On August 25, 2026, Phase IIIa results from the REDEFINE 1 trial (NCT05567796) confirmed that a once-weekly combination of cagrilintide 2.4 mg and semaglutide 2.4 mg reduced mean body weight by 22.7% over 68 weeks in adults with overweight or obesity, with 60% of treated participants crossing the 20% loss threshold and 23% reaching 30% or more. The findings, published by Garvey and colleagues in The New England Journal of Medicine, represent the largest mean weight reduction yet recorded for a non-surgical pharmacotherapy in a registrational obesity study, as reported by Applied Clinical Trials Online. The trial enrolled 3,417 adults across 22 countries who carried a body-mass index of 30 or higher, or 27 or higher with at least one weight-related comorbidity, and excluded those with type 2 diabetes.
Internal comparators isolate the amylin contribution
Participants were randomized in a 21:3:3:7 ratio to the combination arm (n = 2,108), semaglutide 2.4 mg alone (n = 302), cagrilintide 2.4 mg alone (n = 302), or placebo (n = 705), with lifestyle counselling provided to every cohort. Coprimary endpoints were relative change in body weight and the proportion achieving at least 5% loss versus placebo; confirmatory secondary endpoints extended to 20%, 25%, and 30% reduction thresholds. Because all four arms sat within a single protocol, the additive contribution of each molecule is visible without cross-trial inference. Semaglutide 2.4 mg alone produced a 16.1% mean weight reduction; cagrilintide 2.4 mg alone produced 11.8%; placebo produced 2.3%. Under the treatment-policy estimand, which includes all randomized participants regardless of adherence, the combination mean was 20.4% versus 3.0% for placebo, a difference of 17.3 percentage points (95% CI: −18.1 to −16.6; P < 0.001). The 22.7% figure corresponds to the trial-product estimand, which accounts for treatment adherence, as detailed in coverage by News-Medical.
Figure 1: REDEFINE 1 randomized-arm weight loss thresholds and the amylin-plus-GLP-1 additive effect.
Cagrilintide is a long-acting analogue of amylin, a peptide co-secreted with insulin from pancreatic beta cells that promotes satiety through pathways distinct from the GLP-1 receptor. Semaglutide, the active ingredient in Wegovy, targets the GLP-1 receptor. The two mechanisms operate on overlapping but non-identical neural circuits governing appetite and gastric emptying. The 6.6-percentage-point gap between the combination and semaglutide monotherapy within this trial suggests the amylin pathway contributes independent weight reduction beyond what GLP-1 agonism achieves alone. Researchers studying cagrilintide's peptide structure note that its acylated backbone extends half-life sufficiently for once-weekly subcutaneous dosing, matching semaglutide's schedule and permitting co-administration in a single injection session.
Cardiometabolic secondary endpoints and tolerability
Secondary analyses tracked blood pressure, lipid panels, C-reactive protein, and liver enzymes through serial blood draws. Systolic blood pressure fell by 10.9 mmHg in the combination arm versus 2.8 mmHg with placebo; diastolic pressure dropped 5.4 mmHg versus 1.7 mmHg. Waist circumference and lipid parameters also improved significantly, according to a summary of the NEJM publication. These shifts are consistent with what GLP-1 agonists produce at scale, and the trial was not powered to adjudicate hard cardiovascular events. That question belongs to REDEFINE 3, the dedicated cardiovascular outcomes study whose completion regulators on both sides of the Atlantic typically expect before broad label claims can be granted.
Gastrointestinal adverse events, principally nausea, vomiting, and constipation, occurred at rates comparable to the semaglutide-alone arm and were mostly mild to moderate in severity, resolving over the treatment period. No new safety signal specific to the amylin component emerged in the 68-week window. The absence of a type 2 diabetes cohort in REDEFINE 1 is a deliberate design choice; the companion REDEFINE 2 trial, led by Lingvay and colleagues, addresses that population separately. For clinicians tracking the broader category of weight loss peptides, the REDEFINE 1 data confirm that amylin analogues can contribute meaningful, independent efficacy when layered onto incretin-based therapy, though the evidence remains bounded by a 68-week observation window in a non-diabetic population.
Regulatory timeline and the next evidentiary hurdle
Novo Nordisk faces a compressed regulatory calendar. A U.S. Food and Drug Administration decision on the CagriSema New Drug Application is expected in the fourth quarter of 2026, according to BioSpace's pipeline tracker, and the company is simultaneously running REDEFINE 3. The European Medicines Agency granted a product-specific paediatric waiver for the cagrilintide-semaglutide combination in August 2023, signalling that the EMA pathway is active in parallel, though European approval will follow its own review clock. Until REDEFINE 3 reports, neither agency is likely to entertain cardiovascular risk-reduction language on the label.
The company has also signalled that a dedicated Phase 3 programme called RENEW will evaluate cagrilintide as monotherapy, a path that could position the amylin analogue for patients who cannot tolerate GLP-1 agonists. Martin Holst, Novo Nordisk's head of clinical development for the compound, described the REDEFINE 1 data as the first Phase 3 evidence for a next-generation amylin therapy and pointed to RENEW as the next investigative step, as quoted by Pharmacy Times. Whether CagriSema ultimately joins the current roster of fda approved peptides for chronic weight management will depend on the fourth-quarter review and on whether the cardiovascular outcomes data satisfy the safety bar that both the FDA and the EMA apply to long-term obesity treatments. The next concrete milestone is advisory committee scheduling, which Novo Nordisk has not publicly dated.
