week 68 average mixed full-dose and reduced-dose participants. Where response is dose-dependent, an average that includes under-dosed participants has to sit below what the full dose alone would produce.
REDEFINE 1 reported two estimands for the same arm, roughly 20 percent under the treatment policy view and roughly 22 to 23 percent under the analysis assuming participants stayed on the intended dose, so any quoted percentage depends on which question it answers.
Tolerability in REDEFINE looked much like tolerability across the incretin class, which is to say dominated by the gut. Discontinuation attributable to adverse events sat at about 6 percent in the REDEFINE 1 combination arm and about 8 percent in REDEFINE 2, against roughly 3 percent on placebo in both, higher than placebo but short of a level that would mark the regimen as broadly intolerable.
Adverse-event discontinuation reached about 6 percent in the REDEFINE 1 combination arm and about 8 percent in REDEFINE 2 against roughly 3 percent on placebo, and 68 weeks of exposure in a few thousand participants cannot rule out rare or long-term harms.
Placed next to published trials of other incretin-based obesity therapies, the roughly 20 percent from REDEFINE 1 sits in the same broad territory as the best results reported for dual GIP and GLP-1 receptor agonism without clearly exceeding them. Reading trials side by side that way is not reliable evidence, because separate studies differ in baseline body weight, demographics, duration, intensity of background lifestyle intervention, dosing rules and which estimand gets quoted, and any one of those can shift a reported percentage by more than the gap being argued over. The program included the only design that settles a comparison of this kind, an open-label 84-week randomized head-to-head under one protocol and one set of rules.
| Head-to-head trial, 84 weeks | Cagrilintide plus semaglutide | Tirzepatide 15 mg |
|---|---|---|
| Mean weight reduction | About 23 percent | About 25.5 percent |
| Primary endpoint, non-inferiority | Not met | Comparator arm |
| Mechanism added to GLP-1 | Amylin analogue: hindbrain satiety signaling, gastric emptying | GIP agonism: adipose tissue, nausea signaling |
| Evidence status | Headline results reported, peer-reviewed publication pending | Previously published |
The open-label 84-week head-to-head trial did not meet its primary endpoint of non-inferiority, with the combination producing about 23 percent weight reduction against about 25.5 percent for tirzepatide 15 mg, which places it as competitive rather than superior on weight reduction.
The most consequential gap is durability. Obesity behaves as a chronic relapsing condition, and the consistent finding across this drug class is substantial regain in the year after treatment stops, which implies the combination would need to be taken indefinitely to hold its effect.
REDEFINE 1 and REDEFINE 2 each ran 68 weeks against a condition treated over decades, and across this drug class stopping treatment is followed by substantial weight regain within the following year.
Trial results and market availability are two different things, and the distinction carries real weight here. CagriSema was submitted for regulatory review on the strength of the REDEFINE data and remains investigational, which means it is not a product a person can ask a clinician to prescribe the way an approved obesity medication can be prescribed.
CagriSema is investigational and approved in no major market, having been submitted to the U.S. FDA in December 2025 with a decision anticipated in late 2026, so it cannot be lawfully dispensed as an approved obesity therapy while that review is pending.
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